Professional Documents
Culture Documents
2019 Book OralSignsOfSystemicDisease
2019 Book OralSignsOfSystemicDisease
Systemic Disease
Nasim Fazel
Editor
123
Oral Signs of Systemic Disease
Nasim Fazel
Editor
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
To my beautiful children, Sina and Monah, who inspire me to
persevere through any challenge and bring so much love and
joy into my life.
Foreword
Oral Signs of Systemic Disease provides valuable insight into solving diag-
nostic challenges. Careful oral examination can provide such clues to the
learned observer. However, the medical education and training of most physi-
cians and other healthcare providers does not emphasize the oral cavity. This
results in a lack of familiarity with normal and abnormal features and the
diagnostic clues they can provide. By contrast, dental education provides the
necessary skills to distinguish between normal and abnormal findings.
However, the dental clinician may not be skilled in placing abnormal features
in the context of a mucocutaneous or systemic condition. Thus, this contribu-
tion serves to educate both physicians and dentists.
Dr. Nasim Fazel is an eminently well-suited editor for Oral Signs of
Systemic Disease. She is a DDS graduate of Northwestern University Dental
School and an MD graduate of the University of Michigan Medical School.
This education was followed by residency training in dermatology at Henry
Ford Hospital in Detroit, Michigan. Dr. Fazel has been a faculty member at
the University of California, Davis in the Department of Dermatology for
more than a decade and a half, where she has developed an oral dermatology
practice and has served as Dermatology Residency Program Director. As a
dual-trained dentist and dermatologist, as well as a consummate educator, Dr.
Fazel brings great knowledge and experience to bear on the topic.
The contributors to this textbook are scholars from broad areas of exper-
tise including dentistry, pediatric dermatology, oral dermatology, oral medi-
cine, oral pathology, microbiology, and medical genetics. Each brings a depth
of knowledge and understanding of the relevance of their topics to the
problem-solving algorithm for the patient with troublesome oral lesions.
Dermatologists know that the skin is often a mirror of systemic diseases.
Those skilled in the diagnosis of challenging oral diseases know that the
mouth is, similarly, a mirror of systemic diseases.
This book will be a valuable addition to medical libraries as a reference
volume and to the personal library of the clinician whose patient has a vexing
oral disease.
Roy S. Rogers
Professor of Dermatology
Mayo Clinic College of Medicine
Scottsdale, AZ, USA
vii
Preface
The conception of Oral Signs of Systemic Disease came about with the inten-
tion to provide a practical reference for the day-to-day practice of clinicians
in the fields of dermatology, dentistry, oral medicine, and otolaryngology. In
addition, the comprehensive nature of this textbook can serve as an educa-
tional tool for students, residents, and fellows in training with the goal of
learning the fundamentals of oral mucosal disease.
Oral Signs of Systemic Disease provides descriptive clinical and oral man-
ifestations and differential diagnoses, including principles of therapy of major
entities, while maintaining a uniform chapter format. I am greatly apprecia-
tive of the authors for their contributions, without whom this textbook would
not have been possible. I would also like to thank Portia Wong, Diane
Lamsback, and Rebekah Collins at Springer Publishing for their time and
support.
ix
Contents
1 Introduction�������������������������������������������������������������������������������������� 1
Parastoo Davari and Nasim Fazel
2 Oral Signs of Gastrointestinal Disease ������������������������������������������ 9
John C. Steele
3 Oral Signs of Hematologic Disease������������������������������������������������ 25
Diana V. Messadi and Ginat W. Mirowski
4 Oral Signs of Endocrine and Metabolic Diseases������������������������� 45
Jaisri R. Thoppay, Thomas P. Sollecito, and Scott S. De Rossi
5 Oral Signs of Nutritional Disease �������������������������������������������������� 63
Stanislav N. Tolkachjov and Alison J. Bruce
6 Oral Signs of Connective Tissue Disease���������������������������������������� 91
Kenisha R. Heath and Nasim Fazel
7 Oral Signs of Vesiculobullous and Autoimmune Disease�������������� 113
Michael Z. Wang, Julia S. Lehman, and Roy Steele Rogers III
8 Oral Signs of Viral Disease�������������������������������������������������������������� 145
Danielle N. Brown, Ramya Kollipara, and Stephen Tyring
9 Oral Signs of Bacterial Disease������������������������������������������������������ 169
Emily W. Shelley and Rochelle R. Torgerson
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases���������������� 193
Ricardo Pérez-Alfonzo, Silvio Alencar-Marques,
Elda Giansante, and Antonio Guzmán-Fawcett
11 Oral Signs of Genetic Disease �������������������������������������������������������� 227
Julio C. Sartori-Valinotti and Jennifer L. Hand
Index���������������������������������������������������������������������������������������������������������� 253
xi
Contributors
xiii
xiv Contributors
Oral signs and symptoms can be a presenting The oral cavity includes four main components:
feature of many systemic diseases, which can aid the mucosa, tongue, dentition, and salivary glands.
the clinician in establishing a definitive diagno-
sis. Immunologic and infectious conditions,
hematologic disorders, vitamin deficiencies, and Oral Mucosa
endocrinopathies, in addition to psychological
disorders and physiologic conditions such as The oral cavity is lined by stratified squamous
pregnancy, can present with oral signs and symp- epithelium. Merkel cells and melanocytes can
toms. Oral signs such as mucosal inflammation also be found throughout the oral mucosa [1].
or infection, discoloration, decreased salivary The turnover time of the epithelial mucosa
flow, dental caries, and bleeding can be indicative ranges from 14 to 24 days, for the buccal mucosa
of a systemic condition. However, these oral and the hard palate, respectively [2]. Various
signs can be overlooked without thorough exami- degrees of keratinization are observed in the epi-
nation of the oral mucosa, thus increasing the thelium of different regions of the oral cavity.
likelihood of delayed diagnosis or misdiagnosis. The gingiva and hard palate are exposed to fric-
Competence in the diagnosis of oral diseases tion and mechanical stress during mastication.
and recognition of their signs and symptoms is Hence, these areas are lined by a keratinized epi-
relevant to all practitioners. However, adequate thelium, which is tightly adherent to the underly-
knowledge and understanding of oral diseases is ing tissues. The dorsal tongue has a specialized
particularly important for specialists such as der- mucosa composed of a mosaic of keratinized and
matologists, dentists, and otolaryngologists. In nonkeratinized epithelium that is firmly attached
this introductory chapter, we briefly review the to the underlying tongue muscles [2, 3]. The epi-
anatomy, histology, physiology, and microbiol- thelium of the floor of the mouth, buccal mucosa,
ogy of the oral mucosa. and the ventral tongue is nonkeratinized allow-
ing for movements that are required for func-
tions such as mastication, swallowing, and
phonation. In addition, the underlying connec-
tive tissue is more flexible than the masticatory
P. Davari · N. Fazel (*) regions of the oral cavity. The specialized
Department of Dermatology, University of California, mucosa of the dorsal tongue represents approxi-
Davis, Sacramento, CA, USA
e-mail: nfazel@ucdavis.edu mately 15% of the surface area of the oral cavity,
Upper lip
Underside
of tongue
Alveolar mucosa
Hard palate
Gingiva
Soft palate
Tongue
Lower lip
Masticatory mucosa
Lining mucosa
Specialized mucosa
Fig. 1.1 Oral cavity regions. (Reprinted with permission from Squier and Kremer [2])
The dorsum of the tongue is lined by lingual The crown includes enamel and dentin enclos-
papillae that are lamina propria projections cov- ing the pulp, while the root contains only dentin
ered by keratinized epithelium. Foliate papillae surrounding the pulp and is covered by cemen-
are small and found on the lateral surfaces of the tum. Enamel is the hard, highly mineralized
tongue. Filiform papillae are the most numerous outer surface of the tooth that protects the dentin
papillae of the tongue. Fungiform papillae are and pulp and serves as the grinding surface dur-
mushroom-shaped, fewer in number, and dis- ing mastication. The interior chamber of the
persed in between the filiform papillae. root contains the radicular pulp, whereas the
Circumvallate papillae, the most prominent and interior chamber of the crown houses the coro-
largest papillae, are located in a V-shaped con- nal pulp. Nerves, blood vessels, and lymphatics
figuration anterior to the sulcus terminalis. Taste pass through the apical foramen (Fig. 1.4). The
buds are present in foliate, circumvallate, and periodontal ligament attaches the tooth to the
fungiform papillae as well as the soft palate and surrounding bony structures of the maxilla and
pharynx [4, 5]. mandibular alveolar processes. The teeth are
enclosed by the gingiva including the free,
attached, papillary, and marginal gingiva. The
Dentition interdental papilla is found between two adja-
cent teeth. The marginal gingiva lines the space
The permanent dentition consists of 8 incisors, between the teeth and the gingiva. The muco-
4 canines, 8 premolars, and 12 molars (Fig. 1.3). gingival line separates the gingiva from the
Each tooth is divided into a root and a crown. alveolar mucosa [4].
Upper
(maxillary)
Lower
(mandibular)
Fig. 1.3 The adult dentition is composed of two incisors, one canine, two premolars, and three molars in each quadrant.
(Reprinted with permission from Weaker [4])
4 P. Davari and N. Fazel
Enamel Enamel
Pulp Pulp
Crown chamber chamber
Crown
Dentin
Dentin
Root canal
Root canal
Root
Root
Accessory
canal Accessory
canal
Cementum Cementum
Apical foramen
Apical foramen
Fig. 1.4 Cross-section of a tooth showing two main blood vessels, nerves, and lymphatics of the pulp. Dentin
parts: the crown and the root. The crown is composed of surrounds the pulp of the root and is covered by cemen-
enamel, dentin, and the pulp chamber, which harbors the tum. (Reprinted with permission from Weaker [4])
Salivary Glands and hard palate, the labial and buccal mucosa,
and the tongue contain several minor salivary
The parotid, submandibular, and sublingual sali- glands [2, 6].
vary glands are the major salivary glands, which
are paired and secrete 95% of the saliva. The
parotid is the largest salivary gland. It is a serous Physiology
gland, producing 30% of the saliva, and has a tri-
angular shape with its base facing the zygomatic The major functions of the oral cavity are masti-
arch and its apex extending to the angle of man- cation, taste, and phonation. The lips prevent the
dible. Diseases of the parotid can affect the major saliva from drooling and the food from spilling
anatomical structures passing through the gland: from the mouth. The tongue has both motor and
the facial nerve, retromandibular vein, and exter- sensory functions and plays a central role in swal-
nal carotid artery. lowing. Molar teeth are necessary for chewing
The submandibular gland is found in the sub- food. The lips, tongue, and palate are essential for
mandibular triangle, which produces approxi- phonation and articulation. A major function of
mately 60%–65% of the saliva. It contains both the oral mucosa is to protect underlying structures
mucous and serous fluids; however, serous secre- from mechanical and chemical injuries. The epi-
tion is more predominant. The sublingual gland, thelium also prevents fluid loss and entry of envi-
the smallest major salivary gland, is located in ronmental toxins and microbial agents. The
the floor of the mouth. It is a mixed gland with masticatory stratum corneum endures the
predominantly mucinous secretion. Minor sali- mechanical forces and shearing stress. The con-
vary glands are concentrated in the submucosa tinuous shedding of the oral mucosa also limits
throughout the walls of the oral cavity. The soft colonization of microbial agents [2]. Saliva lubri-
1 Introduction 5
cates the oral mucosa, which facilitates the func- zoa, fungi, and archaea [8]. The oral cavity is a
tions of phonation, mastication, food bolus suitable environment for microbial agents to thrive
formation, and swallowing. It also protects the due to its stable temperature, pH and the presence
oral mucosa from mechanical injuries such as of saliva as a medium [9]. Carbohydrates, lipids,
abrasion and contains enzymes that aid in the and proteins in dietary food and salivary glycopro-
digestion of carbohydrates. In addition to its anti- teins in addition to exuded serum proteins from the
microbial properties, saliva enhances the removal gingival sulci provide nutrients for the oral micro-
of microorganisms and desquamated cells from biota [10]. The microbiome composition of the
the oral mucosa and has a protective role in the oral cavity varies in different sites. The tongue has
prevention of dental caries. As a buffer, it modu- the highest density of microorganisms containing
lates the pH and protects the oral mucosa and different microbial communities such as
teeth from the acidic environment caused by the Veillonella atypica and Porphyromonas gingivalis,
ingestion of food or gastroesophageal reflux [7]. while the tooth surface provides a unique microen-
vironment for microbial biofilms containing
Streptococcus mutans, Actinomyces, Eubacterium,
Oral Microbiome and Peptostreptococcus. Figure 1.5 demonstrates
the heterogeneity of the oral microbiome within
Despite constant desquamation of the oral mucosa, the different anatomical areas of the oral cavity
the oral cavity contains a dense population of [9]. Bacteria are frequently responsible for the
microorganisms including bacteria, viruses, proto- major microbiome-related diseases of the oral cav-
Gingival crevice
Tooth surface Fusobacterium,
Streptococcus mutans, Prevotella,
Actinomyces, Porphyromonas
Eubacterium,
Peptostreptococcus
Oropharyngeal region
Tonsil Streptococcus salivarius,
Streptococcus viridans, Streptococcus mutans,
Neisseria species, Streptococcus anginosus,
Haemophilus influenzae, Streptococcus pyogenes,
coagulase-negative Streptococcus pneumoniae,
Staphylococci Haemophilus influenza,
Haemophilus parainfluenzae
Fig. 1.5 Major microbial agents residing in the oral cavity and oropharyngeal region. (Reprinted with permission from
Lim et al. [9])
6 P. Davari and N. Fazel
ity including dental caries, endodontic infections, and cheeks and evaluate the buccal mucosa,
gingivitis, and periodontitis. The correlation teeth, and alveolar ridges. The patient should be
between oral diseases and systemic conditions asked to raise the tongue and touch the palate to
such as cardiovascular diseases, head and neck adequately examine the floor of the mouth and
cancers, and diabetes mellitus warrants further the ventral tongue. The lateral tongue and floor
characterization of the oral microbiome [8, 9]. The of the mouth are best observed by retracting the
commensal microbiome provides a healthy envi- tongue using a tongue blade or a gauze wrapped
ronment in the oral cavity and prevents overgrowth around the tip of the tongue. The posterior oro-
of pathogens such as candida and Staphylococcus pharynx can be inspected using a dental mirror.
aureus. Some microbial species such as The presence of hypoglossal and glossopharyn-
Streptococcus salivarius have shown protective geal nerve palsy can be assessed, if the patient’s
effects against periodontitis and halitosis in in vitro condition warrants it. To detect hypoglossal
and in vivo studies, respectively [11, 12]. Nitrate- palsy, the examiner should initially look for
reducing bacteria such as Actinomyces and signs of atrophy, fasciculation, or tongue devia-
Veillonella convert nitrates to nitrites, which may tion while the tongue is in a resting position.
lower the risk of dental caries. Acidified nitrites The tongue deviates toward the affected side
may restrict the growth of cariogenic bacteria via when the patient protrudes the tongue. The
the antimicrobial effect of oxides of nitrogen such glossopharyngeal nerve can be assessed by
as nitric oxide [13–15]. inducing the gag reflex. Movement of the soft
palate and uvula should be also assessed; in
hypoglossal nerve palsy, the soft palate and
Principles of the Oral Examination uvula deviate to the unaffected side while the
patient says “Ah” [16].
Comprehensive examination of the oral cavity
includes visual inspection and palpation of the
various anatomical structures within the oral cav- Palpation
ity. Partial and complete removable prostheses
should be removed prior to examination of the If an abnormality is noted on visual inspection,
oral mucosa. Adequate lighting and proper posi- the suspected area should be palpated to assess
tioning of the patient is of significant importance the consistency, texture, and depth of the lesion.
in conducting an oral examination. The patient’s The face and neck should also be palpated for any
head should be stable and well positioned to abnormalities to include palpation of the anterior/
allow visualization of all mucosal surfaces. posterior cervical, submandibular, and supracla-
A tongue blade or a cotton gauze is used to retract vicular lymph nodes [16].
the tongue and allow adequate exposure to vari-
ous sites within the oral cavity [16].
Summary
a b
Fig. 2.1 (a) OFG – This figure shows swelling of the lower lip (anterior view). (b) OFG – This figure shows swelling
of the lower lip (lateral view)
2 Oral Signs of Gastrointestinal Disease 11
[6]. Two small case series using anti-TNFα flora inducing an excessive immunological
treatment have been reported showing a good short- response [20].
term response in the management of recalcitrant
OFG with infliximab [16] and thalidomide [17]. Clinical Manifestations
Unfortunately, a significant number of those taking The main symptom is of diarrhea with associ-
infliximab lost efficacy over time. ated blood and mucous. Other symptoms
Dietary modification can be of significant ben- include abdominal pain, nausea, fever, rectal
efit. An initial study published in 2006 involving 32 urgency, and tenesmus [1, 20]. UC is associated
patients showed a statistically significant improve- with an increased incidence of chronic active
ment in global lip and oral inflammatory scores hepatitis, primary biliary cirrhosis, sclerosing
after 8 weeks adhering to a cinnamon- and benzo- cholangitis, and colon cancer. Toxic megacolon
ate-free diet [11]. A review of the literature by the may develop possibly necessitating an urgent
same research group in 2011 demonstrated that this colectomy.
diet can be beneficial in 54–78% of patients with
23% requiring no adjunctive therapies [18]. They ral Signs and Symptoms
O
also noted that the results of patch testing for cin- There are no oral signs and symptoms specific to
namaldehyde and benzoates did not predict success UC. However, there can be oral signs of iron defi-
or failure in adhering to this diet. More recently, the ciency anemia if there is significant blood loss such
same group has tested a low phenolic acid diet with as aphthous ulcers, angular cheilitis, and glossitis.
micronutrient supplementation [19] since phenolic Pyostomatitis vegetans can present as the sole oral
acids are among the constituents restricted in a cin- manifestation of UC. Please see the section on
namon- and benzoate- free diet. The conclusion Pyostomatitis vegetans for further information. A
was that this new diet holds potential promise but recent small case-control study [21] examining the
larger-scale studies are required. oral manifestations of UC patients versus a control
The clinician should consider referral to gas- group without gastrointestinal disease reported that
troenterology, especially in children, for a the presence of a tongue coating and the symptoms
thorough work-up to rule out inflammatory bowel of dry mouth, halitosis, and taste changes were
disease. more common in the former group.
Differential Diagnosis
Ulcerative Colitis Please see the next section on Pyostomatitis
vegetans.
Ulcerative colitis (UC) is a chronic inflammatory
bowel disease that mainly affects the large intes- Treatment Recommendations
tine (colon) and rectum (proctitis). The main medication classes used to treat UC
include aminosalicylates, corticosteroids, immu-
Epidemiology nosuppressants, and antibiotics. Surgery, as men-
The worldwide incidence of UC varies from 0.5 to tioned above, has a role and can “cure” UC
24.5/100,000 [1]. There is a decreased incidence following total colectomy [1].
of UC in smokers. In the USA, UC affects between Correction of any underlying iron deficiency
250,000 and 500,000 people with an annual inci- can help control the symptoms of oral ulcers,
dence of two to seven per 100,000 [20]. angular cheilitis, or glossitis. Topical corticoste-
roids and analgesics can be prescribed to manage
Etiopathogenesis the pain and discomfort associated with ulcers.
An inflammatory cell infiltrate affects only the Antimicrobials can be prescribed to manage
mucosa and submucosa. The current theory is angular cheilitis depending on the implicated
that the mucosal immune system becomes organism, which are usually either a Candida
dysregulated, which results in normal micro- species or Staphylococcus aureus.
14 J. C. Steele
It would be sensible to refer a patient with PV [28]. Only 10–15% of this population have been
who does not have any IBD symptoms for a gas- diagnosed and treated; therefore a large number
troenterology consultation to exclude any silent of cases remain undiagnosed [27, 31]. There is a
disease [15, 24]. higher prevalence among relatives of patients
In the presence of IBD, medical or surgical with celiac disease, and this has been calculated
interventions (total colectomy for UC) are the at 1:22 for first-degree relatives and 1:39 for
main management considerations. second-degree relatives [28, 32]. In a recently
There have been a number of case reports/ published large study, the prevalence of celiac
small case series [22, 23] reporting that the fol- disease in the United States was calculated at
lowing systemic treatments may be helpful in the 0.71% (1 in 141), but the authors acknowledged
management of PV: corticosteroids, dapsone, sul- that most cases were in fact undiagnosed [33].
fasalazine, sulfamethoxypyridazine, azathioprine,
cyclosporine, and isotretinoin. A single case Etiopathogenesis
report found success with topical tacrolimus [26]. There is a genetic and environmental basis to the
development of celiac disease.
celiac disease [27]. Other signs and symptoms Enamel defects (enamel hypoplasia, pitting,
include deficiencies in vitamin D leading to grooving, and partial/complete loss of enamel)
osteoporosis, short stature, malabsorption result- have been observed in celiac disease patient
ing in hematinic deficiencies, extreme weakness, cohorts [27, 31]. The prevalence of dental enamel
fatigue, myalgias, headaches, liver function hypoplasia among celiac patients is reported to be
abnormalities, menstrual irregularities, infertility, in the range 10–97% according to various studies
and adverse pregnancy outcomes [28, 29, 31]. [27, 28], although there is debate in the literature
Celiac disease is often associated with other as to whether there is a true association [34].
conditions, most notably Type 1 diabetes mellitus There are two theories as to how enamel defects
and autoimmune thyroiditis as they have a com- arise. The first concerns malabsorption of calcium
mon genetic background [30]. Other associations and phosphorus during enamel formation, which
include selective IgA deficiency and various chro- leads to nutritional deficiencies such as hypocal-
mosomal disorders including Down syndrome, cemia resulting in hypomineralization [35]. The
Turner syndrome, and Williams syndrome [27]. second relates to immune disturbances against the
enamel organ itself during enamel formation [28,
ral Signs and Symptoms
O 31, 34]. An association between delayed eruption
Celiac disease can be suspected in individuals of teeth [27] has been identified in up to 27%.
with both oral mucosal and dental signs and A case-control study involving 300 celiac
symptoms. patients reported that 33% were affected by
Aphthous ulcers (Fig. 2.7) are associated with enamel hypoplasia and 8.3% by recurrent aph-
celiac disease although the cause is unknown. thous ulcers and 20% had experienced a delay in
The ulcers may be due to malabsorption leading dental eruption. The results for the control group
to a hematinic deficiency [31]. The highest preva- were 11%, 3%, and 8%, respectively [34].
lence that has been observed in celiac patient
subgroups has been in children, adolescents, and Differential Diagnosis
women and measures approximately 20% [29]. The differential diagnoses for the cause of enamel
Dermatitis herpetiformis, the cutaneous mani- defects [29, 31] and other factors predisposing to
festation of celiac disease, can present in the oral the formation of aphthous-like ulcers [36, 37] are
cavity in the form of erosions and desquamative seen in Tables 2.5 and 2.6, respectively.
gingivitis.
Another oral soft tissue sign that has been Treatment Recommendations
noted is papillary atrophy of the tongue, which Adhering to a strict gluten-free diet for life is the
can appear red and be painful. It is postulated that mainstay of treatment in the management of both
this is due to malabsorption of hematinics [29]. typical and atypical celiac disease. Compliance can
be difficult especially in teenagers [28]. Aphthous
ulcers often regress when patients are on a gluten-
free diet [28], but topical agents (steroids, analge-
sics, and antiseptics) may have to be considered in
the interim while a patient is adapting to a new diet.
Table 2.6 Factors predisposing to the formation of Table 2.7 Orofacial signs of Gardner’s syndrome
aphthous-like ulcers
Dental Congenitally missing teeth
Behçet’s disease Dentigerous cysts
Cyclic neutropenia Hypodontia
Hematinic deficiencies Hypercementosis
HIV disease Impacted/unerupted teeth
MAGIC syndrome (mouth and genital ulcers with Odontomas
inflamed cartilage) Supernumerary teeth
PFAPA (periodic fever, aphthous stomatitis, Osteomas Can affect the maxilla or mandible
pharyngitis, and cervical adenitis) Soft tissue Epidermoid cysts
Sweet’s syndrome Fibromas
Trauma
Table 2.8 Differential diagnosis of intestinal polyposis • Family history of PJS and any number of ham-
syndromes
artomatous polyps
Basal cell nevus syndrome • Family history of PJS and mucocutaneous
Bannayan-Ruvalcaba-Riley syndrome
pigmentation
Cowden’s syndrome
Cronkhite-Canada syndrome
• Any number of hamartomatous polyps and
Familial adenomatous polyposis (FAP) syndrome mucocutaneous pigmentation
Familial juvenile polyposis
Hereditary mixed polyposis Epidemiology
Hyperplastic polyposis syndrome There are various estimates for the prevalence of
MYH-associated polyposis (MAP) PJS, which range from 1 in 8500 live births to
Peutz-Jeghers syndrome
1 in 200,000 live births depending on the popula-
Turcot’s syndrome
tion sampled. There is no discrepancy based on
sex or ethnicity [43, 44].
Table 2.9 Differential diagnosis of mucocutaneous oral colonoscopy and upper gastrointestinal endos-
pigmentation
copy are indicated at age 8 years and video cap-
Becker’s nevi sule endoscopy should be performed every
Carney complex
3 years, if polyps are found at the initial examina-
Cowden syndrome
Laugier-Hunziker syndrome
tion. Polypectomy of enlarging polyps is the sur-
Leopard syndrome gical intervention of choice.
Melanotic macules/ephelides/nevi/lentigines
Nevi of Ota
Malabsorption Conditions
shades of brown and black [44]. They first appear Malabsorption is a term that encompasses various
in infancy and can also affect other oral sites processes with many causes whereby nutrients are
including the buccal mucosa, labial mucosa, pal- not fully absorbed from the gastrointestinal tract.
ate, and tongue [43, 44]. Lentigines can present Malabsorption can arise from maldigestion,
periorally on the skin as well as other sites includ- mucosal or mural problems, or microbial causes
ing perianally and on the fingers and toes [46]. [47]. A consequence of malabsorption is malnu-
Anemia as a result of gastrointestinal/rectal trition. Hematinic (ferritin, folate, and vitamin
bleeding can be indicated by the presence of oral B12) deficiencies caused by malabsorption can
ulcers, glossitis, or angular cheilitis. lead to oral signs and symptoms.
The most common causes of hematinic mal-
Differential Diagnosis absorption that can present with oral manifesta-
The differential diagnosis of intestinal polyposis tions include Crohn’s disease, celiac disease, and
[38, 43, 45] and mucocutaneous oral pigmentation pernicious anemia.
[43] are summarized in Tables 2.8 (see section on The different causes of malabsorption that can
Gardner’s Syndrome) and 2.9, respectively. contribute to each of the aforementioned hematinic
deficiencies are outlined in Table 2.10 [47–49].
Treatment Recommendations The epidemiology and etiopathogenesis of
There is no medically indicated requirement to Crohn’s disease and celiac disease have been
remove any mucocutaneous pigmentation elaborated on earlier in this chapter. To discuss
although the appearance may be cosmetically all of the other less common causes mentioned in
unappealing and, thus, has a psychosocial impact Table 2.10 in detail would be beyond the scope of
on the patient [15]. Camouflage makeup can be this chapter. However, a brief description of per-
used to conservatively cover up any hyperpigmen- nicious anemia follows.
tation. Various modalities have been used to Pernicious anemia is an autoimmune macro-
remove such pigmentation; however, there is no cytic anemia that is caused by vitamin B12
definitive treatment recommendation to be made. (cobalamin) deficiency. Intrinsic factor, which
Approaches utilized include filtered intense is produced by gastric parietal cells, is required
pulse light, Q-switch ruby laser, and CO2-based to absorb vitamin B12. Autoantibodies act
lasers [46]. against both gastric parietal cells and intrinsic
Surveillance is the key to managing the intes- factor resulting in a deficiency of B12 [48, 50].
tinal polyps. A recent review paper [46] acknowl- Pernicious anemia is associated with the devel-
edges that there is no consensus as to how and opment of gastric adenocarcinoma and atrophic
when this is undertaken. The role of surveillance body gastritis [50].
is to detect large polyps that may predispose to
obstruction/intussusception or bleeding and also Clinical Manifestations
to detect any cancerous changes as early as pos- General signs of malabsorption include unin-
sible [46]. The authors conclude that a baseline tentional weight loss or failure to thrive in
20 J. C. Steele
Table 2.10 Malabsorptive causes of hematinic Table 2.11 Differential diagnosis for an oral burning
deficiencies sensation
B12 Atrophic gastritis Local causes Allergy/contact sensitivity
Blind loop syndrome Dry mouth
Celiac disease Infection (fungal/viral)
Crohn’s disease Mucosal lesions (e.g., geographic
Gastrectomy – partial/total tongue, oral lichen planus)
Ileal resection/disease Pain conditions (e.g., postherpetic
Long-term use of acid-reducing drugs neuralgia)
Parasitic/bacterial infections of the small Trauma (friction from grinding/
intestine clenching teeth/loose dentures)
Bacterial overgrowth Systemic Endocrine (diabetes/hypothyroidism)
Fish tapeworm (diphyllobothriasis) causes Hematinic deficiency
Giardiasis HIV disease
Pernicious anemia Medication side effects
Tropical sprue Sjögren’s syndrome (dry mouth)
Zollinger-Ellison syndrome
Ferritin Celiac disease
Crohn’s disease Gastroesophageal Reflux Disease
Folate Celiac disease
Tropical sprue
Gastroesophageal reflux disease (GERD) is a
chronic disease and occurs when there is involun-
children. The main clinical manifestations of tary projection of gastric acid from the stomach
malabsorption with respect to hematinics are upwards through the esophagus. The acid can be
those of anemia such as fatigue, lethargy, pal- regurgitated into the oral cavity. There are many
lor, and breathlessness. reasons as to why this occurs, but it is more com-
monly seen in obesity, pregnancy, patients with a
ral Signs and Symptoms
O hiatal hernia, smokers, and a high-fat diet.
Hematinic deficiencies (ferritin, folate, and vita-
min B12) are implicated in the development of Epidemiology
recurrent oral ulceration (aphthous ulcers), a sus- It is estimated that seven million people in the
ceptibility to developing infection (angular chei- United States have some symptoms of GERD
litis), a burning sensation of the oral mucosal and that 50% of those diagnosed are between the
tissues (stomatodynia), and the development of ages of 45 and 64 [51].
atrophic glossitis (beefy red tongue), which can
be painful [15]. Etiopathogenesis
Problems with the lower esophageal sphincter
Differential Diagnosis such as transient relaxation or hypotonia can
Please see Table 2.6 for factors predisposing to result in GERD. Other etiological factors include
the formation of aphthous-like ulcers. Please see changes to the gastroesophageal anti-reflux bar-
Table 2.11 for the differential diagnosis of an oral rier, which may occur with a slipping hiatal her-
burning sensation. nia and inadequate esophageal peristalsis [52].
anti-TNF-α therapy for orofacial granulomatosis. J disease in the United States. Am J Gastroenterol.
Oral Pathol Med. 2011;40:14–9. 2012;107(10):1538–44.
17. Hegarty A, Hodgson T, Porter S. Thalidomide for 34. Costacurta M, Maturo P, Bartolino M, Docimo R. Oral
the treatment of recalcitrant oral Crohn’s disease and manifestations of coeliac disease. A clinical-statistic
orofacial granulomatosis. Oral Surg Oral Med Oral study. Oral Implantol (Rome). 2010;3(1):12–9.
Pathol Oral Radiol Endod. 2003;95(5):576–85. 35. Elli L, Pigatto PD, Guzzi G, Bardella MT. New dental
18. Campbell HE, Escudier MP, Patel P, Challacombe enamel defects in coeliac disease. Clin Exp Dermatol.
SJ, Sanderson JD, Lomer MCE. Review article: cin- 2011;36(3):309–10.
namon- and benzoate-free diet as a primary treatment 36. Jurge S, Kuffer R, Scully C, Porter SR. Mucosal dis-
for orofacial granulomatosis. Aliment Pharmacol ease series. Number VI. Recurrent aphthous stomati-
Ther. 2011;34:687–701. tis. Oral Dis. 2006;12(1):1–21.
19. Campbell HE, Escudier MP, Milligan P, Challacombe 37. Chavan M, Jain H, Diwan N, Khedkar S, Shete A,
SJ, Sanderson JD, Lomer MC. Development pf a low Durkar S. Recurrent aphthous stomatitis: a review. J
phenolic acid diet for the management of orofacial Oral Pathol Med. 2012;41(8):577–83.
granulomatosis. J Hum Nutr Diet. 2013;26(6):527–37. 38. Chimenos-Kϋstner E, Pascual M, Blanco I, Finestres
20. Langan RC, Gotsch PB, Krafczyk MA, Skillinge
F. Hereditary familial polyposis and Gardner’s syn-
DD. Ulcerative colitis: diagnosis and treatment. Am drome: contribution of the odonto-stomatology exam-
Fam Physician. 2007;76(9):1323–30. ination in its diagnosis and a case description. Med
21. Elahi M, Telkabadi M, Samadi V, Vakili H. Association Oral Patol Oral Cir Bucal. 2005;10(5):402–9.
of oral manifestations with ulcerative colitis. 39. Smud D, Augustin G, Kekez T, Kinda E, Majerovic
Gastroenterol Hepatol Bed Bench. 2012;5(3):155–60. M, Jelincic Z. Gardner’s syndrome: genetic testing
22. Hegarty AM, Barrett AW, Scully C. Pyostomatitis
and colonoscopy are indicated in adolescents and
vegetans. Clin Exp Dermatol. 2004;29(1):1–7. young adults with cranial osteomas: a case report.
23. Konstantopoulou M, O’Dwyer EM, Steele JC, Field World J Gastroenterol. 2007;13(28):3900–3.
EA, Lewis MAO, Macfarlane AW. Pyodermatitis- 40. Cankaya AB, Erdem MA, Isler SC, Cifter M, Olgac
pyostomatitis vegetans complicated by methicillin- V, Kasapoglu C, et al. Oral and maxillofacial con-
resistant Staphylococcus aureus infection. Clin Exp siderations in Gardner’s syndrome. Int J Med Sci.
Dermatol. 2005;30(6):666–8. 2012;9(2):137–41.
24. Femiano F, Lanza A, Buonaiuto C, Perillo L,
41. Cristofaro MG, Giudice A, Amantea M, Riccelli
Dell’Ermo A, Cirillo N. Pyostomatitis vegetans: a U, Giudice M. Gardner’s syndrome: a clinical and
review of the literature. Med Oral Patol Oral Cir genetic study of a family. Oral Surg Oral Med Oral
Bucal. 2009;14(3):E114–7. Pathol Oral Radiol. 2013;115(3):e1–6.
25.
Nico MM, Hussein TP, Aoki V, Lourenco 42. Woo VL, Abdelsayed R. Oral manifestations of inter-
SV. Pyostomatitis vegetans and its relation to inflam- nal malignancy and paraneoplastic syndromes. Dent
matory bowel disease, pyoderma gangrenosum, pyo- Clin N Am. 2008;52(1):203–30.
dermatitis vegetans, and pemphigus. J Oral Pathol 43. Higham P, Alawi F, Stoopler ET. Medical management
Med. 2012;41(8):584–8. update: Peutz Jeghers syndrome. Oral Surg Oral Med
26. Werchniak AE, Storm CA, Plunkett RW, Beutner
Oral Pathol Oral Radiol Endod. 2010;109(1):5–11.
EH, Dinulos JG. Treatment of pyostomatitis veg- 44. Riegert-Johnson D, Gleeson FC, Westra W, Hefferon
etans with topical tacrolimus. J Am Acad Dermatol. T, Wong Kee Song LM, Spurck L, et al. In: Riegert-
2005;52(4):722–3. Johnson DL, Boardman LA, Hefferon T, Roberts
27. Rivera E, Assiri A, Guandalini S. Celiac disease. Oral M, editors. Cancer syndromes [internet]. Bethesda:
Dis. 2013;19(7):635–41. National Center for Biotechnology Information (US);
28. Guandalini S, Assiri A. Celiac disease. JAMA Pediatr. 2009.. 2008 Jul 18 [updated 2008 Aug 09]. http://
2014;168(3):272–8. www.ncbi.nlm.nih.gov/books/NBK1826/ Accessed
29. Ferraz EG, Campos Ede J, Sarmento VA, Silva
19 Sept 2014.
LR. Pediatr Dent. 2012;34(7):485–8. 45. Omundsen M, Lam FF. The other colonic polyposis
30. Nenna R, Guandalini S, Popp A, Kurppa. Coeliac dis- syndromes. ANZ J Surg. 2012;82:675–81.
ease. Autoimmune Dis. 2014;2014:623784. 46. Beggs AD, Latchford AR, Vasen HFA, Moslein G,
31. Rashid M, Zarkadas M, Anca A, Limeback H. Oral Alonso A, Aretz S, et al. Peutz-Jeghers syndrome: a
manifestations of celiac disease: a clinical guide for systematic review and recommendations for manage-
dentists. J Can Dent Assoc. 2011;77:b39. ment. Gut. 2010;59:975–86.
32. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence 47. Owens SR, Greenson JK. The pathology of mal-
of celiac disease in at-risk and not-at-risk groups in absorption: current concepts. Histopathology.
the United States. Arch Intern Med. 2003;163(3): 2007;50(1):64–82.
268–92. 48. Bizzaro N, Antico A. Diagnosis and classification of
33.
Rubio-Tapia A, Ludvigsson JF, Brantner TL, pernicious anemia. Autoimmun Rev. 2014;13(4–5):
Murray JA, Everhart JE. The prevalence of celiac 565–8.
2 Oral Signs of Gastrointestinal Disease 23
Introduction Leukemia
Clinical Manifestations
Oral manifestations are more prevalent in acute history. Furthermore, cultures and cytologic
(versus chronic) and myeloid (versus lymphoid) smears with fluorescent antibody smears should
leukemias. Findings include gingival hypertro- be obtained in order to differentiate oral ulcers of
phy, petechiae, ecchymosis, ulcers, and hemor- viral etiology in patients receiving immunosup-
rhage especially spontaneous gingival bleeding. pressive chemotherapy [10].
Viral, fungal, and bacterial oral infections are a
common consequence of immunosuppression
[6]. The direct effect of chemotherapeutic drugs Treatment Recommendations
on the oral mucosa may result in ulcers that must
be differentiated from herpes simplex virus In general, treatment of the underlying disease
(HSV) or cytomegalovirus (CMV) [7]. Mental with chemotherapy and/or HSCT will improve the
nerve neuropathy, “numb chin syndrome,” is a oral manifestations of leukemia. Secondary infec-
rare presenting complaint [8]. tions must be treated appropriately. Supportive
Gingival hyperplasia is most commonly asso- care with kaolin and pectin plus diphenhydramine
ciated with AML and acute promyelocytic leuke- oral rinses can be used to reduce mucosal pain.
mia. The gingiva appears markedly edematous,
erythematous, and friable (Fig. 3.1). Gingival
hyperplasia improves with chemotherapy [9]. Lymphomas
Complications of hematopoietic stem cell
transplantation (HSCT) include lichenoid or ker- Etiopathogenesis
atotic papules and plaques, desquamative gingi-
vitis, atrophy, and ulcerations [10]. Lymphomas are solid tumor malignancies involv-
ing B and T lymphocytes and monocytes. These
tumors develop most commonly in the lymph
Differential Diagnosis nodes and less frequently in extra-nodal sites.
The etiology is unknown, but identified risk fac-
A biopsy of the hypertrophic gingival tissues will tors include immunodeficiency states, viral infec-
confirm the diagnosis of leukemic infiltrates. The tions, and chemical exposures [11].
clinical differential of acquired medication- One classification scheme differentiates
induced gingival hyperplasia (anticonvulsants, Hodgkin lymphoma (HL) from non-Hodgkin
calcium channel blockers, and immunosuppres- lymphoma (NHL) [12]. HL predominantly
sants) must be ruled out by a thorough medication affects adolescents and young adults with an
3 Oral Signs of Hematologic Disease 27
additional prevalence peak in middle age. HL lymphoid tissues of Waldeyer’s ring as well as
used to be a uniformly fatal disease, but modern the vestibule and gingivae. Painless, soft masses,
modes of diagnosis and treatment have given a with or without traumatic ulceration, may also
newly diagnosed patient a more than 90% chance involve the palate and buccal mucosa. These
of cure. NHL typically presents in middle-aged lesions have been described as slow-growing,
to older individuals. Both HL and NHL occur painless, bluish soft masses; palatal lesions have
more commonly in men [13]. been confused with minor salivary gland tumors
(Fig. 3.3). Intraosseous lesions maybe associated
with loose teeth and paresthesia of the face.
Clinical Manifestations Major salivary gland enlargement may also be a
presenting sign of NHL [16].
Clinical manifestations of lymphomas are diverse AIDS-associated lymphoma is typically a
but frequently include painless lymphadenopa- non-Hodgkin B-cell lymphoma that presents as a
thy, hepatosplenomegaly, and secondary infec-
tions. The symptoms of fever, night sweats, and
weight loss (B-cell lymphoma symptoms) as well
as pruritus suggest advanced disease and portend
a poor prognosis. The diagnosis is based on his-
tologic (Fig. 3.2) and immohistochemical find-
ings in diseased tissues [11].
Fig. 3.2 High-power
micrograph (400x) of
uniform neoplastic cells
of lymphocytic series
with minimal cytoplasm
in B cell lymphoma.
(Courtesy of Dr. YiLing
Lin UCLA School of
Dentistry)
28 D. V. Messadi and G. W. Mirowski
Treatment Recommendations
Clinical Manifestations
The regular administration of recombinant granulo-
cyte colony-stimulating factor (G-CSF) diminishes The most common presenting symptom in MM
the frequency and severity of symptoms, reduces is bone pain caused by osteolytic lesions or
gingival and dental complications, and reduces the pathologic fractures due to bone destruction.
risk of sepsis during periods of severe neutropenia. Anemia and petechial hemorrhages may also be
30 D. V. Messadi and G. W. Mirowski
seen [28]. Hemorrhage and infection are major Oral Signs and Symptoms
concerns in patients with MM. Bleeding may
result from several causes, including thrombocy- A variety of oral manifestations in MM have been
topenia, abnormal platelet function, or abnormal described. Up to 30% of patients will have
coagulation [29]. involvement of the mandible with associated
Patients may also present with hypercalcemia, swelling, pain, paresthesias, and tooth loss.
proteinuria, renal failure, or thrombocytopenia. Additionally, gingival bleeding or oral petechiae
The radiographic finding of multiple “punched- may be seen, if bone marrow infiltration by malig-
out” well-defined or ragged radiolucencies is nant plasma cells causes thrombocytopenia. In
highly suggestive of advanced MM (Fig. 3.5). rare instances, MM can produce extramedullary
These may be especially evident on skull films. plasmacytomas. When located in the oral cavity,
Renal failure may be the presenting sign as a these lesions are most commonly found on the
result of tumor produced immunoglobulin accu- gingivae or hard palate and appear as dome-
mulation in the kidneys. Light chains (Bence shaped masses that have a tendency to ulcerate.
Jones protein) may be found in the urine in
30–50% of patients [30].
Differential Diagnosis
Fig. 3.6 High-power
micrograph (400x)
showing sheets of
malignant plasma cells
in a patient with
multiple myeloma.
(Courtesy of Dr. Yi-Ling
Lin UCLA, School of
Dentistry)
3 Oral Signs of Hematologic Disease 31
Clinical Manifestations
deposits may be seen on H and E and are cell. Peripheral monocytes found in normal blood
confirmed by Congo red, Thioflavin T, or crys- can differentiate into macrophages and intersti-
tal violet stains. Once histologic specimens are tial dendritic cells that may travel through lym-
stained with Congo red, they are examined phatics to draining lymph nodes. There are
with polarized microscopy to demonstrate the probably two populations of circulating myeloid
characteristic apple green birefringence. dendritic cells that can differentiate into commit-
Immunohistochemical stains may include ted dendritic cells. Expression array results sup-
kappa and lambda light chain, beta-amyloid A4 port the notion that one of these could become
protein, transthyretin, and beta 2-microglobu- the pathologic dendritic cell in LCH [39].
lin to demonstrate extracellular amyloid depos-
its. Immunofixation electrophoresis of serum
or urine may also be used to detect and charac- Clinical Manifestations
terize circulating proteins [37].
LCH has a broad spectrum of clinical manifesta-
tions depending on the site and extent of organ
Treatment Recommendations involvement. There are three forms of LCH, the
diffuse form previously referred to as Letterer-
No effective therapy is available for most forms Siwe disease and the localized variant previously
of amyloidosis. Surgical debulking of the tongue referred to as Hand-Schüller-Christian disease,
is done with limited success [38]. Treatment with while the third form, eosinophilic granuloma, is
antibiotics and anti-inflammatory agents will aid the most common form. LCH is a rare disease
in the control of secondary amyloidosis. Renal that predominantly affects infants and children
transplantation may stop the progress of hemodi- and rarely adults [40]. Diffuse LCH most com-
alysis-associated amyloidosis, but it will not monly affects infants and is characterized by
reverse deposits in bones and joints. widespread involvement of the viscera, poten-
Treatment of primary and multiple myeloma- tially leading to death. Skin lesions are common
associated amyloidosis with colchicine, predni- and include papules, plaques, vesicles, and hem-
sone, and melphalan may improve the prognosis orrhagic nodules, all of which may manifest in a
in patients without renal or cardiac involvement. pattern similar to that of seborrheic dermatitis
[41]. The localized variant is a childhood dis-
ease that consists of the triad of diabetes insipi-
Langerhans Cell Histiocytosis dus, lytic bone lesions, and proptosis [42].
Eosinophilic granuloma presents in young adults.
Etiopathogenesis Radiolucent bone lesions can occur anywhere but
are most common in flat bones [43]. Some
Langerhans cell histiocytosis (LCH) formerly patients have mild, localized pain due to isolated
known as histiocytosis X is a rare condition of bone lesions, whereas others develop rapidly pro-
unknown etiology and pathogenesis character- gressive systemic disease involving nearly every
ized by destructive tissue infiltration by abnormal organ system. Definitive diagnosis of LCH
histiocytes mixed with lymphocytes and eosino- requires histologic confirmation [44].
phils. LCH was thought to be derived from the
morphologically similar Langerhans cells, which
are specialized dendritic cells found in the skin Oral Signs and Symptoms
and mucosa. However, gene expression array
data have shown that the skin Langerhans cell is LCH commonly affects bone, with 10–20% of
not the cell of origin for LCH. Rather, it is a patients having involvement of the maxilla or
myeloid dendritic cell that expresses the same mandible, the symptoms of which can mimic an
antigens (CD1a, CD207) as the skin Langerhans odontogenic infection or periodontal disease [45].
3 Oral Signs of Hematologic Disease 33
Biopsy is necessary to establish a diagnosis Platelets are small, non-nucleated cells in the
because the inflammation and ulcerations are blood that play a critical role in hemostasis [51].
clinically nonspecific. Histology reveals pale Fragmentation of megakaryocytes results in
Langerhans cells with bi-lobed nuclei, which platelet formation. Thrombocytopenia is charac-
resemble coffee beans. Clusters of eosinophils terized by a reduction in platelet count (±2 stan-
also may be present. The diagnosis of LCH is dard deviations from normal, where normal is
confirmed by the characteristic morphology and typically 150,000–450,000 platelets per microli-
the presence of CD1a or CD207 (Langerin) posi- ter). Thrombocytopenia may occur due to auto-
tive histiocytic cells [39, 44]. immune destruction (including connective tissue
Evaluation of the patient with LCH should disease), splenic sequestration, bone marrow
include whole-body radiographic skeletal survey infiltration by tumor cells, and infection (infec-
or bone scintigraphy and serum studies to assess tious mononucleosis) or as an adverse drug reac-
for diabetes insipidus and hypercalcemia [47]. tion. Pseudothrombocytopenia is the result of
in vitro platelet clumping and should be differen-
tiated from true thrombocytopenia.
Treatment Recommendations
Etiopathogenesis
Presentations consist of petechiae, purpura, and buccal mucosa (Fig. 3.8). Purpura and mucocuta-
bleeding including epistaxis, hematuria, menor- neous bleeding resulting in hemorrhagic bullae
rhagia, gastrointestinal bleeding, and intracranial that appear deep red to black are associated with
hemorrhage. Other findings include organomeg- very low platelet counts [1].
aly or skeletal abnormalities. Neurologic defects
and joint or extensive soft tissue bleeding suggest
a coagulation defect as in DIC. Ischemic limbs or Differential Diagnosis
skin necrosis raises the specter of heparin-
induced thrombocytopenia. The associated clinical findings may help to
In addition to spontaneous bleeding that occurs focus the differential: fever suggests infection,
when the platelets fall below 10,000–20,000 sepsis, or DIC; lymphadenopathy may be associ-
platelets per microliter, thrombocytopenia can ated with infection, lymphoma, or other malig-
complicate or prevent the effective treatment of a nancy; thrombosis may be due to heparin,
variety of condition such as chemotherapy or anti- antiphospholipid antibodies, or paroxysmal noc-
viral therapy for hepatitis C or surgery. turnal hemoglobinuria; neurologic findings may
be associated with vitamin B12 or copper
deficiency [51].
Oral Signs and Symptoms
to limit bleeding. Specific treatment recommen- brittleness, and increased fractures in patients
dations depend on the degree of thrombocytope- who require bone marrow expansion in patients
nia and the procedure indicated. For dermatologic with beta thalassemia major. Children with severe
procedures and/or dental extractions, platelet anemia appear pale and listless, have a poor
transfusion and application of local measures appetite, and exhibit slowed growth and delayed
(such as fibrinolytic mouth rinses or absorbable puberty, and their urine may be dark due to hemo-
hemostat) during extraction are safe and effective globinuria. Children may also be jaundiced. Bone
to limit postoperative bleeding [55]. problems in the face are common [57]. Hydrops
fetalis results when there is loss of all four alpha
globin genes. Severe anemia resulting in intra-
Thalassemias uterine demise is typical. Impaired growth and
delayed development is common as is extramed-
Thalassemias are a group of inherited diseases ullary hematopoiesis and bone deformities
that are characterized by genetic defects in hemo- [58, 59]. Endocrinologic insufficiencies are due
globin production resulting in ineffective eryth- to both chronic anemia and from iron overload
ropoiesis and subsequent hemolysis. secondary to transfusion dependence. In second-
ary craniosynostosis, the premature sutural fusion
is of unknown etiology.
Epidemiology
The thalassemias affect 4.83% of the world’s pop- Oral Signs and Symptoms
ulation with a worldwide prevalence of alpha and
beta thalassemia trait of 1.7% [56]. Males and In addition to the pallor of the mucosa due to
females are equally affected. The epidemiology of anemia and yellowing of the mucosa due to jaun-
specific diseases depends on the geographic dice, the bones of the face and skull may show
area and the diseased population being studied. “hair on end” striations due to vertical trabecula-
Most affected individuals are from Africa, the tion secondary to expansion of hematopoiesis.
Mediterranean area, and Southeast Asia. The diploic space is enlarged, while the outer
plate is thinned [60]. Much less common is
involvement of the facial bones resulting in fron-
Etiopathogenesis tal enlargement of the head, expansion of the
maxillary bones, and malalignment of the denti-
Hemoglobin is composed of two alpha globin tion (hemolytic facies) [58].
and two beta globin protein molecules. The pre-
dominant hemoglobin in adults is hemoglobin
A. Four types of alpha thalassemia and three Treatment Recommendations
forms of beta thalassemia have been described.
Iron overload, in patients who are transfusion
dependent (such as in thalassemia), must be
Clinical Manifestations avoided by the use of chelating agents.
Vitamin B12 is an essential water-soluble nutrient Megaloblastic anemia presents with symptoms of
that is a naturally occurring cobalamin (contains burning tongue and or lips associated with atrophic
cobalt). Fifty percent of vitamin B12 is present in glossitis and cheilitis. Occasionally, RAS may be
food. Both gastric acid and pepsin help to free the noted. Folate and vitamin B12 deficiencies have
tightly bound vitamin B12 from ingested proteins. been implicated as contributing factors to RAS,
Intrinsic factor (IF) helps bind vitamin B12 soon and in some patients, aphthae will improve follow-
after leaving the acidic environment of the stom- ing folate and vitamin B12 repletion [1, 62–65].
ach, and the two are then absorbed in the small
intestine. Medications that block acid secretions
also hinder the release of protein-bound vitamin Differential Diagnosis
B12 and thus contribute to decreased absorption.
Supplemental vitamin B12 is not protein-bound The diagnosis of vitamin B12 deficiency can be
and thus not impacted by proton pump inhibitors distinguished from folate deficiency by direct
that block the secretion of gastric acid [61]. measurement of serum vitamin B12 levels or the
Vitamin B12 deficiency is less common than detection of elevated serum methylmalonic acid.
folate deficiency but may be seen in the elderly,
vegetarians, and patients with pernicious anemia
(see below), HIV, or gastrointestinal disease. Treatment Recommendations
Folate is also a water-soluble B vitamin that is
present in food but can be supplemented. Folic Most patients are treated with exogenous cobala-
acid is composed of a p-aminobenzoic molecule min or folate. Transfusion therapy is rarely
linked to a pteridine ring and one molecule of required unless the patient has severe uncompen-
glutamic acid. As a coenzyme, folate helps to sated or life threatening anemia.
transfer single carbons, which is essential in the
metabolism of amino acids as well as DNA and
RNA synthesis. Potential etiologies of folate Pernicious Anemia
deficiency include inadequate dietary intake,
malabsorption, or increased folate consumption, Pernicious anemia (PA) is a complex clinical
which may occur during pregnancy and periods condition. Alterations in the IF-mediated vitamin
of rapid growth or as a result of chronic B12 absorption due to loss of parietal cells, small
inflammation. intestine disorders, genetic mutations, and/or
gastric surgery account for many cases of PA
[61]. Autoantibodies targeting gastric parietal
Clinical Manifestations cells are found in 90% of cases, but this is of low
specificity as anti-parietal cells may be seen in
The clinical findings in both megaloblastic anemia patients without megaloblastic anemia and in
and pernicious anemia are very similar. Fatigue, other autoimmune disorders. Antibodies that tar-
weakness, and difficulty breathing are typical. get IF are seen in 60% of patients with PA and are
Patients may notice tingling or a burning sensation highly specific [66]. It is the IF that is necessary
of the skin and numbness or weakness of the legs. for absorption of the water-soluble essential
Mood alteration, disorientation, memory loss, and nutrient vitamin B12.
decrease in cognition may be noted as well.
Myelopathy results in uncontrolled spasms and
lack of equilibrium. Urinary incontinence is com- Epidemiology
mon as well. In the developing fetus, vitamin B12
deficiency may result in neural tube defects. PA is seen in 2% of adults [61].
3 Oral Signs of Hematologic Disease 37
PA is a complex disorder that involves the blood, A diagnosis of iron deficiency anemia is suggested
immune system, and the gastrointestinal tract. PA by the finding of microcytic, hypochromic anemia in
occurs in individuals who are unable to absorb conjunction with decreased serum iron (<60 μg/dl),
vitamin B12 due to lack of IF [67]. decreased serum ferritin (<15 μg/dl), and elevated
total iron-binding capacity (>400 μg/dl). Plummer-
Vinson syndrome primarily affects middle-aged
Clinical Manifestations women and is characterized by iron deficiency ane-
mia, glossitis, glossodynia, and esophageal strictures
In addition to the usual clinical manifestations of or webs. These patients have an increased risk of
anemia such as fatigue, weakness, and difficulty oral and pharyngeal carcinoma.
breathing, neurologic complications may be seen in
90% of vitamin B12-deficient patients. The neuro-
psychiatric findings include ataxia, loss of vibratory Epidemiology
sensation, dementia, or psychosis. Patients may
notice tingling or burning feelings on the skin and Iron deficiency anemia is the most common cause
numbness or weakness of the legs. Mood alteration, of anemia worldwide. More than a quarter of the
disorientation, memory loss, and decrease in cogni- world’s population is anemic and half of those are
tion may be noted as well. Myelopathy results in iron deficient. Women of reproductive age are
uncontrolled spasms, lack of equilibrium, and uri- most commonly affected as both menstruation and
nary incontinence. In the developing fetus, vitamin pregnancy increase the propensity to develop iron
B12 deficiency may result in neural tube defects. deficiency [70]. Other populations at risk include
athletes, obese patients who have undergone
bariatric surgery, and young children [71].
Oral Signs and Symptoms Epidemiological studies show variable association
between iron deficiency and RAS, but replace-
The classic oral finding in PA is the presence of a ment therapy may not impact the clinical course of
painful or burning, atrophic tongue or “bald” RAS [63, 64].
tongue [68, 69]. Loss of both the filiform and
fungiform papillae results in atrophy of the oral
mucosa exhibited by erythema and glossitis. Etiopathogenesis
Angular cheilitis may also occur in addition to
alterations in taste sensation (dysgeusia) [69]. Iron deficiency anemia may result from insuffi-
cient dietary intake or malabsorption of iron,
chronic blood loss, hemolysis, and/or pregnancy.
Differential Diagnosis
crisis. Patients may suffer from strokes, splenic Acknowledgment We would like to acknowledge Mr.
Michael Gordon for his editorial support.
infarcts, splenic sequestration, and increased sus-
ceptibility to infection. Leg ulcers, pulmonary
hypertension, and renal end-organ damage are
predominantly seen in adults with SCD.
References
1. Schlosser BJ, Pirigyi M, Mirowski GW. Oral mani-
festations of hematologic and nutritional diseases.
Oral Signs and Symptoms Otolaryngol Clin N Am. 2011;44(1):183–203., vii.
https://doi.org/10.1016/j.otc.2010.09.007.
2. Burket LW, Greenberg MS, Glick M, Ship JA. Burket’s
The most common oral manifestations of SCD oral medicine. 11th ed. Hamilton: BC Decker; 2008.
are pallor or jaundice particularly involving the 3. Vogel VG, Fisher RE. Epidemiology and etiology of
soft palate or floor of the mouth. Increased preva- leukemia. Curr Opin Oncol. 1993;5(1):26–34.
lence of dental caries and poor oral hygiene in 4. Swerdlow SH, International Agency for Research on
Cancer, World Health Organization. WHO classifi-
these patients is associated with low socioeco- cation of tumours of haematopoietic and lymphoid
nomic status. No significant role was found in the tissues, World Health Organization classification
patients’ dietary habits or frequency of tooth of tumours. 4th ed. Lyon: International Agency for
brushing [80, 81]. In addition, patients may Research on Cancer; 2008.
5. Cho-Vega JH, Medeiros LJ, Prieto VG,
develop sudden onset of pain or necrosis in previ- Vega F. Leukemia cutis. Am J Clin Pathol.
ously healthy teeth due to sickle crisis [82]. 2008;129(1):130–42. https://doi.org/10.1309/
Overgrowth of the midface, anesthesia of the WYACYWF6NGM3WBRT.
mandibular nerve, asymptomatic necrosis of the 6. Hou GL, Huang JS, Tsai CC. Analysis of oral mani-
festations of leukemia: a retrospective study. Oral Dis.
neurovascular canal, and gingival overgrowth are 1997;3(1):31–8.
well described [82]. Overgrowth of the midface, 7. Weckx LL, Hidal LB, Marcucci G. Oral manifesta-
frontal bossing, exposure of the maxillary teeth, tions of leukemia. Ear Nose Throat J. 1990;69(5):341–
and maxillary bone overgrowth may result in a 2.. 5–6
8. Hiraki A, Nakamura S, Abe K, Takenoshita Y,
depressed nasal bridge with resultant malocclu- Horinouchi Y, Shinohara M, et al. Numb chin syn-
sion in conjunction with a characteristic facial drome as an initial symptom of acute lymphocytic
profile. Osteomyelitis of the mandible is a rare leukemia: report of three cases. Oral Surg Oral Med
complication [83, 84]. Infarction of branches of Oral Pathol Oral Radiol Endod. 1997;83(5):555–61.
9. Cooper CL, Loewen R, Shore T. Gingival hyperplasia
the mandibular nerve, due to vaso-occlusion, complicating acute myelomonocytic leukemia. J Can
rarely causes persistent anesthesia of the teeth, Dent Assoc. 2000;66(2):78–9.
gingivae, or oral mucosa [85, 86]. 10. Neville BW, Damm DD, White DK. Color atlas of
clinical oral pathology. 2nd ed. Baltimore: Williams
& Wilkins; 1999.
11. Word ZH, Matasar MJ. Advances in the diagno-
Differential Diagnosis sis and management of lymphoma. Blood Lymphat
Cancer: Targets Ther. 2012;2012(2):29–55. https://
Patients with SCD must be evaluated to rule out doi.org/10.2147/BLCTT.S15554.
12. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein
other causes of anemia, pain, osteomyelitis, den- H, Jaffe ES. The 2008 WHO classification of lym-
tal abscesses, or facial trauma. phoid neoplasms and beyond: evolving concepts and
practical applications. Blood. 2011;117(19):5019–32.
https://doi.org/10.1182/blood-2011-01-293050.
13. Townsend W, Linch D. Hodgkin’s lymphoma in
Treatment Recommendations adults. Lancet. 2012;380(9844):836–47. https://doi.
org/10.1016/S0140-6736(12)60035-X.
Correction of anemia prior to any surgery for 14. Molyneux EM, Rochford R, Griffin B, Newton R,
treatment of fractures or osteomyelitis is recom- Jackson G, Menon G, et al. Burkitt’s lymphoma.
Lancet. 2012;379(9822):1234–44. https://doi.
mended. Postoperative antibiotic coverage is also org/10.1016/S0140-6736(11)61177-X.
indicated.
3 Oral Signs of Hematologic Disease 41
42. Hoover K, Rosenthal D, Mankin H. Langerhans cell 59. Javid B, Said-Al-Naief N. Craniofacial manifestations
histiocytosis. Skelet Radiol. 2007;36(2):95–104. of β-thalassemia major. Oral Surg Oral Med Oral
https://doi.org/10.1007/s00256-006-0193-2. Pathol Oral Radiol. 2015;119(1):e33–40.
43. Stull MA, Kransdorf MJ, Devaney KO. Langerhans 60. Azam M, Bhatti N. Hair on end appearance. Arch Dis
cell histiocytosis of bone. Radiographics. Child. 2006;91(9):735.
1992;12(4):801–23. 61. Stover PJ. Vitamin B12 and older adults. Curr Opin
44. Windebank K, Nanduri V. Langerhans cell histiocy- Clin Nutr Metab Care. 2010;13:24–7.
tosis. Arch Dis Child. 2009;94(11):904–8. https://doi. 62. Koybasi S, Parlak AH, Serin E, Yilmaz F, Serin
org/10.1136/adc.2007.125872. D. Recurrent aphthous stomatitis: investigation
45. Milian MA, Bagan JV, Jimenez Y, Perez A, Scully of possible etiologic factors. Am J Otolaryngol.
C, Antoniades D. Langerhans’ cell histiocytosis 2006;27(4):229–32.
restricted to the oral mucosa. Oral Surg Oral Med 63. Piskin S, Sayan C, Durukan N, Senol M. Serum iron,
Oral Pathol Oral Radiol Endod. 2001;91(1):76–9. ferritin, folic acid, and vitamin B12 levels in recurrent
https://doi.org/10.1067/moe.2001.110031. aphthous stomatitis. J Eur Acad Dermatol Venereol.
46. Hicks J, Flaitz CM. Langerhans cell histiocytosis: 2002;16(1):66–7.
current insights in a molecular age with emphasis 64. Scully C, Gorsky M, Lozada-Nur F. The diagno-
on clinical oral and maxillofacial pathology practice. sis and management of recurrent aphthous sto-
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. matitis: a consensus approach. J Am Dent Assoc.
2005;100(2 Suppl):S42–66. https://doi.org/10.1016/j. 2003;134(2):200–7.
tripleo.2005.06.016. 65. Patton LL, Brahim JS, Travis WD. Mandibular osteo-
47. Götz G, Fichter J. Langerhans’-cell histiocytosis in 58 myelitis in a patient with sickle cell anemia: report of
adults. Eur J Med Res. 2004;9(11):510–4. case. J Am Dent Assoc. 1990;121(5):602–4.
48. Annibali S, Cristalli MP, Solidani M, Ciavarella D, 66. Bizarro N. Diagnosis and classification of pernicious
La Monaca G, Suriano MM, et al. Langerhans cell anemia. Autoimmun Rev. 2014;13:565–8.
histiocytosis: oral/periodontal involvement in adult 67. Stabler SP. Vitamin B12 Deficiency. New Engl J Med.
patients. Oral Dis. 2009;15(8):596–601. https://doi. 2013;368:149–60.
org/10.1111/j.1601-0825.2009.01601.x. 68. Macleod RI, Hamilton PJ, Soames JV. Quantitative
49. Abla O, Egeler RM, Weitzman S. Langerhans cell exfoliative oral cytology in iron-deficiency and
histiocytosis: current concepts and treatments. megaloblastic anemia. Anal Quant Cytol Histol.
Cancer Treat Rev. 2010;36(4):354–9. https://doi. 1988;10(3):176–80.
org/10.1016/j.ctrv.2010.02.012. 69. Lee HJ, Jo DY. Images in clinical medicine. A smooth,
50. Gadner H, Grois N, Potschger U, Minkov M, Arico shiny tongue. N Engl J Med. 2009;360(6):e8.
M, Braier J, et al. Improved outcome in multisys- 70. Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK,
tem Langerhans cell histiocytosis is associated with Johns N, Lozano R, et al. A systematic analysis of
therapy intensification. Blood. 2008;111(5):2556–62. global anemia burden from 1990 to 2010. Blood.
https://doi.org/10.1182/blood-2007-08-106211. 2014;123(5):615.
51. Sekhon SS, Roy V. Thrombocytopenia in adults: a 71. Love AL, Billett HH. Obesity, bariatric surgery and
practical approach to evaluation and management. iron deficiency: true, true true and related. Am J
South Med J. 2006;99(5):491–8. Hematol. 2008;83:403–9.
52. Priziola JL, Smythe MA, Dager WE. Drug-induced 72. Eisen D, Lynch DP. Oral manifestations of systemic
thrombocytopenia in critically ill patients. Crit Care diseases. The mouth: diagnosis and treatment. St.
Med. 2010;38(Suppl):S145–54. Louis: Mosby; 1998. p. 212–36.
53. Aster RH, Boughie DW. Drug-induced immune
73. Cawson RA, Odell EW. Cawson's essentials of oral
thrombocytopenia. N Engl J Med. 2007;357:580–7. pathology and oral medicine. 8th ed. Edinburgh:
54. Israels S, Schwetz N, Boyar R, McNicol A. Bleeding Churchill Livingstone/Elsevier; 2008.
disorders: characterization, dental considerations and 74. Deloughery TG. Microcytic anemia. N Engl J Med.
management. J Can Dent Assoc. 2006;72(9):827. 2014;371(14):1324–31.. 2010
55. Fillmore WJ, Leavitt BD, Arce K. Dental extractions 75. Tefferi AB, Suman VJ, Sobell JL, Codd MB,
in the thrombocytopenic patient. Oral Surg Oral Med Silverstein MN, Melton LJ 3rd. Trends in the inci-
Oral Pathol Oral Radiol. 117(4):e300. dence of polycythemia vera among Olmsted Coutny,
56. Rund D, RachmiIewitz E. β-Thalassemia. N Engl J Minnesota resident, 1935–1989. Am J Hematol.
Med. 2005;353:1135–46. 1994:4789–93.
57. Perisano C, Marzetti E, Spinelli MS, Calla C, Graci C, 76. Najean Y, Rain JD, Billotey C. Epidemiological data
Maccauro G. PhysiopathoIogy of bone modifications in polycythaemia vera: a study of 842 cases. Hematol
in β -thalassemia. Hindawi Publishing Corporation Cell Ther. 1998;40:159–65.
Anemia Volume 2012, Article ID 320737, 5 p. 77.
Lele MV. Oral manifestations of polycy-
58. Vogiatzi MG, Macklin EA, Fung EB, Cheung AM, thaemia rubra vera. J All India Dent Assoc.
Vichinsky E, Olivieri N, et al. Bone disease in 1965;37(11):345–8.
thalassemia: a frequent and still unresolved problem. 78. Ruparella PB, Ruparella KP, Shirolkar R, Tipathy
J Bone Miner Res. 2009;24(3):543–57. A. Chronic myeloproliferative disorders: a rarest case
3 Oral Signs of Hematologic Disease 43
with oral manifestations and dental management. J patients with sickle cell disease. Am J Med Sci.
Indian Aca Oral Med Radio. 2012;24(2):155–7. 2013;345(3):234–7.
79. Creary M, Williamson W, Kulkarni R. Sickle cell 83.
Shroyer JV 3rd, Lew D, Abreo F, Unhold
disease: current activities, health implications, and GP. Osteomyelitis of the mandible as a result of sickle
future directions. J Women's Health (Larchmt). cell disease. Report and literature review. Oral Surg
2007;16:575–82. Oral Med Oral Pathol. 1991;72(1):25–8.
80. Laurence B, George D, Woods D, Shosanya A, Katz 84. Friedlander AH, Genser L, Swerdloff M. Mental
RV, Lanzkron S, et al. The association between sickle nerve neuropathy: a complication of sickle-cell crisis.
cell disease and dental caries in African Americans. Oral Surg Oral Med Oral Pathol. 1980;49(1):15–7.
Spec Care Dentist. 2006;26:95–100. 85. Gregory G, Olujohungbe A. Mandibular nerve neu-
81. Luna AC, Rodrigues MJ, Menezes VA, Marques KM, ropathy in sickle cell disease. Local factors. Oral Surg
Santos FA. Caries prevalence and socioeconomic fac- Oral Med Oral Pathol. 1994;77(1):66–9.
tors in children with sickle cell anemia. Braz Oral 86. Kelleher M, Bishop K, Briggs P. Oral complications
Res. 2012;26:43–9. associated with sickle cell anemia: a review and case
82. Javed F, Correa FO, Nooh N, Almas K, Romanos report. Oral Surg Oral Med Oral Pathol Oral Radiol
GE, Al-Hezaimi K. Orofacial manifestations in Endod. 1996;82(2):225–8.
Oral Signs of Endocrine
and Metabolic Diseases
4
Jaisri R. Thoppay, Thomas P. Sollecito,
and Scott S. De Rossi
associations with HLA-B8, HLA-DR3, and exposure leading to a bronzing effect is the hall-
HLA-DR4 alleles have been observed. However, mark of primary adrenal insufficiency. Oral
specific HLA associations have not been identi- mucosal hyperpigmentation is seen in 80–94%
fied [1–3]. of patients characteristically presenting as dif-
fuse patchy brown macular pigmentation of the
buccal mucosa, gingiva, palate, and dorsal and
Clinical Manifestations ventral tongue (Fig. 4.1). This appearance is
directly related to increased levels of b-lipotro-
Addison’s disease patients present with chronic pin or ACTH, which stimulates melanocytes, in
nonspecific signs and symptoms that can often turn leading to the bronzing effect and hyper-
lead to a delay in diagnosis. The disease progres- pigmentation. This hyperpigmentation may be
sion may develop over a period of months. The homogeneous or blotchy and therefore, may be
clinical manifestations of Addison’s disease do more difficult to discern from physiologic or
not begin to appear until at least 90% of the adre- racial pigmentation [7]. Oral manifestations,
nal gland is destroyed. The clinical presentation particularly oral pigmentation may be the first
is secondary to the deficiency of cortisol and sign of the disease preceding the cutaneous
aldosterone. Cortisol deficiency leads to altered manifestations.
glucose, fat, and protein metabolism, resulting in The oral hyperpigmentation is histologically
weakness, fatigue, weight loss, inability to toler- characterized by an increase in melanin in the
ate stress, and hypotension [4, 5]. General clini- basal layer, without an obvious increased num-
cal signs and symptoms and related laboratory ber of melanocytes [8]. Cases of oral squamous
abnormalities are listed in Table 4.2. cell carcinoma have been reported in type I
PGAS, which presents in association with can-
didiasis, hypoparathyroidism, and adrenal fail-
Oral Signs and Symptoms ure. The critical pathogenic pathway implicated
in squamous cell carcinoma development is
Darkening of the orofacial skin, vermillion unclear; however, speculation regarding the
border of the lips along with other areas of sun presence of chronic mucocutaneous candidiasis
4 Oral Signs of Endocrine and Metabolic Diseases 47
Differential Diagnosis
p roduction of melanin. Systemic disorders associ- hypothyroidism is 0.6–12 per 1000 in women
ated with the presence of oral pigmented melano- and 1.3–4 per 1000 in men. The prevalence of
cytic lesions may include Peutz-Jeghers and other hypothyroidism and SCH in the US population is
familial hamartoma syndromes. 0.3% and 4.3%, respectively, as estimated by the
A thorough history will aid the clinician in National Health and Nutrition Examination
prompting a diagnostic workup for oral hyper- Survey III data (http://www.cdc.gov/nchs/
pigmentation to differentiate between various nhanes/nh3data.htm Accessed December 2014).
conditions associated with hyperpigmentation. Furthermore, head and neck cancer radiation
When hyperpigmented areas are diffuse, further therapy may result in hypothyroidism, which
examination for underlying diseases or syn- accounts for 10–45% of the cases [10, 11].
dromes is warranted. Biopsy can be performed as
a gold standard to rule out malignancy in case of
an isolated lesion or a lesion that is atypical from Etiopathogenesis
the other areas of hyperpigmentation [8].
Hypothyroidism can be caused by primary thy-
roid failure, or it may be secondary to pituitary
Treatment Recommendations dysfunction. Common causes of primary thyroid
failure are autoimmune thyroiditis, idiopathic
Oral hyperpigmentation from Addison’s disease is atrophy, treatment with radioactive iodide, thy-
often asymptomatic, and therefore no specific roidectomy, and drug use such as prolonged use
treatment is recommended. However, facial pig- of antithyroid drugs, lithium, and amiodarone.
mentation may be reduced by minimizing sun Less common causes include congenital dyshor-
exposure and using sunscreen. Periodic monitoring monogenesis, cretinism, and occasionally infil-
of these lesions is important as malignant lesions trative disease. The most common cause of
have been reported in PGAS type I syndrome [9]. secondary hypothyroidism is centrally mediated
Treatment of the underlying adrenal insufficiency deficiency of thyrotropin-releasing hormone or
may reverse the mucosal hyperpigmentation. thyroid-stimulating hormone. This can occur as
a result of pituitary tumors, infection, and infil-
trative disorders such as sarcoidosis, lymphoma,
Hypothyroidism hemochromatosis, and histiocytosis [10, 12].
Differential Diagnosis
Hyperthyroidism may be seen in all ages but usu- Oral Signs and Symptoms
ally presents with symptoms in the second to fifth
decades of life. The prevalence of hyperthyroidism Hyperthyroidism during the development and
is more common in women with a ratio of 5:1. The eruption of primary teeth can lead to early
reported prevalence is 0.5–2% in women. The exfoliation of primary teeth and premature erup-
most common form of hyperthyroid disease is tion of permanent teeth. Though limited evidence
Grave’s disease (aka autoimmune diffuse toxic is available in humans (due to the complexity of
goiter), which comprises 60–80% of cases. About metabolic diseases), animal studies support the
1–2% of hyperthyroid patients may experience correlation [26]. Also there is limited data avail-
thyrotoxic emergency characterized by hyperpy- able on hyperthyroidism and its association with
rexia, dehydration, organ failure, atrial fibrillation, periodontal disease [27]. Although rare, hyper-
congestive heart failure, confusion, agitation, thyroidism can be caused by an ectopic thyroid
delirium, psychosis, seizures, or coma [24, 25]. gland presenting as a mass at the base of the
tongue. This may be diagnosed as an incidental
finding on routine oral examination or by the
Etiopathogenesis patient who may complain of pain or dysphagia.
Osteoporosis secondary to hyperthyroidism may
The most common causes of hyperthyroidism are affect the maxilla and mandible. Oral burning
Grave’s disease, toxic multinodular goiter and salivary gland enlargement have also been
(Plummer disease), and toxic solitary hyperfunc- reported [22, 28].
tioning nodules. Occasionally inflammation of
the thyroid gland (thyroiditis) results in the
release of stored hormone resulting in thyrotoxi- Differential Diagnosis
cosis. Rarely, hyperthyroidism can be secondary
to a pituitary adenoma, levothyroxine overdose, Patients may present with unequivocal clinical
inadequate iodine supplementation, drug-induced manifestations of the disease such as a thyroid
hyperthyroidism, differentiated thyroid carcino- mass or ophthalmic changes that may prompt
mas and/or their metastases, ectopic thyroid, and workup for hyperthyroidism. Some patients may
familial non-autoimmune hyperthyroidism. have fewer and less obvious clinical signs, as in
During pregnancy a temporary hyperthyroid state subclinical cases. Other manifestations may
may occur due to human chorionic gonadotropin include osteoporosis and cardiovascular disease
excess with elevation in T3, T4, and suppression such as atrial fibrillation and tachycardia.
of TSH [24, 25].
Treatment Recommendations
Clinical Manifestations
In order to provide optimal oral health care to
The clinical presentation of hyperthyroidism var- these patients, clinicians should understand the
ies from asymptomatic (subclinical) to life threat- disease, its treatment, and the disease impact on
52 J. R. Thoppay et al.
oral structures. Cardiac complications are an thorough history (including current manage-
important consideration with surgical proce- ment for hyperthyroidism), physical examina-
dures as hyperthyroidism may be associated tion, and thyroid hormone levels should be
with atrial fibrillation, congestive heart failure, obtained while treating these patients. Patient
angina, and pulmonary hypertension. Preventive should be assessed for any limitations or contra-
measures should be considered while treating indications to local anesthetic with epinephrine
elderly patients with thyroid dysfunction. A for dental procedures [22, 29].
4 Oral Signs of Endocrine and Metabolic Diseases 53
Pituitary adenomas can result from hypothalamic Craniofacial changes may be a preliminary sign
dysfunction. Evidence indicates that intrinsic of hyperpituitarism. Orofacial manifestations
pituicyte alterations may lead to tumor forma- should prompt the oral health care provider to
tion. Mutation of the GNAS1 gene, which results further evaluate. Resultant malocclusion can be
54 J. R. Thoppay et al.
Clinical Manifestations have been reported in both the maxilla and man-
dible. This phenomenon is considered pathogno-
Hyperparathyroidism is most common in post- monic of hyperparathyroidism secondary to
menopausal women, although it can occur in chronic renal disease [39].
persons of all ages, including pregnant women. Histopathological examination of brown
It can be asymptomatic, and often hypercalce- tumors is characterized by vascular fibroblastic
mia presents as an incidental finding, which stroma with numerous osteoclast-like multinu-
upon further diagnostic testing may be associ- cleated giant cells. The presence of hemorrhage,
ated with elevated serum PTH levels [35, 37] hemosiderin, and hypervascularity leads to the
(Table 4.6). brown color [39, 40].
Oral manifestations may include bony changes The differential diagnosis for brown tumor
resulting in jaw expansion and/or extraoral or should include central giant cell granuloma,
intraoral soft tissue swelling due to dentoalveolar ameloblastoma,
aneurysmal bone cyst,
pathology. Dental changes associated with cherubism, reparative granuloma, fibrous dyspla-
hyperparathyroidism include abnormally narrow sia, and giant cell tumors.
dental pulp chambers, generalized loss of the lam-
ina dura of the roots of teeth, and generalized
demineralization of medullary bones causing the Treatment Recommendations
characteristic “ground glass appearance” radio-
graphically. Brown tumors are osseous lesions that Treatment for hyperparathyroidism-related mani-
develop in maxillofacial and mandibular bones in festations involves surgical excision of bony
both primary (4.5%) and secondary (1.5%) hyper- lesions and managing the underlying hyperpara-
parathyroidism as a component of a metabolic thyroidism and associated systemic complica-
bone disease known as osteitis fibrosa cystica. tions which can best be achieved with an
Brown tumors are considered a reparative cellular interdisciplinary approach. Bone healing in these
process rather than a true neoplasm. These tumors patients may be compromised. Thus, parathyroid
56 J. R. Thoppay et al.
levels must be controlled prior to surgical bone serum amyloid A, is typically reactive secondary
reconstruction for improved outcomes. to chronic inflammation [41].
Amyloidosis is a rare clinical disorder caused Amyloidosis is a condition that can be clinically
by extracellular and/or intracellular deposi- asymptomatic for a very long time. Amyloid
tion of insoluble amyloid fibrils that alter the deposits can occur locally in any tissue or may
normal function of tissues. Amyloidosis was involve several organs in multisystem amyloido-
formerly, broadly categorized as primary sys- sis, therefore resulting in a wide range of clinical
temic amyloidosis, secondary systemic amy- manifestations. Progressive nephropathy leading
loidosis, hereditary systemic amyloidosis, to renal failure including heavy proteinuria
and localized amyloidosis. Amyloidosis is (usually in the nephrotic range) is seen in these
also classified as amyloid associated amyloi- patients. Other signs and symptoms include
dosis (AA) and amyloid light chain (AL) edema, hepatosplenomegaly, heart failure, poly-
amyloidosis [41]. neuropathy, carpal tunnel syndrome, malabsorp-
tion of unknown cause, and orthostatic
hypotension. Rare occasions of primary cutaneous
Epidemiology nodular amyloidosis have also been reported [41].
sis AA can be associated with metabolic syn- erythropoietic porphyria (CEP), and hepatoerythro-
drome and periodontal disease. Amyloidosis poietic porphyria (HEP). Porphyria cutanea tarda is
rarely occurs in the sublingual gland [46, 47]. the most common type of porphyria. Porphyria is
caused by a genetic defect leading to dysfunction of
various enzymes in the heme biosynthetic pathway
Differential Diagnosis leading to insufficient production of heme and
accumulation of porphyrins (heme precursors),
Macroglossia may be due to various causes which can be toxic in high concentrations [48].
that should be considered in the differential diagno-
sis other than amyloidosis. Macroglossia can
be congenital as seen in Down’s syn- Epidemiology
drome, Beckwith-Wiedemann syndrome, and
mucopolysaccharidoses. Acquired macroglossia The exact prevalence of porphyria is unknown rang-
can occur as a result of carcinoma, hemangioma, ing from 1 in 500 to 1 in 50,000 worldwide. The
plasmocytoma, lymphangioma, acromegaly, prevalence of some forms of porphyria is unknown
Ludwig’s angina, sarcoidosis, intubation injury, and because the genetic mutation associated with the
rarely nutritional deficiencies. Pseudomacroglossia disease may not cause signs or symptoms [49].
is caused by abnormal positioning and displace-
ment of the tongue due to enlarged tonsils/adenoids,
low palate, abnormalities in the maxillary or man- Etiopathogenesis
dibular arches, oral cavity neoplasms, and occasion-
ally habitual posturing [44, 45]. Porphyrias result from a deficiency of any of the last
seven enzymes of the heme biosynthetic pathway or
from increased activity of the first enzyme ALA
Treatment Recommendations synthase-2 (ALAS 2) in the pathway. When an
enzyme of heme synthesis is deficient or defective,
Amyloidosis is diagnosed by identifying amyloid any other heme precursors or their substrates nor-
on histopathologic examination of oral mucosa mally modified by that enzyme may accumulate in
and/or skin. In cases of progressive macroglossia, the bone marrow, liver, skin, or other tissues and can
surgical reduction can be considered to improve have neurotoxic effects. These precursors may be
complications associated with swallowing, respi- elevated in the blood and be excreted in urine, bile,
ration, cosmetic appearance, and patient comfort or stool [49]. Porphyria cutanea tarda (PCT) is the
[44]. Accurate diagnosis is essential for the treat- most common of the porphyrias and results from a
ment of this condition disease. A poor prognosis deficiency of the enzyme uroporphyrinogen decar-
is associated with the AL type, especially when boxylase (UROD). PCT is essentially an acquired
accompanied by multiple myeloma and in the disease, but some individuals have a genetic (auto-
setting of cardiac amyloidosis. somal dominant) deficiency of UROD that contrib-
utes to the development of PCT [48].
Porphyrias
Clinical Manifestations
Porphyrias are a group of rare, genetically related
metabolic disorders. At least eight different varia- Acute intermittent porphyria generally involves
tions can affect the nervous system, skin, and occa- the nervous system. VP, HCP, ALAD porphyria
sionally other organs. These include acute types though acute may or may not involve neuro
intermittent porphyria (AIP), ALAD porphyria visceral symptoms. Cutaneous porphyrias may
(ADP), variegate porphyria (VP), hereditary copro- have triggers and may manifest as itching or bul-
porphyria (HCP), porphyria cutenea tarda (PCT), lae that can heal with scarring. The clinical mani-
erythropoietic protoporphyria (EPP), congenital festations are listed in the Table 4.7.
58 J. R. Thoppay et al.
Hemochromatosis
Differential Diagnosis
Hemochromatosis is a common form of iron
Differential diagnosis includes dentinogenesis overload disease, due to altered iron
imperfecta, tetracycline-induced staining, or metabolism.
extrinsic causes of staining such as tobacco.
Epidemiology
Treatment Recommendations
Hemochromatosis is one of the most common
Patients with porphyria pose unique challenges genetic disorders in the USA, affecting about 1
with regards to treatment planning. Specific million people, mostly Caucasians.
4 Oral Signs of Endocrine and Metabolic Diseases 59
Treatment Recommendations
Oral Signs and Symptoms
Early diagnosis of this condition often has a good
The primary oral manifestation of hereditary prognosis. However, a delay in diagnosis can be
hemochromatosis is areas of blue-gray to brown fatal. A thorough history and laboratory evalua-
tion prior to dentoalveolar procedures may reduce 16. Loevy HT, Aduss H, Rosenthal IM. Tooth erup-
tion and craniofacial development in congenital
the risk of complications associated with existent hypothyroidism: report of case. J Am Dent Assoc.
liver dysfunction. Furthermore, drugs that are 1987;115(3):429.
metabolized by the liver should be used with cau- 17. Young ER. The thyroid gland and the dental practitio-
tion in these patients [55, 56]. ner. J Can Dent Assoc. 1989;55(11):903–7.
18. Gupta R, Goel K, Solanki J, Gupta S. Oral manifesta-
tions of hypothyroidism: a case report. J Clin Diagn
Res. 2014;8(5):ZD20–2.
References 19. Kumar LK, Kurien NM, Jacob MM, Menon PV,
Khalam SA. Lingual thyroid. Ann Maxillofac Surg.
1. Brandão Neto RA, Carvalho JF. Diagnosis and clas- 2015;5(1):104–7.
sification of Addison’s disease (autoimmune adrenal- 20. Santangelo G, Pellino G, De Falco N, Colella G,
itis). Autoimmun Rev. 2014;13(4–5):408–11. D’Amato S, Maglione MG, et al. Prevalence, diag-
2. Tucci V, Sokari T. The clinical manifestations, diag- nosis and management of ectopic thyroid glands. Int J
nosis, and treatment of adrenal emergencies. Emerg Surg. 2015;28:S1–6.
Med Clin North Am. 2014;32(2):465–84. 21. Femiano F, Gombos F, Esposito V, Nunziata M,
3. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal Scully C. Burning mouth syndrome (BMS): evalu-
insufficiency. Lancet. 2014;383(9935):2152–67. ation of thyroid and taste. Med Oral Patol Oral Cir
4. Brooke AM, Monson JP. Addison’s disease. Medicine. Bucal. 2006;11(1):E22–5.
2005;33(11):20–2. 22. Pinto A, Glick M. Management of patients with thy-
5. Løvås K, Husebye ES. Addison’s disease. Lancet. roid disease: oral health considerations. J Am Dent
2005;365(9476):2058–61. Assoc. 2002;133(7):849–58.
6. Tiemensma J, Andela CD, Kaptein AA, Romijn JA, 23. Ekmektzoglou KA, Zografos GC. A concomitant
van der Mast RC, Biermasz NR, et al. Psychological review of the effects of diabetes mellitus and hypo-
morbidity and impaired quality of life in patients with thyroidism in wound healing. World J Gastroenterol.
stable treatment for primary adrenal insufficiency: 2006;12(17):2721–9.
cross-sectional study and review of the literature. Eur 24. Menconi F, Marcocci C, Marinò M. Diagnosis and
J Endocrinol. 2014;171(2):171–82. classification of Graves’ disease. Autoimmun Rev.
7. Nieman LK, Chanco Turner ML. Addison’s disease. 2014;13(4–5):398–402.
Clin Dermatol. 2006;24(4):276–80. 25.
Devereaux D, Tewelde SZ. Hyperthyroidism
8. Meleti M, Vescovi P, Mooi WJ, van der Waal and thyrotoxicosis. Emerg Med Clin North Am.
I. Pigmented lesions of the oral mucosa and peri- 2014;32(2):277–92.
oral tissues: a flow-chart for the diagnosis and 26. Poumpros E, Loberg E, Engstrom C. Thyroid function
some recommendations for the management. Oral and root resorption. Angle Orthod. 1994;64(5):389–
Surg Oral Med Oral Pathol Oral Radiol Endod. 93; discussion 394.
2008;105(5):606–16. 27. Zahid TM, Wang BY, Cohen RE. The effects of thy-
9. Böckle BC, Wilhelm M, Müller H, Götsch C, Sepp roid hormone abnormalities on periodontal disease
NT. Oral mucous squamous cell carcinoma – an antici- status. J Int Acad Periodontol. 2011;13(3):80.
pated consequence of autoimmune polyendocrinopa- 28. Guerra G, Cinelli M, Mesolella M, Tafuri D, Rocca A,
thy-candidiasis-ectodermal dystrophy (APECED). J Amato B, et al. Morphological, diagnostic and surgi-
Am Acad Dermatol. 2010;62(5):864–8. cal features of ectopic thyroid gland: a review of liter-
10. Almandoz JP, Gharib H. Hypothyroidism: etiol-
ature. Int J Surg. 2014;12(Supplement 1(0)):S3–S11.
ogy, diagnosis, and management. Med Clin N Am. 29. Huber MA, Terezhalmy GT. Risk stratification and
2012;96(2):203–21. dental management of the patient with thyroid dys-
11. Golden SH, Robinson KA, Saldanha I, Anton B,
function. Quintessence Int. 2008;39(2):139–50.
Ladenson PW. Prevalence and incidence of endo- 30. Samarasinghe S, Emanuele MA, Mazhari A. Chapter
crine and metabolic disorders in the United States: 47 – Neurology of the pituitary. In: Handbook of
a comprehensive review. J Clin Endocrinol Metab. Clinical Neurology. Philadelphia: Elsevier; 2012.
2009;94(6):1853–78. p. 685–701.
12.
Franklyn JA. Hypothyroidism. Medicine. 31. Arafah BM, Nasrallah MP. Pituitary tumors: patho-
2009;37(8):426–9. physiology, clinical manifestations and management.
13. Roberts CG, Ladenson PW. Hypothyroidism. Lancet. Endocr Relat Cancer. 2001;8(4):287–305.
2004;363(9411):793–803. 32. Lania A, Spada A. G-protein and signalling in pitu-
14. Caturegli P, De Remigis A, Rose NR. Hashimoto thy- itary tumours. Horm Res. 2009;71(2):95–100.
roiditis: clinical and diagnostic criteria. Autoimmun 33. Chanson P, Salenave S, Kamenicky P. Chapter 14 –
Rev. 2014;13(4–5):391–7. Acromegaly. In: Handbook of Clinical Neurology.
15. Chandna S, Bathla M. Oral manifestations of thyroid Philadelphia: Elsevier; 2012. p. 197–219.
disorders and its management. Indian J Endocrinol 34. Ayuk J, Sheppard MC. Growth hormone and its disor-
Metab. 2011;12(suppl2):s113–6. ders. Postgrad Med J. 2006;82(963):24–30.
4 Oral Signs of Endocrine and Metabolic Diseases 61
Table 5.1 Clinical and oral manifestations, workup, and treatment of nutritional deficiencies
Deficiency Clinical findings Oral findings Testing Treatmenta
Iron Pallor Mucosal pallor Hemoglobin (low) Oral ferrous sulfate
Weakness Angular stomatitis Hematocrit (low) 300 mg BID
Fatigue Glossitis MCV (low) Parenteral available
Ferritin (low)
Iron level (low)
TIBC (high)
Thiamine (B1) Tachycardia Painful vesicular Test for signs of alcohol IV thiamine
Hypotension mucosal eruption abuse 200–500 mg TID
Nystagmus Ulceration of the Electrolytes for 5–7 days
Ophthalmoplegia buccal mucosa, CBC and smear followed by oral
Ataxia mouth floor, palate Liver function tests thiamine 100 mg
TID for 1–2 weeks
Blood sugar level
then 100 mg daily
Memory Hyperesthesia Magnesium
abnormalities B12
Folate Laboratory testing
Calcium should not delay
Phosphate therapy
Blood alcohol
concentrations
Confabulation Burning tongue MRI or CT head
Riboflavin (B2) Oro-oculo-genital Glossitis (magenta) Plasma erythrocyte Oral riboflavin
syndrome glutathione reductase 1–3 mg/day for
Conjunctivitis Cheilitis activation coefficient (high) children
Angular palpebritis Angular stomatitis Pyridoxamine phosphate 10–20 mg/day for
Photophobia Edema of oxidase activity (low) adults
Pruritic scaling oropharyngeal
Perineal rash mucosa
Seborrheic
dermatitis-like rash
Pyridoxine (B6) Seborrheic Angular stomatitis Plasma pyridoxal-5- Oral pyridoxine
dermatitis-like rash Gingival erythema phosphate level (low) 30 mg/day
Intertrigo Urine 4-pyridoxic acid (low)
Neuropathy Small aphthous
Paresthesias ulcerations
Dysesthesias Atrophic glossitis
Burning tongue
Cyanocobalamin Pallor Angular cheilitis Serum vitamin B12 (low) Oral B12,
(B12) Weakness Painful glossitis 1000 mcg/day
Fatigue Recurrent aphthous Methylmalonic acid (high) OR
Ataxia ulcers IM or subcutaneous
Psychological Diffuse erythematous Homocysteine (high) 1000 mcg weekly
disturbances mucositis MCV (high) IM until
Mucosal pallor CBC and smear normalization of
Burning tongue Antiparietal cell Ab serum B12 levels or
for 8 weeks
Anti-IF Ab
empirically
Folate (B9) Pallor Diffuse stomatitis Serum folate level Folic acid 1 mg/day
Weakness Serum vitamin B12
Fatigue Angular cheilitis CBC and smear Confirm B12 WNL
Atrophic glossitis
Small lingual ulcers
with “fiery red
borders”
Burning tongue
5 Oral Signs of Nutritional Disease 65
Table 5.1 (continued)
Deficiency Clinical findings Oral findings Testing Treatmenta
Biotin (B7) Alopecia Perioral dermatitis Serum biotin Biotin 150 mcg
Hair brittleness Urinary biotin catabolites daily
Easy hair plucking Atrophy patches of and 3-hydroxyisovaleric Supplements
lingual papillae acid (high) available in doses of
Seborrheic Generalized mucosal 2500 or 5000 mcg
dermatitis-like erythema
intertriginous rash Dry crusted lips
Vitamin C Perifollicular Signs in dentulous CBC with smear Oral ascorbic acid
hyperkeratosis patients Serum ascorbic acid 250 mg daily
Hemorrhage
Petechia or Gingival swelling Iron studies OR
ecchymoses 100 mg TID
Arthralgia Bleeding OR
Corkscrew hairs Ecchymoses 1000 mg split over 4
Osteopenia Loose teeth daily doses
If severe: 1000 mg
daily for 2 weeks
Maintenance
therapy 250 mg
weekly
Replace iron, if low
Vitamin A Ophthalmopathy Salivary Serum retinol If night blindness is
Night blindness hypofunction Zinc and iron levels present: IM vitamin
Bitot’s spots Xerostomia Ophthalmology consultation A 100,000 IU single
Xerosis Keratinization of dose
Acneiform papules salivary glands
Follicular keratosis Enamel fissures and If chronic vitamin A
pits deficiency is
Oral leukoplakia present: vitamin A
Corkscrew hairs Hypervitaminosis A 50,000 IU until
Easy hair plucking Dry, scaly, fissured retinol levels
Petechia lips, gingival normalize
Phrynoderma erythema,
gingivitis,
exfoliative angular
cheilitis
Vitamin D Rickets or Typically seen in Serum 25-hydroxyvitamin Treatment depends
osteomalacia rickets D on age, sex,
Diffuse osteopenia Loss of periodontal Calcium comorbid conditions
attachment Ionized calcium
Enlarged Phosphate 600 IU for age 1–70
metaphyses or pregnant or
breastfeeding
Long bone bowing Enamel pitting and Parathyroid hormone 800 IU for age >71
Rachitic rosary hypoplasia
Vitamin K Ecchymoses Gingival erythema Prothrombin time (high) Oral phytonadione
Petechia and bleeding Serum vitamin K (K1) 2.5–25 mg
daily
Petechia Serum uncarboxylated
Ecchymoses osteocalcin (high) OR
Hematomas of oral IM/IV/SC 10 mg
mucosa once
(continued)
66 S. N. Tolkachjov and A. J. Bruce
Table 5.1 (continued)
Deficiency Clinical findings Oral findings Testing Treatmenta
Zinc Eczematous, Perioral dermatitis Serum zinc level Oral zinc sulfate
erythematous, sparing upper lip 50 mg/day for
vesiculobullous, or 6 months
pustular acrofacial Angular cheilitis OR
and intertriginous Oral ulcerations 15–30 mg/kg/day
dermatitis Flattening of filiform for adults
Diarrhea papillae
Pneumonia Hypogeusia 0.5–1.0 mg/kg/day
Poor wound healing for children
Growth delay Xerostomia Hair zinc level
Zinc-dependent enzymes
activities
Niacin (B3) 3 Ds: dementia, Prodromal burning of Serum niacin Oral nicotinamide
dermatitis, and mucosa Serum tryptophan 100 mg TID for
diarrhea Whole blood nicotinamide 3–4 weeks
Photosensitivity Erythema of the adenine dinucleotide (NAD)
Dyspigmentation lingual tip (early) and nicotinamide adenine OR
Cracking and Tongue swelling and dinucleotide (NADP) levels 500 mg daily for
crusting of skin burning and NAD/NADP ratio (low) 1 week with
Depression “Fiery scarlet hue” of transition to
Anxiety tongue 100–300 mg daily
Hallucinations Smooth erythematous for 3–4 weeks
Casal’s necklace: tongue Adults: 100 mg
photosensitive Pseudomembrane every 6 h until CNS
erythema and Patchy inflammation Urinary 1-methyl-2- and GI symptoms
dyschromia around mucosa pyridone-5-carboxamide resolve
the neck Ulceration of lingual (2-PYR) and Maintenance
margin and buccal 1-methylnicotinamide therapy with 50 mg
mucosa (1-MN) (more sensitive) every 8–12 h until
Angular cheilitis cutaneous
symptoms resolve
Gingival erythema
Children: 10–50 mg
Dental caries
every 6 h
MCV mean corpuscular volume, BID twice daily, TIBC total iron biding capacity, IV intravenous, TID three times daily,
CBC complete blood count, MRI magnetic resonance imaging, CT computerized tomography, Ab antibody, IF intrinsic
factor, WNL within normal limits, IU international units, SC subcutaneously
a
Treatment course are suggestions, and each patient should be clinically evaluated for comorbidities affecting absorp-
tion and metabolism of each vitamin and mineral
IDA may occur secondary to malabsorption [15, 16]. Specifically, the lingual changes are
states, abnormal bleeding, as well as diets high in manifest as a glossitis with atrophy of the papil-
oxalates, coffee, tea, and phytate [10, 12, 13]. lae resulting in swelling and complaints of sore-
Ascorbic acid deficiency may also decrease iron ness and a burning sensation [17, 18] (Fig. 5.1).
absorption [14]. Continued atrophy and eventual balding of the
Clinical manifestations of IDA include gener- dorsal tongue is secondary to a decrease in lin-
alized pallor, weakness, and fatigue. Central ner- gual epithelial keratinization and eventual loss of
vous system (CNS) changes such as dementia papillae [17]. Atrophy of the tongue and angular
have also been associated with anemia [11]. stomatitis are not specific for IDA, however, and
In the oral cavity, oral mucosal pallor is the may be seen in other B-complex vitamin defi-
characteristic sign of IDA, but this may be asso- ciencies. The glossitis of vitamin B12 deficiency
ciated with angular stomatitis and lingual changes and IDA can be exacerbated by candidiasis [18].
5 Oral Signs of Nutritional Disease 67
Fig. 5.1 Erosive glossitis and mucosal pallor associated Fig. 5.2 Angular cheilitis and mucosal pallor in a patient
with iron deficiency anemia with combined vitamins B2 and B6 deficiency
Additionally, since iron absorption depends on oral findings. Furthermore, multiple vitamins
adequate vitamin C, the characteristic signs of may be deficient in the same patient. Studies
hemorrhagic gingivitis seen in scurvy may also assessing nutritional status in women of low
occur in IDA secondary to ascorbic acid socioeconomic groups showed that a majority of
deficiency [14, 19]. this population had vitamin B6 and vitamin B2
Importantly, an association between Plummer- deficiencies (Fig. 5.2) [23, 24]. Glossitis and
Vinson syndrome (PVS), with its concomitant angular stomatitis, formerly thought to be pathog-
anemia, and increased risk of oral and hypopha- nomonic for riboflavin deficiency, may be seen in
ryngeal carcinoma has been proposed [20–22]. any of the B-vitamin disorders, as well as previ-
PVS is a triad of angular stomatitis, glossitis, and ously mentioned IDA. Nonetheless, glossitis,
dysphagia, seen with IDA and esophageal webs, with an associated burning sensation, is the hall-
which consistently respond to iron therapy [22]. mark finding in B-complex vitamin deficiencies
In patients with PVS, a detailed oral cavity exam- [23, 24]. Initially noted as hypertrophy, erythema,
ination and review of systems is prudent in order and inflammation of the lingual papillae, the
to assess for possible malignant transformation. fissured appearance of early glossitis eventually
The differential diagnosis of IDA and its oral evolves to a smooth glazed appearance from pap-
manifestations includes vitamin B12 deficiency, illary atrophy [23]. This atrophy may be further
folate deficiency, and other causes of anemia exacerbated, if elderly patients have concomitant
such as anemia of chronic disease. sarcopenia (loss of skeletal muscle secondary to
The treatment of anemia depends on its etiol- malnutrition and age), affecting the tongue [25].
ogy, and the treatment of IDA specifically is con- While not specific for these deficiencies, a con-
tingent upon absorption status. In the case of stellation of glossitis and angular stomatitis
normal vitamin C levels and normal gastrointesti- should raise suspicion for a vitamin deficit.
nal (GI) function, oral ferrous sulfate 300 mg twice
daily may be used. Parenteral iron may also be
administered, if the GI system is compromised. Thiamine (Vitamin B1, Aneurin)
showed the prevalence of thiamine deficiency to thought to contribute to national prevalence dif-
be 10.5% in Yunnan province in China [33]. ferences in WE [38].
While malnutrition and polished rice diet are Traditionally, hypermetabolic states, such as
typically associated with thiamine deficiency, a pregnancy, fevers, exercise, and diets high in
study of 118 elderly hospitalized patients in a milled (polished) rice, have been risk factors for
geriatric ward showed moderate thiamine defi- thiamine deficiency [39]. Alcohol abuse, chronic
ciency in up to 40% of patients [34]. disability, and poor access to nutritional food also
Thiamine deficiency produces a group of dis- negatively impact thiamine levels [39, 40].
orders manifest with neurologic and/or cardiac Additionally patients with cyclic vomiting,
dysfunction. “Wet beriberi” is a cardiovascular anorexia, bulimia, and hyperemesis gravidarum
dysfunction characterized by tachycardia and may also be at risk.
hypotension, mimicking acute coronary syn- Thiamine deficiency is typically not associ-
drome and shock [27]. “Dry beriberi” usually ated with oral manifestations and when reported
refers to the effects of thiamine deficiency on the is rare and non-specific [41]. Notwithstanding,
peripheral nervous system causing wasting and however, painful vesicular eruptions and eventual
partial paralysis. Lower extremity weakness, ulceration affecting the buccal mucosa, floor of
calf pain, edema, and foot drop may be seen the mouth, and occasionally palate have rarely
[35]. This often occurs in tandem with central been reported [42]. Recurrent aphthous stomati-
nervous system abnormalities due to thiamine tis (RAS) has also been shown to be associated
deficiency manifesting as Wernicke’s encepha- with low vitamin B1 levels [43, 44]. Glossitis
lopathy (WE), which is the constellation of acute was also noted in a patient with thiamine-respon-
ophthalmoplegia, gait ataxia, and an abnormal sive wet beriberi [45]. Hyperesthesia and a burn-
mental state [36]. The classic triad, however, is ing tongue sensation have also been reported [4].
only seen in 16% of patients in whom necropsy In infants with vitamin B1 deficiency, erythema
studies were confirmatory of WE [36]. of the papillae over the anterior third or apex of
Korsakoff’s psychosis is another presentation of the tongue has been shown to precede glossitis.
thiamine deficiency affecting the CNS, charac- Additionally, pinpoint herpetiform vesicles on
terized by memory abnormalities, anterograde the buccal mucosa, ventral tongue, and palate
and variable retrograde, as well as confabulation have been described [4, 46, 47].
[37]. Neurologic symptoms of thiamine defi- Since oral signs are often absent or non-spe-
ciency therefore manifest as “dry beriberi,” WE cific, correlation between neurologic, cardiac,
(the aforementioned triad of nystagmus, oph- and autonomic findings is necessary, if a thia-
thalmoplegia, and ataxia), and Wernicke- mine deficiency is suspected. Additional signs of
Korsakoff syndrome (WKS – the latter poor hygiene, alcohol use, or malnutrition such
encompassing WE and Korsakoff’s psychosis). as cheilitis, glossitis, and bleeding gums can be
MRI visualization and postmortem biopsy dem- helpful clues [48]. Most patients with WKS have
onstrating atrophy of the mammillary bodies, a history of alcohol abuse and present in acute
thalamus, or the periaqueductal gray matter are settings and are therefore unlikely to be initially
consistent with WKS [37]. seen by an outpatient dermatologist or dentist.
Sechi and Serra reviewed previous population Treatment of patients with WE or WKS will
studies of WE prevalence, citing a 0–2.2% preva- depend on the patient’s state of malnutrition.
lence in the US population and a 1.7–2.8% preva- Recommendations also change depending on
lence in Australia. While the authors considered whether prophylactic dosing or treatment dosing
alcohol abuse as a common etiological factor for are needed. IV thiamine 200–500 mg three times
WE, they were not able to find a correlation daily for 5–7 days followed by oral thiamine 100 mg
between the prevalence of WE and national alco- three times daily for 1–2 weeks, then 100 mg daily
hol consumption data. Therefore, national thia- thereafter, is a reasonable regimen for patients with
mine supplementation and dietary habits are also severe WKS and thiamine deficiency [48].
5 Oral Signs of Nutritional Disease 69
a nemia may be secondary to other etiologies such elderly, as well as patients taking medications
medication use or illicit drug effects. Ataxia and interfering with folate metabolism, such as metho-
loss of vibration and proprioception should also trexate or antipsychotics, are at risk of folic acid
alert a clinician to the possibility of tertiary syphi- deficiency [3]. In the aforementioned study on
lis or other neurologic diseases. 2563 folate samples with 4 demonstrating defi-
The replacement route of vitamin B12 defi- ciency, 1 patient had a malabsorption syndrome, 1
ciency depends on the absorption status of the was an alcoholic, 1 had schizophrenia, and in the
patient. If enteral absorption is possible, oral last patient, no obvious etiologic factor was identi-
replacement with 1000 mcg/day may be given fied [89]. Biliary stasis can also cause an immedi-
[101, 102]. If parietal cells and the terminal ileum ate drop in serum folate levels [93, 106]. Physiologic
are destroyed or absent or the patient is deficient and pathologic states with hyperproliferation or
in intrinsic factor, intramuscular (IM) monthly growth of tissues, such as pregnancy, hemolysis,
vitamin B12 injections may be given [85, 102]. leukemia, and exfoliative dermatitis, may also
One thousand micrograms weekly IM or subcu- lower serum folate concentration [93].
taneously have been suggested until the normal- Megaloblastic anemia is the typical measur-
ization of serum vitamin B12 levels, or for able hematologic presentation of folate defi-
8 weeks, if used empirically. Levels of cyanoco- ciency. Homocysteine levels alone would be
balamin after an IM injection may be exhausted elevated in folate deficiency, as opposed to both
within 3 weeks; therefore, ongoing monthly sup- methylmalonic acid and homocysteine elevations
plementation is recommended in patients with in vitamin B12 deficiency. Clinically, CNS signs
pernicious anemia, if parenteral supplementation are more closely associated with vitamin B12
is required [85]. deficiency and will progress in the absence of
supplementation. No other consistent clinical
findings are noted with folate-deficient patients.
Folic Acid It is important to remember, however, that folate
deficiency in pregnant women is associated with
With the fortification of cereal and other foods, fetal neural tube defects.
folate deficiency is almost nonexistent in the While most general signs of folate deficiency
USA. In a recent study of 2563 red blood cell are unremarkable, the oral cavity can be signifi-
folate samples in a large urban inpatient hospital, cantly involved and symptomatic in affected indi-
only 4 samples (0.16%) were found to be in the viduals. The earliest complaints may be
deficient range [89]. But this low prevalence is significant burning and soreness, and these sensa-
not ubiquitous. In a Swiss population of preg- tions may persist throughout the clinical course
nant women, 4% had low serum folate levels and until the patient is appropriately treated [1, 3, 5,
63% of women were taking folate supplementa- 41]. The burning sensation of the tongue can be
tion [103]. In Jordan, a study of pregnant women quite severe. Diffuse stomatitis and angular chei-
in 2010 demonstrated the prevalence of folate litis may also be present. Atrophic glossitis with
deficiency and insufficiency to be 13.6% and small lingual ulcers with “fiery red borders” have
82.9%, respectively [104]. Multiple nutrients, also been described [5, 42].
including folate, were measured in 1163 Chinese Since folate therapy may mask a vitamin B12
pregnant women. In the cohort with anemia – deficiency, checking vitamin B12 levels and per-
44% of the overall study population – folate defi- forming a CNS examination prior to treating with
ciency was found in 22.7% [105]. In older folate is recommended [93, 107]. Multiple folate
Belgian patients diagnosed with all forms of dosing regimens, ranging from 400 mcg to 5 g,
anemia, folate deficiency typically makes up have been proposed, depending on pregnancy
5.5% of the etiologies [8, 9]. status, risk for neural tube defects, and concur-
Folate is present in fruits, grains, nuts, poultry, rent medication use. A dose of 1 mg/day is an
and dark green leafy vegetables. Alcoholics and the appropriate therapy for chronic deficiency [85].
5 Oral Signs of Nutritional Disease 73
Biotin is sometimes called vitamin B7 or vitamin Vitamin C (aka ascorbic acid) deficiency has been
H. It may be found in nuts, legumes, and cooked studied extensively in multiple population studies.
egg yolks. Biotin supplements are also quite popu- Most authors have focused on lower socioeco-
lar due to anecdotal efficacy in various forms of nomic groups, and indeed, studies from the UK
alopecia. Biotin deficiency may be acquired due to and North America have estimated one in five
anticonvulsant therapy or excess ingestion of raw men and one in nine women being deficient in
eggs. Avidin, a glycoprotein in raw eggs, binds to vitamin C [118]. In the US population, 13% were
biotin, making it unavailable in tissues [108, 109]. deficient in vitamin C from 1988 to 1994, but this
Anticonvulsants, on the other hand, increase biotin prevalence decreased to 7.1% in a 2009 follow-up
breakdown [110, 111]. Biotin deficiency may also study [119, 120]. The groups that were found to
be seen when infants are weaned from breastfeed- be most at risk were smokers, those who did not
ing [112]. Genetic or inborn forms of biotin defi- use vitamin C supplements, and non-Hispanic
ciency include biotinidase deficiency and Black males [119]. Low socioeconomic status
holocarboxylase deficiency [113, 114]. In the gen- was consistently associated with risk for defi-
eral population, the highest estimated incidence of ciency [120]. When looking at gender in the lower
biotinidase deficiency is 1:35,000 [115]. income groups in Glasgow, 26% of men and 14%
Alopecia, brittleness, and easy plucking of of women, ages 25–74, had insufficient serum
hair may clinically present in patients with a bio- vitamin C levels [121]. Additionally, in the UK,
tin deficiency [35]. A seborrheic dermatitis-like 25% of men and 16% of women over 19 years of
rash in the intertriginous areas may be noted, in age had low vitamin C levels [122]. In Toronto,
association with periorificial dermatitis [58]. 14% of non-smoking women ages 20–29 had
Intraoral signs of biotin deficiency are vitamin C deficiency [123]. In a 2003 Mexican
extremely rare. These may include patches of study, Villalpando et al. found that 40% of women
atrophy of the lingual papillae and generalized between 12 and 49 years of age were deficient
mucosal erythema [42]. Dry crusted lips and [124]. Additionally, in 5638 randomly selected
periorificial dermatitis are more common [42]. people in India, 45.7% of individuals from south-
Zinc deficiency, pellagra, and other eczema- ern India and 73.9% of individuals from northern
toid dermatitides should be considered in the dif- India were vitamin C deficient. Male sex, tobacco
ferential diagnosis of biotin deficiency. Since use, and older age were all considered risk factors
many of these signs and symptoms are non-spe- for vitamin C deficiency in this population, most
cific, urinary testing with excreted 3-methylcroto- of whom had poor nutrition at baseline [118].
nylglycine, 3-hydroxyisovaleric acid, and Another study from western India showed that
methylcitric acid can be done, showing significant only 9.6% and 13% of men and women, respec-
elevation in patients with biotin deficiency [112]. tively, were deficient; however, over half had sub-
Serum biotin can be measured but is a less sensi- optimal vitamin C levels [125].
tive marker of tissue levels, as compared with the The elderly and patients with Roux-en-Y
urinary biotin catabolites [110]. gastric bypass, in addition to tobacco users and
Biotin has been described as a “nontoxic” lower income groups, are at risk of vitamin C
supplement. Toxicity has not been documented in deficiency. From 145 consecutive patients
humans, and doses as high as 200 mg orally and admitted to an acute geriatric ward in France,
20 mg intravenously have been used [116, 117]. 12% had clinical symptoms and signs of scurvy,
For biotin replacement, 150 mcg daily is recom- such as perifollicular hyperkeratosis, bruising,
mended [58]. Supplements on the market, how- easy bleeding, and gingivitis [126]. In 1163
ever, may come in doses of 2500 or 5000 mcg pregnant Chinese women, in the anemia cohort,
and often combined with B-complex vitamins 64% were also deficient in ascorbic acid [105].
and vitamin C. 32.9% of patients having undergone a Roux-
74 S. N. Tolkachjov and A. J. Bruce
en-Y gastric bypass surgery in Brazil demon- pallor secondary to anemia [129]. Halitosis may
strated a significant reduction in vitamin C also be noted [131]. A study of gingivitis and
levels [127]. Since vitamin C is found in fresh periodontitis in healthy and diabetic patients
fruits, vegetables, and semi-skimmed milk, demonstrated low levels of ascorbic acid in
patients on strictly fast food diets without sup- healthy subjects with gingivitis and diabetics
plementation are also at risk [128]. Furthermore, with periodontitis. Supplementation with ascor-
cooking or prolonged storage of food may also bic acid improved these symptoms [132].
decrease the available vitamin C [129]. Scurvy should be considered, if a patient pres-
Since ascorbic acid is a necessary cofactor for ents with the “four Hs” including hemorrhagic
collagen biosynthesis, including pericapillary signs, hyperkeratosis, hematologic abnormalities,
collagen, bleeding is the cardinal clinical sign of and hypochondriasis [128, 133]. Other differen-
vitamin C deficiency, secondary to weakened tial diagnoses include leukemia, musculoskeletal
vascular walls and capillary fragility [128, 129]. infections, bleeding diatheses, vasculitides, and
Additionally, anemia is also a hallmark of scurvy, vitamin K deficiency [128]. Although iron defi-
since ascorbic acid aids iron absorption by reduc- ciency may be concomitant with vitamin C defi-
ing it to a ferrous state [128]. Symptoms similar ciency, patients may have a slightly elevated mean
to those in patients with IDA may manifest. corpuscular volume (MCV) or microcytosis and a
Scurvy, the symptomatic form of severe vitamin reduced serum ascorbic acid level upon labora-
C deficiency, is manifest by perifollicular hyper- tory assessment [129].
keratosis and hemorrhage, petechia or ecchymo- Treatment with 250 mg of ascorbic acid orally
ses, arthralgia, corkscrew hairs, and osteopenia twice daily, 100 mg three times daily, or 1000 mg
[35, 126, 128]. Signs of easy bleeding from daily split over four doses, depending on dosing
venous puncture sites may also be seen. preference, are all recommended treatment
Oral signs of scurvy are typically only seen in options [41, 131, 134]. Patients with severe defi-
patients with teeth [5, 63, 128, 130]. Oral mani- ciency may benefit from the 1000 mg regimen for
festations and an accurate history may be the 2 weeks followed by maintenance therapy with
only clues to a diagnosis of vitamin C deficiency 250 mg weekly [134]. If iron replacement is
[131]. These manifestations include extensive needed, a supplement of iron and vitamin C is
gingival swelling, bleeding, petechia, and loose also available in a combination form of ferrous
teeth (Fig. 5.5) [63, 131]. Erythema may involve fumarate and ascorbic acid [135].
the labial-free gingival margins adjacent to the
teeth, and spontaneous hemorrhage can occur
due to vascular instability [128, 131]. Edentulous Fat-Soluble Vitamin Deficiencies
areas of the mucosa and gingiva may demonstrate
Vitamin A
prevalence of VAD in China was 10%. No gender children in Ethiopia [140]. Cutaneous signs of
differences existed, but prevalence increased VAD are xerosis, acneiform papules, follicular
with age [33]. In Brazil, 546 schoolchildren keratosis, corkscrew hairs similar to those of vita-
between 7 and 14 years of age demonstrated a min C deficiency, easy hair plucking, and pete-
27.5% prevalence of VAD, as demonstrated by chia [35]. Phrynoderma, “frog skin,” is also seen
retinol values <30 μg/dL. Lower weight and in chronic VAD [144, 145]. The xerophthalmia of
younger age were thought to be variables predis- VAD is a common cause of blindness in child-
posing children to VAD [136]. In Panama and El hood [146].
Salvador, as defined by serum retinol <20 μg/dL, Salivary hypofunction, as manifested by xero-
the prevalence of VAD in children less than stomia, is frequently associated with VAD. Patients
5 years of age was 6 and 36%, respectively [137]. complain of dry mouth and are at increased risk of
In Bangladesh, severe VAD in preschool chil- oral infections such as candidiasis due to lower
dren, demonstrated by night blindness, was 0.6% levels of protective enzymes and an altered muco-
by 1996; however, subclinical VAD was high sal barrier [147]. The teeth of patients with VAD
[138]. In the same study, the prevalence of night may demonstrate alterations of enamel including
blindness in rural mothers was 1.4% [138]. fissures and pits [4]. The teeth may also appear to
Similarly, in Nepal, the prevalence of night blind- be white and “unglazed” [4]. Oral leukoplakia
ness was 5% in women and 1% among school- may be seen and has been demonstrated to
aged children. Low serum retinol levels were respond to vitamin A therapy in these cases [148].
found in 32.3% of children and 16.6% of women In an era of systemic retinoid use, it is impor-
[139]. In Ethiopia, 37.7% of children had VAD tant to also be familiar with the potential risk of
and 0.8% had night blindness [140]. hypervitaminosis A. Oral manifestations of this
Risk factors for VAD, as suggested by these excess are dry, scaly, fissured lips, gingival ery-
studies, are male gender, older age in children, thema, gingivitis, and exfoliative angular cheilitis
wasting or low body weight, and living in a rural [3, 4, 41].
setting [33, 139, 140]. However, the Brazilian The differential diagnosis of VAD includes
study showed that younger age groups and lower scurvy, ichthyosis vulgaris or other ichthyotic
body weight were associated with VAD risk as conditions, and asteatotic dermatitis.
opposed to heavier and older patients tested in Treatment of VAD deficiency depends on the
the study population [136]. Nevertheless, chil- severity of symptoms and etiology of the defi-
dren in general are an at-risk group for VAD and ciency. For xerostomia, artificial saliva and soft,
the associated sequelae. In women, risks for VAD nonirritating foods, such as soup, may be used
include age less than 20 years, pregnancy, and a [149]. For VAD associated with night blindness
rural setting [139]. Other groups at risk for VAD and a clear diagnosis of low retinol levels, an IM
are patients with short bowel syndrome, of whom injection of 100,000 international units (IU) of
5% have been shown to have VAD in a prospec- vitamin A may be given as a single dose [150]. In
tive US study [141]. Additionally, in an Australian cases of chronic vitamin A deficiency, such as
study, 13% of patients with cystic fibrosis (CF) patients with bariatric surgery, a daily dose of
were deficient in vitamin A [142]. Patients with 50,000 IU of vitamin A may be used until retinol
CF, exocrine pancreatic insufficiency, and biliary levels normalize. However, treatment should be
stasis often have vitamin A and other fat-soluble undertaken on a case-by-case basis, and patients
vitamin deficiencies, due to malabsorption. should be monitored for signs of vitamin A excess.
Another unique patient population shown to have
acute VAD is children with measles [143].
Clinical manifestations of VAD include oph- Vitamin D
thalmopathy with night blindness and Bitot’s
spots – areas of keratin deposition on the con- Vitamin D has been a popular topic of investiga-
junctiva. Bitot’s spots were found in 1.7% of all tion in recent years. Its importance in calcium
76 S. N. Tolkachjov and A. J. Bruce
absorption and homeostasis is well established; heavier counterparts [151]. Other major determi-
however, vitamin D levels and clinical correla- nants of vitamin D status were altitude, exercise,
tions are being investigated in almost all fields of and serum albumin-corrected calcium [155].
medicine. Among population studies, addressing Deficiency is typically seen in the spring and
the epidemiology of vitamin D deficiency varies winter, except for patients in Brazil, who demon-
with season of the year, level of ultraviolet light strated lowest concentrations of 25(OH)D in the
exposure, and ethnicity. 25-Hydroxyvitamin D2 summer [33, 151, 153, 156]. An evaluation of
and sometimes 25-hydroxyvitamin D3 – 25(OH) 635 patients in Sao Paulo, Brazil, identified male
D – are the vitamin D metabolites used for sex, high body mass index (BMI), high waist cir-
screening patients’ sera in order to assess for cumference, low physical activity, tobacco and
deficiency. Blood levels of vitamin D metabolites alcohol use, younger age, low family income,
with deficiency and insufficiency vary for each darker skin color, and season of the year, as risk
study, depending on selected laboratory ranges factors for vitamin D deficiency [156]. Lastly,
and cutoffs. Patients with insufficiency have patients with fat malabsorption are at risk of defi-
higher levels of vitamin D than those with a defi- ciency. Notably, 15.5% of CF patients in Australia
ciency. In the USA, Whites have higher vitamin demonstrated a vitamin D deficiency [142]. Since
D levels than Blacks and Hispanics [151]. In the 25-hydroxyvitamin D3 is synthesized in the liver,
month of January, 65.4% of non-Hispanic Blacks patients with cholestasis or liver cirrhosis are
are estimated to be deficient versus 28.9% of prone to deficiency in functional forms of vita-
Hispanics and 14% of Whites. Insufficiency rates min D. Ultraviolet light (UVB) converts 7-dihy-
in these groups are 84.2%, 56.3%, and 34.8%, drocholestorol (provitamin D3) in the skin to
respectively [152]. In Ireland, 40.1% of adult previtamin D3. Subsequently, this form is con-
individuals had 25(OH)D levels inadequate for verted to vitamin D3 by the keratinocytes and
bone health at the level of <50 nmol/L [153]. eventually is transferred to the liver and kidneys
Vitamin D deficiency, defined as <30 nmol/L in for conversion to 25-hydroxyvitamin D3 and
this study, was prevalent in 6.7% of this popula- 1,25-dihydroxyvitamin D3, respectively [157].
tion [153]. In a large national study in Mexico, This partially explains why patients with darker
the prevalence of vitamin D insufficiency, as skin types and those with liver disease have been
defined by 25(OH)D <50 nmol/L, was 24%, shown to have lower levels of 25(OH)D [158].
10%, 8%, and 10% for preschoolers, school-aged Ergocalciferol (vitamin D2) and cholecalciferol
children, adolescents, and adults, respectively. (vitamin D3) can be ingested as supplements;
The overall deficiency prevalence, defined by however, only vitamin D3 is also endogenously
25(OH)D <20 nmol/L, was actually less than 1% synthesized with exposure to sunlight [157].
in all age groups [154]. When evaluating the Clinical manifestations of severe vitamin D
presence of chronic kidney disease (CKD) in deficiency are manifest as rickets. Rickets may
association with vitamin D deficiency, in a cohort be secondary to improper intake or malabsorp-
of 1145 patients, vitamin D concentrations and tion of vitamin D or due to congenital aberrant
deficiency status were similar in the CKD and homeostasis of phosphorus, calcium, and para-
healthy groups. In this study 11.8% of patients thyroid hormone [159–163]. Patients demon-
had CKD without dialysis, and 69.1% had either strate diffuse osteopenia and enlarged
deficient or insufficient levels of 25(OH)D, as metaphyses, as evidenced by radiographic
compared to 75.3% of the healthy subjects – films, long bone bowing, and prominent nod-
hence very similar rates [155]. ules at the costochondral joints, known as
Typically, children have higher 25(OH)D lev- rachitic rosary. Patients with genetic vitamin D
els than adults, and males have higher intake and deficiency or pseudo-vitamin D deficiency
levels of vitamin D than females [151]. Leaner rickets (PDDR), secondary to CYP27B1 muta-
individuals have higher 25(OH)D concentrations tion, may also demonstrate failure to thrive,
and are more likely to use supplements than their hypotonia, and growth retardation [163]. The
5 Oral Signs of Nutritional Disease 77
VKDB was 3.3%, with rural areas being dispro- Chinese study from 1995 to 2006, 50–70% of
portionately affected [33]. In special popula- people were found to be zinc deficient [33]. An
tions, such as patients with inflammatory bowel astounding 90% of women in Malawi were
disease (IBD), the prevalence of VKD is 54% found to be deficient in zinc [180]. The genetic
and 43% in CD and ulcerative colitis (UC), form of AE, typically secondary to SLC39A4
respectively [175]. In CF children, low vitamin mutations on chromosome 8q24.3, encoding the
K was demonstrated in 29% of patients, a find- Zip4 zinc transporter, has an incidence of 1 in
ing partially explained by the malabsorption of 500,000 children [177].
fat-soluble vitamins in this patient population In addition to genetic AE, vegans, alcoholics,
[142]. VKD was seen in 63% of patients with as well as patients with HIV, CF, and IBD are at
chronic pancreatitis, half of whom had alcohol risk for zinc deficiency [181]. Some infants dem-
abuse as the driving etiology [176]. Since vita- onstrate zinc deficiency, if the mother’s milk has
min K may be ingested in food and synthesized low zinc levels, as seen in mothers with the
by gut bacteria, patients with abnormalities in SLC30A2 mutation [182, 183]. Patients on TPN
gut flora may also be deficient. Drugs interfer- and some enteral nutrition (EN) formulas may
ing with the action of vitamin K, such as warfa- also demonstrate a deficiency [184].
rin and fluoroquinolones, may also cause the An eczematous, erythematous, vesiculobul-
signs of VKD. lous, or pustular acrofacial and intertriginous der-
As discussed, bleeding tendencies, evidenced matitis may be seen with AE [35]. Diarrhea and
by a prolonged prothrombin time on laboratory pneumonia are also associated with zinc defi-
evaluation, and osteoporosis clinically are the ciency. Wound healing and growth may also be
major clinical and radiological manifestations of impaired [185, 186].
VKD. Perioral and periorificial eczematous to pus-
Oral manifestations of VKD include gingival tular dermatitis are characteristically seen in
erythema and bleeding, especially after brushing AE. Angular cheilitis with oral ulcerations may
of teeth. Petechia, ecchymoses, and hematomas also be present [143, 187, 188]. A “U-shaped
of the oral mucosa may also be present. Severely or horseshoe-shaped configuration” is used to
deficient patients may demonstrate constant slow describe perioral dermatitis of zinc deficiency
bleeding from the gums [4, 41]. due to sparing of the upper lip [58]. Intraoral
Vitamin C deficiency may mimic VKD. Other findings may include flattening of the filiform
differential diagnoses for the oral manifestations papillae, impaired healing, and sensations of
of VKD are leukemia and vasculitides. hypogeusia and xerostomia [35, 181, 189,
Oral phytonadione (K1) is typically used in 190]. Associated diarrhea and eczematous and
patients with normal absorption and metabolism bullous dermatitis of acral surfaces may
of vitamin K. If patients have fat malabsorption, accompany the periorificial and oral findings
such as those with CF or pancreatitis, oral mena- (Fig. 5.6).
dione, a synthetic provitamin of vitamin K, may The differential diagnosis of AE includes dia-
be used. IM or subcutaneous forms of vitamin K per dermatitis, protein malnutrition, vitamin A
are also available. deficiency or excess, certain forms of psoriasis,
necrolytic migratory erythema, and other causes
of periorificial dermatitis, including other vita-
Zinc Deficiency min deficiencies.
Therapeutic recommendations are inconsis-
Zinc deficiency, termed acrodermatitis entero- tent. Oral supplementation with zinc sulfate
pathica (AE) when symptomatic, is quite com- 50 mg daily for 6 months is reasonable. Also, a
mon in subclinical testing. An estimated 20% of potential weight-based dosing regimen is
the world population is zinc deficient, particu- 0.5–1.0 mg/kg/day for children and 15–30 mg/
larly in low-income settings [177–179]. In a kg/day for adults [35, 181, 191].
5 Oral Signs of Nutritional Disease 79
a b
Fig. 5.6 Acrodermatitis enteropathica – zinc deficiency – titis and superficial ulcerations of the buttocks and
in a patient with a Roux-en-Y gastric bypass procedure. intergluteal cleft. (c) Significant acrally distributed des-
(a) Glossitis and angular cheilitis. (b) Eczematous derma- quamation and scaling
cacy of replacement therapy with vitamin BC hematinic deficiencies and cast doubt on the
capsules (containing 10 mg of vitamin B1, 5 mg effectiveness of replacement therapy in symptom
of vitamin B2, 5 mg of vitamin B6, 5 μg of vita- resolution [206, 207]. Further investigation is
min B12, 20 mg of calcium pantothenate, 50 mg clearly needed. With the current body of evi-
of nicotinamide, and 60 mg of calcium) and cor- dence, it is prudent to evaluate patients with BMS
responding hematinics, such as vitamin B12, for nutritional deficiencies including iron,
folate, and iron, in which specific cohorts of B-vitamins, vitamin C, and zinc (Table 5.2). An
patients were deficient [202]. One hundred and empiric therapeutic trial of vitamin BC may be
seventy-seven patients (44%) of the treated beneficial to patients. Hormonal changes and
patients with primary and secondary BMS with psychological disorders have also been impli-
hematinic deficiencies had complete remission cated, but no causality has been established, and
of their BMS symptoms [202]. Of the 177 com- a multifactorial origin for BMS is likely [208].
plete responders, 62 patients lacking definite In patients presenting with symptoms of a
hematinic deficiencies also had a complete sore or burning mouth, a broad differential diag-
remission of their BMS symptoms. A majority nosis must be considered, and secondary etiolo-
of patients with BMS and hematinic deficien- gies must be ruled out before primary BMS is
cies responded to therapy; however, just under diagnosed. A complete history and a careful
half of patients with IDA and BMS had symp- physical exam of the oral cavity should aid in
tom remission [202]. ruling out local or systemic causes. Cultures may
IDA has often been associated with the symp- be done, as candidiasis and coliform bacterial
toms of burning mouth. In an evaluation of 75 infections have been associated with a burning
patients with IDA and 150 controls, 14 patients had sensation [209].
IDA and BMS. It was found that IDA patients had a As discussed, hematinic deficiencies should
higher frequency of oral symptoms than their always be considered in patients with symptoms
matched controls, and burning oral mucosa was such as dysgeusia, subjective xerostomia, or
found in 76% of the IDA group [19]. In another glossodynia. Abnormalities of the tongue and/or
population of 276 patients with BMS, it was found mucosa may be evident, but signs may be subtle
that 26.8% had a low serum zinc level [204]. Oral and difficult to appreciate, particularly in mild or
zinc at the dose of 14.1 mg/day was administered to early stage deficiencies. Therefore, screening
a treatment group with zinc deficiency, and change tests for nutritional deficiencies, as well as auto-
in pain intensity from baseline was evaluated using immune conditions, are frequently done when
a numerical pain scale. The pain scale in the treat- evaluating patients with BMS [208]. While some
ment group dropped from 8.1 to 4.1 versus 7.7– authors suggest neurological imaging, we recom-
6.7 in controls. The authors concluded that zinc mend that history, physical examination, and
replacement may be beneficial for the treatment of review of systems guide clinicians when deciding
BMS in a specific subset of patients with zinc insuf- on the need for imaging.
ficiency [204]. Lastly, an interesting case report of a
46-year-old female with BMS, who failed amitrip-
tyline, gabapentin, and pregabalin, suggested that Recurrent Aphthous Stomatitis
the addition of 3 g daily of vitamin C completely
resolved her symptoms [205]. In this patient, evalu- Recurrent aphthous ulcers may be associated
ation for deficiency of other vitamins and minerals with a multitude of systemic diseases, as well as
was negative; however, a vitamin C level was not several nutritional deficiencies. Nutritional insuf-
tested. ficiencies should be considered in patients with
These reports allude to potential therapeutic RAS, especially when other aforementioned
avenues with nutritional supplementation in signs or symptoms are present, concurrently.
BMS patients deficient in vitamins and minerals, Specifically, RAS has been commonly associated
although other studies refute the etiologic role of with IDA, vitamin B12 deficiency, and folate
82 S. N. Tolkachjov and A. J. Bruce
BMS and RAS are two common clinical sce- 15. Darby WJ. The oral manifestations of iron defi-
ciency. JAMA. 1946;130:830–5.
narios where screening for associated nutritional 16. Jacobs A, Cavill I. The oral lesions of iron defi-
insufficiencies may provide opportunities for ciency anaemia: pyridoxine and riboflavin status. Br
helpful therapeutic intervention. Appropriate J Haematol. 1968;14:291–5.
therapy can lead to resolution of symptoms and 17. Monto RW, Rizek RA, Fine G. Observations on the
exfolative cytology and histology of the oral mucous
confirm the diagnosis. A high index of suspicion membranes in iron deficiency. Oral Surg Oral Med
is paramount in identifying nutritional insuffi- Oral Pathol. 1961;14:965–74.
ciencies, and knowledge of the symptoms and 18. Lu SY, Wu HC. Initial diagnosis of anemia from sore
signs that may occur in the oral cavity can lead to mouth and improved classification of anemias by
MCV and RDW in 30 patients. Oral Surg Oral Med
prompt diagnosis and therapy. Oral Pathol Oral Radiol Endod. 2004;98:679–85.
19. Wu YC, Wang YP, Chang JY, Cheng SJ, Chen HM,
Sun A. Oral manifestations and blood profile in
patients with iron deficiency anemia. J Formosan
References Med Assoc. 2014;113:83–7.
20. Larsson LG, Sandstrom A, Westling P. Relationship
1. Boyd LD, Palmer CA. Nutrition and oral health. of Plummer-Vinson disease to cancer of the
Saddle River: Prentice-Hall; 2001. upper alimentary tract in Sweden. Cancer Res.
2. Weinberg MA. Anatomy of the periodontal struc- 1975;35:3308–16.
tures: the healthy state. Saddle River: Pearson 21. Richie JP Jr, Kleinman W, Marina P, Abraham P,
Prentice-Hall; 2006. Wynder EL, Muscat JE. Blood iron, glutathione, and
3. Thomas DM, Mirowski GW. Nutrition and oral micronutrient levels and the risk of oral cancer. Nutr
mucosal diseases. Clin Dermatol. 2010;28:426–31. Cancer. 2008;60:474–82.
4. Khadim MI. Oral manifestations of malnutrition 22. Tahara T, Shibata T, Okubo M, Yoshioka D, Ishizuka
I. The effect of vitamins. JPMA. 1981;31:44–8. T, Sumi K, et al. A case of Plummer-Vinson syn-
5. Dreizen S. Oral indications of the deficiency states. drome showing rapid improvement of Dysphagia
Postgrad Med. 1971;49:97–102. and esophageal web after two weeks of iron therapy.
6. Cutright DE, Bauer H. Cell renewal in the oral Case Rep Gastroenterol. 2014;8:211–5.
mucosa and skin of the rat. I. Turnover time. Oral 23. Prema K, Srikantia SG. Clinical grading of lingual
Surg Oral Med Oral Pathol. 1967;23:249–59. lesions in vitamin B-complex deficiency. Indian J
7. Dreizen S. The mouth as an indicator of internal Med Res. 1980;72:537–45.
nutritional problems. Pediatrician. 1989;16:139–46. 24. Bamji MS, Prema K, Rama Lakshmi BA, Ahmed
8. Balducci L, Ershler WB, Krantz S. Anemia in the F, Jacob CM. Oral contraceptive use and vitamin
elderly-clinical findings and impact on health. Crit nutrition status of malnourished women-effects of
Rev Oncol Hematol. 2006;58:156–65. continuous and intermittent vitamin supplements. J
9. Joosten E, Pelemans W, Hiele M, Noyen J, Verhaeghe Steroid Biochem. 1979;11:487–91.
R, Boogaerts MA. Prevalence and causes of anaemia 25. Tamura F, Kikutani T, Tohara T, Yoshida M, Yaegaki
in a geriatric hospitalized population. Gerontology. K. Tongue thickness relates to nutritional status in
1992;38:111–7. the elderly. Dysphagia. 2012;27:556–61.
10. Ania BJ, Suman VJ, Fairbanks VF, Rademacher 26. Manzo L, Locatelli C, Candura SM, Costa
DM, Melton LJ 3rd. Incidence of anemia in older LG. Nutrition and alcohol neurotoxicity.
people: an epidemiologic study in a well defined Neurotoxicology. 1994;15:555–65.
population. J Am Geriatr Soc. 1997;45:825–31. 27. Long L, Cai XD, Bao J, Wu AM, Tian Q, Lu
11. Chung SD, Sheu JJ, Kao LT, Lin HC, Kang ZQ. Total parenteral nutrition caused Wernicke’s
JH. Dementia is associated with iron-deficiency ane- encephalopathy accompanied by wet beriberi. Am J
mia in females: a population-based study. J Neurol Case Rep. 2014;15:52–5.
Sci. 2014;346(1–2):90–3. 28. Wooley JA. Characteristics of thiamin and its rel-
12. Ma G, Li Y, Jin Y, Zhai F, Kok FJ, Yang X. Phytate evance to the management of heart failure. Nutr Clin
intake and molar ratios of phytate to zinc, iron and Pract. 2008;23:487–93.
calcium in the diets of people in China. Eur J Clin 29. Aykroyd WR. Nutritional problems of urban com-
Nutr. 2007;61:368–74. munities. Proc Nutr Soc. 1970;29:148–50.
13. Zijp IM, Korver O, Tijburg LB. Effect of tea and 30. Dahlberg K. Medical care of Cambodian refugees.
other dietary factors on iron absorption. Crit Rev JAMA. 1980;243:1062–5.
Food Sci Nutr. 2000;40:371–98. 31. Thanangkul O, Whitaker JA. Childhood thiamine
14. Lane DJ, Richardson DR. The active role of vitamin deficiency in northern Thailand. Am J Clin Nutr.
C in mammalian iron metabolism: much more than 1966;18:275–7.
just enhanced iron absorption! Free Radic Biol Med. 32. Tang CM, Rolfe M, Wells JC, Cham K. Outbreak of
2014;75C:69–83. beriberi in The Gambia. Lancet. 1989;2:206–7.
84 S. N. Tolkachjov and A. J. Bruce
33. Wong AY, Chan EW, Chui CS, Sutcliffe AG, Wong people and its relationship to milk intake. Am J Clin
IC. The phenomenon of micronutrient deficiency Nutr. 1993;58:85–90.
among children in China: a systematic review of the 52. Wilson JM. Riboflavin deficiency in late pregnancy:
literature. Public Health Nutr. 2014;17:2605–18. a problem in south Asia too? Trans R Soc Trop Med
34. Pepersack T, Garbusinski J, Robberecht J, Beyer Hyg. 1988;82:656.
I, Willems D, Fuss M. Clinical relevance of thia- 53. Nichols EK, Talley LE, Birungi N, McClelland A,
mine status amongst hospitalized elderly patients. Madraa E, Chandia AB, et al. Suspected outbreak
Gerontology. 1999;45:96–101. of riboflavin deficiency among populations reli-
35. Jensen GL, Binkley J. Clinical manifestations of ant on food assistance: a case study of drought-
nutrient deficiency. JPEN. 2002;26:S29–33. stricken Karamoja, Uganda, 2009–2010. PLoS One.
36. Harper CG, Giles M, Finlay-Jones R. Clinical signs 2013;8:e62976.
in the Wernicke-Korsakoff complex: a retrospec- 54. Bates CJ, Prentice A, Cole TJ, Van Der Pols JC,
tive analysis of 131 cases diagnosed at necropsy. J Doyle W, Finch S, et al. Micronutrients: highlights
Neurol Neurosurg Psychiatry. 1986;49:341–5. and research challenges from the 1994–5 national
37. Becker DA, Ingala EE, Martinez-Lage M, Price RS, diet and nutrition survey of people aged 65 years and
Galetta SL. Dry Beriberi and Wernicke’s encepha- over. Br J Nutr. 1999;82:7–15.
lopathy following gastric lap band surgery. J Clin 55. Cimino JA, Epel R, Cooperman JM. Effect of diet on
Neurosci. 2012;19:1050–2. vitamin deficiencies in retarded individuals receiv-
38. Sechi G, Serra A. Wernicke’s encephalopathy: new ing drugs. Drug Nutr Interact. 1985;3:201–4.
clinical settings and recent advances in diagnosis 56. Pelliccione N, Pinto J, Huang YP, Rivlin
and management. Lancet Neurol. 2007;6:442–55. RS. Accelerated development of riboflavin defi-
39. Rolfe M, Walker RW, Samba KN, Cham K. Urban ciency by treatment with chlorpromazine. Biochem
beriberi in The Gambia, West Africa. Trans R Soc Pharmacol. 1983;32:2949–53.
Trop Med Hyg. 1993;87:114–5. 57. Jacobs EC. Oculo-oro-genital syndrome: a defi-
40. Johnson KA, Bernard MA, Funderburg K. Vitamin ciency disease. Ann Intern Med. 1951;35:1049–54.
nutrition in older adults. Clin Geriatr Med. 58. Jen M, Yan AC. Syndromes associated with nutri-
2002;18:773–99. tional deficiency and excess. Clin Dermatol.
41. Schlosser BJ, Pirigyi M, Mirowski GW. Oral mani- 2010;28:669–85.
festations of hematologic and nutritional diseases. 59. Rosenblum IA, Jallaffe N. The oral manifestations
Otolaryngol Clin N Am. 2011;44:183–203, vii. of vitamin deficiencies. JAMA. 1941:2245–8.
42. Eisen D, Lynch DL. The mouth: diagnosis and treat- 60. Jolliffe N, Fein HD, Rosenblum IA. Riboflavin defi-
ment. St. Louis: Mosby-Year Book; 1998. ciency in man. N Engl J Med. 1939;221:921.
43. Haisraeli-Shalish M, Livneh A, Katz J, Doolman R, 61. Lo CS. Riboflavin status of adolescents in southern
Sela BA. Recurrent aphthous stomatitis and thia- China. Average intake of riboflavin and clinical find-
mine deficiency. Oral Surg Oral Med Oral Pathol ings. Med J Aust. 1984;141:635–7.
Oral Radiol Endod. 1996;82:634–6. 62. Tavares NR, Moreira PA, Amaral TF. Riboflavin
44. Nolan A, Mcintosh WB, Allam BF, Lamey supplementation and biomarkers of cardiovas-
PJ. Recurrent aphthous ulceration: vitamin B1, B2 cular disease in the elderly. J Nutr Health Aging.
and B6 status and response to replacement therapy. J 2009;13:441–6.
Oral Pathol Med. 1991;20:389–91. 63. Mulliken RA, Casner MJ. Oral manifestations
45. Mendoza CE, Rodriguez F, Rosenberg DG. Reversal of systemic disease. Emerg Med Clin N Am.
of refractory congestive heart failure after thiamine 2000;18:565–75.
supplementation: report of a case and review of liter- 64. Durso SC. Oral manifestations of disease. New York:
ature. J Cardiovasc Pharmacol Ther. 2003;8:313–6. McGraw Hill; 2008.
46. Weisberger D. Lesions of the oral mucosa treated 65. Sebrell WH, Butler RE. Riboflavin deficiency
with special vitamins. Am J Orthod. 1941;27:25. in man: preliminary note. Public Health Rep.
47. Stones HH. Oral manifestations in systemic dis- 1938;53:2282.
eases; hypervitaminoses and blood dyscrasias. Ann 66. Vinodkumar M, Rajagopalan S. Efficacy of fortifica-
R Coll Surg Engl. 1951;9:234–44. tion of school meals with ferrous glycine phosphate
48. Latt N, Dore G. Thiamine in the treatment of and riboflavin against anemia and angular stoma-
Wernicke encephalopathy in patients with alcohol titis in schoolchildren. Food Nutr Bull. 2009;30:
use disorders. Intern Med J. 2014;44:911–5. 260–4.
49. Powers HJ. Riboflavin (vitamin B-2) and health. Am 67. Sun A, Wu KM, Wang YP, Lin HP, Chen HM,
J Clin Nutr. 2003;77:1352–60. Chiang CP. Burning mouth syndrome: a review and
50. Oppenheimer SJ, Bull R, Thurnham DI. Riboflavin update. J Oral Pathol Med. 2013;42:649–55.
deficiency in Madang infants. Papua New Guinea 68. Zaridze DG, Trapeznikov NN. Risk factors for can-
Med J. 1983;26:17–20. cer of the oral cavity and esophagus in a high inci-
51. Boisvert WA, Castaneda C, Mendoza I, Langeloh dence region. Vopr Onkol. 1986;32:31–6.
G, Solomons NW, Gershoff SN, et al. Prevalence 69. Podlodowska J, Szumilo J, Podlodowski W,
of riboflavin deficiency among Guatemalan elderly Staroslawska E, Burdan F. Epidemiology and risk
5 Oral Signs of Nutritional Disease 85
factors of the oral carcinoma. Pol Merkur Lekarski. 84. Clayton PT. B6-responsive disorders: a model
2012;32:135–7. of vitamin dependency. J Inherit Metab Dis.
70. Petridou E, Zavras AI, Lefatzis D, Dessypris N, 2006;29:317–26.
Laskaris G, Dokianakis G, et al. The role of diet and 85. Radler DR, Lister T. Nutrient deficiencies associated
specific micronutrients in the etiology of oral carci- with nutrition-focused physical findings of the oral
noma. Cancer. 2002;94:2981–8. cavity. Nutr Clin Pract. 2013;28:710–21.
71. Joosten E, Van Den Berg A, Riezler R, Naurath HJ, 86. Foca FJ. Motor and sensory neuropathy secondary
Lindenbaum J, Stabler SP, et al. Metabolic evidence to excessive pyridoxine ingestion. Arch Phys Med
that deficiencies of vitamin B-12 (cobalamin), folate, Rehabil. 1985;66:634–6.
and vitamin B-6 occur commonly in elderly people. 87. Schaumburg H, Kaplan J, Windebank A, Vick N,
Am J Clin Nutr. 1993;58:468–76. Rasmus S, Pleasure D, et al. Sensory neuropathy
72. Kjeldby IK, Fosnes GS, Ligaarden SC, Farup from pyridoxine abuse. A new megavitamin syn-
PG. Vitamin B6 deficiency and diseases in elderly drome. N Engl J Med. 1983;309:445–8.
people – a study in nursing homes. BMC Geriatr. 88. Gupta AK, Damji A, Uppaluri A. Vitamin B12 defi-
2013;13:13. ciency. Prevalence among South Asians at a Toronto
73. Gonzalez-Gross M, Sola R, Albers U, Barrios clinic. Can Fam Physician. 2004;50:743–7.
L, Alder M, Castillo MJ, et al. B-vitamins and 89. Gudgeon P, Cavalcanti R. Folate testing in hospital
homocysteine in Spanish institutionalized elderly. inpatients. Am J Med. 2015;128(1):56–9.
International journal for vitamin and nutrition 90. Allen LH. How common is vitamin B-12 deficiency?
research. Internationale Zeitschrift fur Vitamin- Am J Clin Nutr. 2009;89:693S–6S.
und Ernahrungsforschung. J Int Vita Nutr. 91. Hunt A, Harrington D, Robinson S. Vitamin B12
2007;77:22–33. deficiency. BMJ. 2014;349:g5226.
74. McCormick DB. Vitamin B6. In: Bowman BA, 92. Cuffe K, Stauffer W, Painter J, Shetty S, Montour
Russell RM, editors. Present knowledge in nutrition. J, Zhou W. Update: vitamin B12 deficiency among
9th ed. Washington, DC: International Life Sciences Bhutanese refugees resettling in the United States,
Institute; 2006. 2012. MMWR. 2014;63:607.
75. Ulvik A, Midttun O, Pedersen ER, Eussen SJ, 93. Snow CF. Laboratory diagnosis of vitamin B12 and
Nygard O, Ueland PM. Evidence for increased folate deficiency: a guide for the primary care physi-
catabolism of vitamin B-6 during systemic inflam- cian. Arch Intern Med. 1999;159:1289–98.
mation. Am J Clin Nutr. 2014;100:250–5. 94. Wickramasinghe SN. Diagnosis of megaloblastic
76. Rall LC, Meydani SN. Vitamin B6 and immune anaemias. Blood Rev. 2006;20:299–318.
competence. Nutr Rev. 1993;51:217–25. 95. Pontes HA, Neto NC, Ferreira KB, Fonseca FP,
77. Moriwaki K, Kanno Y, Nakamoto H, Okada H, Vallinoto GM, Pontes FS, et al. Oral manifestations
Suzuki H. Vitamin B6 deficiency in elderly patients of vitamin B12 deficiency: a case report. J Can Dent
on chronic peritoneal dialysis. Adv Perit Dial. Assoc. 2009;75(7):533–7.
Conference on Peritoneal Dialysis. 2000;16:308–12. 96. Field EA, Speechley JA, Rugman FR, Varga E,
78. Masse PG, Boudreau J, Tranchant CC, Ouellette R, Tyldesley WR. Oral signs and symptoms in patients
Ericson KL. Type 1 diabetes impairs vitamin B(6) with undiagnosed vitamin B12 deficiency. J Oral
metabolism at an early stage of women's adulthood. Pathol Med. 1995;24:468–70.
Appl Physiol Nutr Metab. 2012;37:167–75. 97. Graells J, Ojeda RM, Muniesa C, Gonzalez J,
79. Corken M, Porter J. Is vitamin B(6) deficiency an Saavedra J. Glossitis with linear lesions: an early
under-recognized risk in patients receiving hae- sign of vitamin B12 deficiency. J Am Acad Dermatol.
modialysis? A systematic review: 2000–2010. 2009;60:498–500.
Nephrology. 2011;16:619–25. 98. Scully C, Gorsky M, Lozada-Nur F. The diagno-
80. Wilson SM, Bivins BN, Russell KA, Bailey sis and management of recurrent aphthous sto-
LB. Oral contraceptive use: impact on folate, vita- matitis: a consensus approach. J Am Dent Assoc.
min B(6), and vitamin B(1)(2) status. Nutr Rev. 2003;134:200–7.
2011;69:572–83. 99. Stoopler ET, Kuperstein AS. Glossitis secondary to
81. Zhou Y, Jiao Y, Wei YH, Zhang GR, Zhang JP, vitamin B12 deficiency anemia. Can Med Assoc J.
Ren JX, et al. Effects of pyridoxine on the intesti- 2013;185:E582.
nal absorption and pharmacokinetics of isoniazid 100. Itoh I, Ikui A, Ikeda M, Tomita H, Souhei E. Taste
in rats. Eur J Drug Metab Pharmacokinet. 2013; disorder involving Hunter’s glossitis following total
38:5–13. gastrectomy. Acta Otolaryngol Suppl. 2002:159–63.
82. Snider DE Jr. Pyridoxine supplementation during 101. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler
isoniazid therapy. Tubercle. 1980;61:191–6. SP. Oral cobalamin therapy in patients who absorb it
83. Stone OJ. Pyridoxine deficiency and antagonism normally. Blood. 1998;92:4879–80.
produce increased ground substance viscosity 102. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler
with resulting seborrheic dermatitis and increased SP, Lindenbaum J. Effective treatment of cobala-
tumor resistance. Med Hypotheses. 1989;30: min deficiency with oral cobalamin. Blood.
277–80. 1998;92:1191–8.
86 S. N. Tolkachjov and A. J. Bruce
103. Hess SY, Zimmermann MB, Brogli S, Hurrell RF. A 119. Hampl JS, Taylor CA, Johnston CS. Vitamin C defi-
national survey of iron and folate status in pregnant ciency and depletion in the United States: the Third
women in Switzerland. Int J Vitam Nutr Res Int J National Health and Nutrition Examination Survey,
Vitam Nutr Res. 2001;71(5):268–73. 1988 to 1994. Am J Public Health. 2004;94:870–5.
104. Serdula MK, Nichols EK, Aburto NJ, Masa’d 120. Schleicher RL, Carroll MD, Ford ES, Lacher
H, Obaid B, Wirth J, et al. Micronutrient sta- DA. Serum vitamin C and the prevalence of vita-
tus in Jordan: 2002 and 2010. Eur J Clin Nutr. min C deficiency in the United States: 2003–2004
2014;68(10):1124–8. National Health and Nutrition Examination Survey
105. Ma AG, Chen XC, Wang Y, Xu RX, Zheng MC, Li (NHANES). Am J Clin Nutr. 2009;90:1252–63.
JS. The multiple vitamin status of Chinese pregnant 121. Wrieden WL, Hannah MK, Bolton-Smith C,
women with anemia and nonanemia in the last tri- Tavendale R, Morrison C, Tunstall-Pedoe
mester. J Nutr Sci Vitaminol. 2004;50:87–92. H. Plasma vitamin C and food choice in the third
106. Hillman RS, Mcguffin R, Campbell C. Alcohol Glasgow MONICA population survey. J Epidemiol
interference with the folate enterohepatic cycle. Community Health. 2000;54:355–60.
Trans Assoc Am Phys. 1977;90:145–56. 122. Mosdol A, Erens B, Brunner EJ. Estimated preva-
107. Smith AD. Folic acid fortification: the good, the bad, lence and predictors of vitamin C deficiency within
and the puzzle of vitamin B-12. Am J Clin Nutr. UK’s low-income population. J Public Health (Oxf).
2007;85:3–5. 2008;30:456–60.
108. Okey R, Pencharz R, Lepkovsky S, Vernon ER, 123. Cahill LE, El-Sohemy A. Vitamin C transporter
Jerome D, Marquette M. Dietary constituents which gene polymorphisms, dietary vitamin C and
may influence the use of food cholesterol. I. Eggs: serum ascorbic acid. J Nutrigenet Nutrigenomics.
biotin and avidin. J Nutr. 1951;44:83–99. 2009;2:292–301.
109. White HB 3rd, Whitehead CC. Role of avidin and 124. Villalpando S, Garcia-Guerra A, Ramirez-Silva CI,
other biotin-binding proteins in the deposition and Mejia-Rodriguez F, Matute G, Shamah-Levy T,
distribution of biotin in chicken eggs. Discovery et al. Iron, zinc and iodide status in Mexican chil-
of a new biotin-binding protein. Biochem J. dren under 12 years and women 12–49 years of age.
1987;241:677–84. A probabilistic national survey. Salud Publica Mex.
110. Mock DM, Dyken ME. Biotin catabolism is acceler- 2003;45(Suppl 4):S520–9.
ated in adults receiving long-term therapy with anti- 125. Chiplonkar SA, Agte VV, Mengale SS, Tarwadi
convulsants. Neurology. 1997;49:1444–7. KV. Are lifestyle factors good predictors of reti-
111. Mock DM, Mock NI, Nelson RP, Lombard nol and vitamin C deficiency in apparently healthy
KA. Disturbances in biotin metabolism in children adults? Eur J Clin Nutr. 2002;56:96–104.
undergoing long-term anticonvulsant therapy. J 126. Raynaud-Simon A, Cohen-Bittan J, Gouronnec A,
Pediatr Gastroenterol Nutr. 1998;26:245–50. Pautas E, Senet P, Verny M, et al. Scurvy in hos-
112. Fujimoto W, Inaoki M, Fukui T, Inoue Y, Kuhara pitalized elderly patients. J Nutr Health Aging.
T. Biotin deficiency in an infant fed with amino acid 2010;14:407–10.
formula. J Dermatol. 2005;32:256–61. 127. Netto BD, Moreira EA, Patino JS, Beninca JP,
113. Tammachote R, Janklat S, Tongkobpetch S, Jordao AA, Frode TS. Influence of Roux-en-Y gas-
Suphapeetiporn K, Shotelersuk V. Holocarboxylase tric bypass surgery on vitamin C, myeloperoxidase,
synthetase deficiency: novel clinical and molecular and oral clinical manifestations: a 2-year follow-up
findings. Clin Genet. 2010;78:88–93. study. Nutr Clin Pract. 2012;27:114–21.
114. Zempleni J, Hassan YI, Wijeratne SS. Biotin and 128. Weinstein M, Babyn P, Zlotkin S. An orange a day
biotinidase deficiency. Expert Rev Endocrinol keeps the doctor away: scurvy in the year 2000.
Metab. 2008;3:715–24. Pediatrics. 2001;108:E55.
115. Moslinger D, Stockler-Ipsiroglu S, Scheibenreiter S, 129. Firth N, Marvan E. Oral lesions in scurvy. Aust Dent
Tiefenthaler M, Muhl A, Seidl R, et al. Clinical and J. 2001;46:298–300.
neuropsychological outcome in 33 patients with bio- 130. Yudkin J. Evolution, history, and nutrition: their
tinidase deficiency ascertained by nationwide new- bearing on oral disease and other diseases of civili-
born screening and family studies in Austria. Eur J zation. Dent Pract Dent Rec. 1965;16:60–4.
Pediatr. 2001;160:277–82. 131. Bacci C, Sivolella S, Pellegrini J, Favero L, Berengo
116. Mock DM. Biotin. Washington, DC: ILSI Nutrition M. A rare case of scurvy in an otherwise healthy
Foundation; 1996. child: diagnosis through oral signs. Pediatr Dent.
117. Fiume MZ. Final report on the safety assessment of 2010;32:536–8.
biotin. Int J Toxicol. 2001;20(Suppl 4):1–12. 132. Gokhale NH, Acharya AB, Patil VS, Trivedi DJ,
118. Ravindran RD, Vashist P, Gupta SK, Young IS, Thakur SL. A short-term evaluation of the rela-
Maraini G, Camparini M, et al. Prevalence and risk tionship between plasma ascorbic acid levels and
factors for vitamin C deficiency in north and south periodontal disease in systemically healthy and
India: a two centre population based study in people type 2 diabetes mellitus subjects. J Diet Suppl.
aged 60 years and over. PLoS One. 2011;6:e28588. 2013;10:93–104.
5 Oral Signs of Nutritional Disease 87
133. Levine M. New concepts in the biology and 149. Rhodus NL, Brown J. The association of xerosto-
biochemistry of ascorbic acid. N Engl J Med. mia and inadequate intake in older adults. J Am Diet
1986;314:892–902. Assoc. 1990;90:1688–92.
134. Amaliya, Timmerman MF, Abbas F, Loos BG, Van 150. Wilson HO, Datta DB. Complications from micro-
Der Weijden GA, Van Winkelhoff AJ, Winkel EG, nutrient deficiency following bariatric surgery. Ann
et al. Java project on periodontal diseases: the rela- Clin Biochem. 2014;51(Pt 6):705–9.
tionship between vitamin C and the severity of peri- 151. Yetley EA. Assessing the vitamin D status of the US
odontitis. J Clin Periodontol. 2007;34:299–304. population. Am J Clin Nutr. 2008;88:558S–64S.
135. Kroser LS. A four year clinical evaluation of 152. Taksler GB, Cutler DM, Giovannucci E, Keating
Vitron-C. A new hematinic containing ferrous fuma- NL. Vitamin D deficiency in minority populations.
rate and ascorbic acid. West Med. 1965;6:314–5. Public Health Nutr. 2014:1–13.
136. De Cassia Ribeiro-Silva R, Nunes IL, Assis 153. Cashman KD, Muldowney S, Mcnulty B, Nugent
AM. Prevalence and factors associated with vitamin A, Fitzgerald AP, Kiely M, et al. Vitamin D status
A deficiency in children and adolescents. J Pediatr. of Irish adults: findings from the National Adult
2014;90:486–92. Nutrition Survey. Br J Nutr. 2013;109:1248–56.
137. Mora JO, Gueri M, Mora OL. Vitamin A deficiency 154. Brito A, Cori H, Olivares M, Fernanda Mujica M,
in Latin America and the Caribbean: an overview. Cediel G, Lopez De Romana D. Less than adequate
Rev Panam Salud Publica. 1998;4:178–86. vitamin D status and intake in Latin America and the
138. Ahmed F. Vitamin A deficiency in Bangladesh: a Caribbean: a problem of unknown magnitude. Food
review and recommendations for improvement. Nutr Bull. 2013;34:52–64.
Public Health Nutr. 1999;2:1–14. 155. Guessous I, Mcclellan W, Kleinbaum D, Vaccarino
139. Gorstein J, Shreshtra RK, Pandey S, Adhikari RK, V, Zoller O, Theler J, et al. Comparisons of serum
Pradhan A. Current status of vitamin A deficiency vitamin d levels, status, and determinants in popula-
and the national vitamin A control program in Nepal: tions with and without chronic kidney disease not
results of the 1998 national micronutrient status sur- requiring renal dialysis: a 24-hour urine collection
vey. Asia Pac J Clin Nutr. 2003;12:96–103. population-based study. J Ren Nutr. 2014;24:303–12.
140. Demissie T, Ali A, Mekonen Y, Haider J, Umeta 156. Martini LA, Verly E Jr, Marchioni DM, Fisberg
M. Magnitude and distribution of vitamin A defi- RM. Prevalence and correlates of calcium and vita-
ciency in Ethiopia. Food Nutr Bull. 2010;31: min D status adequacy in adolescents, adults, and
234–41. elderly from the Health Survey-Sao Paulo. Nutrition.
141. Luo M, Estivariz CF, Schleicher RL, Bazargan N, 2013;29:845–50.
Leader LM, Galloway JR, et al. Prospective analysis 157. Holick MF. McCollum award lecture, 1994: vitamin
of serum carotenoids, vitamin A, and tocopherols in D – new horizons for the 21st century. Am J Clin
adults with short bowel syndrome undergoing intes- Nutr. 1994;60:619–30.
tinal rehabilitation. Nutrition. 2009;25:400–7. 158. Signorello LB, Williams SM, Zheng W, Smith
142. Rana M, Wong-See D, Katz T, Gaskin K, Whitehead JR, Long J, Cai Q, et al. Blood vitamin d levels in
B, Jaffe A, et al. Fat-soluble vitamin deficiency in relation to genetic estimation of African ances-
children and adolescents with cystic fibrosis. J Clin try. Cancer Epidemiol Biomark Prev. 2010;19:
Pathol. 2014;67:605–8. 2325–31.
143. Goskowicz M, Eichenfield LF. Cutaneous findings 159. Goodman JR, Gelbier MJ, Bennett JH, Winter
of nutritional deficiencies in children. Curr Opin GB. Dental problems associated with hypophos-
Pediatr. 1993;5:441–5. phataemic vitamin D resistant rickets. Int J Paediatr
144. Miller SJ. Nutritional deficiency and the skin. J Am Dent. 1998;8:19–28.
Acad Dermatol. 1989;21:1–30. 160. Rathore R, Nalawade TM, Pateel D, Mallikarjuna
145. Jolly M. Vitamin A deficiency: a review. II. J Oral R. Oral manifestations of vitamin D resistant
Ther Pharmacol. 1967;3:439–51. rickets in orthopantomogram. BMJ Case Rep.
146. Sherwin JC, Reacher MH, Dean WH, Ngondi 2013;12:2013.
J. Epidemiology of vitamin A deficiency and 161. Souza AP, Kobayashi TY, Lourenco Neto N, Silva
xerophthalmia in at-risk populations. Trans R Soc SM, Machado MA, Oliveira TM. Dental manifesta-
Trop Med Hyg. 2012;106:205–14. tions of patient with vitamin D-resistant rickets. J
147. Hillman JD. Principles of microbial ecology and Appl Oral Sci. 2013;21(6):601–6.
their application to xerostomia-associated opportu- 162. Su JM, Li Y, Ye XW, Wu ZF. Oral findings of hypo-
nistic infections of the oral cavity. Adv Dent Res. phosphatemic vitamin D-resistant rickets: report of
1996;10:66–8. two cases. Chin Med J. 2007;120:1468–70.
148. Silverman S Jr, Eisenberg E, Renstrup G. A study 163. Glorieux FH, Pettifor JM. Vitamin D/dietary cal-
of the effects of high doses of vitamin a on oral cium deficiency rickets and pseudo-vitamin D defi-
leukoplakia (hyperkeratosis), including toxicity, ciency rickets. Bonekey Rep. 2014;3:524.
liver function and skeletal metabolism. J Oral Ther 164. Balion C, Griffith LE, Strifler L, Henderson M,
Pharmacol. 1965;2:9–23. Patterson C, Heckman G, et al. Vitamin D, cognition,
88 S. N. Tolkachjov and A. J. Bruce
and dementia: a systematic review and meta-analy- 178. Tuerk MJ, Fazel N. Zinc deficiency. Curr Opin
sis. Neurology. 2012;79:1397–405. Gastroenterol. 2009;25:136–43.
165. Zambrano M, Nikitakis NG, Sanchez-Quevedo MC, 179. Wuehler SE, Peerson JM, Brown KH. Use of national
Sauk JJ, Sedano H, Rivera H. Oral and dental mani- food balance data to estimate the adequacy of zinc in
festations of vitamin D-dependent rickets type I: national food supplies: methodology and regional
report of a pediatric case. Oral Surg Oral Med Oral estimates. Public Health Nutr. 2005;8:812–9.
Pathol Oral Radiol Endod. 2003;95:705–9. 180. Siyame EW, Hurst R, Wawer AA, Young SD,
166. Dietrich T, Joshipura KJ, Dawson-Hughes B, Broadley MR, Chilimba AD, et al. A high preva-
Bischoff-Ferrari HA. Association between serum lence of zinc- but not iron-deficiency among women
concentrations of 25-hydroxyvitamin D3 and peri- in rural Malawi: a cross-sectional study. Int J Vitam
odontal disease in the US population. Am J Clin Nutr Res Int Z Vitam Ernahrungsforschung J Int
Nutr. 2004;80:108–13. Vitaminologie Nutr. 2013;83:176–87.
167. Krall EA, Wehler C, Garcia RI, Harris SS, 181. Hambidge M. Human zinc deficiency. J Nutr.
Dawson-Hughes B. Calcium and vitamin D supple- 2000;130:1344S–9S.
ments reduce tooth loss in the elderly. Am J Med. 182. Miletta MC, Bieri A, Kernland K, Schoni MH,
2001;111:452–6. Petkovic V, Fluck, et al. Transient neonatal zinc defi-
168. Jou PC, Tomecki KJ. Sunscreens in the United ciency caused by a heterozygous G87R mutation in
States: current status and future outlook. Adv Exp the zinc transporter ZnT-2 (SLC30A2) gene in the
Med Biol. 2014;810:464–84. mother highlighting the importance of Zn (2+) for
169. Zeeb H, Greinert R. The role of vitamin D in can- normal growth and development. Int J Endocrinol.
cer prevention: does UV protection conflict with the 2013;259189.
need to raise low levels of vitamin D? Deutsches 183. Qian L, Wang B, Tang N, Zhang W, Cai
Arzteblatt Int. 2010;107:638–43. W. Polymorphisms of SLC30A2 and selected
170. Bilinski K, Talbot P. Vitamin d supplementa- perinatal factors associated with low milk zinc in
tion in Australia: implications for the develop- Chinese breastfeeding women. Early Hum Dev.
ment of supplementation guidelines. J Nutr Metab. 2012;88:663–8.
2014;2014:374208. 184. Changela A, Javaiya H, Changela K, Davanos E,
171. Schoon EJ, Muller MC, Vermeer C, Schurgers Rickenbach K. Acrodermatitis enteropathica during
LJ, Brummer RJ, Stockbrugger RW. Low serum adequate enteral nutrition. JPEN. 2012;36:235–7.
and bone vitamin K status in patients with long- 185. Mayo-Wilson E, Imdad A, Junior J, Dean S, Bhutta
standing Crohn’s disease: another pathogenetic ZA. Preventive zinc supplementation for children,
factor of osteoporosis in Crohn’s disease? Gut. and the effect of additional iron: a systematic review
2001;48:473–7. and meta-analysis. BMJ Open. 2014;4:e004647.
172. Shea MK, Booth SL, Miller ME, Burke GL, Chen 186. Mayo-Wilson E, Junior JA, Imdad A, Dean S, Chan
H, Cushman M, et al. Association between circulat- XH, Chan ES, et al. Zinc supplementation for pre-
ing vitamin K1 and coronary calcium progression venting mortality, morbidity, and growth failure in
in community-dwelling adults: the Multi-Ethnic children aged 6 months to 12 years of age. Cochrane
Study of Atherosclerosis. Am J Clin Nutr. Database Syst Rev. 2014;5:CD009384.
2013;98:197–208. 187. Gehrig KA, Dinulos JGH. Acrodermatitis due
173. Urano A, Hotta M, Ohwada R, Araki M. Vitamin K to nutritional deficiency. Curr Opin Pediatr.
deficiency evaluated by serum levels of undercar- 2010;22:107–12.
boxylated osteocalcin in patients with anorexia ner- 188. Lott JP, Reeve J, Ko C, Girardi M. Periorificial
vosa with bone loss. Clin Nutr. 2015;34(3):443–8. dermatitis and erosive inguinal plaques in a
174. Vermeer C. Vitamin K: the effect on health beyond 57-year-old woman. Acquired zinc deficiency acro-
coagulation – an overview. Food Nutr Res. 2012;56. dermatitis enteropathica (ADE). JAMA Dermatol.
175. Nowak JK, Grzybowska-Chlebowczyk U, 2013;149:357–63.
Landowski P, Szaflarska-Poplawska A, Klincewicz 189. Heath ML, Sidbury R. Cutaneous manifesta-
B, Adamczak D, et al. Prevalence and correlates of tions of nutritional deficiency. Curr Opin Pediatr.
vitamin K deficiency in children with inflammatory 2006;18:417–22.
bowel disease. Sci Rep. 2014;4:4768. 190. Touger-Decker R. Oral manifestations of nutri-
176. Sikkens EC, Cahen DL, Koch AD, Braat H, Poley ent deficiencies. Mt Sinai J Med New York.
JW, Kuipers EJ, et al. The prevalence of fat-soluble 1998;65:355–61.
vitamin deficiencies and a decreased bone mass in 191. Dubas LE, Waymire DM, Adams BB. Resident
patients with chronic pancreatitis. Pancreatology. rounds: part II study aid: nutritional deficiencies. J
2013;13:238–42. Drugs Dermatol. 2013;12:816–7.
177. Corbo MD, Lam J. Zinc deficiency and its manage- 192. Spies TD, Cooper C. The diagnosis of pellagra.
ment in the pediatric population: a literature review Intern Clin. 1937:4.
and proposed etiologic classification. J Am Acad 193. Oldham MA, Ivkovic A. Pellagrous encephalopathy
Dermatol. 2013;69:616–624 e1. presenting as alcohol withdrawal delirium: a case
5 Oral Signs of Nutritional Disease 89
series and literature review. Addict Sci Clin Pract. min-supplement treatments in patients with burning
2012;7:12. mouth syndrome. J Oral Pathol Med. 2013;42:474–9.
194. Paulionis L, Kane SL, Meckling KA. Vitamin status 203. Lamey PJ, Hammond A, Allam BF, Mcintosh
and cognitive function in a long-term care popula- WB. Vitamin status of patients with burning mouth
tion. BMC Geriatr. 2005;5:16. syndrome and the response to replacement therapy.
195. Jacobson EL. Niacin deficiency and cancer in Br Dent J. 1986;160:81–4.
women. J Am Coll Nutr. 1993;12:412–6. 204. Cho GS, Han MW, Lee B, Roh JL, Choi SH, Cho
196. Ishii N, Nishihara Y. Pellagra among chronic KJ, et al. Zinc deficiency may be a cause of burn-
alcoholics: clinical and pathological study of 20 ing mouth syndrome as zinc replacement ther-
necropsy cases. J Neurol Neurosurg Psychiatry. apy has therapeutic effects. J Oral Pathol Med.
1981;44:209–15. 2010;39:722–7.
197. Castiello RJ, Lynch PJ. Pellagra and the carcinoid 205. Murray EL. Burning mouth syndrome response to
syndrome. Arch Dermatol. 1972;105:574–7. high-dose vitamin C. Headache. 2014;54:169.
198. Shah GM, Shah RG, Veillette H, Kirkland JB, 206. Hugoson A, Thorstensson B. Vitamin B status and
Pasieka JL, Warner RR. Biochemical assessment of response to replacement therapy in patients with
niacin deficiency among carcinoid cancer patients. burning mouth syndrome. Acta Odontol Scand.
Am J Gastroenterol. 2005;100:2307–14. 1991;49:367–75.
199. Isaac S. The “gauntlet” of pellagra. Int J Dermatol. 207. Vucicevic-Boras V, Topic B, Cekic-Arambasin A,
1998;37:599. Zadro R, Stavljenic-Rukavina A. Lack of association
200. Lin HP, Wang YP, Chen HM, Kuo YS, Lang MJ, between burning mouth syndrome and hematinic
Sun A. Significant association of hematinic defi- deficiencies. Eur J Med Res. 2001;6:409–12.
ciencies and high blood homocysteine levels with 208. Aravindhan R, Vidyalakshmi S, Kumar MS,
burning mouth syndrome. J Formosan Med Assoc. Satheesh C, Balasubramanium AM, Prasad
2013;112:319–25. VS. Burning mouth syndrome: a review on its diag-
201. Kohorst JJ, Bruce AJ, Torgerson RR, Schenck LA, nostic and therapeutic approach. J Pharm Bioallied
Davis MD. A population-based study of the inci- Sci. 2014;6:S21–5.
dence of burning mouth syndrome. Mayo Clin Proc. 209. Samaranayake LP, Lamb AB, Lamey PJ, MacFarlane
2014;89(11):1545–52. TW. Oral carriage of Candida species and coliforms
202. Sun A, Lin HP, Wang YP, Chen HM, Cheng SJ, in patients with burning mouth syndrome. J Oral
Chiang CP. Significant reduction of serum homo- Pathol Med. 1989;18:233–5.
cysteine level and oral symptoms after different vita-
Oral Signs of Connective Tissue
Disease
6
Kenisha R. Heath and Nasim Fazel
In this chapter, we aim to discuss the epidemi- arthritis (RA), systemic lupus erythematosus, and
ology, pathogenesis, differential diagnosis, and systemic sclerosis in which case it is referred to
treatment of oral manifestations encountered in as secondary SS. Although the presence of sicca
the autoimmune diseases of Sjögren’s syndrome symptoms is the hallmark of SS, any organ or
(SS), systemic lupus erythematosus (SLE), sys- mucosal surface may be involved. Thus, SS may
temic sclerosis (SSc), mixed connective tissue present with a wide spectrum of clinical manifes-
disease (MCTD), and dermatomyositis (DM). tations and complications [3].
Systemic autoimmune conditions are estimated Until recently there were a number of diag-
to affect 5%–8% of Americans [1]. Oral manifes- nostic guidelines for primary SS including the
tations are encountered with high frequency and Copenhagen, Japanese, Greek, Californian-Fox
are often the first clinical signs or symptoms of (CF), and European Community (EC) [4]. The
the disease. CF and EC criteria were the most commonly
used yet they differed so much that almost ten
times the number of cases would be diagnosed
Sjögren’s Syndrome by the European criteria than by the American
[5]. This discrepancy in diagnostic criteria led
Epidemiology to great difficulty in determining information
regarding prevalence. The American-European
Sjögren’s syndrome (SS) is an autoimmune Consensus Group classification criteria, aka
disorder characterized by chronic lymphocytic American-European criteria, were therefore
infiltration of the secretory glands, particularly developed to obtain a more uniform classifica-
the salivary and lacrimal glands with reduc- tion system and have been used since 2002 as
tion of gland function causing dryness of the the “gold standard” for the diagnosis of SS [6].
mucosal surfaces [2]. Sjögren’s syndrome may The American-European criteria are based on
occur alone as primary SS or in association with the presence of at least four out six diagnostic
another autoimmune disease such as rheumatoid symptoms in which one of the four must include
either the presence of anti-60 kD Ro antibodies
K. R. Heath or supportive histopathology (Table 6.1) [7].
Air Force Institute of Technology, Information regarding the prevalence of SS
Wright-Patterson AFB, OH, USA has been largely difficult to obtain, yet we know
N. Fazel (*) that primary SS represents one of the three most
Department of Dermatology, University of California, common autoimmune disorders with an e stimated
Davis, Sacramento, CA, USA
e-mail: nfazel@ucdavis.edu annual incidence of approximately 7 per 100,000
Table 6.1 Sjögren’s syndrome diagnostic criteriaa based upregulated on epithelial cells in the lacrimal and
on combined European-American consensus
salivary glands leading to activation of B lympho-
I. Ocular symptoms – at least one of the following: cytes within the glandular microenvironment. The
troublesome dry eyes persisting for more than
3 months, recurrent sensation of sand or gravel in eyes,
B lymphocytes, under the influence of T-helper
tear substitute use >3 times/day lymphocytes, produce antibodies to SS-A anti-
II. Oral symptoms – at least one of the following: dry gens. This triggers the formation of immune
mouth every day >3 months, recurrent swollen salivary complexes, which contain anti-SS-A and ribonu-
glands as an adult, need fluids to aid in swallowing
cleoproteins that bind to HLA-DR positive den-
foods
III. Objective evidence of dry eyes – at least one of the dritic cells. The lymphocytes and epithelial cells
following: Schirmer test (<5 mm in 5 min), rose bengal secrete pro-inflammatory cytokines that influence
score (>4, according to the van Bijsterveld scoring the inflammatory response. Meanwhile, defects in
system) post-signal transduction in T-cells leads to apop-
IV. Objective evidence of salivary gland involvement –
salivary gland scintigraphy (delayed uptake, etc.),
tosis. It is believed that these immunologic effects
parotid sialography (at least 1 present), unstimulated in genetically predisposed individuals (i.e., posi-
salivary flow <1.5 mL in 15 min tive for HLA DR3) leads to an immune response
V. Histopathological features – lacrimal gland biopsy to the SS-A antigen. Ultimately, this gives rise to
samples with focus score >1, minor salivary glands,
immune complexes that stimulate Toll receptors
focus score >1 (greater than 50 lymphocytes/4 mm2 of
glandular tissue) to yield the characteristic interferon type 1 signa-
VI. Laboratory abnormality – anti-60-kDa Ro (SS-A) ture [11].
a
Four of the six must be present for classification as
Sjögren’s syndrome, but one of the four must be either V
or VI (A) Clinical Manifestations
and a prevalence of 43 per 100,000 [8, 9]. Women Although keratoconjunctivitis sicca symptoms
are affected more often than men at a ratio of 9:1, of dry mouth and dry eyes are the hallmarks of
and there appears to be two peaks with regard to the syndrome, any organ or mucosal surface may
age, the first occurring during the 20s–30s and be involved [12]. Systemic manifestations can be
the second after menopause [10]. categorized into non-visceral (skin, arthralgia,
myalgia) and visceral (lung, heart, kidney, gas-
trointestinal, endocrine, central and peripheral
Etiopathogenesis nervous system).
Visceral Manifestations
stomia occurs, the protein content of the saliva is tensive agents (beta-blockers, calcium channel
also altered, and production of secretory IgA is blockers, and angiotensin-converting enzyme
decreased, which leads to a weakening of the anti- inhibitors) can also decrease salivary flow [29].
bacterial defense system against dental caries and Outside of medications, the differential diag-
oral opportunistic infections [22]. Specifically, nosis of SS involves consideration for diseases
chronic erythematous candidiasis is reported in that cause sicca symptoms and/or salivary or lac-
70%–75% of patients with SS. Candida coloni- rimal gland enlargement. The list of possible con-
zation causes a dry, cracked, and erythematous ditions is quite extensive, but a few discussed in
appearance at the corners of the mouth, erythem- this chapter include age-related sicca syndrome,
atous mucosal lesions, denture-associated stoma- benign lymphoepithelial sialadenitis and dacryo-
titis, and glossodynia. Additionally, patients with adenitis, sarcoidosis, human immunodeficiency
SS display a much lower parotid salivary pH and virus (HIV), graft-versus-host disease (GVHD),
buffer capacity when compared to healthy indi- and systemic vasculitis.
viduals, which can increase the risk of dental car- Age-related sicca syndrome occurs when tear
ies and erosion [24]. Often dental caries occur at and unstimulated saliva production decline with
tooth-restoration interfaces and at locations that age. This is most likely a result of age-related
are not usually prone to caries such as the necks histologic alterations in the lacrimal and salivary
of the teeth. Progressive dental erosion may sub- glands. It can be differentiated from SS because
sequently lead to tooth loss. As such, SS patients the usual immune-mediated histologic changes
have often been reported to have a higher rate seen in SS, and SS-related antibodies (anti-Ro/
of premature loss of teeth or a higher Decayed, SSA and anti-La/SSB) are usually absent in these
Missing, Filled Teeth (DMFT) index compared patients [30, 31]. Patients with benign lympho-
with the general population [11, 25]. epithelial sialadenitis and dacryoadenitis show
Other oral symptoms associated with SS lymphocytic infiltration of the lacrimal and/or
include difficulty with chewing, speaking, and major salivary glands with acinar atrophy lead-
swallowing secondary to intraoral dryness as ing to symptoms similar to those seen in SS and
well as sensitivity to flavorful foods, altered or should be considered appropriately. Similarly,
diminished taste, oral pain, and coughing or sarcoidosis may be considered in the differential
choking episodes [26]. Finally, swelling of the diagnosis of patients with parotid and lacrimal
salivary glands have been commonly reported gland enlargement. Biopsy may be necessary,
in the SS patient population with parotid gland if the distinction cannot be readily made based
swelling, in particular, reported in 30%–40% of upon the clinical findings [32]. Patients with HIV
patients [27]. When sudden swelling of a single infection may display diffuse CD8 lymphocytosis
gland occurs, it is suggestive of infection, while syndrome, which may mimic SS, though the inci-
chronic asymptomatic involvement of multiple dence has significantly declined with antiretrovi-
glands with lymphadenopathy is more suggestive ral therapy. Those affected may develop parotid
of lymphoma [28]. gland enlargement, sicca symptoms, and lym-
phocytic interstitial pneumonitis. Salivary gland
biopsies show a CD8-predominant lymphocytic
Differential Diagnosis infiltrate, which is helpful in differentiating the
virus from SS [33]. Symptoms seen in those with
With respect to the most common SS symptom GVHD after allogeneic hematopoietic stem cell
of xerostomia, it has been proven that a num- transplantation may include dry eyes and dry
ber of medications can also lead to dry mouth. mouth and should be considered in patients with
Whereas cholinergic innervation maintains saliva these presenting symptoms. Additionally, IgG4
production, use of anticholinergic drugs thereby plasmacytic infiltration underlies several related
decreases such production. Diuretics, antidepres- forms of lacrimal and salivary gland disease,
sants, alpha-adrenergic agents, and antihyper- including orbital inflammatory pseudotumor,
6 Oral Signs of Connective Tissue Disease 95
chronic sclerosing sialadenitis (Küttner tumor), salivary stimulants are a reasonable treatment
and Mikulicz disease. These IgG4-related dis- option. However, trials of low-dose steroids or
eases (IgG4-RD) can be distinguished from SS immunosuppressive drugs, such as methotrex-
by their associated clinical and laboratory fea- ate, cyclosporine, and azathioprine, have shown
tures, and the distinct histopathologic findings no improvement in lacrimal or salivary function
seen in IgG4-RD [34]. [10]. Hydroxychloroquine, which is effective for
Systemic vasculitis should also be considered many of the extraglandular features of the dis-
as bilateral parotid and submandibular gland ease, appears to have no effect on salivary or lac-
enlargement may occur in Wegener’s granuloma- rimal flow [39].
tosis. It can be differentiated from SS by clinical, Pilocarpine and cevimeline hydrochloride are
laboratory, and histologic differences. Finally, cholinergic agents with muscarinic agonist activ-
lymphoma and other hematologic malignancies ity used in the treatment of xerostomia. They are
should be considered as malignant infiltration of effective in increasing salivary flow and improv-
the parotid glands may also present as bilateral ing symptoms of dry mouth. Symptomatic
salivary and lacrimal gland enlargement [35, 36]. improvement from the use of pilocarpine may
take up to 6 weeks with the most prevailing side
effects being flushing, sweating, diarrhea, and
Treatment urinary frequency. Pilocarpine may be started at
5 mg once daily increasing to twice daily after
Currently, there is no cure for SS, nor is there any 1 week up to 5 mg four times daily. Cevimeline,
treatment that will restore the irreversible dam- believed to be more selective than pilocarpine,
age to the glands. Alleviating symptoms through predominantly affects the M1 and M3 recep-
medical therapy is the primary goal in the treat- tors, which are particularly prevalent in exocrine
ment of SS. With that, the treatment of salivary glands. Two controlled clinical trials showed sig-
or lacrimal impairment is often approached by nificant improvement in subjective and objective
one or more of four methods: general measures, symptoms of dry eyes and mouth in patients tak-
replacement, stimulation, and disease-modifying ing cevimeline 30 mg three times daily. A higher
drugs [3]. dose of 60 mg three times daily was poorly toler-
General measures taken to minimize the loss ated due to increased side effects of headaches,
of water from secretions by evaporation include increased sweating, abdominal pain, and nausea.
the use of humidifiers and emollients such as Due to the side effect profile, pilocarpine should
petroleum jelly on the lips to prevent crack- be used first, with preference given to relatively
ing and dryness. Meticulous oral hygiene and young patients with a good reserve of salivary
regular dental exams are also important [37]. and lacrimal function [40, 41].
Replacement incorporates the use of saliva sub- Biologics have also been used to stimulate
stitutes in the form of sprays, lozenges, or gels salivary gland function although studies show
to relieve oral discomfort and to keep the mouth conflicting evidence of efficacy with TFN-alpha
moist. Compliance with regular use of saliva inhibitors including infliximab and etanercept
substitutes can be limited by complaints of an [42–44]. Because B-cells play a vital role in
unpleasant taste and can be expensive. Other the pathogenesis of many autoimmune dis-
products used to alleviate dryness include mucin eases, antibodies that are antagonistic to B-cells
lozenges, oral rinses, and toothpastes containing have been utilized to manage these diseases.
salivary proteins, which have not been shown to Epratuzumab, the first antagonistic antibody
significantly improve saliva production [38]. to the B-cell marker CD22, appears to function
Increasing evidence suggests that secre- by immune modulation of B-cells [45]. It func-
tory failure of the salivary and lacrimal glands tions as a humanized IgG1 monoclonal antibody
is due to the inhibitory effects of inflammation against the CD22 antigen and downregulates the
rather than destruction of exocrine tissue. Thus, B-cell receptor [46]. Epratuzumab was originally
96 K. R. Heath and N. Fazel
developed for the treatment of non-Hodgkin’s million people with an estimated prevalence of
lymphoma and has now been found to be effec- 20–150 per 100,000 and a female-to-male ratio
tive in primary SS as well as SLE. Rituximab, of 9:1 [50]. It is two to three times more likely to
known for its tolerance and short-term efficacy, affect African-American females and can occur
is an anti-CD20 antibody, which is effective in at any age in both sexes but in women is often
various autoimmune diseases. Rituximab targets diagnosed during the childbearing years [51].
B-cells, suggesting that B-cells may play a role in
the etiopathogenesis of SS [45, 47].
Additionally, electrical stimulation of the Etiopathogenesis
tongue and hard palate has been shown to be use-
ful in stimulating salivary flow in patients with As in many autoimmune diseases, the underly-
SS and can be considered [48]. Secondary effects ing pathophysiologic mechanism that triggers
of oral candidiasis can be treated with topical the autoimmune response in SLE remains largely
and/or systemic antifungal agents [11]. unknown. However, genetics, ethnicity, hor-
monal and immune dysregulation, and environ-
mental factors such as infectious agents, stress,
Conclusion and diet, have all been identified as contributing
factors [52].
Sjögren’s syndrome causes a spectrum of oral The characteristic disease findings in SLE
problems, including xerostomia, dental caries, include inflammation, abnormalities in the blood
candidiasis, and inflammation of the oral mucosa. vessels, and immune-complex deposition. A hall-
Swollen sublingual and parotid glands, as well mark immunologic presentation is generalized
as lymphocytic infiltrates, are a hallmark of autoantibody production directed to self-antigens
SS. Though the exact etiology of SS is unknown, of the nucleus, cytoplasm, cell surface, soluble
a variety of immunologic factors are thought to IgG, and coagulation factors. Antinuclear anti-
be responsible. Oral symptoms secondary to SS bodies (ANA), in particular, are found in 95% of
can be challenging to treat. Optimal hydration, SLE patients [52]. Antibodies to double-strand
saliva substitutes, meticulous oral hygiene, and (ds) DNA (anti-ds DNA) and Smith antigen
candida prophylaxis are important general mea- (anti-Sm) target small nuclear ribonucleoproteins
sures. Secretory sialagogues have been proven and are unique to SLE and found in the sera of
to be the main medical therapy with beneficial 40% and 30% of patients, respectively [53]. The
effects, if contraindications do not exist as well production of autoantibodies is believed to initi-
as biologics. ate an immune-complex-mediated inflammatory
response causing tissue injury [54].
ing a diagnosis of SLE, oropharyngeal manifes- may affect the entire oropharyngeal cavity. Other
tations of the disease are important [49]. Oral oropharyngeal signs and symptoms include oral
ulcerations affecting the gingiva, buccal mucosa, candidiasis with a prevalence ranging from 4% to
hard and soft palate, as well as the tongue and 75%; dysphagia, with a prevalence ranging from
lips may occur [71, 72] (Figs. 6.3 and 6.4). The 11% to 75%; and xerostomia, with a prevalence
classic oral lupus lesion is a whitish plaque with of 1%–100% [57].
erythema in the center and keratotic striae at Skin or intraoral biopsy is generally required
the periphery with or without telangiectasias. for diagnosis where histologic characteristics
However, the pattern of the oral lesions may dif- include lichenoid mucositis with acanthosis and
fer among different types of lupus [73]. Most deep perivascular infiltrate, hyperkeratosis with
lesions are round, but they may also be linear, keratotic plugs, liquefaction necrosis, thicken-
fissured, or ulcerated lesions, which most com- ing of the basement membrane, atrophy of the
monly affect the hard palate. In the bullous form rete ridges, edema in the lamina propria, a sub-
of SLE, multiple blisters may be seen, which epithelial mononuclear infiltrate, and periodic
acid-Schiff-positive deposits. Direct immuno-
fluorescence is often positive and shows linear
deposits of IgG or IgM and/or C3 in the base-
ment membrane zone. The base of the ulcer often
reveals CD4+ T lymphocytes [74, 75].
Differential Diagnosis
and the presence of high titers of antibodies Other conditions to consider in the differential
against U1 ribonucleoprotein (RNP), is often dif- diagnosis include Adult Still’s disease (ASD),
ficult to diagnose since many of its characteris- serum sickness, fibromyalgia, multiple sclerosis,
tic features occur sequentially and often over a malignancies, and infections such as cytomegalo-
period of years. Furthermore, some patients with virus, Epstein-Barr virus, human parvovirus B19,
MCTD may evolve into another connective tis- human immunodeficiency virus, and the hepatitis
sue disease, including SLE [76]. Therefore, it is B and C viruses [78].
important to consider MCTD in the differential
diagnosis of SLE.
Patients with undifferentiated connective tis- Treatment
sue disease (UCTD) have signs and symptoms
suggestive of a systemic autoimmune disease The treatment course for SLE varies from patient
but do not satisfy the classification criteria for a to patient given that it is a multiorgan system dis-
defined connective tissue disease. These patients ease. Therapy usually involves nonsteroidal anti-
may have symptoms such as arthritis and arthral- inflammatory drugs (NSAIDs), corticosteroids,
gias, Raynaud’s phenomenon, and serological antimalarial agents, and immunosuppressive
findings that are difficult to distinguish from drugs. These drugs may be used alone or in combi-
early phases of SLE [77]. nation depending upon the severity of symptoms.
Patients with systemic sclerosis (SSc) and Arthritis and serositis are often controlled with
SLE share similar symptoms. The coexistence NSAIDs or aspirin. Use of these agents requires
of Raynaud’s phenomenon and gastroesopha- vigilance on part of the physician because they
geal reflux is typically observed in SSc, but can detrimentally affect renal function or cause
these findings may also be seen in patients with drug-induced hepatitis. Treatment with chlo-
SLE. Histology may help differentiate the two roquine and hydroxychloroquine is a consider-
as well as laboratory investigations including ation, if arthritis symptoms are not controlled
ANA, which is frequently positive in both SLE with NSAIDs. Similarly, NSAIDS are used ini-
and SSc, while other serologies such as anti- tially in the treatment of pleurisy and pericarditis.
double-stranded DNA (dsDNA) and anti-Smith Corticosteroids should be considered, if symptom
(Sm) antibodies are more commonly present in relief is not found with NSAIDs and infection and
SLE [78]. thromboembolic phenomena have been ruled out.
Constitutional symptoms, skin lesions, neu- Cutaneous manifestations have traditionally been
ropathy, and renal dysfunction commonly seen in responsive to topical corticosteroids or antima-
SLE can also be seen in the setting of medium larial agents. Severe discoid lupus and cutaneous
and small vessel vasculitides such as polyarteri- vasculitis, however, usually necessitate the use of
tis nodosa, granulomatosis with polyangiitis, or systemic corticosteroids. Steroid therapy is also
microscopic polyangiitis. initiated to treat patients with thrombocytope-
Dermatomyositis (DM) and polymyositis nia and hemolytic anemia. Immunosuppressive
(PM) should also be considered in the differential agents should be considered, if no response is
diagnosis of SLE especially for those presenting seen with steroid therapy. Cyclophosphamide
with myositis or proximal muscle weakness. A and glucocorticoids have shown efficacy in treat-
positive ANA is observed in approximately 30% ing lupus nephritis and angiopathy [72].
of patients with DM and PM, compared to a There are limited controlled studies on the
much larger proportion in SLE. The character- management of SLE-associated oral lesions.
istic skin findings of DM including Gottron’s Potent topical corticosteroids are often admin-
papules, heliotrope rash, photodistributed poiki- istered initially; however, intralesional cortico-
loderma, and the absence of SLE findings such as steroids may also be considered. Thalidomide,
oral ulcers, arthritis, nephritis, and hematologic clofazimine, and methotrexate have also been
abnormalities can differentiate the two [78]. used for treatment [79, 80].
100 K. R. Heath and N. Fazel
Systemic Sclerosis
Clinical Manifestations
Epidemiology
Raynaud’s phenomenon is commonly seen in
Systemic sclerosis (SSc) is a chronic, immune- patients with SSc characterized by an initial
mediated condition within the scleroderma spec- white color change to the skin due to exposure
trum of disorders characterized by inflammation to cold temperatures. As a consequence, the
and fibrotic changes, which can compromise reduced blood supply to the fingers, toes, nose,
the function of multiple organ systems [81]. or earlobes may lead to cyanosis. Other mani-
Systemic sclerosis is relatively rare with an esti- festations include smooth, taut, stretched, and
mated prevalence of 1–2/10,000. There appears mask-like facies due to subcutaneous collagen
to be two peaks of onset; in the early 1930s and deposition (Fig. 6.5). More serious sequelae
mid-1950s with a female predominance of 5:1,
though environmentally induced disease is gen-
erally more common in men [82, 83]. The disease
often occurs in conjunction with other autoim-
mune diseases such as SLE [84].
Etiopathogenesis
Epidemiology
Clinical Manifestations
Mixed connective tissue disease (MCTD) is a
systemic autoimmune disease first described in Early clinical manifestations of MCTD often
1972 as a condition displaying mixed features of include fever, malaise, arthralgias and myal-
6 Oral Signs of Connective Tissue Disease 103
gias. Although almost any organ system can diography. Furthermore, vasculopathy in MCTD
be affected by MCTD, there are four clinical is usually similar to SSc and is characterized
features that point toward MCTD rather than by intimal proliferation and hypertrophy of the
other connective tissue disorders: Raynaud’s media that affects small and medium-sized ves-
phenomenon, the absence of severe renal and sels [106, 107].
central nervous system disease, the presence of Gastrointestinal involvement is common
severe arthritis and the insidious onset of pulmo- (66–74%) and often represents a major feature
nary hypertension, and anti-U1 RNP antibodies of overlap with SSc. Esophageal dysfunction is
[99–101]. Raynaud’s phenomenon (RP) is one the most prevalent gastrointestinal manifestation,
of the most consistent features of MCTD, which which is initially subclinical but often presents
appears in approximately 75%–90% of patients as dysphagia when symptomatic. Esophageal
and may precede other clinical manifestations dysmotility and gastroesophageal reflux disease
by months or years [102]. Also, almost 70% of occur more frequently in patients who have clini-
patients develop swollen hands and sausage-like cal manifestations mostly related to SSc rather
digits [99]. Superficial vasculitis of the digits, than SLE. Other gastrointestinal manifestations
acrosclerosis, calcinosis cutis, discoid plaques, described include mesenteric vasculitis, colonic
and a malar rash can also occur [100]. perforation, protein-losing enteropathy, acute
Joint involvement varies from minimal pancreatitis, hemoperitoneum, diarrhea, and
arthralgias, arthritis, erosions typical of rheu- chronic active hepatitis [108].
matoid arthritis to arthritis mutilans. In general, Renal involvement is one of the major com-
polyarthralgia is an early and common symptom plications of MCTD though often asymptomatic.
in MCTD, occurring in approximately 60% of In some studies, it has been observed in approxi-
patients, and may be accompanied by joint defor- mately 25% of patients [109]. Severe renal dis-
mities with radiographic changes. Rheumatoid ease is rare, and the presence of anti-U1 RNP
factor can be positive in up to 70% of patients antibodies may be protective against the develop-
with MCTD [99, 103, 104]. Between 80% and ment of diffuse proliferative glomerulonephritis
90% of patients develop muscle involvement. (GNF). Membranous and mesangial GNF are
Proximal muscles are more frequently affected the most common presentation although focal or
with elevation of creatinine kinase; however, it diffuse proliferative GNF can also be present. In
does not present a specific pattern that differenti- addition, immune-complex-mediated nephritis
ates it from other connective tissue diseases with has been reported [110].
muscle involvement. Electromyography is typi- Leukopenia, anemia of chronic disease,
cal of inflammatory myopathy, although, focal broad-based hypergammaglobulinemia, and
myositis may also occur [99]. positive Coombs test without hemolysis are the
Pulmonary abnormalities are found in most frequently reported hematological features.
about 85% of MCTD patients though most Interestingly, although they are not specific for
have an asymptomatic course. Fibrosis, inter- MCTD, anemia and leukopenia tend to correlate
stitial lung disease, pulmonary arterial hyper- with disease activity and usually improve with
tension, dyspnea, and pleuritic chest pain can treatment. Other less common features include
arise. Radiographic findings include interstitial thrombocytopenia, thrombotic thrombocytope-
changes, pleural effusions, pneumonic infiltrates, nic purpura (TTP), and red cell aplasia [102].
and pleural thickening [105]. Trigeminal neuralgia is the most common
Approximately 30% of MCTD patients have manifestation of the peripheral nervous system
symptomatic heart disease. The most frequent in MCTD. Headaches and peripheral neuropa-
manifestation is pericarditis (10%–29%), which thies have also been reported. Some patients
is usually mild. Myocarditis, conduction distur- can develop aseptic meningitis with increased
bances, and abnormal left ventricular diastolic concentrations of interferon gamma (IFN-γ),
filling (26%) have also been detected by echocar- interleukin-6 (IL-6), and higher titers of anti-
104 K. R. Heath and N. Fazel
some patients experience mild self-limited dis- with a connective tissue disease occurs more
ease, whereas others develop severe major organ often in younger women with a higher prevalence
involvement. The worst prognosis and highest in African-Americans [121, 122].
mortality are associated with the presence of
pulmonary arterial hypertension. Treatment of
MCTD is individualized depending upon the Etiopathogenesis
specific clinical manifestations and potential
need for aggressive treatment for life-threatening The etiology of DM is unknown; however, there
manifestations. Further prospective clinical trials appears to be immunogenetic markers correlated
are needed to evaluate its clinical course, long- with the disease. Like other autoimmune disor-
term prognosis, and response to therapy. ders, it is possible that DM is due to an interaction
between environmental factors and an immu-
nogenetic predisposition to the disease [123].
Dermatomyositis Studies of histocompatibility antigen prevalence
have demonstrated that HLA-B8, -B14, -DR3,
Epidemiology -DRw52, and -DQA1 are associated with derma-
tomyositis [124]. Both juvenile and adult forms
The idiopathic inflammatory myopathies (IIM) have been associated with infectious agents such
comprise a heterogeneous group of autoimmune as influenza A or B1 and hepatitis B, although lit-
muscle disorders characterized by progressive tle scientific evidence has demonstrated a virus as
muscle weakness. Although they are uncommon the causative factor. Additionally, a small study
conditions, their importance has increasingly hypothesized that a host response to Coxsackie
been recognized because of the associated mor- B virus could be related to the pathophysiology
bidity and mortality. Dermatomyositis (DM) is of juvenile DM. Picornaviruses have also been
a subtype of IIM with characteristic cutaneous thought to be a possible cause of the disease.
manifestations. In 1975, Bohan and Peter wrote Finally, one study found that 29 of 58 patients
a classic article that suggested a set of criteria to with DM had positive serologic titers for the pro-
aid in the diagnosis and classification of dermato- tozoa Toxoplasma gondii [122].
myositis and polymyositis (PM). These included
progressive, proximal, and symmetric weakness,
increased concentration of muscle enzymes, Clinical Manifestations
abnormal electromyogram, abnormal muscle
biopsy sample, and compatible cutaneous dis- A characteristic feature of DM is skin rash, partic-
ease [119]. Dermatomyositis has many signs and ularly on the face, which precedes, accompanies,
symptoms that involve the orofacial regions and or follows progressive proximal muscle weak-
is therefore relevant to oral health care providers. ness. The skin lesions can be transient, atypical,
Information about the incidence and preva- or completely absent. When the rash does occur,
lence of DM is limited because of the rarity of the it typically presents as a violaceous to dusky ery-
disease. Yet a population-based study confirmed thema of the eyelids and periorbital area with or
an incidence of 9.63 cases per million persons without edema. This is known as the heliotrope
and a bimodal age distribution of children under rash, which is characteristic of DM and rarely
18 years and adults in their late 40s to early 60s seen in SLE or scleroderma. Additionally, raised
[120]. Several studies have found a preponder- violaceous papules affecting the metatarsopha-
ance of female over male patients, commonly langeal and interphalangeal joints are considered
1.5–2.0:1 with an equal sex ratio in older patients a pathognomonic sign of DM, known as Gottron’s
with malignancy. The average age at diagnosis is papules. Telangiectasia within the lesions is com-
approximately 40 years, whereas that associated mon [125]. These lesions may be clinically con-
with malignancy is 55 years. DM/PM associated fused with lesions of lupus erythematosus or with
106 K. R. Heath and N. Fazel
Though the risk of oral malignancy in those Differential diagnoses of early skin manifes-
with DM is unclear, several cases of oral can- tations of dermatomyositis include polymorphic
cer associated with DM have been reported. light eruption, SLE, contact dermatitis, lichen pla-
Squamous cell carcinoma of the tongue, for nus, seborrheic dermatitis, psoriasis, and atopic
example, occurred following transient ulcers dermatitis. The facial erythema seen in DM should
in the same area in a 19-year-old male patient, be differentiated from lupus erythematosus, rosa-
1 year after the onset of DM. Another study cea, seborrheic dermatitis, and atopic dermatitis.
reported squamous cell carcinoma of the tongue Clinical distinction may be difficult in some cases,
arising after steroid therapy in an elderly DM but histopathological assessment is helpful [126].
patient [125]. Other conditions to consider in the differential
diagnosis of DM include trichinosis which can
cause periorbital swelling and edema similar to
Differential Diagnosis that seen in DM, HIV infection, and drugs such
as penicillamine, NSAIDs, practolol, hydroxy-
The diagnosis of DM has been largely based urea, and pravastatin [122].
on the combination of classic skin manifesta-
tions, proximal muscle weakness, and elevated
serum creatine kinase (CK), which is the most Treatment
sensitive diagnostic enzyme test. Levels of this
enzyme can increase by a factor of 50 in active The goal of treatment is to manage symptoms
DM but can be normal as well [127]. Muscle and prevent further disability, which most often
biopsy characteristically reveals perifascicular requires a multidisciplinary approach in the medi-
muscle fiber atrophy of two to ten layers, which cal management of these patients. Corticosteroid
is considered diagnostic even in the absence of treatment represents the mainstay of therapy for
inflammation [133]. The inflammatory infiltra- DM. Traditionally, prednisone 0.5–1.0 mg/kg
tion of B-cells and CD4 T-cells, when present, is given and continued for at least 6 weeks after
is mainly perivascular and peripheral to the fas- myositis symptoms are clinically controlled and
cicles. Serum autoantibodies are common in enzymes normalize. The dose is then slowly
DM patients, and ANA is frequently positive. tapered over a period lasting 1.5–2 times as long
Myositis-specific antibodies have been identi- as the period of active treatment. Approximately
fied in DM such as the anti-Jo-1 antibody, often 25% of patients will not respond to systemic
associated with interstitial lung disease and par- corticosteroids. Early intervention with steroid-
tially responsive to therapy, and anti-Mi-2 anti- sparing agents, therefore, may be an effective
bodies, which are considered DM specific and alternative. These include immunosuppressive
associated with treatment responsiveness [125]. agents such as methotrexate, azathioprine, cyclo-
Although studies have shown that these serum phosphamide, mycophenolate mofetil, chloram-
markers correlate with disease activity, response bucil, or cyclosporin. Some studies report that
to therapy, and prognosis, the findings have not 50%–75% of patients treated with these agents
been consistent. Therefore, their clinical applica- will respond with a decrease in enzyme concen-
tions are limited. Muscle biopsies and electromy- trations or a decrease in required corticosteroid
ography can be used as confirmatory tests, while dose. In a recent report, Ramanan et al. demon-
noninvasive diagnostic procedures such as MRI strated that the early addition of methotrexate
and ultrasound are also helpful [125, 134]. The allowed a more aggressive taper of corticosteroid
characteristic skin findings in combination with therapy and resulted in equal control with less ste-
muscle weakness and appropriate laboratory roid-related toxicity [123]. Additionally, hydroxy-
data can provide straightforward evidence for the chloroquine in doses of 200–400 mg per day is
diagnosis of DM. Unfortunately, many cases do effective in about 80% of patients when used as a
not present in this manner. steroid-sparing agent [135]. Patients who do not
108 K. R. Heath and N. Fazel
Markusse HM. Involvement of the peripheral nervous complaints (xerostomia) in Sjögren’s syndrome. Ann
system in primary Sjögren’s syndrome. Ann Rheum Rheum Dis. 1999;58:465–73.
Dis. 2001;60:876–81. 39.
Kruize AA, Hene RJ, Kallenberg CG, van
21. Napeñas JJ, Rouleau TS. Oral complications of
Bijsterveld OP, van der Heide A, Kater L, et al.
Sjögren’s syndrome. Oral Maxillofac Surg Clin N Hydroxychloroquine treatment for primary Sjogren’s
Am. 2014;26:55–62. syndrome; a two year, double blind cross over trial.
22. Astor FC, Hanft KL, Ciocon JO. Xerostomia: a
Ann Rheum Dis. 1993;52:60–4.
prevalent condition in the elderly. Ear Nose Throat J. 40. Petrone D, Condemi JJ, Fife R, Gluck O, Cohen
1999;78:476–9. S, Dalgin P. A double-blind, randomized,
23. Mavragani CP, Moutsopoulos NM, Moutsopoulos
placebo-controlled study of cevimeline in Sjogren’s
HM. The management of Sjögren’s syndrome. Nat syndrome patients with xerostomia and keratocon-
Clin Pract Rheumatol. 2006;2:252–61. junctivitis sicca. Arthritis Rheum. 2002;46:748–54.
24. Perdson AM, Reibel J, Nordgarden H, Bergrem HO,
41. Fife RS, Chase WF, Dore RK, Wiesenhutter CW,
Jensen JL, Nauntofte B. Primary Sjögren’s syndrome: Lockhart PB, Tindal E, et al. Cevimeline for the treat-
salivary gland function and clinical oral findings. Oral ment of xerostomia in patients with Sjögren syndrome: a
Dis. 1999;5:128–38. randomized trial. Arch Intern Med. 2002;162:1293–300.
25. Gonzalez S, Sung H, Sepulveda D, Gonzalez MJ, 42. Thanou-Stavraki A, James JA. Primary Sjögren’s
Molina C. Oral manifestations and their treatment in syndrome: current and prospective therapies. Semin
Sjögren’s syndrome. Oral Dis. 2014;20(2):153–61. Arthritis Rheum. 2008;37(5):273–92.
26. Soto-Rojas AE, Kraus A. The oral side of Sjögren 43. Steinfeld SD, Demols P, Salmon I, Kiss R, Appelboom
syndrome. Diagnosis and treatment. A review. Arch T. Infliximab in patients with primary Sjögren’s
Med Res. 2002;33:96–106. syndrome: a pilot study. Arthritis Rheumatol.
27. Pertovaara M, Korpela M, Uusitalo H, Pukander 2001;44:2371–5.
J, Miettinen A, Helin H, et al. Clinical follow up 44. Sankar V, Brennan MT, Kok MR, Leakan RA, Smith
study of 87 patients with sicca symptoms (dry- JA, Manny J, et al. Etanercept in Sjögren’s syndrome:
ness of eyes or mouth, or both). Ann Rheum Dis. a twelve-week randomized, double-blind, placebo-
1999;58:423–7. controlled pilot clinical trial. Arthritis Rheumatol.
28. Harris NL. Lymphoid proliferations of the salivary 2004;50:2240–5.
glands. Am J Clin Pathol. 1999;111:S94–103. 45. Goldenberg DM. Epratuzumab in the therapy of
29. Russell SL, Reisine S. Investigation of xerostomia in oncological and immunological diseases. Expert Rev
patients with rheumatoid arthritis. J Am Dent Assoc. Anticancer Ther. 2006;6:1341–53.
1998;129:733–9. 46. Steinfeld SD, Tant L, Burmester GR, Teoh NK,
30. Percival RS, Challacombe SJ, Marsh PD. Flow rates of Wegener WA, Goldenberg DM, et al. Epratuzumab
resting whole and stimulated parotid saliva in relation (humanized anti-CD22 antibody) in primary Sjögren’s
to age and gender. J Dent Res. 1994;73(8):1416–20. syndrome: an open-label phase I/II study. Arthritis
31. Scott J. Qualitative and quantitative observations on Res Ther. 2006;8:129.
the histology of human labial salivary glands obtained 47. Ramos-Casals M, Brito-Zerón P. Emerging bio-
post mortem. J Biol Buccale. 1980;8(3):187–200. logical therapies in primary Sjögren’s syndrome.
32. Greenburg G, Anderson R, Sharpstone P, James
Rheumatology. 2007;46:1389–96.
DG. Enlargement of parotid gland due to sarcoidosis. 48. Steller M, Chou L, Daniels TE. Electrical stimulation
Br Med J. 1964;2(5413):861–2. of salivary flow in patients with Sjögren’s syndrome.
33. Kazi S, Cohen PR, Williams F, Schempp R, Reveille J Dent Res. 1988;67:1334–7.
JD. The diffuse infiltrative lymphocytosis syndrome. 49. Fortuna G, Brennan M. Systemic lupus erythematosus
Clinical and immunogenetic features in 35 patients. epidemiology, pathophysiology, manifestations, and
AIDS. 1996;10(4):385. management. Dent Clin N Am. 2013;57:631–55.
34. Cheuk W, Chan JK. IgG4-related sclerosing disease: 50. Schur PH, Hahn BH. Epidemiology and pathogenesis
a critical appraisal of an evolving clinicopathologic of systemic lupus erythematosus. In: Basow DS, edi-
entity. Adv Anat Pathol. 2010;17(5):303. tor. UpToDate. Netherlands: Wolters Kluwer; 2013.
35. Liu SY, Vlantis AC, Lee WC. Bilateral parotid and Retrieved 17 Sept 2014.
submandibular gland enlargement: rare features 51. Pons-Estel GJ, Alacron GS, Scofield L, Reinlib L,
of Wegener’s granulomatosis. J Laryngol Otol. Cooper GS. Understanding the epidemiology and
2003;117(2):148–50. progression of systemic lupus erythematous. Semin
36. Feinstein AJ, Ciarleglio MM, Cong X, Otremba
Arthritis Rheum. 2010;39:257–68.
MD, Judson BL. Parotid gland lymphoma: prog- 52.
Pisetsky DS. Systemic lupus erythematosus.
nostic analysis of 2140 patients. Laryngoscope. A. Epidemiology, pathology, and pathogenesis. In:
2013;123(5):1199. Klippel JH, Crofford LJ, Stone JH, Weyand CM, edi-
37. Amarasena R, Bowman S. Sjögren’s syndrome. Clin tors. Primer on the rheumatic diseases. Atlanta: The
Med. 2007;7:53–6. Arthritis Foundation; 2001. p. 329–52.
38. Van der Reijden WA, Vissink A, Veerman E, Nieuw- 53. Tan EM, Cohen AS, Fries JF, Masi AT, McShane
Amerongen AV. Treatment of oral dryness related DJ, Rothfield NF, et al. The 1982 revised criteria for
110 K. R. Heath and N. Fazel
86. Reveille JD, Solomon DH. Evidence-based guide- 102. Ortega-Hernandez OD, Shoenfeld Y. Mixed connec-
lines for the use of immunologic tests: anticentro- tive tissue disease: an overview of clinical manifes-
mere, Scl-70, and nucleolar antibodies. American tations, diagnosis and treatment. Best Pract Res Clin
College of Rheumatology Ad Hoc Committee Rheumatol. 2012;26:61–72.
of Immunologic Testing Guidelines. Arthritis 103. Ramos-Niembro F, Alarcon-Segovia D, Hernandez-
Rheumatol. 2003;49(3):399. Ortiz J. Articular manifestations of mixed con-
87. Tan FK, Arnett FC, Antohi S, Saito S, Mirarchi A, nective tissue disease. Arthritis Rheum. 1979;22:
Spiera H, et al. Autoantibodies to the extracellular 43–51.
matrix microfibrillar protein, fibrillin-1, in patients 104. Mimura Y, Ihn H, Jinnin M, Asano Y, Yamane
with scleroderma and other connective tissue dis- K, Tamaki K. Rheumatoid factor isotypes in
eases. J Immunol. 1999;163(2):1066. mixed connective tissue disease. Clin Rheumatol.
88. Bunn CC, Black CM. Systemic sclerosis: an autoan- 2006;25(4):572.
tibody mosaic. Clin Exp Immunol. 1999;117(2):207. 105. Sullivan WD, Hurst DJ, Harmon CE, Esther JH,
89. Islam NM, Bhattacharyya I, Cohen DM. Common Agia GA, Maltby JD, et al. A prospective evalua-
oral manifestations of systemic disease. Otolaryngol tion emphasizing pulmonary involvement in patients
Clin N Am. 2011;44:161–82. with mixed connective tissue disease. Medicine.
90. Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, 1984;63(2):92.
Cooper KD, Elder MJ, et al. The first international 106. Alpert MA, Goldberg SH, Singsen BH, Durham JB,
consensus on mucous membrane pemphigoid. Arch Sharp GC, Ahmad M, et al. Cardiovascular manifes-
Dermatol. 2002;138:370–9. tations of mixed connective tissue disease in adults.
91. Rout PG, Hamburger J, Potts AJ. Orofacial radio- Circulation. 1983;68:1182–93.
logical manifestations of systemic sclerosis. 107. Ungprasert P, Wannarong T, Panichsillapakit T,
Dentomaxillofac Radiol. 1996;25:193–6. Cheungpasitporn W, Thongprayoon C, Ahmed S,
92. Varga J. Diagnosis and differential diagnosis of et al. Cardiac involvement in mixed connective tis-
systemic sclerosis (scleroderma) in adults. In: sue disease: a systematic review. Intern J Cardiol.
UpToDate; 2014. Retrieved 09 Oct 2014 from http:// 2014;171(3):326–30.. Epub 2013 Dec 29
www.uptodate.com/contents/diagnosis-and-differ- 108. Marshall JB, Kretschmar JM, Gerhardt DC, Winship
ential-diagnosis-of-systemic-sclerosis-scleroderma- DH, Winn D, Treadwell EL, et al. Gastrointestinal
inadults?source=search_result&search=systemic+sc manifestations of mixed connective tissue disease.
lerosis&selectedTitle=4%7E150. Gastroenterology. 1990;98:1232–8.
93. Minkin W, Rabhan N. Mixed connective tissue dis- 109. Kitridou RC, Akmal M, Turkel SB, Ehresmann GR,
ease. Arch Dermatol. 1976;112:1535–8. Quismorio FP Jr, Massry SG. Renal involvement
94. Bennett RM. Anti-U1 RNP antibodies in mixed in mixed connective tissue disease: a longitudinal
connective tissue disease. In: UpToDate; 2014. clinicopathologic study. Semin Arthritis Rheum.
Retrieved 12 Oct 2014 from http://www.uptodate. 1986;16:135–45.
com/contents/anti-u1-rnp-antibodies-in-mixed-con- 110. Bennett RM, Spargo BH. Immune complex nephrop-
nective-tissue-disease?source=search_result&searc athy in mixed connective tissue disease. Am J Med.
h=mixed+connective+tissue+disease&selectedTitle 1977;63:534–41.
=4%7E73. 111. Klasser GD, Balasubramaniam R, Epstein
95. Sharp GC. Diagnostic criteria for classification of J. Topical review-connective tissue diseases: orofa-
MCTD. In: Kasukawa R, Sharp GC, editors. Mixed cial manifestations including pain. J Orofac Pain.
connective tissue. Diseases and anti-nuclear antibod- 2007;21:171–84.
ies. Amsterdam: Elsevier; 1987. p. 23–32. 112. Fujita Y, Fujii T, Nakashima R, Tanaka M, Mimori
96. Greidinger EL, Hoffman RW. Autoantibodies in the T. Aseptic meningitis in mixed connective tissue
pathogenesis of mixed connective tissue disease. disease: cytokine and anti-U1RNP antibodies in
Rheum Dis Clin N Am. 2005;31:437–50. cerebrospinal fluids from two different cases. Mod
97. Datta SK, Zhang L, Xu L. T-helper cell intrinsic Rheumatol. 2008;18:184–8.
defect in lupus that break peripheral tolerance to 113. Gonzales TS, Coleman GC. Periodontal manifesta-
nuclear autoantigens. J Mol Med. 2005;83:267–78. tions of collagen vascular disorders. Periodontology.
98. Hoffman RW. T cells in the pathogenesis of systemic 2000;1999(21):94–105.
lupus erythematosus. Clin Immunol. 2004;113:4–13. 114. Prystowsky SD. Mixed connective tissue disease.
99. Bennett RM, O’Connell DJ. The arthritis of West J Med. 1980;132:288–93.
mixed connective tissue disease. Ann Rheum Dis. 115. Hoffman RW, Sharp GC, Deutscher SL. Analysis
1987;37(5):397–403. of anti-U1 RNA antibodies in patients with con-
100. Pope JE. Other manifestations of mixed con- nective tissue disease. Association with HLA and
nective tissue disease. Rheum Dis Clin N Am. clinical manifestations of disease. Arthritis Rheum.
2005;31(3):519. 1995;38:1837–44.
101. Hassoun PM. Pulmonary arterial hypertension com- 116. Ha Hassan AB, Nikitina-Zake L, Padyukov L,
plicating connective tissue diseases. Sem Respir Crit Karlsson G, Gupta M, Lundberg IE, et al. MICA4/
Care Med. 2009;30(4):429. HLA-DRB1*04/TNF1 haplotype is associated with
112 K. R. Heath and N. Fazel
mixed connective tissue disease in Swedish patients. ment in polymyositis and in dermatomyositis. J
Hum Immunol. 2003;64:290–6. Rheumatol. 1998;25:1336–43.
117. Kim P, Grossman JM. Treatment of mixed con- 129. Gonzalez-Lopez L, Gamez-Nava JI, Sanchez L,
nective tissue disease. Rheum Dis Clin N Am. Rosas S, Suarez-Almazor M, Cardona-Munoz
2005;31:549–65. C, et al. Cardiac manifestations in dermato-
118. Lundberg I. The prognosis of mixed connective tis- polymyositis. Clin Exp Rheumatol. 1996;14:
sue disease. Rheum Dis Clin N Am. 2005;31:535–47. 373–9.
119. Bohan A, Peter JB. Polymyositis and derma- 130. Hill CL, Zhang Y, Sigurgeirsson B, Pukkala E,
tomyositis (first of two parts). N Engl J Med. Mellemkajaer L, Airio A, et al. Frequency of spe-
1975;292:344–7. cific cancer types in dermatomyositis and polymyo-
120. Na SJ, Kim SM, Sunwoo IN, Choi YC. Clinical sitis: a population-based study. Lancet. 2001;357:
characteristics and outcomes of juvenile and adult 96–100.
dermatomyositis. J Kor Med Sci. 2009;24:715–21. 131. Keil H. The manifestations in the skin and mucous
121. Medsger TA, Dawson WN, Masi AT. The epidemiol- membranes in dermatomyositis, with special refer-
ogy of polymyositis. Am J Med. 1970;48:715–23. ence to the differential diagnosis from systemic lupus
122. Kovacs SO, Kovacs SC. Dermatomyositis. J Am erythematosus. Ann Intern Med. 1942;16:828–31.
Acad Dermatol. 1998;39(6):899–920. 132. Sanger RG, Kirby JW. The oral and facial manifesta-
123. Callen JP, Wortmann RL. Dermatomyositis. Clin tions of dermatomyositis with calcinosis. Oral Surg
Dermatol. 2006;24:363–73. Oral Med Oral Pathol Oral Radiol. 1973;35:476–88.
124. Appleyard ST, Dunn MJ, Dubowitz V, et al. Increased 133. Mammen AL. Dermatomyositis and polymyositis:
expression of HLA ABC class I antigens by muscle clinical presentation, autoantibodies, and pathogen-
fibers in Duchenne muscular dystrophy, inflamma- esis. Ann N Y Acad Sci. 2010;1184:134–53.
tory myopathy, and other neuromuscular disorders. 134. Curiel RV, Jones R, Brindle K. Magnetic resonance
Lancet. 1985;1:361–3. imaging of the idiopathic inflammatory myopathies:
125. Tanaka TI, Geist SM. Dermatomyositis: a contem- structural and clinical aspects. Ann N Y Acad Sci.
porary review for oral health care providers. Med 2009;1154:101–14.
Manag Pharmacol Updat. 2012;114(5):e1–8. 135. Woo TY, Callen JP, Voorhees JJ, Bickers DR, Hanno
126. Callen JP. Dermatomyositis. Lancet. 2000;355:53–7. R, Hawkins C. Cutaneous lesions of dermatomyosi-
127. Dalakas MC. Polymyositis, dermatomyosi- tis are improved by hydroxychloroquine. J Am Acad
tis, and inclusion-body myositis. N Engl J Med. Dermatol. 1984;10:590–600.
1991;325:1487–98. 136. Zieglschmid-Adams ME, Pandya AG, Cohen SB,
128. Marie I, Hatron P-Y, Hachulla E, Wallaert B, Sontheimer RD. Treatment of dermatomyositis with
Michon-Pasturel U, Devulder B. Pulmonary involve- methotrexate. J Am Acad Dermatol. 1995;32:754–7.
Oral Signs of Vesiculobullous
and Autoimmune Disease
7
Michael Z. Wang, Julia S. Lehman,
and Roy Steele Rogers III
Treatment Recommendations
Clinical Manifestations
Bullous Pemphigoid
Differential Diagnosis
Epidemiology
The differential diagnosis of PNP includes major
aphthous stomatitis, chemotherapy-induced stoma- Bullous pemphigoid (BP) is the most common
titis, bullous pemphigoid, pemphigus vulgaris, autoimmune blistering disorder, with an annual
mucous membrane pemphigoid, erythema multi- incidence of 6–21 cases per million. In persons
forme, Stevens-Johnson syndrome, toxic epidermal over 80 years old, the incidence substantially
necrolysis, graft-versus-host disease, lichen planus, rises to 150–330 per million per year [55, 56].
persistent herpes simplex virus infection, and Oral involvement in BP is seen in 10–30% of
Mycoplasma pneumoniae-associated mucositis. patients.
118 M. Z. Wang et al.
Clinical Manifestations
Differential Diagnosis
When the oral mucosa is affected in BP, severely
painful desquamative gingivitis (DG) with dis- Oral vesicular and bullous lesions may be seen
crete vesicles and erosions is the most common with mucous membrane pemphigoid, bullous
presentation. The oral presentation is usually lichen planus, dermatitis herpetiformis, and bul-
accompanied by cutaneous blisters. lous systemic lupus erythematosus. Given the
fragility of oral bullae and vesicles, erosive oral
diseases are also in the differential diagnosis,
Oral Signs and Symptoms including acute herpetic gingivostomatitis, linear
IgA bullous dermatosis, paraneoplastic pemphi-
A minority of patients with BP present with oral gus/paraneoplastic autoimmune multiorgan syn-
lesions. Oral mucosal disease is associated with a drome, lichen planus, erythema multiforme, and
slower response to treatment. Oral lesions of BP Stevens-Johnson syndrome. In this setting, cuta-
may be painful. Oral bullae and vesicles are neous findings of intact tense bullae would sup-
smaller and more fragile compared to their cuta- port a clinical diagnosis of BP; however,
neous counterparts; hence, discrete erosions with clinicians should be mindful that the cutaneous
areas of sparing are more commonly the clinical presentation of BP is not always bullous. The dif-
presentation. When the oral mucosa is involved, ferential diagnosis for DG includes acute
scarring is a possibility. Severe DG may be an necrotizing ulcerative gingivostomatitis (ANUG)
oral presentation of BP, a feature shared with and acute herpetic gingivostomatitis (AHGS)
MMP. Gingival involvement commonly affects a where erythema, edema, and necrosis occur at
large area with an overlying thin white mem- the interdental papillae. MMP may also present
brane. Nikolsky’s sign is negative. Extra-oral with DG and may also involve the conjunctiva,
mucosal sites including ocular, nasal, pharyn- other extra-oral mucosal sites, and the skin. If a
geal, perianal, vulvar, and urethral surfaces can BP patient has a bleeding disorder or is taking
7 Oral Signs of Vesiculobullous and Autoimmune Disease 119
target antigens being type VII collagen, laminin- medications such as azathioprine may also act as
332, and laminin-311. Serologies for
adjunctive therapy to systemic corticosteroids.
autoantibodies are frequently negative, due to Rituximab is found to be effective in recalcitrant
low circulating antibody concentrations. An addi- MMP, and its addition to conventional therapy
tional adjunctive testing method for detecting increases the likelihood of disease control and
IgG and IgA autoantibodies of BPAG2 NC16a may also result in faster remission. Multiple
subunit can be performed from whole saliva [75]. courses of Rituximab treatment are frequently
needed. When MMP is under control, systemic
corticosteroids should be tapered. IVIG is also
Differential Diagnosis under investigation for MMP treatment, and
disease-modifying potential has been found for
Through histopathology and DIF testing, MMP beta-4 integrin-related MMP [68]. Plasmapheresis
can be distinguished from pemphigus, non-MMP and etanercept have been reported to be effective
drug-induced cicatrization, oral lichen planus, in isolated cases [76, 77].
lupus erythematosus, graft-versus-host disease, When the disease is limited to the oral mucosa,
erythema multiforme, and SJS/TEN. Due to systemic dapsone therapy is very effective with a
shared histopathological and DIF features, clini- 50% remission, off treatment outcome [78].
cal differentiation must be made between MMP Local treatment with high potency topical corti-
and BP, anti-p200 pemphigoid, anti-p105 pem- costeroids or calcineurin inhibitors may be
phigoid, anti-p450 pemphigoid, linear IgA bul- administered initially. Other treatment options
lous dermatosis (LABD), and epidermolysis include tetracycline, nicotinamide, colchicine,
bullosa acquisita (EBA). Clinically, MMP is pre- low-dose systemic corticosteroids, and immuno-
dominantly mucosal, whereas cutaneous disease suppressant therapy. Surgical relief of scarred tis-
predominates in BP, LABD, and EBA. When DG sue can be considered once the disease is in
is the primary feature, differential diagnosis remission [65–92].
includes MMP, lichen planus, pemphigus, con-
tact stomatitis, and estrogen imbalance from
menopause or hysterectomy. Lichen Planus
Epidemiology
Treatment Recommendations
Oral lichen planus (OLP) is observed in up to 4%
The goals of MMP treatment are disease control, of the population, with varying prevalence depend-
symptomatic relief, and prevention of complica- ing on geographic regions. All ethnicities are
tions. The treatment choice should be guided by affected [93], with a higher prevalence in women
sites of involvement, severity, and progression. than men [94]. In contrast, OLP is rare in children
Ocular, genital, nasopharyngeal, esophageal, and and adolescents, and it typically affects adults
laryngeal mucosal involvement may evolve into between the age of 30 and 60 years old [95].
long-lasting functional deficit. Hence, careful
questioning of symptoms and clinical examina-
tion of all mucosal areas is critical. When rele- Etiopathogenesis
vant, consultation with ophthalmology and other
specialties should be sought. Minimization of The pathogenesis of OLP is hypothesized to be a
irritation, trauma, secondary infection, and mal- T cell-mediated chronic inflammatory disorder.
nutrition is also an integral part of management. Investigations toward antigen-specific and non-
Rapidly evolving and severe MMP can be specific mechanisms are ongoing. Moreover,
treated by a combination of systemic corticoste- studies on the genetic aspects of the disease are
roids and cyclophosphamide. Immunosuppressive also one of the focuses for understanding the
122 M. Z. Wang et al.
Clinical Manifestations
Signs and Symptoms
Differential Diagnosis
Treatment Recommendations
divided into EM minor and major based on the keratinocytes through all layers of the epidermis.
clinical appearance [111]. Severe papillary edema, subepithelial and
The onset of EM can begin 1–2 weeks after a intraepithelial vesiculation, and a perivascular
triggering event. The typical duration of EM is lymphocytic infiltrate may be observed. These
1–4 weeks; however, 10–37% of patients are changes are more prominent in early-stage
affected by recurrent EM. EM minor accompa- lesions. Nonspecific immune deposits of IgM,
nied by mucosal involvement is typically mild C3, and fibrin may be detected on DIF testing,
and limited to one mucosal site, without systemic whereas IIF testing is negative. In severe cases,
symptoms. EM major is described as severe complete blood count, liver and renal function
mucosal disease with bullous lesions and sys- tests, chest X-ray, and cultures (blood, sputum,
temic symptoms (Fig. 7.11). Oral lesions can be urine, stool, and wound) should be considered
the only presentation in nearly half of EM patients. along with HSV and mycoplasma serologies.
Extra-oral mucosal involvement includes the
eyes, nose, esophagus, and genitalia.
Oral lesions are typically most pronounced Differential Diagnosis
anteriorly and more likely to involve non-
keratinized mucosa (buccal, labial, and alveolar The differential diagnosis of EM includes major
mucosae, ventral tongue, floor of the mouth, and aphthous stomatitis, chemotherapy-induced sto-
soft palate). The vermilion border is also fre- matitis, bullous pemphigoid, pemphigus vulgaris,
quently affected. Mucosal vesicles and bullae PNP/PAMS, MMP, SJS/TEN, GVHD, lichen pla-
rapidly rupture becoming erosions, accompanied nus, persistent HSV infection without EM, and
by erythema and swelling, hemorrhagic crusting, non-EM Mycoplasma pneumoniae-induced muco-
and mucosal sloughing. When diffuse, the clini- sitis. When mucositis is extensive, GVHD, SJS/
cal presentation can be indistinguishable from TEN, pemphigus vulgaris, and PNP/PAMS must
other erosive oral diseases. be considered due to high morbidity and mortality.
Cutaneous features of EM include typical or Compared to pemphigus vulgaris, EM rarely
palpable atypical targetoid lesions (only two shows severe gingivitis. When cutaneous involve-
zones or poorly defined border) on the face and ment is sparse, Mycoplasma pneumoniae-induced
extremities, whereas SJS/TEN presents with mucositis is proposed to be an independent entity
macular atypical target lesions or purpuric mac- from EM; however, oral mucosa-limited EM is not
ules that are predominantly truncal or general- uncommonly reported. The differentiation is made
ized. Nikolsky sign is negative in EM. with the aid of a detailed history, review of sys-
The histopathological features of EM are vac- tems, careful oral examination, HSV PCR, biopsy
uolar degeneration of the BMZ with dyskeratotic for histopathological examination, DIF, and IIF.
Treatment Recommendations
Prophylactic antiviral therapy for at least causative agents include antibiotics (sulfon-
6 months is recommended in the treatment of amides, tetracyclines, aminopenicillins, cephalo-
HSV-related and idiopathic recurrent EM. sporins, and quinolones), sulfasalazine, and
Cyclosporine can also provide benefit to control nonsteroidal anti-inflammatory drugs.
recurrent EM [112]. Supportive care with anal- A genetic component of SJS/TEN is present
gesics and nutrition is essential, and hospital in various ethnic groups. In Han Chinese with
care is recommended when symptoms are severe. SJS/TEN, strong associations are found between
Ophthalmological care should be initiated aromatic anticonvulsants (carbamazepine, phe-
early when ocular involvement is suspected nytoin, oxcarbazepine, lamotrigine) and HLA-
[105–123]. B*1502, as well as allopurinol and HLA-B*5801.
The same associations between carbamazepine
and HLA-B*1502 are also found in Thai,
Stevens-Johnson Syndrome Malaysian, and South Indian populations. For
and Toxic Epidermal Necrolysis individuals of European descent, an association
between carbamazepine and HLA-A*3101, allo-
Epidemiology purinol and HLA-B*5801, as well as abacavir
and HLA-B*5701 have been reported. Similar to
The combined annual incidence of SJS/TEN is Han Chinese patients, an association of
estimated to be up to seven per million cases allopurinol-
induced SJS/TEN with HLA-
[124]. The disease is found in all age groups but B*5801 has also been identified in African-
more commonly in female and Asian descen- Americans patients.
dants. HIV-infected patients have a thousand-fold
increase in the prevalence of SJS/TEN [125].
Mucosal involvement is present in nearly all SJS/ Clinical Manifestations
TEN patients.
Widespread mucocutaneous denudation occurs
in SJS/TEN, frequently with constitutional symp-
Etiopathogenesis toms and multi-organ involvement.
p alate, and vermilion border of the lips are the Table 7.2 The severity of illness is measured by Severity
most frequently affected oral sites. of Illness Score for Toxic Epidermal Necrolysis
(SCORTEN). One point is added for each criterion [126]:
Characteristic features of the lesions are pain-
HPI factors:
ful, diffuse, irregular, and hemorrhagic ero-
Age >40
sions that can be seen with gray-white Cancer or hematologic malignancy
pseudomembranes and hemorrhagic crusting. BSA detachment on day 1 >10%
A positive Nikolsky sign and Asboe Hansen Vitals and labs:
sign may also present in this condition. Long- Heart rate >120 beats per minute
term oral sequelae include xerostomia, peri- Serum urea level (>10 mmol/l, or 28 mg/dl)
odontal disease, gingival inflammation, Serum bicarbonate level (<20 mmol/l)
Serum glucose level (>14 mmol/l, or 252 mg/dl)
synechiae, and dysesthesia.
Total score (mortality rate)
The differentiation of SJS and TEN is based 0–1 (3.2%)
upon clinical appearance. SJS has less than 10% 2 (12.2%)
of the body surface area (BSA) detachment, with 3 (35.5%)
erythematous or purpuric macules or flat atypical 4 (58.3%)
target lesions. SJS and TEN overlap has BSA ≥5 (90.0%)
detachment between 10% and 30%. TEN may
cause more than 30% BSA detachment.
Frequently, the extent and severity of epidermal Other differential diagnoses include acute
detachment is not correlated with the severity of herpetic gingivostomatitis, aphthous stomatitis,
the oral presentation (Table 7.2). PNP/PAMS, MMP, linear IgA dermatosis,
Histopathological features include full-lichen planus, systemic lupus erythematosus,
thickness epidermal necrosis, subepidermal split- staphylococcal- scalded skin syndrome (SSSS),
ting, and endothelial apoptosis. Strong staining and GVHD. Of these, SSSS is distinguished by
of high-mobility group protein B1 (HMGB1) in the absence of mucosal involvement. PNP/PAMS
necrotic keratinocytes is a potential emerging may mimic the targetoid lesions in SJS/TEN and
marker for SJS/TEN. In addition, Bcl-2 expres- EM. However, PNP/PAMS and other autoim-
sion in the dermal infiltrate is also considered as mune bullous diseases are identified through pat-
a potential marker. terns noted in DIF testing. Acute GVHD is
difficult to distinguish from SJS/TEN, by sharing
similarities in presentation of a bullous eruption
Differential Diagnosis with erosions, as well as full-thickness epidermal
necrosis. In addition, a clinical history of bone
Early presentations of SJS/TEN can be difficult marrow and/or allogeneic hematopoietic stem
to differentiate from EM major. In general, SJS/ cell transplant within weeks, diarrhea and eleva-
TEN tend to show increased keratinocyte apopto- tion of liver enzymes may be seen as extracutane-
sis and epidermal necrosis compared to EM, ous manifestations of GVHD.
although the microscopic features of these enti-
ties do overlap. Generally, the clinical course will
help to distinguish these entities. Treatment Recommendations
The clinical presentation of EM includes the
presence of classic cutaneous target lesions (three When BSA involvement is over 30%, hospital-
zones with defined border) or palpable raised ization is required, and the mortality of the dis-
atypical targetoid lesions (only two zones or ease can be 30–40% despite all possible efforts,
poorly defined border), whereas SJS/TEN com- with Chinese descendants having the highest
monly presents with flat atypical targetoid mortality. When less than 10% of the BSA is
lesions. In addition, SJS/TEN tends to have epi- affected with no severe systemic involvement,
dermal exfoliation and bullae formation. the mortality rate is less than 5%, and complete
128 M. Z. Wang et al.
diseases include type 1 diabetes mellitus, lupus microabscesses. In early lesions, lymphocytic
erythematosus, Sjögren syndrome, sarcoidosis, vit- inflammation may be prominent.
iligo, pernicious anemia, and rheumatoid arthritis. DIF of perilesional normal-appearing skin or
Therefore, screening with thyroid stimulating hor- mucosa is paramount, with the pathognomonic
mone, anti-thyroid peroxidase antibody, glucose, features of granular deposition of IgA along the
hemoglobin A1C, complete blood count, antinu- DEJ and stippling in the dermal papillae. DIF
clear antibody (ANA), and vitamin B 12 are among testing on oral biopsy can be positive without
further investigations to consider in a patient with clinically active oral disease, and in contrast, DIF
DH. Splenic atrophy and lymphoma are complica- testing of the oral mucosa is negative in celiac
tions associated with long-standing untreated DH disease without DH. IIF with IgA on monkey
and GSE [135]. esophagus endomysium (EMA) has sensitivity of
90% and specificity of 96% [136].
Laboratory testing for IgA autoantibodies to
Clinical Manifestations TTG has a sensitivity of 89.1% and specificity of
97.6% for the diagnosis of DH [137]. Other test-
Oral involvement is rare in DH but intraoral ves- able autoantibodies have targets against gliadin
icles and erosions can be seen. Cutaneous and endomysium. Autoantibody serologies are
involvement is characteristically pruritic vesicles less sensitive when patients do not exhibit total
that are heavily excoriated. The typical anatomic villus atrophy. These serological tests are espe-
distribution includes the extensor elbows and cially useful when DIF testing is negative and
knees, upper back, scalp, and sacrum. may serve as an alert for sampling errors. In this
situation, appropriate considerations include re-
biopsy and gastroenterology work-up. When a
Oral Signs and Symptoms patient has selective IgA deficiency, IgG sero-
logical testing should be used instead of IgA;
Although oral lesions are rare in DH, they can however, it has lesser diagnostic sensitivity.
be the initial manifestations as early as 6 months
prior to the onset of a cutaneous eruption. The
buccal mucosa and the surfaces underneath den- Differential Diagnosis
tures are the oral locations often affected in
DH. Vesicles, pseudo-vesicles, erythematous DH-associated diseases, such as GSE, lupus ery-
erosions, and purpura are potential oral findings thematosus, and Sjögren syndrome, may have
in DH. Small papules can be found on the max- oral symptoms independently or in conjunction
illary ridge and alveolar mucosa, which may with DH. Enamel defects found in celiac disease
coalesce into plaques extending onto the hard without DH are the same as enamel defects found
palate. Oral lesions are typically burning or in DH. Other oral clinical differential diagnoses
painful. Enamel defects are found in 80% of include viral infections, other immunobullous
childhood and 53% of adult DH cases, which disorders, and bullous lichen planus.
most frequently present as horizontal grooves.
Cutaneous lesions are commonly extremely
pruritic erosions on extensor surfaces and acral Treatment Recommendations
purpura.
On histopathology, neutrophilic microab- In some patients, DH can be treated success-
scesses in the dermal papillae with fibrin, leuko- fully with a gluten-free diet. Some patients
cytoclastic debris, and edema are observed. require additional treatment with dapsone,
These findings are nonspecific. Separation at the which is the standard agent used for DH treat-
BMZ may occur, and occasional apoptotic kerati- ment. It inhibits neutrophil chemotaxis and
nocytes may be present above the papillary adhesion. Dapsone also protects cells from
130 M. Z. Wang et al.
Differential Diagnosis
Treatment Recommendations
Table 7.3 Overview of EB subtypes and their associated proteins and genes [162, 163]
EB type Subcategory EB subtype Protein Gene
EBS Suprabasal Lethal acantholytic EB Plakophilin-1 PKP1
Plakophilin deficiency Desmoplakin DSP
Superficialis Unknown
Basal Localized (Weber-Cockayne) Keratin 5, Keratin 14 KRT5, KRT14
Dowling-Meara Keratin 5, Keratin 14 KRT5, KRT14
Other generalized (Koebner) Keratin 5, Keratin 14 KRT5, KRT14
Mottled pigmentation Keratin 5 KRT5
Migratory circinate Keratin 5 KRT5
Autosomal recessive Keratin 14 KRT14
Muscular dystrophy Plectin PLEC1
Ogna Plectin PLEC1
Pyloric atresia a6b4 integrin ITGA6, ITGB4
JEB Herlitz Herlitz Laminin 332 LAMA3, LAMB3, LAMC2
Non-Herlitz Non-Herlitz, generalized Laminin 332, Collagen LAMA3, LAMB3, LAMC2,
XVII COL17A1
Non-Herlitz, inversa Laminin 332 LAMA3, LAMB3, LAMC2
Non-Herlitz, localized Collagen XVII COL17A1
LOC syndrome Alpha chain of LAMA3
Laminin 332
Pyloric atresia a6b4 integrin ITGA6, ITGB4
Late onset Unknown
DEB Dominant Generalized Collagen VII COL7A1
Acral Collagen VII COL7A1
Pretibial Collagen VII COL7A1
Pruriginosa Collagen VII COL7A1
Nails only Collagen VII COL7A1
Bullous dermolysis of the Collagen VII COL7A1
newborn
Recessive Severe generalized Collagen VII COL7A1
(Hallopeau-Siemens)
Generalized other Collagen VII COL7A1
Inversa Collagen VII COL7A1
Pretibial Collagen VII COL7A1
Pruriginosa Collagen VII COL7A1
Centripetalis Collagen VII COL7A1
Bullous dermolysis of the Collagen VII COL7A1
newborn
Mixed Kindler – Kindlin-1 KIND1
EB syndrome
severely hinder the neonate’s ability to suckle. are at higher risk of developing dental caries.
Oral blistering in Kindler syndrome can also be Enamel developmental defects include hypopla-
severe and prominent in neonates with scarring sia, pitting, horizontal bands, and white mottled
potential, and the fragility diminishes with age enamel, which most prominently affects the
(Table 7.4). molars. Despite the absence of enamel defects in
The Herlitz type of JEB is characterized by DEB, the combination of scarring and limited
exuberant perioral granulation tissue leading to ability in maintaining oral hygiene frequently
microstomia and loss of lip mobility. Oral archi- leads to dental caries for DEB patients as well.
tecture, salivation, and soft tissue mobility are Kindler syndrome can have enamel hypoplasia,
preserved both in EBS and JEB. Enamel defects as well as marked periodontal disease. This is due
are distinctive features of JEB. Patients with JEB to kindlin-1, which affects adhesion of the oral
134 M. Z. Wang et al.
Etiopathogenesis
level should be considered in the work-up for vit- patients, recent onset of disease and darker skin
iligo patients. types are the factors that increase the likelihood
Histopathology demonstrates absence of of a favorable therapeutic response.
melanocytes and suprabasilar vacuolar changes. Treatment is guided by the degree in which
Suprabasilar clear cells, perivascular mononu- vitiligo impacts the patient’s quality of life. The
clear inflammation, epidermal thinning and no-treatment option should be discussed, because
effacement, sweat gland degeneration, and fol- there is no known treatment that can alter the
licular degeneration are additional features that natural disease process. Medically, topical
can be observed on histopathology. corticosteroids, calcineurin inhibitors, or a com-
bination of betamethasone and calcipotriol are
common choices for oral mucosal therapy [183–
Differential Diagnosis 186]. When potent topical corticosteroids are
used, the risk of atrophy is a consideration. For
In contrast to the depigmentation of vitiligo, the external component of the lips, narrowband
white discoloration is seen in leukoplakia, leuko- UVB light therapy, excimer laser, and helium-
edema, and white sponge nevus. Albinism also neon laser therapy are options [183, 187].
results in depigmentation within the oral cavity, Responders to excimer laser were found with
but it is accompanied by a lack of pigmentation Fitzpatrick skin types III or above. Systemic and
through the entire body. Other causes of leuko- surgical treatments are not common practice for
derma include post-inflammatory hypopigmenta- isolated disease. Minocycline, antioxidants, folic
tion, chemical- or trauma-induced leukoderma, acid and vitamin B12 supplementation, as well as
lichen sclerosus, sarcoidosis, discoid lupus ery- ginkgo have been reported to arrest disease pro-
thematosus, corticosteroid- and hydroquinone- gression, although convincing validation is cur-
induced hypopigmentation, and amelanotic rently lacking [179–194].
melanoma.
References
Treatment Recommendations
1. Ahmed AR, Graham J, Jordon RE, Provost
TT. Pemphigus: current concepts. Ann Intern Med.
Patient education is quintessential in the man- 1980;92(3):396–405.
agement of vitiligo. Sun protection can help to 2. Becker BA, Gaspari AA. Pemphigus vulgaris and
reduce the contrast between areas of leuko- vegetans. Dermatol Clin. 1993;11(3):429–52.
derma and their surrounding normally pig- 3. Ahmed AR, Nguyen T, Kaveri S, Spigelman
ZS. First line treatment of pemphigus vulgaris with
mented skin, and sun protection is also important a novel protocol in patients with contraindications
in skin cancer prevention. Trauma avoidance to systemic corticosteroids and immunosuppres-
aids in the prevention of Koebner phenomenon sive agents: preliminary retrospective study with
that could induce further discoloration. a seven year follow-up. Int Immunopharmacol.
2016;34:25–31.
Cosmetic cover-up with lipsticks and tattooing 4. Sagi L, Sherer Y, Trau H, Shoenfeld Y. Pemphigus and
are available for the lips, although tattooing infectious agents. Autoimmun Rev. 2008;8(1):33–5.
risks further development of vitiligo due to 5. Krain LS. Pemphigus. Epidemiologic and survival
trauma. The psychosocial impact of vitiligo characteristics of 59 patients, 1955–1973. Arch
Dermatol. 1974;110(6):862–5.
should be considered, and resources such as 6. Helander SD, Rogers RS 3rd. The sensitivity and
support groups are helpful (Vitiligo Support specificity of direct immunofluorescence testing
International, https://www.vitiligosupport.org). in disorders of mucous membranes. J Am Acad
Due to a lack of melanocyte reservoirs from the Dermatol. 1994;30(1):65–75.
7. Shamim T, Varghese VI, Shameena PM, Sudha
absence of hair follicles, oral vitiligo is expected S. Pemphigus vulgaris in oral cavity: clinical anal-
to be more resistant to treatment when com- ysis of 71 cases. Med Oral Patol Oral Cir Bucal.
pared to its cutaneous counterpart. Younger 2008;13(10):E622–6.
138 M. Z. Wang et al.
8. Ahmed AR, Spigelman Z, Cavacini LA, Posner 23. Tabrizi MN, Chams-Davatchi C, Esmaeeli N,
MR. Treatment of pemphigus vulgaris with ritux- Noormohammadpoor P, Safar F, Etemadzadeh H,
imab and intravenous immune globulin. N Engl J et al. Accelerating effects of epidermal growth fac-
Med. 2006;355(17):1772–9. tor on skin lesions of pemphigus vulgaris: a double-
9. Robinson JC, Lozada-Nur F, Frieden I. Oral pemphi- blind, randomized, controlled trial. J Eur Acad
gus vulgaris: a review of the literature and a report Dermatol Venereol. 2007;21(1):79–84.
on the management of 12 cases. Oral Surg Oral Med 24. Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs
Oral Pathol Oral Radiol Endod. 1997;84(4):349–55. DA, Kory M, et al. Paraneoplastic pemphigus. An
10. Ding X, Aoki V, Mascaro JM Jr, Lopez-Swiderski autoimmune mucocutaneous disease associated with
A, Diaz LA, Fairley JA. Mucosal and mucocu- neoplasia. N Engl J Med. 1990;323(25):1729–35.
taneous (generalized) pemphigus vulgaris show 25. Czernik A, Camilleri M, Pittelkow MR, Grando
distinct autoantibody profiles. J Invest Dermatol. SA. Paraneoplastic autoimmune multior-
1997;109(4):592–6. gan syndrome: 20 years after. Int J Dermatol.
11. Atzmony L, Hodak E, Gdalevich M, Rosenbaum O, 2011;50(8):905–14.
Mimouni D. Treatment of pemphigus vulgaris and 26. Poot AM, Diercks GF, Kramer D, Schepens I,
pemphigus foliaceus: a systematic review and meta- Klunder G, Hashimoto T, et al. Laboratory diag-
analysis. Am J Clin Dermatol. 2014;15(6):503–15. nosis of paraneoplastic pemphigus. Br J Dermatol.
12. Harman KE, Seed PT, Gratian MJ, Bhogal BS, 2013;169(5):1016–24.
Challacombe SJ, Black MM. The severity of 27. Yong AA, Tey HL. Paraneoplastic pemphigus.
cutaneous and oral pemphigus is related to des- Australas J Dermatol. 2013;54(4):241–50.
moglein 1 and 3 antibody levels. Br J Dermatol. 28. Poot AM, Siland J, Jonkman MF, Pas HH,
2001;144(4):775–80. Diercks GF. Direct and indirect immunofluores-
13. Scully C, Paes De Almeida O, Porter SR, Gilkes cence staining patterns in the diagnosis of para-
JJ. Pemphigus vulgaris: the manifestations and long- neoplastic pemphigus. Br J Dermatol. 2016;174(4):
term management of 55 patients with oral lesions. Br 912–5.
J Dermatol. 1999;140(1):84–9. 29. Joly P, Richard C, Gilbert D, Courville P, Chosidow
14. Mignogna MD, Lo Muzio L, Galloro G, Satriano O, Roujeau JC, et al. Sensitivity and specificity of
RA, Ruocco V, Bucci E. Oral pemphigus: clinical clinical, histologic, and immunologic features in the
significance of esophageal involvement: report of diagnosis of paraneoplastic pemphigus. J Am Acad
eight cases. Oral Surg Oral Med Oral Pathol Oral Dermatol. 2000;43(4):619–26.
Radiol Endod. 1997;84(2):179–84. 30. Helou J, Allbritton J, Anhalt GJ. Accuracy of indi-
15. Dagistan S, Goregen M, Miloglu O, Cakur B. Oral rect immunofluorescence testing in the diagnosis of
pemphigus vulgaris: a case report with review of the paraneoplastic pemphigus. J Am Acad Dermatol.
literature. J Oral Sci. 2008;50(3):359–62. 1995;32(3):441–7.
16. Meurer M, Millns JL, Rogers RS 3rd, Jordon 31. Murrell DF. Blistering diseases: clinical features,
RE. Oral pemphigus vulgaris. A report of ten cases. pathogenesis, treatment. New York: Springer; 2015.
Arch Dermatol. 1977;113(11):1520–4. p. XXI.. 752
17. Sirois D, Leigh JE, Sollecito TP. Oral pemphigus vul- 32. Schoen H, Foedinger D, Derfler K, Amann
garis preceding cutaneous lesions: recognition and G, Rappersberger K, Stingl G, Volc-Platzer
diagnosis. J Am Dent Assoc. 2000;131(8):1156–60. B. Immunoapheresis in paraneoplastic pemphigus.
18. Vinay K, Kanwar AJ, Mittal A, Dogra S, Minz RW, Arch Dermatol. 1998;134(6):706–10.
Hashimoto T. Intralesional rituximab in the treat- 33. Jansen T, Plewig G, Anhalt GJ. Paraneoplastic pem-
ment of refractory oral pemphigus vulgaris. JAMA phigus with clinical features of erosive lichen planus
Dermatol. 2015;151(8):878–82. associated with Castleman’s tumor. Dermatology.
19. Carson PJ, Hameed A, Ahmed AR. Influence of 1995;190(3):245–50.
treatment on the clinical course of pemphigus vul- 34. Bech R, Baumgartner-Nielsen J, Peterslund NA,
garis. J Am Acad Dermatol. 1996;34(4):645–52. Steiniche T, Bang K, Deleuran M, et al. Alemtuzumab
20. Rogers RS 3rd, Van Hale HM. Immunopathologic (ALZ) is an effective treatment for both primary and
diagnosis of oral mucosal inflammatory diseases. relapsed severe paraneoplastic pemphigus (PNP)
Australas J Dermatol. 1986;27(2):51–7. associated to B-cell chronic lymphocytic leukemia
21. Harman KE, Albert S, Black MM, British (CLL). Blood. 2007;110(11):1.
Association of Dermatologists. Guidelines for the 35. Horn TD, Anhalt GJ. Histologic features of
management of pemphigus vulgaris. Br J Dermatol. paraneoplastic pemphigus. Arch Dermatol.
2003;149(5):926–37. 1992;128(8):1091–5.
22. Michailidou EZ, Belazi MA, Markopoulos 36. Nousari HC, Brodsky RA, Jones RJ, Grever MR,
AK, Tsatsos MI, Mourellou ON, Antoniades Anhalt GJ. Immunoablative high-dose cyclophos-
DZ. Epidemiologic survey of pemphigus vulgaris phamide without stem cell rescue in paraneoplastic
with oral manifestations in northern Greece: ret- pemphigus: report of a case and review of this new
rospective study of 129 patients. Int J Dermatol. therapy for severe autoimmune disease. J Am Acad
2007;46(4):356–61. Dermatol. 1999;40(5 Pt 1):750–4.
7 Oral Signs of Vesiculobullous and Autoimmune Disease 139
37. Kaplan I, Hodak E, Ackerman L, Mimouni D, 53. Kitagawa C, Nakajima K, Aoyama Y, Fujioka A,
Anhalt GJ, Calderon S. Neoplasms associated with Nakajima H, Tarutani M, et al. A typical case of
paraneoplastic pemphigus: a review with emphasis paraneoplastic pemphigus without detection of
on non-hematologic malignancy and oral mucosal malignancy: effectiveness of plasma exchange. Acta
manifestations. Oral Oncol. 2004;40(6):553–62. Derm Venereol. 2014;94(3):359–61.
38. Ghigliotti G, Di Zenzo G, Cozzani E, Rongioletti F, 54. Williams JV, Marks JG Jr, Billingsley EM. Use
De Col E, Pastorino C, et al. Paraneoplastic autoim- of mycophenolate mofetil in the treatment
mune multi-organ syndrome: association with retro- of paraneoplastic pemphigus. Br J Dermatol.
peritoneal Kaposi’s sarcoma. Acta Derm Venereol. 2000;142(3):506–8.
2016;96(2):261–2. 55. Kershenovich R, Hodak E, Mimouni D. Diagnosis
39. Anhalt GJ. Paraneoplastic pemphigus. J Investig and classification of pemphigus and bullous pemphi-
Dermatol Symp Proc. 2004;9(1):29–33. goid. Autoimmun Rev. 2014;13(4–5):477–81.
40. Kimyai-Asadi A, Jih MH. Paraneoplastic pemphi- 56. Schmidt E, Zillikens D. Pemphigoid diseases.
gus. Int J Dermatol. 2001;40(6):367–72. Lancet. 2013;381(9863):320–32.
41. Mutasim DF, Pelc NJ, Anhalt GJ. Paraneoplastic 57. Laskaris G, Nicolis G. Immunopathology of oral
pemphigus. Dermatol Clin. 1993;11(3): mucosa in bullous pemphigoid. Oral Surg Oral Med
473–81. Oral Pathol. 1980;50(4):340–5.
42. Zhu X, Zhang B. Paraneoplastic pemphigus. J 58. Chuah SY, Tan SH, Chua SH, Tang MB, Lim YL,
Dermatol. 2007;34(8):503–11. Neoh CY, et al. A retrospective review of the ther-
43. Namba C, Tohyama M, Hanakawa Y, Murakami apeutic response with remission in patients with
M, Shirakata Y, Matsumoto T, et al. Paraneoplastic newly diagnosed bullous pemphigoid. Australas J
pemphigus associated with fatal bronchiolitis oblit- Dermatol. 2014;55(2):149–51.
erans and intractable mucosal erosions: treatment 59. Hodge L, Marsden RA, Black MM, Bhogal B,
with cyclosporin in addition to steroid, rituximab Corbett MF. Bullous pemphigoid: the frequency of
and intravenous immunoglobulin. J Dermatol. mucosal involvement and concurrent malignancy
2016;43(4):419–22. related to indirect immunofluorescence findings. Br
44. Ghandi N, Ghanadan A, Azizian MR, Hejazi P, J Dermatol. 1981;105(1):65–9.
Aghazadeh N, Tavousi P, et al. Paraneoplastic pem- 60. Lo Schiavo A, Ruocco E, Brancaccio G, Caccavale
phigus associated with inflammatory myofibroblas- S, Ruocco V, Wolf R. Bullous pemphigoid: etiology,
tic tumour of the mediastinum: a favourable response pathogenesis, and inducing factors: facts and contro-
to treatment and review of the literature. Australas J versies. Clin Dermatol. 2013;31(4):391–9.
Dermatol. 2015;56(2):120–3. 61. Person JR, Rogers RS 3rd. Bullous and cicatri-
45. Camisa C, Helm TN. Paraneoplastic pemphigus is cial pemphigoid. Clinical, histopathologic, and
a distinct neoplasia-induced autoimmune disease. immunopathologic correlations. Mayo Clin Proc.
Arch Dermatol. 1993;129(7):883–6. 1977;52(1):54–66.
46. Didona D, Paolino G, Richetta A, Cantisani C, 62. Shklar G, Meyer I, Zacarian SA. Oral lesions
Moliterni E, Calvieri S, et al. Paraneoplastic pem- in bullous pemphigoid. Arch Dermatol.
phigus: a trait d’union between dermatology and 1969;99(6):663–70.
oncology. Adv Mod Oncol Res. 2015;1(2):7. 63. Venning VA, Frith PA, Bron AJ, Millard PR,
47. Descamps V, Belaich S. Paraneoplastic pemphigus. Wojnarowska F. Mucosal involvement in bullous and
Presse Med. 1999;28(7):363–7. cicatricial pemphigoid. A clinical and immunopath-
48. Martel P, Joly P. Paraneoplastic pemphigus. Ann ological study. Br J Dermatol. 1988;118(1):7–15.
Dermatol Venereol. 2001;128(11):1256–9. 64. Williams DM. Vesiculo-bullous mucocutaneous dis-
49. Preisz K, Karpati S. Paraneoplastic pemphigus. Orv ease: benign mucous membrane and bullous pem-
Hetil. 2007;148(21):979–83. phigoid. J Oral Pathol Med. 1990;19(1):16–23.
50. Wang R, Li J, Wang M, Hao H, Chen X, Li R, et al. 65. Ghohestani RF, Nicolas JF, Rousselle P, Claudy
Prevalence of myasthenia gravis and associated AL. Identification of a 168-kDa mucosal antigen in
autoantibodies in paraneoplastic pemphigus and a subset of patients with cicatricial pemphigoid. J
their correlations with symptoms and prognosis. Br Invest Dermatol. 1996;107(1):136–9.
J Dermatol. 2015;172(4):968–75. 66. Carrozzo M, Dametto E, Fasano ME, Broccoletti R,
51. Leger S, Picard D, Ingen-Housz-Oro S, Arnault Carbone M, Rendine S, et al. Interleukin-4RA gene
JP, Aubin F, Carsuzaa F, et al. Prognostic fac- polymorphism is associated with oral mucous mem-
tors of paraneoplastic pemphigus. Arch Dermatol. brane pemphigoid. Oral Dis. 2014;20(3):275–80.
2012;148(10):1165–72. 67. Oyama N, Setterfield JF, Powell AM, Sakuma-
52. Heizmann M, Itin P, Wernli M, Borradori L, Bargetzi Oyama Y, Albert S, Bhogal BS, et al. Bullous
MJ. Successful treatment of paraneoplastic pem- pemphigoid antigen II (BP180) and its soluble extra-
phigus in follicular NHL with rituximab: report cellular domains are major autoantigens in mucous
of a case and review of treatment for paraneoplas- membrane pemphigoid: the pathogenic relevance
tic pemphigus in NHL and CLL. Am J Hematol. to HLA class II alleles and disease severity. Br J
2001;66(2):142–4. Dermatol. 2006;154(1):90–8.
140 M. Z. Wang et al.
68. Rabelo DF, Nguyen T, Caufield BA, Ahmed 82. Hayakawa T, Furumura M, Fukano H, Li X, Ishii
AR. Mucous membrane pemphigoid in two half- N, Hamada T, et al. Diagnosis of oral mucous mem-
sisters. The potential roles of autoantibodies to brane pemphigoid by means of combined serologic
beta4 integrin subunits and HLA-DQbeta1*0301. J testing. Oral Surg Oral Med Oral Pathol Oral Radiol.
Dermatol Case Rep. 2014;8(1):9–12. 2014;117(4):483–96.
69. Xu HH, Werth VP, Parisi E, Sollecito TP. Mucous 83. Messmer EM, Hintschich CR, Partscht K, Messer
membrane pemphigoid. Dent Clin N Am. G, Kampik A. Ocular cicatricial pemphigoid.
2013;57(4):611–30. Retrospective analysis of risk factors and complica-
70. Shklar G, McCarthy PL. Oral lesions of mucous tions. Ophthalmologe. 2000;97(2):113–20.
membrane pemphigoid. A study of 85 cases. Arch 84. Murrell DF, Marinovic B, Caux F, Prost C, Ahmed
Otolaryngol. 1971;93(4):354–64. R, Wozniak K, et al. Definitions and outcome mea-
71. Grattan CE, Small D, Kennedy CT, Scully C. Oral sures for mucous membrane pemphigoid: recom-
herpes simplex infection in bullous pemphigoid. mendations of an international panel of experts. J
Oral Surg Oral Med Oral Pathol. 1986;61(1):40–3. Am Acad Dermatol. 2015;72(1):168–74.
72. Maley A, Warren M, Haberman I, Swerlick R, 85. Rogers RS 3rd, Mehregan DA. Dapsone ther-
Kharod-Dholakia B, Feldman R. Rituximab com- apy of cicatricial pemphigoid. Semin Dermatol.
bined with conventional therapy versus conventional 1988;7(3):201–5.
therapy alone for the treatment of mucous mem- 86. Rogers RS, Sheridan PJ, Jordon RE. Desquamative
brane pemphigoid (MMP). J Am Acad Dermatol. gingivitis. Clinical, histopathologic, and immuno-
2016;74(5):835–40. pathologic investigations. Oral Surg Oral Med Oral
73. Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Pathol. 1976;42(3):316–27.
Cooper KD, Elder MJ, et al. The first international 87. Rogers RS 3rd, Sheridan PJ, Nightingale
consensus on mucous membrane pemphigoid: SH. Desquamative gingivitis: clinical, histopatho-
definition, diagnostic criteria, pathogenic factors, logic, immunopathologic, and therapeutic observa-
medical treatment, and prognostic indicators. Arch tions. J Am Acad Dermatol. 1982;7(6):729–35.
Dermatol. 2002;138(3):370–9. 88. Scully C, Lo Muzio L. Oral mucosal diseases:
74. Setterfield J, Shirlaw PJ, Kerr-Muir M, Neill S, mucous membrane pemphigoid. Br J Oral Maxillofac
Bhogal BS, Morgan P, et al. Mucous membrane Surg. 2008;46(5):358–66.
pemphigoid: a dual circulating antibody response 89. Serrano TL, et al. Mucous membrane pemphigoid:
with IgG and IgA signifies a more severe and persis- diagnosis and sequel. Int Arch Otorhinolaryngol.
tent disease. Br J Dermatol. 1998;138(4):602–10. 2014;18(S 01):1.
75. Ali S, Kelly C, Challacombe SJ, Donaldson AN, 90. Shetty S, Ahmed AR. Critical analysis of the use
Dart JK, Gleeson M, et al. Salivary IgA and IgG of rituximab in mucous membrane pemphigoid:
antibodies to bullous pemphigoid 180 noncol- a review of the literature. J Am Acad Dermatol.
lagenous domain 16a as diagnostic biomarkers in 2013;68(3):499–506.
mucous membrane pemphigoid. Br J Dermatol. 91. Taylor J, McMillan R, Shephard M, Setterfield J,
2016;174(5):1022–9. Ahmed R, Carrozzo M, et al. World Workshop on
76. Sacher C, Hunzelmann N. Cicatricial pemphi- Oral Medicine VI: a systematic review of the treat-
goid (mucous membrane pemphigoid): current ment of mucous membrane pemphigoid. Oral Surg
and emerging therapeutic approaches. Am J Clin Oral Med Oral Pathol Oral Radiol. 2015;120(2):161–
Dermatol. 2005;6(2):93–103. 71 e20.
77. Canizares MJ, Smith DI, Conners MS, Maverick 92. Yeh SW, Usman AQ, Ahmed AR. Profile of auto-
KJ, Heffernan MP. Successful treatment of mucous antibody to basement membrane zone proteins
membrane pemphigoid with etanercept in 3 patients. in patients with mucous membrane pemphigoid:
Arch Dermatol. 2006;142(11):1457–61. long-term follow up and influence of therapy. Clin
78. Rogers RS 3rd. Mucous membrane pemphi- Immunol. 2004;112(3):268–72.
goid. Dermatology at the millennium. Nashville: 93. Greer RO, McDowell JD, Hoernig G. Oral lichen
Parthenon Publishing; 1999. p. 5. planus: a premalignant disease? Pro Pathol Case
79. Hanson RD, Olsen KD, Rogers RS 3rd. Upper Rev. 1999;4:7.
aerodigestive tract manifestations of cicatricial pem- 94. Nagao T, Ikeda N, Fukano H, Hashimoto S,
phigoid. Ann Otol Rhinol Laryngol. 1988;97(5 Pt Shimozato K, Warnakulasuriya S. Incidence rates
1):493–9. for oral leukoplakia and lichen planus in a Japanese
80. Darling MR, Daley T. Blistering mucocutane- population. J Oral Pathol Med. 2005;34(9):532–9.
ous diseases of the oral mucosa – a review: part 1. 95. Farhi D, Dupin N. Pathophysiology, etiologic fac-
Mucous membrane pemphigoid. J Can Dent Assoc. tors, and clinical management of oral lichen pla-
2005;71(11):851–4. nus, part I: facts and controversies. Clin Dermatol.
81. Di Zenzo G, Carrozzo M, Chan LS. Urban legend 2010;28(1):100–8.
series: mucous membrane pemphigoid. Oral Dis. 96. Porter SR, Kirby A, Olsen I, Barrett W. Immunologic
2014;20(1):35–54. aspects of dermal and oral lichen planus: a review.
7 Oral Signs of Vesiculobullous and Autoimmune Disease 141
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 113. Assier H, Bastuji-Garin S, Revuz J, Roujeau
1997;83(3):358–66. JC. Erythema multiforme with mucous membrane
97. Lodi G, Scully C, Carrozzo M, Griffiths M, involvement and Stevens-Johnson syndrome are
Sugerman PB, Thongprasom K. Current controver- clinically different disorders with distinct causes.
sies in oral lichen planus: report of an international Arch Dermatol. 1995;131(5):539–43.
consensus meeting. Part 2. Clinical management and 114. Bastuji-Garin S, Rzany B, Stern RS, Shear NH,
malignant transformation. Oral Surg Oral Med Oral Naldi L, Roujeau JC. Clinical classification of cases
Pathol Oral Radiol Endod. 2005;100(2):164–78. of toxic epidermal necrolysis, Stevens-Johnson syn-
98. Au J, Patel D, Campbell JH. Oral lichen planus. Oral drome, and erythema multiforme. Arch Dermatol.
Maxillofac Surg Clin N Am. 2013;25(1):93–100.. vii 1993;129(1):92–6.
99. Ismail SB, Kumar SK, Zain RB. Oral lichen planus 115. Brown RS. Oral erythema multiforme: trends and
and lichenoid reactions: etiopathogenesis, diagnosis, clinical findings of a large retrospective: European
management and malignant transformation. J Oral case series. Oral Surg Oral Med Oral Pathol Oral
Sci. 2007;49(2):89–106. Radiol. 2016;121(6):681.
100. Laeijendecker R, Dekker SK, Burger PM, Mulder 116. Canavan TN, Mathes EF, Frieden I, Shinkai
PG, Van Joost T, Neumann MH. Oral lichen planus K. Mycoplasma pneumoniae-induced rash and muco-
and allergy to dental amalgam restorations. Arch sitis as a syndrome distinct from Stevens-Johnson
Dermatol. 2004;140(12):1434–8. syndrome and erythema multiforme: a systematic
101. Olson MA, Rogers RS 3rd, Bruce AJ. Oral lichen review. J Am Acad Dermatol. 2015;72(2):239–45.
planus. Clin Dermatol. 2016;34(4):495–504. 117. Celentano A, Tovaru S, Yap T, Adamo D, Aria
102. Parashar P. Oral lichen planus. Otolaryngol Clin N M, Mignogna MD. Oral erythema multiforme:
Am. 2011;44(1):89–107.. vi trends and clinical findings of a large retrospec-
103. Pavlovsky L, Israeli M, Sagy E, Berg AL, David M, tive European case series. Oral Surg Oral Med Oral
Shemer A, et al. Lichen planopilaris is associated Pathol Oral Radiol. 2015;120(6):707–16.
with HLA DRB1*11 and DQB1*03 alleles. Acta 118. Joseph RH, Haddad FA, Matthews AL, Maroufi A,
Derm Venereol. 2015;95(2):177–80. Monroe B, Reynolds M. Erythema multiforme after
104. Sugerman PB, Savage NW, Zhou X, Walsh LJ, orf virus infection: a report of two cases and litera-
Bigby M. Oral lichen planus. Clin Dermatol. ture review. Epidemiol Infect. 2015;143(2):385–90.
2000;18(5):533–9. 119. Joseph TI, Vargheese G, George D, Sathyan P. Drug
105. Wetter DA, Davis MD. Recurrent erythema mul- induced oral erythema multiforme: a rare and less
tiforme: clinical characteristics, etiologic asso- recognized variant of erythema multiforme. J Oral
ciations, and treatment in a series of 48 patients at Maxillofac Pathol. 2012;16(1):145–8.
Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 120. Kishore BN, Ankadavar NS, Kamath GH, Martis
2010;62(1):45–53. J. Varicella zoster with erythema multiforme in a
106. Huff JC, Weston WL, Tonnesen MG. Erythema young girl: a rare association. Indian J Dermatol.
multiforme: a critical review of characteristics, diag- 2014;59(3):299–301.
nostic criteria, and causes. J Am Acad Dermatol. 121. Patil B, Hegde S, Naik S, Sharma R. Oral blistering –
1983;8(6):763–75. report of two cases of erythema multiforme & litera-
107. Scully C, Bagan J. Oral mucosal diseases: ery- ture review. J Clin Diagn Res. 2013;7(9):2080–3.
thema multiforme. Br J Oral Maxillofac Surg. 122. Rogers RS 3rd. Pseudo-Behcet’s disease. Dermatol
2008;46(2):90–5. Clin. 2003;21(1):49–61.
108. Ayangco L, Rogers RS 3rd. Oral manifesta- 123. Samim F, Auluck A, Zed C, Williams PM. Erythema
tions of erythema multiforme. Dermatol Clin. multiforme: a review of epidemiology, pathogenesis,
2003;21(1):195–205. clinical features, and treatment. Dent Clin N Am.
109. Lozada-Nur F, Gorsky M, Silverman S Jr. Oral ery- 2013;57(4):583–96.
thema multiforme: clinical observations and treat- 124. Schwartz RA, McDonough PH, Lee BW. Toxic epi-
ment of 95 patients. Oral Surg Oral Med Oral Pathol. dermal necrolysis: part I. Introduction, history, clas-
1989;67(1):36–40. sification, clinical features, systemic manifestations,
110. Sokumbi O, Wetter DA. Clinical features, diagno- etiology, and immunopathogenesis. J Am Acad
sis, and treatment of erythema multiforme: a review Dermatol. 2013;69(2):173 e1–13.. quiz 185–6
for the practicing dermatologist. Int J Dermatol. 125. Mittmann N, Knowles SR, Koo M, Shear NH,
2012;51(8):889–902. Rachlis A, Rourke SB. Incidence of toxic epider-
111. Leaute-Labreze C, Lamireau T, Chawki D, Maleville mal necrolysis and Stevens-Johnson Syndrome in
J, Taïeb A. Diagnosis, classification, and manage- an HIV cohort: an observational, retrospective case
ment of erythema multiforme and Stevens-Johnson series study. Am J Clin Dermatol. 2012;13(1):49–54.
syndrome. Arch Dis Child. 2000;83(4):347–52. 126. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau
112. Bakis S, Zagarella S. Intermittent oral cyclosporin for JC, Revuz J, Wolkenstein P. SCORTEN: a severity-
recurrent herpes simplex-associated erythema multi- of-illness score for toxic epidermal necrolysis.
forme. Australas J Dermatol. 2005;46(1):18–20. J Invest Dermatol. 2000;115(2):149–53.
142 M. Z. Wang et al.
127. Lu N, Rai SK, Terkeltaub R, Kim SC, Menendez 143. Hietanen J, Reunala T. IgA deposits in the oral
ME, Choi HK. Racial disparities in the risk of mucosa of patients with dermatitis herpetifor-
Stevens-Johnson syndrome and toxic epidermal mis and linear IgA disease. Scand J Dent Res.
necrolysis as urate-lowering drug adverse events 1984;92(3):230–4.
in the United States. Semin Arthritis Rheum. 144. Katz SI. Dermatitis herpetiformis. Clinical, his-
2016;46(2):253–8. tologic, therapeutic and laboratory clues. Int J
128. Miliszewski MA, Kirchhof MG, Sikora S, Papp Dermatol. 1978;17(7):529–35.
A, Dutz JP. Stevens-Johnson syndrome and toxic 145. Nicolas ME, Krause PK, Gibson LE, Murray
epidermal necrolysis: an analysis of triggers and JA. Dermatitis herpetiformis. Int J Dermatol.
implications for improving prevention. Am J Med. 2003;42(8):588–600.
2016;129(11):1221–5. 146. Nisengard RJ, Chorzelski T, Maciejowska E, Kryst
129. Schwartz RA, McDonough PH, Lee BW. Toxic L. Dermatitis herpetiformis: IgA deposits in gingiva,
epidermal necrolysis: part II. Prognosis, sequelae, buccal mucosa, and skin. Oral Surg Oral Med Oral
diagnosis, differential diagnosis, prevention, and Pathol. 1982;54(1):22–5.
treatment. J Am Acad Dermatol. 2013;69(2):187 147. Sawant P, Kshar A, Byakodi R, Paranjpe
e1–16.. quiz 203–4 A. Immunofluorescence in oral mucosal dis-
130. Stern RS. Recurrence of Stevens-Johnson syn- eases –a review. Oral Surg Oral Med Oral Radiol.
drome and toxic epidermal necrolysis. JAMA. 2014;2(1):5.
2014;312(15):1590–1. 148. Chan LS, Regezi JA, Cooper KD. Oral manifesta-
131. Salmi TT, Hervonen K, Kautiainen H, Collin P, tions of linear IgA disease. J Am Acad Dermatol.
Reunala T. Prevalence and incidence of dermati- 1990;22(2 Pt 2):362–5.
tis herpetiformis: a 40-year prospective study from 149. Kelly SE, Frith PA, Millard PR, Wojnarowska F,
Finland. Br J Dermatol. 2011;165(2):354–9. Black MM. A clinicopathological study of mucosal
132. Bolotin D, Petronic-Rosic V. Dermatitis her- involvement in linear IgA disease. Br J Dermatol.
petiformis. Part I. Epidemiology, pathogenesis, 1988;119(2):161–70.
and clinical presentation. J Am Acad Dermatol. 150. Leonard JN, Wright P, Williams DM, Gilkes
2011;64(6):1017–24; quiz 1025–6 JJ, Haffenden GP, McMinn RM, et al. The rela-
133. Smith JB, Tulloch JE, Meyer LJ, Zone JJ. The inci- tionship between linear IgA disease and benign
dence and prevalence of dermatitis herpetiformis in mucous membrane pemphigoid. Br J Dermatol.
Utah. Arch Dermatol. 1992;128(12):1608–10. 1984;110(3):307–14.
134. Karpati S. Dermatitis herpetiformis: close to unrav- 151. Porter SR, Bain SE, Scully CM. Linear IgA disease
elling a disease. J Dermatol Sci. 2004;34(2):83–90. manifesting as recalcitrant desquamative gingivi-
135. Bolotin D, Petronic-Rosic V. Dermatitis herpetifor- tis. Oral Surg Oral Med Oral Pathol. 1992;74(2):
mis. Part II. Diagnosis, management, and prognosis. 179–82.
J Am Acad Dermatol. 2011;64(6):1027–33; quiz 152. O’Regan E, Bane A, Flint S, Timon C, Toner
1033–4 M. Linear IgA disease presenting as desquama-
136. Peters MS, McEvoy MT. IgA antiendomysial anti- tive gingivitis: a pattern poorly recognized in
bodies in dermatitis herpetiformis. J Am Acad medicine. Arch Otolaryngol Head Neck Surg.
Dermatol. 1989;21(6):1225–31. 2004;130(4):469–72.
137. Dieterich W, Laag E, Bruckner-Tuderman L, 153. Fine JD, Neises GR, Katz SI. Immunofluorescence
Reunala T, Kárpáti S, Zágoni T, et al. Antibodies and immunoelectron microscopic studies in cica-
to tissue transglutaminase as serologic markers tricial pemphigoid. J Invest Dermatol. 1984;82(1):
in patients with dermatitis herpetiformis. J Invest 39–43.
Dermatol. 1999;113(1):133–6. 154. Coelho S, Tellechea O, Reis JP, Mariano A,
138. Griffiths CE, Leonard JN, Fry L. Dermatitis herpeti- Figueiredo A. Vancomycin-associated linear IgA
formis exacerbated by indomethacin. Br J Dermatol. bullous dermatosis mimicking toxic epidermal
1985;112(4):443–5. necrolysis. Int J Dermatol. 2006;45(8):995–6.
139. Bardella MT, Fredella C, Saladino V, Trovato C, 155. Cohen DM, Bhattacharyya I, Zunt SL, Tomich
Cesana BM, Quatrini M, et al. Gluten intolerance: CE. Linear IgA disease histopathologically and
gender- and age-related differences in symptoms. clinically masquerading as lichen planus. Oral
Scand J Gastroenterol. 2005;40(1):15–9. Surg Oral Med Oral Pathol Oral Radiol Endod.
140. Economopoulou P, Laskaris G. Dermatitis herpeti- 1999;88(2):196–201.
formis: oral lesions as an early manifestation. Oral 156. Green ST, Natarajan S. Linear IgA disease and
Surg Oral Med Oral Pathol. 1986;62(1):77–80. oesophageal carcinoma. J R Soc Med. 1987;80(1):
141. Fraser NG, Kerr NW, Donald D. Oral lesions 48–9.
in dermatitis herpetiformis. Br J Dermatol. 157. Marinkovich MP, Taylor TB, Keene DR, Burgeson
1973;89(5):439–50. RE, Zone JJ. LAD-1, the linear IgA bullous derma-
142. Sansaricqa FC, Petronic-Rosic V. Dermatitis herpeti- tosis autoantigen, is a novel 120-kDa anchoring fila-
formis: what practitioners need to know. Pract Gastr. ment protein synthesized by epidermal cells. J Invest
2012;111:39–44. Dermatol. 1996;106(4):734–8.
7 Oral Signs of Vesiculobullous and Autoimmune Disease 143
158. McEvoy MT, Connolly SM. Linear IgA dermatosis: 174. Stephenson P, Lamey PJ, Scully C, Prime SS. Angina
association with malignancy. J Am Acad Dermatol. bullosa haemorrhagica: clinical and laboratory fea-
1990;22(1):59–63. tures in 30 patients. Oral Surg Oral Med Oral Pathol.
159. Ongole R, Praveen BN, editors. Textbook of oral 1987;63(5):560–5.
medicine, oral diagnosis and oral radiology. 2nd ed. 175. High AS, Main DM. Angina bullosa haemorrhagica:
New Delhi: Elsevier India; 2014. p. 924. a complication of long-term steroid inhaler use. Br
160. Sago J, Hall RP. Dapsone. Dermatol Ther. Dent J. 1988;165(5):176–9.
2002;15:11. 176. Kurban M, Kibbi AG, Ghosn S. Expanding the his-
161. Yomada M, Komai A, Hashimato T. Sublamina tologic spectrum of angina bullosa h emorrhagica:
densa-type linear IgA bullous dermatosis success- report of one case. Am J Dermatopathol.
fully treated with oral tetracycline and niacinamide. 2007;29(5):477–9.
Br J Dermatol. 1999;141(3):608–9. 177. Shashikumar B, Reddy RR, Harish M. Oral hem-
162. Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner- orrhagic blister: an enigma. Indian J Dermatol.
Tuderman L, Heagerty A, et al. The classification 2013;58(5):407.
of inherited epidermolysis bullosa (EB): report 178. Shoor H, Mutalik S, Pai KM. Angina bul-
of the Third International Consensus Meeting on losa haemorrhagica. BMJ Case Rep.
Diagnosis and Classification of EB. J Am Acad 2013;2013:bcr2013200352.
Dermatol. 2008;58(6):931–50. 179. Alikhan A, Felsten LM, Daly M, Petronic-Rosic
163. Intong LR, Murrell DF. Inherited epidermolysis bul- V. Vitiligo: a comprehensive overview Part
losa: new diagnostic criteria and classification. Clin I. Introduction, epidemiology, quality of life, diagno-
Dermatol. 2012;30(1):70–7. sis, differential diagnosis, associations, histopathol-
164. Youssefian L, Vahidnezhad H, Uitto J. Kindler syn- ogy, etiology, and work-up. J Am Acad Dermatol.
drome. In: Pagon RA, et al., editors. GeneReviews 2011;65(3):473–91.
(R). Seattle: University of Washington; 1993. 180. Nagarajan A, Masthan MK, Sankar LS,
165. Murauer EM, Koller U, Pellegrini G, De Luca M, Narayanasamy AB, Elumalai R. Oral manifestations
Bauer JW. Advances in gene/cell therapy in epider- of vitiligo. Indian J Dermatol. 2015;60(1):103.
molysis bullosa. Keio J Med. 2015;64(2):21–5. 181. Lawoyin D, Brown R, Reid E, Sam F, Obayomi
166. Osborn MJ, Starker CG, McElroy AN, Webber T. Concurrent presentation of cutaneous and oral soft
BR, Riddle MJ, Xia L, et al. TALEN-based gene tissue vitiligo: a case report and literature review. Int
correction for epidermolysis bullosa. Mol Ther. J Dent Sci. 2007;5:5.
2013;21(6):1151–9. 182. Dawber RP. Clinical associations of vitiligo.
167. Tolar J, McGrath JA, Xia L, Riddle MJ, Lees CJ, Postgrad Med J. 1970;46(535):276–7.
Eide C, et al. Patient-specific naturally gene-reverted 183. Bordere AC, Lambert J, van Geel N. Current and
induced pluripotent stem cells in recessive dys- emerging therapy for the management of vit-
trophic epidermolysis bullosa. J Invest Dermatol. iligo. Clin Cosmet Investig Dermatol. 2009;2:
2014;134(5):1246–54. 15–25.
168. Aberdam D, Aguzzi A, Baudoin C, Galliano MF, 184. Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo:
Ortonne JP, Meneguzzi G. Developmental expres- a comprehensive overview Part II: treatment options
sion of nicein adhesion protein (laminin-5) subunits and approach to treatment. J Am Acad Dermatol.
suggests multiple morphogenic roles. Cell Adhes 2011;65(3):493–514.
Commun. 1994;2(2):115–29. 185. Gawkrodger DJ, Ormerod AD, Shaw L, Mauri-
169. Asaka T, Akiyama M, Domon T, Nishie W, Natsuga Sole I, Whitton ME, Watts MJ, et al. Guideline
K, Fujita Y, et al. Type XVII collagen is a key for the diagnosis and management of vitiligo. Br J
player in tooth enamel formation. Am J Pathol. Dermatol. 2008;159(5):1051–76.
2009;174(1):91–100. 186. Whitton ME, Ashcroft DM, Gonzalez U. Therapeutic
170. Kudva P, Jain R. Periodontal manifestation of epi- interventions for vitiligo. J Am Acad Dermatol.
dermolysis bullosa: looking through the lens. J 2008;59(4):713–7.
Indian Soc Periodontol. 2016;20(1):72–4. 187. Al-Otaibi SR, Zadeh VB, Al-Abdulrazzaq AH,
171. Siegel DH, Ashton GH, Penagos HG, Lee JV, Feiler Tarrab SM, Al-Owaidi HA, Mahrous R, et al.
HS, Wilhelmsen KC, et al. Loss of kindlin-1, a Using a 308-nm excimer laser to treat vitiligo in
human homolog of the Caenorhabditis elegans Asians. Acta Dermatovenerol Alp Pannonica Adriat.
actin-extracellular-matrix linker protein UNC- 2009;18(1):13–9.
112, causes Kindler syndrome. Am J Hum Genet. 188. Ashok N, Karunakaran A, Singh P, Rodrigues J,
2003;73(1):174–87. Ashok N, Tarakji B, et al. Gingival vitiligo: report of
172. Wright JT. Oral manifestations in the epi- a case and review of the literature. Case Rep Dent.
dermolysis bullosa spectrum. Dermatol Clin. 2014;2014:874025.
2010;28(1):159–64. 189. Juhlin L, Olsson MJ. Improvement of vitiligo after
173. Wright JT, Fine JD, Johnson LB. Oral soft tissues oral treatment with vitamin B12 and folic acid
in hereditary epidermolysis bullosa. Oral Surg Oral and the importance of sun exposure. Acta Derm
Med Oral Pathol. 1991;71(4):440–6. Venereol. 1997;77(6):460–2.
144 M. Z. Wang et al.
190. Parsad D, Pandhi R, Juneja A. Effectiveness of oral 193. McHepange UO, Gao XH, Liu YY, Liu YB,
Ginkgo biloba in treating limited, slowly spreading Ma L, Zhang L, Chen HD. Vitiligo in North-
vitiligo. Clin Exp Dermatol. 2003;28(3):285–7. Eastern China: an association between muco-
191. Parsad D, Kanwar A. Oral minocycline in the treat- sal and acrofacial lesions. Acta Derm Venereol.
ment of vitiligo – a preliminary study. Dermatol 2010;90(2):136–40.
Ther. 2010;23(3):305–7. 194. Powell FC, Dicken CH. Psoriasis and vitiligo. Acta
192. Dave S, Thappa DM, Dsouza M. Clinical predictors Derm Venereol. 1983;63(3):246–9.
of outcome in vitiligo. Indian J Dermatol Venereol
Leprol. 2002;68(6):323–5.
Oral Signs of Viral Disease
8
Danielle N. Brown, Ramya Kollipara,
and Stephen Tyring
Herpes Simplex Infections the belt.” Primary inoculation with the virus
leads to local replication in epithelial cells.
Viral disease of the soft tissues of the mouth, oral Following the primary disease, the virus travels
pharynx, and salivary glands is often encountered in a retrograde fashion and becomes dormant in
in practice in both children and adults. The clini- sensory ganglia [4]. HSV-1 typically resides in
cal manifestations and implications dramatically the trigeminal ganglia, and HSV-2 typically
vary depending on the specific virus involved resides in the sacral ganglia [2]. Recurrence of
(Table 8.1). The prevalence of herpes simplex disease occurs when the virus travels in an
virus 1 (HSV-1) infection increases with age, anterograde fashion from the sensory ganglia
with rates as high as 90% in the seventh decade back to the epithelium and causes an outbreak of
of life. In contrast, since HSV-2 is primarily sex- grouped vesicles. Any type of physiological
ually transmitted, prevalence does not increase stress can lead to reactivation of the virus. HSV-1
linearly with age. In the US, HSV-2 prevalence is is primarily transmitted through oral secretions,
estimated to be around 22% for people aged and HSV-2 is primarily transmitted through gen-
12–70 years. HSV-2 is much more prevalent in ital secretions [2].
women and among groups who engage in high-
risk sexual behavior [1].
The Herpesviridae family contains over 80 rimary Acute Herpetic
P
herpes viruses [2]. HSV-1 and HSV-2 are envel- Gingivostomatitis
oped, double-stranded DNA viruses [3]. HSV-1
is referred to as causing disease “above the belt,” Primary herpetic gingivostomatitis (PHGS)
while HSV-2 classically causes disease “below occurs as a result of initial exposure to the herpes
virus. Clinical manifestations can include general
D. N. Brown malaise, fever, nausea, vomiting, and lymphade-
Department of Pediatrics, Massachusetts General nopathy. Following these symptoms, vesiculoul-
Hospital for Children, Boston, MA, USA cerative lesions appear on the palate, tongue, lips,
R. Kollipara (*) gingiva, or buccal mucosa (Fig. 8.1) [4]. The ini-
Dermatology, Cosmetic Laser Dermatology, tial lesions rupture and coalesce to form painful
San Diego, CA, USA round, superficial ulcers. The gingiva will appear
e-mail: rkollipara@clderm.com
edematous and inflamed. PHGS occurs most
S. Tyring commonly in young children and young adults
Department of Dermatology, University of Texas
Health Sciences Center at Houston, [4]. The differential diagnosis for PHGS includes
Houston, TX, USA impetigo, hand-foot-mouth disease, herpangina,
Virus Oral signs Other signs and symptoms Differential diagnosis Treatment
Primary acute HSV Vesiculoulcerative lesions on the Malaise, fever, nausea, Impetigo, HFMD, herpangina, Oral antivirals,
herpetic palate, tongue, lips, gingiva, buccal vomiting, EM, pemphigus vulgaris, antipyretics; topical
gingivostomatitis mucosa; superficial, painful ulcers; lymphadenopathy acute necrotizing ulcerative anesthetics
inflamed gingiva gingivitis
Herpes labialis and HSV Grouped vesicles that rupture and Prodrome of tingling, Aphthous ulcers, intraoral Oral or topical antivirals;
recurrent intraoral coalesce to form ulcers burning, and pain herpes zoster topical anesthetics
herpes
Herpes zoster VZV Unilateral painful macular, papular, Unilateral dermatomal pain EM, lupus, insect bites, Oral antivirals, topical or
vesicular; V2: lesions can involve rosacea, linear IgA bullous oral anesthetics
malar region, temporal region, dermatosis
lateral nose, upper lip, upper palate;
V3: tongue, buccal mucosa, lower
lip, and lower third of the face
Varicella VZV Vesicles and ulcers on the tongue,Constitutional symptoms, Staphylococcus aureus Oral acyclovir
palate, gingiva, buccal mucosa, ormaculopapular then infection, contact dermatitis,
oropharynx vesicular exanthem (“dew insect bite, enterovirus
drops on rose petal” infection
Hand, foot, and Typically, Vesicles on the palate, tongue, and Erythematous macules that Aphthous ulcers, HSV Symptomatic treatment
mouth disease coxsackievirus A16 and buccal mucosa that rupture and form form white vesicles on gingivostomatitis, herpangina,
enterovirus 71 shallow ulcers with a hands, feet, and buttocks oral varicella
pseudomembrane and pink halo
Herpangina Coxsackievirus group A Vesicles on soft palate, tonsillar Constitutional symptoms, Aphthous ulcers, HSV-1 Supportive care
serotypes, less pillars, uvula, posterior oropharynx, encephalitis, aseptic infection
commonly coxsackie B, fauces progressing to ulcers with a meningitis
echovirus, and pseudomembrane and pink halo
enterovirus
Molluscum Poxvirus Pale or erythematous papules on the Asymptomatic, skin- None reported in literature Cryotherapy, curettage,
contagiosum lips, buccal mucosa, gingiva, palatal colored papules with cantharidin,
mucosa, or retromolar region central depression podophyllotoxin
Common warts HPV genotypes 1, 2, 4, White, firm papules or nodules on Verrucous papules Squamous cell papillomas or Surgical excision,
and 7 the hard palate, vermillion border, involving the skin condyloma acuminata podophyllin
gingiva, anterior tongue, or lips
D. N. Brown et al.
Condyloma HPV genotypes 6, 11 Pink or white sessile or Lesions similar in Leukoplakia Cryosurgery,
acuminatum pendunculated papules or morphology involving the electrocautery, surgical
cauliflower-like lesions involving genital mucosa excision, laser excision
the palate, lips, labial mucosa, or
tongue
Focal epithelial HPV genotypes 13, 32 Intraoral papules on the tongue, None Verruca vulgaris, condyloma Surgical excision,
hyperplasia labial mucosa, buccal mucosa acuminata cryotherapy, CO2 laser
therapy
Infectious EBV Pharyngitis, petechial hemorrhages Posterior cervical HIV, CMV infection, Antipyretics
mononucleosis of the soft palate and oropharynx, lymphadenopathy, toxoplasmosis, streptococcal
8 Oral Signs of Viral Disease
Virus Oral signs Other signs and symptoms Differential diagnosis Treatment
Rubella Rubivirus Red macules or petechiae on the Erythematous Measles, mononucelosis Symptomatic therapy
soft palate (Forscheimer’s spots) maculopapular rash,
postauricular, cervical,
suboccipital
lymphadenopathy,
constitutional symptoms
Mumps Paramyxoviridae Painful unilateral or bilateral Constitutional symptoms, EBV, parainfluenza types 1 Analgesics, antipyretics,
parotitis (ear lobe elevation that epididymo-orchitis, and 3, influenza A, hot or cold compresses
conceals angle of mandible), bilateral orchitis, coxsackievirus, adenovirus,
edematous and inflamed opening of oophoritis, encephalitis, parvovirus B19, lymphocytic
Stensen’s duct, bilateral deafness, pancreatitis choriomeningitis virus, HIV,
submandibular or sublingual drugs, malnutrition
salivary gland inflammation
Measles Morbillivirus Koplik spots (white-gray papules) at Cough, coryza, Parovirus B19 infection Vitamin A
the posterior buccal mucosa conjunctivitis,
erythematous,
maculopapular exanthem
Abbreviations: HSV herpes simplex virus, VZV varicella zoster virus, HPV human papillomavirus, EBV Epstein-Barr virus, HIV human immunodeficiency virus, HHV-8 human
herpesvirus 8, CMV cytomegalovirus, HFMD hand, foot, and mouth disease, EM erythema multiforme
D. N. Brown et al.
8 Oral Signs of Viral Disease 149
and coalesce to form superficial ulcers. The dif- papular, vesicular, and pustular. The pustules
ferential diagnosis for RIH includes aphthous eventually crust over. The rash is located in a uni-
ulcers and intraoral herpes zoster [2]. Aphthous lateral dermatomal distribution. The lesions typi-
ulcers do not have a vesicular stage and are most cally cause intense burning pain but may also
commonly found on nonkeratinized epithelium cause dysesthesia or itching [15].
[8]. To differentiate herpes zoster infection from Herpes zoster infection of the trigeminal
RIH, immunohistochemical studies, direct nerve, specifically the maxillary or mandibular
immunofluorescence studies, or HSV-1 and branches, occurs in roughly 20% of cases [16].
HSV-2 PCR analysis must be conducted [2]. Patients may initially present with tooth pain or
Treatment for both RHL and RIH in immuno- unilateral dermatomal pain. When infection of
competent individuals is largely based on reducing the left or right maxillary nerve (V2) occurs,
symptomatology through the use of ice or topical lesions may appear unilaterally on the mid-face
anesthetics [6]. Antiviral therapy may reduce viral to include the temporal region, malar region, lat-
shedding and the duration of disease [9]. FDA- eral nose, upper lip, and upper palate [17].
approved therapies for RHL include topical acy- Infection of the mandibular branch of the trigem-
clovir, penciclovir, and docosanol as well as oral inal nerve (V3) will result in unilateral lesions on
acyclovir, famciclovir, and valacyclovir [10]. the tongue, buccal mucosa, lower lip, and lower
third of the face (Fig. 8.4) [18].
The differential diagnosis for herpes zoster
Herpes Zoster includes EM, lupus, insect bites, rosacea, or linear
IgA bullous dermatosis [19]. Biopsy can be per-
Herpes zoster, an infection caused by varicella formed to differentiate when clinical evaluation is
zoster virus (VZV), is commonly referred to as not diagnostic [19]. PCR analysis or direct immu-
shingles. Prior to the introduction of Zostavax, nofluorescence studies can be used to d ifferentiate
after 45 years of age, incidence linearly increased herpes zoster from HSV-1 or -2 infections. Herpes
to reach a rate of about 10.7 per 1000 in 80-year- zoster involving the face should be treated
old individuals [11]. Zostavax has been FDA with antiviral medications. FDA-approved
approved for individuals over the age of 50 and is medications for the treatment of herpes zoster
currently recommended by the Advisory include acyclovir, valacyclovir, and famciclovir
Committee on Immunization Practices for all
individuals over the age of 60. Vaccination has
been shown to reduce zoster incidence of disease
by over 60% in individuals 65 years or older,
bringing the incidence to 5.42 per 1000 [12].
VZV, also classified as human herpes virus 3
(HHV-3), is an enveloped, double-stranded DNA
virus. VZV, like HSV1 and HSV2, is an alphaher-
pesvirus and, thus, initially infects mucoepithe-
lial cells before residing latent in neurons. The
virus is responsible for causing chicken pox in
primary infection [13]. After primary infection,
the virus travels to remain latent in sensory and
cranial nerve ganglia. Reactivation of the virus
causes herpes zoster infection, a painful rash typ-
ically limited to 1–3 dermatomes [14].
Herpes zoster manifests with a 2–3-day pro-
dromal stage of localized tingling and burning Fig. 8.4 Pathologic changes seen on right unilateral side
of elderly male patient’s tongue and chin, representing a
pain prior to development of a rash. The rash herpes outbreak due to varicella zoster virus (VZV).
evolves through the following stages: macular, (Courtesy of CDC/Robert E. Sumpter)
8 Oral Signs of Viral Disease 151
cases are in children under 10 years old but can with widespread vesicubullous eruption, “eczema
also occur in older children and in adults exposed coxsackium,” purpuric lesions, or an eruption
to children in child care [34]. Approximately similar to Gianotti-Crosti and has a higher inci-
11% of exposed adults are infected with HFMD, dence of onychomadesis [35].
and 1% of these adults are symptomatic [35]. In If cutaneous lesions are not present, then the
the last 16 years, there have been several large oral HFMD lesions could be mistaken for aph-
outbreaks in China and in the United States [34]. thous ulcers, HSV gingivostomatitis, herpangina,
HFMD is caused by viruses in the enterovirus or oral varicella [37]. The diagnosis of HFMD is
genus, typically coxsackievirus A16 and enterovi- primarily clinical, but laboratory confirmation
rus 71, and sometimes A5, A6, A7, A9, A10, B2, can be used in severe or atypical cases. Laboratory
and B5 [36]. Of note, in recent years, there have testing options include viral culture, PCR analy-
been outbreaks of HFMD in adults caused by cox- sis to detect viral RNA, and IgM-capture enzyme
sackievirus A6 (CVA6). Outbreaks have occurred linked immunosorbent assay (ELISA). Samples
in Europe, Asia, and the United States [35]. HFMD can be collected from the serum, stool, throat, or
is spread via orofecal and respiratory routes [37]. vesicles. HFMD is self-limited and treatment is
The incubation period is 3–5 days [34]. symptomatic. The CDC recommends frequent
HFMD begins with a prodromal phase of handwashing after toileting, disinfecting used
fever, malaise, abdominal pain, and myalgia. surfaces, and avoiding contact with infected
Oral lesions on the palate, tongue, and buccal utensils to prevent spread of HFMD [34].
mucosa appear at the same time or a short time
before cutaneous lesions. Mucosal lesions begin
as vesicles that eventually rupture, leading to the Herpangina
development of shallow ulcers (Fig. 8.6). These
ulcers have a pseudomembrane and are encircled Herpangina is a benign viral illness with primar-
by an erythematous halo [6]. Cutaneous lesions ily oral manifestations. It is caused by many of
on the hands, feet, and buttocks present as the coxsackievirus group A serotypes (1–6, 8, 10,
3–7 mm erythematous, elliptical macules that and 22) and uncommonly by coxsackievirus
rapidly transform into pale, white, oval vesicles. group B, echovirus, and enterovirus 71 [6, 38].
These lesions can be asymptomatic, tender, or These viruses are transmitted via contaminated
painful. The vesicles ulcerate/encrust over droplets of saliva, but fecal-oral transmission can
2–3 days and heal without any scarring in 1 week also occur. After oral infection, the virus multi-
[37]. CVA6 tends to cause more severe disease plies within the cells of the lower gastrointestinal
tract and eventually viremia ensues [38].
Herpangina commonly occurs in the summer and
fall months [6]. It affects children less than
5 years old and, rarely, adults [38]. Outbreaks
have occurred in daycare centers, military com-
munities, schools, and summer camps.
In the prodromal phase of herpangina, patients
manifest high fever, malaise, headache, pharyn-
gitis, and dysphagia. Soon after, small vesicles
appear on the soft palate, tonsillar pillars, uvula,
posterior oropharynx, and fauces and eventually
ulcerate (Fig. 8.7). These ulcers are topped by a
pseudomembrane and with an erythematous halo.
Fig. 8.6 Oropharyngeal ulcers associated with hand,
foot, and mouth disease due to infection with coxsackievi-
Symptoms resolve in 1 week. Complications of
rus. (Reprinted from Silverman and Miller [124], with herpangina are rare including encephalitis and
permission from Elsevier) aseptic meningitis [6, 38].
8 Oral Signs of Viral Disease 153
Fig. 8.10 Condyloma acuminata found on the lateral Fig. 8.11 Focal epithelial hyperplasia (Heck’s disease)
border of the tongue. (Reprinted from Pringle [46], with manifesting as multiple mucosal-colored papules on the
permission from Elsevier and Thomas Daley, DDS, MSc, tongue. (Reprinted from Lynch [6], with permission from
London, Ontario, Canada) Elsevier)
diagnoses [50]. The development of squamous on the tongue, labial mucosa, and buccal mucosa
cell carcinoma has been associated with condy- [46, 47].
loma acuminata when the lesions contain high- The differential diagnosis for FEH includes
risk HPV genotypes. Oral condyloma acuminata both verruca vulgaris and condyloma acuminata.
should be removed via cryosurgery, electrocau- The clinician should screen for HPV 6 and 11 via
tery, surgical excision, or laser excision [49]. an in vitro nucleic acid hybridization assay to
Patients must be monitored for recurrence [50]. rule out condyloma acuminata. Condyloma acu-
minata, if diagnosed in childhood, should raise
suspicion for sexual abuse [54]. In children, a full
ocal Epithelial Hyperplasia (Heck’s
F physical exam should be conducted to look for
Disease) signs of sexual abuse. If the exam does not reveal
signs of sexual abuse or infection with sexually
Focal epithelial hyperplasia (FEH), or Heck’s transmitted HPV genotypes, and the child’s eth-
disease, is caused by infection with members of nicity is one known to have a high prevalence of
the alpha-HPV genus, specifically genotypes 13 the disease, then the diagnosis of FEH can be
and 32 [45]. Transmission of the virus is most made [54]. Lesions will naturally regress in an
likely via direct contact with the oral mucosa average of 18 months, and, typically, treatment is
[51]. It is most prevalent in the Native American, unnecessary [54]. The lesions may be removed
Mexican, and Eskimo populations, specifically through surgical excision, cryotherapy, or CO2
in children with the HLA-DR4 allele [52]. FEH laser therapy. Additionally, there are reports in
is found in children and young adults and is the literature of the use of topical interferon,
more prevalent in females than males [53]. imiquimod, electrocoagulation, and electrodessi-
While other disease manifestations of HPV can cation for the treatment of FEH [51].
be found on numerous epithelial surfaces, FEH
is specific to the oral cavity and is asymptom-
atic. The disease manifests as intraoral papules Epstein Barr Virus
that give the mucosa a cobblestoned appearance (Infectious Mononucleosis)
(Fig. 8.11) [46]. Each individual lesion varies in
diameter from 0.3 to 1 cm; however, FEH typi- Ninety-five percent of adults worldwide are
cally manifests as multiple, grouped lesions of seropositive for Epstein-Barr virus (EBV), the
varying size [28]. The papules are similar in etiologic agent of infectious mononucleosis. In
color to that of the oral mucosa. FEH is found developed countries, half of the population is
156 D. N. Brown et al.
It is recommended that all HIV-positive individu- a clinical diagnosis; however, definitive diagnos-
als receive antiretroviral therapy (ART) to pre- tic methods include exfoliative cytology via
vent transmission and progression of the disease. scraping or biopsy of the lesion. Following
Oral manifestations of HIV disease include oral obtainment of tissue, EBV is detected from cells
hairy leukoplakia, aphthous ulcers, immune through PCR, immunohistochemistry, or in situ
thrombocytopenic purpura, salivary gland dis- hybridization [72]. OHL is a chronic condition in
ease, and Kaposi’s sarcoma. which the plaques heal and reappear over time.
Treatment is unnecessary; however, the plaques
may regress with initiation of ART or with high-
Oral Hairy Leukoplakia dose acyclovir or ganciclovir [73].
subsequent studies such as bronchoscopy or chest may present similarly to EBV mononucleosis,
CT based on the patient’s symptoms. KS is not with flu-like symptoms, cervical lymphadenopa-
curable but may regress with HAART treatment thy, and low-grade hepatitis [5].
[95]. Intraoral lesions may be treated via exci- In the immunocompromised, specifically
sion, sclerotherapy, intralesional vincristine, or transplant recipients, cancer patients, or individu-
radiotherapy [94]. Systemic chemotherapy with als with HIV/AIDS, CMV infection can manifest
interferon, sirolimus, or liposomal anthracyclines as retinitis, gastrointestinal, and CNS disease
has been FDA approved for the treatment of KS [99]. Transplant patients may present with “CMV
and is reserved for severe, progressive disease syndrome,” or hepatomegaly, fever, leukopenia,
and cases with symptomatic involvement of the and arthralgias [100]. CMV is the most common
viscera or lungs [95]. cause of infection in transplant recipients [101].
In these patients, CMV can infect any organ [99].
In HIV-positive individuals, the highest risk of
Cytomegalovirus CMV infection occurs when the CD4+ cell count
drops below 50 cells/μL. The most common
The prevalence of CMV ranges from 50% to CMV-associated infection in this population is
100% in the general population [96]. In immuno- retinitis [102]. CMV prophylaxis is not currently
competent individuals, the majority of these standard of care, but may be used for HIV-
infections are asymptomatic; however, in neo- positive patients with CD4 <50 [103]. HAART is
nates and the immunosuppressed, CMV infection the most effective method of preventing CMV in
causes significant morbidity and mortality [96]. this population [102]. Finally, CMV is the most
CMV is the leading infectious cause of congeni- common infectious cause of fetal abnormalities.
tal abnormalities and of nongenetic deafness. Congenital CMV causes pneumonia and gastro-
Congenital infection with CMV may lead to mor- intestinal, ocular, and neurologic disease via
tality or severe neurologic impairment [97]. maternal transmission.
CMV is a member of the Herpesviridae fam- Oral lesions of CMV in the immunocompro-
ily. Viral transmission can occur through blood, mised present as painful, punched-out lesions on
genital fluid, breast milk, or saliva [98]. After pri- various oral surfaces (Fig. 8.18) [104]. These
mary infection, the virus remains dormant in ulcerations appear as well-circumscribed lesions
lymphocytes and salivary glands. Infection in without induration. Unlike aphthous ulcers, CMV
healthy individuals is typically asymptomatic but ulcers do not have a surrounding erythematous
8 Oral Signs of Viral Disease 161
halo. CMV lesions are most commonly found on then disseminates to multiple organs via the lym-
the labial mucosa, tongue, buccal mucosa, gin- phatic system [106]. The incubation period for
giva, or oropharynx [69]. In the immunosup- rubella is 14–15 days prior to the onset of fever
pressed, the presence of oral ulcers should always and rash. The rubella virus is shed for 2 weeks,
raise suspicion for CMV infection. Oral ulcer- starting 1 week prior to onset of the rash [109].
ation in the immunocompromised may be second- Infection rates are highest in the late winter and
ary to neoplasm, aphthous ulcer, or protozoan, early spring [106].
bacterial, fungal, and viral (including HSV and Fifty percent of postnatal infections do not
CMV) infections [77]. have clinical manifestations. In those with clini-
Diagnosis based on clinical findings is insuf- cal manifestations, a prodromal phase with
ficient. Histopathology, revealing characteristic headache, sore throat, anorexia, nausea, fever,
cells with intranuclear “owl’s eye” inclusions, is lethargy, and eye pain may be present.
the most sensitive diagnostic method [104, 105]. Postauricular, cervical, and suboccipital lymph-
Diagnosis of oral CMV infection is pertinent as it adenopathy develops 1–5 days before the exan-
may be the initial presentation of systemic CMV them appears. The exanthem, described as an
infection in the immunocompromised individual erythematous maculopapular rash, begins on the
[104]. In the HIV/AIDS population, oral ulcers face and then spreads to the rest of the body in
are commonly coinfected with both HSV and 24 h. The rash recedes on the 3rd day [106]. An
CMV [105]. Additionally, in HIV-positive indi- enanthem, consisting of red macules or petechiae
viduals, oral CMV lesions are highly suggestive on the soft palate (Forschheimer spots), may be
of very low CD4+ counts and may allow for a present (Fig. 8.19) [110].
diagnosis of AIDS. Antiviral medications, pri- Rubella can be diagnosed via IgM antibody
marily ganciclovir, valganciclovir, and cidofovir, detection assay (most common) or demonstration
are used to treat CMV infection [101]. of a fourfold increase in IgG antibody or viral
Immunosuppressed patients may benefit from culture of a nasopharyngeal specimen. The IgM
prophylactic antiviral therapy. antibody can be detected by assays 4 days after
the exanthem appears and can remain in the
serum for 6–8 weeks [111]. Rubella is treated
Rubella symptomatically [106].
body fluids and symptoms of coryza, cough, and the region. Detection of serum measles IgM anti-
sneezing are the most severe [122]. body or a fourfold increase in serum measles IgG
The clinical manifestations of measles can be antibody titer can confirm the diagnosis of mea-
grouped into the prodromal and exanthemous sles [122]. The WHO recommends daily vitamin
phases. Signs and symptoms of the prodromal A therapy for children with measles [120].
phase include fever of 39–40 °C, malaise, This chapter has provided an overview of the
anorexia, coryza, conjunctivitis, rhinitis, cough, epidemiology, pathogenesis, differential diagno-
pharyngitis, and tracheitis. These symptoms sis, diagnostic studies, and treatment for viral eti-
worsen progressively until the classic erythema- ologies causing oral disease manifestations.
tous, maculopapular rash of measles appears. Clinical criteria for the diagnosis of oral viral dis-
The rash begins on the face and behind the ears ease include the precise location, size, color, and
and then spreads to the trunk and extremities morphology of the oral lesions. The specific pop-
before resolving in 3–5 days [122]. ulation group and the presence or absence of both
The oral sign of measles is Koplik spots, systemic and localized prodromal symptoms
which are white-gray papules that begin on the associated with each viral disease serve as diag-
posterior buccal mucosa and spread to the rest of nostic clues. As described in this chapter, subtle
the oral mucosa (Fig. 8.20). Occasionally, the differentiating characteristics of viral oral disease
mucosal lips may be involved. Koplik spots manifestations serve as tools for diagnosis.
appear in the prodromal stage, but it is unclear if
they appear at the beginning of the prodromal
phase or just 1 or 2 days before the exanthemous References
phase. They are noted to last until the onset of the
exanthemous phase [123]. Of note, although 1. Smith J, Robinson N. Age specific prevalence of
Koplik spots are considered pathognomonic for infection with herpes simplex virus types 2 and I: a
measles, they have also been noted in parvovirus global review. J Infect Dis. 2002;186(Suppl 1):3–28.
2. Fatahzadeh M. Human herpes simplex virus infec-
B19 infection [123]. tions: epidemiology, pathogenesis, symptomatology,
Physicians should consider measles, if a diagnosis and management. J Am Acad Dermatol.
patient demonstrates the classical signs and 2007;57(5):737–63.
symptoms, especially if there is an outbreak in 3. Roizman B. The organization of the herpes simplex
virus genome. Ann Rev Genet. 1979;13:25–7.
4. Arduino P, Porter S. Herpes simplex virus type 1
infection: overview on relevant clinico-pathologic
features. J Oral Pathol Med. 2008;37:107–21.
5. Stoopler E. Oral herpetic infections (HSV 1-8). Dent
Clin N Am. 2005;49(1):15–29.
6. Lynch D. Oral viral infections. Clin Dermatol.
2000;18(5):619–28.
7. Simmons A. Clinical manifestations and treatment
considerations of herpes simplex virus infection. J
Infect Dis. 2002;186(Suppl 1):71–7.
8. Eisen D. The clinical characteristics of intraoral her-
pes simplex virus infections in 52 immunocompe-
tent patients. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod. 1998;86:432–7.
9. Leflore S, Anderson P, Fletcher C. A risk-benefit
evaluation of acyclovir for the treatment and pro-
phylaxis of herpes simplex infections. Drug Saf.
2000;23(2):131–42.
10. Brady R, Bernstein D. Treatment of herpes simplex
infections. Antivir Res. 2004;61:73–81.
Fig. 8.20 Koplik spots of measles shown as white-gray 11. Yawn BP, Saddier P, Wollan PC, St Sauver JL,
papules on the buccal mucosa. (Reprinted from Patel et al. Kurland MJ, Sy LS. A population-based study of the
[127], with permission from Elsevier) incidence and complication rates of herpes zoster
164 D. N. Brown et al.
before zoster vaccine introduction. Mayo Clin Proc. 28. Heerden V. Oral manifestations of viral infections. S
2007;82:1341–9. A Fam Pract. 2006;48(8):20–4.
12. Oxman M, Levin MJ, Johnson GR, Schmader KE, 29. Na SY, Son YM, Lee HY, Baek JO, Roh JY, Lee
Straus SE, Gelb LD, et al. A vaccine to prevent her- JR. A case of varicella combined with hand-foot-
pes zoster and postherpetic neuralgia in older adults. mouth disease in a healthy child. Ann Dermatol.
N Engl J Med. 2005;352:2271–84. 2009;21(1):98–101.
13. Gringe B. Herpesviruses: latency and reactivation- 30. Kolokotronis A, Louloudiadis K, Fotiou G, Matiais
viral strategies and host response. J Oral Microbiol. A. Oral manifestations of infections due to varicella
2013;25(5). https://doi.org/10.3402/jom.v5i0.22766. zoster virus in otherwise healthy children. J Clin
14. Gilden D, Cohrs R, Mahalingam R. Clinical and Pediatr Dent. 2001;25(2):107–12.
molecular pathogenesis of varicella virus infection. 31. American Academy of Pediatrics Committee on
Viral Immunol. 2004;16(3):243–58. Infectious Diseases. The use of oral acyclovir in
15. Cohen J. Herpes zoster. N Engl J Med. otherwise healthy children with varicella. Pediatrics.
2013;369:255–63. 1993;91(3):674–6.
16. Greenberg MS. Ulcerative, vesicular, and bul- 32. Belay ED, Bresee JS, Holman RC, Khan AS,
lous lesions. In: Greenberg MS, Glick M, editors. Shahriari A, Schonberger LB. Reye’s syndrome in
Burket’s oral medicine: diagnosis and treatment. the United States from 1981 through 1997. N Engl J
10th ed. Ontario: Decker; 2003. p. 50–84. Med. 1999;340:1377–82.
17. Manjunath BR, Chidambar YS, Telkar S, Japatti S, 33. Wallace MR, Bowler WA, Murray NB, Brodine SK,
Choudary L, Dodamani A. Oral complications of Oldfield EC 3rd. Treatment of adult varicella with
herpes zoster infection- report of 3 cases. Int J Dent oral acyclovir: a randomized, placebo-controlled
Clin. 2010;2(4):70–3. trial. Ann Intern Med. 1992;117(5):358–63.
18. Srikrishna K, Prabhat MPV, Balmuri P, Sudhakar 34. Repass G, Palmer WC, Stancampiano FF. Hand,
S, Ramaraju D. Herpes zoster: report of a treated foot, and mouth disease: identifying and manag-
case with review of literature. J Ind Acad Oral Med ing an acute viral syndrome. Cleve Clin J Med.
Radiol. 2012;24(1):51–5. 2014;8199:537–43.
19. Hoyt B, Bhawan J. Histological spectrum of cuta- 35. Downing C, Ramirez-Fort MK, Doan HQ, Benoist
neous herpes infections. Am J Dermatopathol. F, Oberste MS, Khan F, et al. Coxsackievirus A6
2014;36(8):609–19. associated hand, foot and mouth disease in adults:
20. Wood M, Johnson R, McKendrick M, Taylor J, clinical presentation and review of the literature. J
Mandal B, Crooks J. A randomized trial of acyclovir Clin Virol. 2014;60:381–6.
for 7 days or 21 days with and without prednisolone 36. Stewart CL, Chu EY, Introcaso CE, Schaffer A,
for treatment of acute herpes zoster. N Engl J Med. James WD. Coxsackievirus A6-induced hand-foot-
1994;330:896–900. mouth disease. JAMA Dermatol. 2013;149(12):
21. Lapolla W, Digiorgio C, Haitz K, Magel G, 1419–21.
Grady J, Lu W, Tyring S. Incidence of posther- 37. Mehta KI, Mahajan VK. Hand foot and mouth dis-
petic neuralgia after combination treatment with ease. Indian Pediatr. 2010;46:345–6.
gabapentin and valacylcovir in patients with acute 38. Slots J. Oral viral infections of adults. Periodontology.
herpes zoster: open-label study. Arch Dermatol. 2000;49:60–86.
2011;147(8):901–7. 39. De Carvalho CH, De Andrade AL, de Oliverira DH,
22. Wharton M. The epidemiology of varicella- Lima E, de Silveira EJ, de Medeiros AM. Intraoral
zoster virus infections. Infect Dis Clin N Am. molluscum contagiosum in a young immuno-
1996;10(3):571–81. computent patient. Oral Maxillofacial Pathol.
23. Kilgore PE, Kruszon-Moran D, Seward JF, Jumaan 2012;114(1):e57–60.
A, Van Loon FP, Forghani B, et al. Varicella in 40. Dohil MA, Lin P, Lee J, et al. The epidemiology
Americans from NHANES III: implications for of molluscum contagiosum in children. J Am Acad
control through routine immunization. J Med Virol. Dermatol. 2006;54:47–54.
2003;70(Suppl 1):111–8. 41. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing
24. Finger R, Hughes JP, Meade BJ, Pelletier AR, H, Favreau AJ, et al. Combined immunodeficiency
Palmer CT. Age-specific incidence of chickenpox. associated with DOCK8 mutations. N Engl J Med.
Public Health Rep. 1994;109(6):750–5. 2009;361:2046–55.
25. Marin M, Meissner HC, Seward JF. Varicella pre- 42. Braue A, Ross G, Varigos G, Kelly H. Epidemiology
vention in the United States: a review of successes and impact of childhood molluscum contagiosum:
and challenges. Pediatrics. 2008;122(3):e744–51. a case series and critical review of the literature.
26. Shapiro ED, Vazquez M, Esposito D, Holabird Pediatr Dermatol. 2005;22:287–94.
N, Steinberg SP, Dziura J, et al. Effectiveness of 2 43. Kreimer AR, Bhatia RK, Messeguer AL, González
doses of varicella vaccine in children. J Infect Dis. P, Herrero R, Giuliano AR. Oral human papil-
2011;203(3):312–5. lomavirus in healthy individuals: a systematic
27. Arvin A. Varicella-zoster virus. Clin Microbiol Rev. review of the literature. Sex Transm Dis. 2010;37:
1996;9(3):361–81. 386–91.
8 Oral Signs of Viral Disease 165
44. Chung C, Bagheri A, Gypsyamber D. Epidemiology 61. Ebell MH. Epstein-Barr virus infectious mononucle-
of oral human papillomavirus. Oral Oncol. osis. Am Fam Physician. 2004;70:1279–87.
2014;50:364–9. 62. World Health Organization. Core Epidemiological
45. Grce M, Marinka M. Human papillomavirus- Slides: HIV/AIDS Estimates; 2014. Powerpoint pre-
associated diseases. Clin Dermatol. 2014;32:253–8. sentation available from: http://www.who.int/hiv/
46. Pringle G. The role of human papillomavirus in oral data/en/. Accessed 19 Oct 2014.
disease. Dent Clin N Am. 2014;58:385–99. 63. Centers for Disease Control and Prevention.
47. Syrjanen S. Human papillomavirus infec- Monitoring selected national HIV prevention and
tions and oral tumors. Med Microbiol Immunol. care objectives by using HIV surveillance data—
2003;192:123–8. United States and 6 U.S. dependent areas—2011. In:
48. Nguyen H, McNiece K, Duong A, Khan F. Human HIV surveillance supplemental report, vol. 18(5);
papillomavirus infections of the oral mucosa 2013.
and upper respiratory tract. Curr Prob Dermatol. 64. Quinn TC. Acute primary HIV infection. JAMA.
2015;45:132–53. 1997;278:58.
49. Jaiswal R, Pandey M, Shukla M, Dip NB, Kumar 65. Centers for Disease Control and Prevention
M. Condyloma acuminatum of the buccal mucosa. and Association of Public Health Laboratories.
Ear Nose Throat J. 2014;93(6):219–23. Laboratory testing for the diagnosis of HIV infec-
50. Prabhu SR, Wilson DF. Human papillomavirus and tion: updated recommendations; 2014. http://stacks.
oral disease- emerging evidence: a review. Aust Den cdc.gov/view/cdc/23447. Accessed 8 Oct 2014.
J. 2013;58:2. 66. Patton LL, Phelan JA, Ramos-Gomez FJ,
51. Said AK, Leao JC, Fedele S, Porter SR. Focal epi- Nittayananta W, Shiboski CH, Mbuguye TL.
thelial hyperplasia—an update. J Oral Pathol Med. Prevalence and classification of HIV- associated oral
2013;42:435–42. lesions. Oral Dis. 2002;8(Suppl 2):98–109.
52. García-Corona C, Vega-Memije E, Mosqueda-Taylor 67. Axell T, Azul AM, Challacombe S, Ficcara G, Flint
A, Yamamoto-Furusho JK, Rodríguez-Carreón AA, S, Greenspan D. Classification and diagnostic criteria
Ruiz-Morales JA, et al. Association of HLA-DR4 for oral lesions in HIV infection. EC-clearinghouse
(DRB1*0404) with human papillomavirus infec- on oral problems related to HIV infection and
tion in patients with focal epithelial hyperplasia. WHO collaborating centre on oral manifestations
Arch Dermatol. 2004;140(10):1227–31. https://doi. of the immunodeficiency virus. J Oral Pathol Med.
org/10.1001/archderm.140.10.1227. 1993;22(7):289–91.
53. González LV, Gaviria AM, Sanclemente G, Rady 68. Lifson AR, Hilton JF, Westenhouse JL, Canchola AJ,
P, Tyring SK, Carlos R, et al. Clinical, histopatho- Samuel MC, Katz MH, et al. Time from HIV sero-
logical and virological findings in patients with conversion to oral candidiasis or hairy leukoplakia
focal epithelial hyperplasia from Colombia. Int J among homosexual and bisexual men enrolled in
Dermatol. 2005;44:274–9. three prospective cohorts. AIDS. 1994;8:73–9.
54. Bennett LK, Hinshaw M. Heck’s disease: diagnosis 69. Patton LL, van der Horst C. Oral infections and other
and susceptibility. Pediatr Dermatol. 2009;26:87–9. manifestations of HIV disease. Infect Dis Clin N
55. Luzuriaga K, Sullivan JL. Infectious mononucleosis. Am. 1999;13(4):879–900.
N Engl J Med. 2010;362(21):1993–2000. 70. Triantos D, Porter SR, Scully C, Teo CG. Oral hairy
56. Crawford DH, Macsween KF, Higgins CD, Thomas leukoplakia: clinicopathologic features, pathogen-
R, McAulay K, Williams H, et al. A cohort study esis, diagnosis, and clinical significance. Clin Infect
among university students: identification of risk Dis. 1997;25:1392–6.
factors for Epstein-Barr virus seroconversion 71. Bhandarkar SS, MacKelfresh J, Fried L, Arbiser
and infectious mononucleosis. Clin Infect Dis. JL. Targeted therapy of oral hairy leukoplakia with
2006;43:276–82. gentian violet. J Am Acad Dermatol. 2008;58:
57. Odumade OA, Hogquist KA, Balfour HH. Progress 711–2.
and problems in understanding and managing pri- 72. Braz-Silva P, Santos R, Schussel J, Gallottini
mary Epstein-Barr virus infections. Clin Microbiol M. Oral hairy leukoplakia diagnosis by Epstein–
Rev. 2011;24(1):193–209. Barr virus in situ hybridization in liquid-based cytol-
58. Thorley-Lawson DA. Epstein-Barr virus: exploit- ogy. Cytopathology. 2013;25(1):21–6. https://doi.
ing the immune system. Nat Rev Immunol. org/10.1111/cyt.12053.
2001;1:75–82. 73. Greenspan JS, Greenspan D. HIV-related oral dis-
59. Hadinoto V, Shapiro M, Greenough TC, Sullivan ease. Lancet. 1996;348:729–33.
JL, Luzuriaga K, Thorley-Lawson DA. On the 74. Patton LL. Oral lesions associated with human
dynamics of acute EBV infection and the pathogen- immunodeficiency virus disease. Dent Clin N Am.
esis of infectious mononucleosis. Blood. 2008;111: 2013;57(4):673–98.
1420–7. 75. Tappuni AR, Kovacevic T, Shirlaw PJ, Challacombe
60. Jenson HB. Acute complications of Epstein-Barr SJ. Clinical assessment of disease severity in
virus infectious mononucleosis. Curr Opin Pediatr. recurrent aphthous stomatitis. J Oral Pathol Med.
2000;12:263–8. 2013;42:635–41.
166 D. N. Brown et al.
76. Kerr A, Ship J. Management strategies for HIV- 89. Schwartz RA. Kaposi’s sarcoma: advances and per-
associated aphthous stomatitis. Am J Clin Dermatol. spectives. J Am Acad Dermatol. 1996;34:804–14.
2003;4(10):669–80. 90. Lemlich G, Schwam L, Lebwohl M. Kaposi’s sar-
77. Reichart PA. Oral ulcerations in HIV infection. Oral coma and acquired immunodeficiency syndrome:
Dis. 1997;3(Suppl 1):180–2. postmortem findings in twenty-four cases. J Am
78. American Society of Hematology. 2011 clinical Acad Dermatol. 1987;16:319–25.
practice guideline on the evaluation and manage- 91. World Health Organization. WHO case definitions
ment of immune thrombocytopenia; 2011. http:// of HIV for surveillance and revised clinical staging
www.hematology.org. Accessed 21 Oct 2014. and immunological classification of HIV-Related
79. Bettaieb A, Fromont P, Louache F, Osksenhendler disease in adults and children; 2006. http://www.
E, Vainchenker W, Duédari N, et al. Presence of who.int/hiv/pub/guidelines/HIVstaging150307.pdf.
cross-reactive antibody between human immuno- Accessed 19 Oct 2014.
deficiency virus (HIV) and platelet glycoproteins 92. Feller L, Jadwat Y, Raubenheimer EJ. Kaposi sar-
in HIV-related immune thrombocytopenic purpura. coma and calcium channel blocker-induced gingival
Blood. 1992;80:162–9. enlargement occurring simultaneously: review of
80. Reid E. Hematologic manifestations of acquired the literature and report of a case. Oral Biosci Med.
immunodeficiency syndrome. In: Lichtman MA, 2004;4:291–7.
Kipps TJ, Seligsohn U, Kaushansky, editors. 93. Pantanowitz L, Khammissa R, Lemmer J, Feller
Williams hematology. 8th ed. China: McGraw-Hill; L. Oral HIV-associated Kaposi sarcoma. J Oral
2010. p. 1175–99. Pathol Med. 2013;42:201–7.
81. Ambler K, Vickars L, Leger C, Foltz L, Montaner JS, 94. Fatahzadeh M, Schwartz RA. Oral Kaposi’s
Harris M, et al. Clinical features, treatment and out- sarcoma: a review and update. Int J Dermatol.
come of HIV-associated immune thrombocytopenia 2013;52:666–72.
in the HAART era. Adv Hematol. 2012;2012:910– 95. Vanni T, Sprinz E, Machado MW, Santana Rde C,
54. https://doi.org/10.1155/2012/910954. Fonseca BA, et al. Systemic treatment of AIDS-
82. Chapple I, Hamburger J. The significance of related Kaposi sarcoma: current status and perspec-
oral health in HIV disease. Sex Transm Infect. tives. Cancer Treat Rev. 2006;32:445–55. https://doi.
2000;76(4):236–43. https://doi.org/10.1136/ org/10.1016/j.ctrv.2006.06.001.
sti.76.4.23. 96. Doumas S, Vladikas A, Papagianni M, Kolokotronis
83. Kazi S, Cohen PR, Williams F, Schempp R, Reveille A. Human cytomegalovirus-associated oral and
JD. The diffuse infiltrative lymphocytosis syndrome: maxillo-facial disease. Clin Microbiol Infect.
clinical and immunogenetic features in 35 patients. 2007;13:557–9.
AIDS. 1996;10(4):385–91. 97. Lazzarotto T, Guerra B, Gabrielli L, Lanari M,
84. Dourmishev LA, Dourmishev AL, Palmeri D, Landini MP. Update on the prevention, diagnosis and
Schwartz RA, Lukac DM. Molecular genetics of management of cytomegalovirus infection during
Kaposi’s sarcoma associated herpesvirus (human pregnancy. Clin Microbiol Infect. 2011;17:1285–93.
herpesvirus-8) epidemiology and pathogenesis. https://doi.org/10.1111/j.1469-0691.2011.03564.x.
Microbiol Mol Biol Rev. 2003;67:175–212. 98. Stoopler ET, Greenberg MS. Update on herpesvirus
85. Bohlius J, Valeri F, Maskew M, Prozesky H, infections. Dent Clin N Am. 2003;47(4):517–32.
Prozesky H, Garone D, Sengayi M, et al. Kaposi’s 99. Bruminhent J, Razonable R. Management of cyto-
sarcoma in HIV-infected patients in South Africa: megalovirus infection and disease in liver transplant
multicohort study in the antiretroviral therapy recipients. World J Hepatol. 2014;6(6):370–83.
era. Int J Cancer. 2014;135:2644–52. https://doi. 100. Taylor GH. Cytomegalovirus. Am Fam Physician.
org/10.1002/ijc.28894. 2003;67(3):519–24.
86. Schwartz R, Micali G, Nasca M, Scuderi L. Kaposi 101. Kotton CN. CMV: prevention, diagnosis and ther-
sarcoma: a continuing conundrum. J Am Acad apy. Am J Transplant. 2013;13:24–40.
Dermatol. 2008;59(2):179–206. 102. Whitcup SM. Cytomegalovirus retinitis in the
87. Russo JJ, Bohenzky RA, Chien MC, Chen J, era of highly active antiretroviral therapy. JAMA.
Yan M, Maddalena D, et al. Nucleotide sequence 2000;283:653–7.
of the Kaposi sarcoma-associated herpesvirus 103. Kaplan J, Masur H, Holmes K. Recommendations
(HHV8). Proc Natl Acad Sci U S A. 1996;93: of the U.S. Public Health Service and the Infectious
14862–7. Diseases Society of America. MMWR Morb Mortal
88. Cattani P, Capuano M, Cerimele F, La Parola IL, Wkly Rep. 2002;51(08):1–46.
Santangelo R, Masini C, et al. Human herpesvi- 104. Dauden E, Fernandez-Buezo G, Fraga J, Cardenoso
rus 8 seroprevalence and evaluation of nonsexual L, Garcia-Diez A. Mucocutaneous presence of
transmission routes by detection of DNA in clinical cytomegalovirus associated with human immu-
specimens from human immunodeficiency virus- nodeficiency virus infection. Arch Dermatol.
seronegative patients from central and southern 2000;137:443–8.
Italy, with and without Kaposi’s sarcoma. J Clin 105. Flaitz C, Nichols M, Hicks M. Herpesviridae-
Microbiol. 1999;37:1150–3. associated persistent mucocutaneous ulcers in
8 Oral Signs of Viral Disease 167
acquired immunodeficiency syndrome. Oral 116. Ennis FA, Jackson D. Isolation of virus during the
Surg Oral Med Oral Pathol Oral Radiol Endod. incubation period of mumps infection. J Pediatr.
1996;81(4):433–41. 1968;72:536–7.
106. Drutz JE. Rubella. Pediatr Rev. 2010;31(3):129–30. 117. Sallberg M. Oral viral infections of children.
107. Castillo-Solorzano C, Matus CR, Flannery B, Periodontology. 2000;49:87–95.
Marsigli C, Tambini G, Andrus JK. The Americas: 118. Grabowsky M. The beginning of the end of the
paving the road toward global measles eradication. J measles and rubella. Arch Pediatr Adolesc Med.
Infect Dis. 2011;204(Suppl 1):270–8. 2014;168(2):108–9.
108. Centers for Disease Control and Prevention (CDC). 119. Centers for Disease Control and Prevention (CDC).
Nationwide rubella epidemic – Japan, 2013. MMWR Brief report: update: mumps activity – United States,
Morb Mortal Wkly Rep. 2013;62:457. January 1-October 7, 2006. MMWR Morb Mortal
109. Banatvala JE, Brown DW. Rubella. Lancet. Wkly Rep. 2006;55(42):1152.
2004;363:1127–37. 120. Duke T, Mgone CS. Measles: not just another viral
110. Baden H, Provan J. Oral lesion of rubella. Arch exanthem. Lancet. 2003;361:763–73.
Dermatol. 1976;112(12):1973. 121. Lessler J, Reich NG, Brookmeyer R, Perl TM,
111. Thomas HI, Morgan-Capner P, Cradock-Watson Nelson KE, Cummings DA. Incubation periods
JE, Enders G, Best JM, O'Shea S. Slow matura- of acute respiratory viral infections: a systematic
tion of IgG1 avidity and persistence of specific review. Lancet Infect Dis. 2009;9:291–300.
IgM in congenital rubella: implications for diag- 122. Moss MJ, Griffin DE. Measles. Lancet.
nosis and immunopathology. J Med Virol. 1993; 2012;379:153–64.
41:196. 123. Battegay R, Itin C, Itin P. Dermatological signs and
112. Dayan GH, Quinlisk MP, Parker AA, Barskey AE, symptoms of measles: a prospective case series
Harris ML, Schwartz JM, et al. Recent resurgence and comparison with the literature. Dermatology.
of mumps in the United States. N Engl J Med. 2012;224:1–4.
2008;358:1580–9. 124. Silverman S, Miller C. Diagnosis and treatment of
113. Whitaker JA, Poland GA. Measles and mumps out- viral infections. Oral Maxillofac Surg Clin N Am.
breaks in the United States: think globally, vaccinate 2003;15(1):79–89.
locally. Vaccine. 2014;32:4703–4. 125. Kayal L, Jayachandran S, Singh K. Idiopathic
114. Hviid A, Rubin S, Muhlemann K. Mumps. Lancet. thrombocytopenic purpura. Contemp Clin Dent.
2008;371:932–44. 2014;5(3):410–4.
115. Richardson M, Elliman D, Maguire H, Simpson 126. Restrepo CS, Ocazionez D. Kaposi’s sarcoma:
J, Nicoll A. Evidence base of incubation periods, imaging overview. Semin Ultrasound CT MRI.
periods of infectiousness and exclusion policies for 2011;32(5):465–9.
the control of communicable diseases in schools 127. Patel LM, Lambert PJ, Gagna CE, Maghari A, Clark
and preschools. Pediatr Infect Dis J. 2001;20: Lambert W. Cutaneous signs of systemic disease.
380–91. Clin Dermatol. 2011;28(5):511–2.
Oral Signs of Bacterial Disease
9
Emily W. Shelley and Rochelle R. Torgerson
The oral manifestations of bacterial diseases ages and races, incidence is highest in young men
are varied ranging from nonspecific ulcers to between the ages of 20 and 29. Rates are also
the nearly pathognomonic strawberry tongue of higher in the African American population and
scarlet fever. The bacterial diseases with oral in urban communities [1]. Since the nineteenth
manifestations range from the highly prevalent century, the worldwide presence of syphilis has
gingivitis/periodontitis to the much rarer diphthe- been influenced by both political and medical
ria, a disease physicians in North America would factors. The first major decline in the preva-
not expect to encounter. This chapter covers the lence of syphilis occurred after the introduction
salient features of the following bacterial dis- of penicillin. While rates have steadily declined
eases with an emphasis upon oral manifestations: for over a century, epidemics have been seen. In
syphilis, gonorrhea, tuberculosis, acute necrotiz- the 1970s–1980s, an increase in both syphilis
ing ulcerative gingivitis, scarlet fever, diphtheria, and HIV was seen among men who had sex with
staphylococcal scalded skin, leprosy, gingivitis/ men. Rates gradually declined with awareness
periodontitis, granuloma inguinale, tularemia, of the diseases, antiretroviral therapy, and safer
and cat scratch disease. sex practices. Another rapid increase was seen
between 1986 and 1990 primarily among hetero-
sexuals and was thought to be associated with an
Syphilis increase in crack cocaine abuse [2, 3]. Despite
falling to record low levels in 1999, 2.6 cases in
Epidemiology 100,000, rates have since been slowly increas-
ing, especially in women and among those in the
Syphilis, a bacterial infection caused by southeastern USA [3].
Treponema pallidum, is almost exclusively con-
tracted through sexual intercourse but can also be
acquired through contact with infectious lesions, Etiopathogenesis
needle sharing, or in utero. While found in all
T. pallidum, a motile, spiral-shaped organ-
E. W. Shelley ism, enters the body either directly through the
Cleveland Medical Center, University Hospitals, mucous membranes or through minute abrasions
Cleveland, OH, USA in the skin. The organism cannot be cultured but
R. R. Torgerson (*) can be detected via dark-field microscopy or
Departments of Dermatology and Obstetrics and serologic testing. After entering through epithe-
Gynecology, Mayo Clinic, Rochester, MN, USA
e-mail: Torgerson.rochelle@mayo.edu lial surfaces, the bacteria multiply at the site of
inoculation and disseminate through blood and manifested by the formation of gummas in the
lymphatics via coordination of both adherence skin and mucosa. The central nervous system
and inherent motility [4]. In primary syphilis, the may be affected causing generalized paresis and
presence of treponemes initiates a host inflam- tabes dorsalis. Cardiovascular involvement can
matory response of predominantly lymphocytes, lead to aortitis and heart failure [8].
plasma cells, and monocytes. These cells in turn
activate macrophages. While this response does
eliminate a large number of treponemes, it is Oral Signs and Symptoms
believed that either resistance to phagocytosis or
downregulation of the immune response allows Oral manifestations may occur during all stages
the infection to spread in the absence of treatment of syphilis. Leuci et al. (2013) performed a ret-
[5]. If allowed to progress, secondary syphilis is rospective literature review that identified 34
characterized by hematologic dissemination of patients reported to have oral syphilis. The mani-
treponemes. It is the host inflammatory response festations among these patients included nonspe-
of secondary and late syphilis that syphilologists cific ulcers (50%), gummas (17%), white patches
now agree is the cause of the clinical manifes- (17%), blistering mucositis (8%), and necrosis of
tations of syphilis [4]. These responses include the dorsum of the tongue (8%) [9]. The chancre of
antibody formation, complement activation, and primary syphilis, most often found in the genital
formation of circulating immune complexes area, can also arise in the oropharynx following
with treponemal outer membrane proteins [5]. oral sex (Fig. 9.1). Kent and Romanelli (2008)
Granulomatous reaction is a hallmark of both found that 40–70% of extragenital ulcers appear
secondary and late syphilis. These granulomas in the mouth [10]. The chancre is a raised, firm,
are histologically nonspecific and may be mis- and painless ulcer that can appear similar to an
taken for other granulomatous processes such as aphthous ulcer [11, 12]. Once eroded, the chan-
sarcoidosis [4]. cre heals, often without treatment, in 3–6 weeks.
If allowed to spread hematogenously, secondary
syphilis may present with oral lesions. These are
Clinical Manifestations characterized by cheilitis, also called syphilitic
perlèche; gray patches on the palate, mucosa, and
Clinical manifestations of syphilis depend on the tongue in addition to erosions on the tongue with
stage. Primary syphilis is marked by the appear- flattened papillae; and condyloma lata (Fig. 9.2)
ance of a chancre, often on the penis, cervix, or [7]. These manifestations are often nonspecific,
vulva. If left untreated, secondary syphilis devel- however, making diagnosis difficult [13].
ops 6–8 weeks after resolution of the chancre.
Systemic symptoms of secondary syphilis pres-
ent as a flu-like illness with malaise, anorexia,
weight loss, fever, sore throat, and generalized,
painful lymphadenopathy [6]. Skin manifesta-
tions of secondary syphilis include the char-
acteristic papulosquamous rash of the trunk,
extremities, and occasionally the palms and soles
and a “moth-eaten” alopecia [7]. The clinical
manifestations of secondary syphilis may resolve
spontaneously without treatment. The infec-
tion then transitions to the latent phase where
it may remain dormant in the liver or spleen for
Fig. 9.1 Primary syphilis in the oral cavity. (Image cour-
3–30 years. If reactivated, tertiary syphilis is tesy of Centers for Disease Control and Prevention https://
marked by the destruction of tissues, clinically phil.cdc.gov/)
9 Oral Signs of Bacterial Disease 171
Differential Diagnosis
than 12 years. Patients aged 2–11 years should that have been implicated including Prevotella,
receive 9 months of daily isoniazid [32]. Fusobacterium, Selenomonas, and spirochetes
There are many different approaches to the such as Treponema and Borrelia [35].
treatment of active TB. The CDC recommends Psychological stress and impaired immune
that all patients with active TB should be started function may also play a role in the pathogenesis
on a four-drug regimen of isoniazid, rifampin, of ANUG [38]. Elevated levels of norepinephrine
pyrazinamide, and ethambutol for 2 months caused by stress may increase vasoconstriction
termed the initial phase. The patient then enters of the interdental papillae, leading to ischemia.
the continuation phase which should last for 4 or Furthermore, excessive corticosteroids affect the
7 months. Drug choice and duration of treatment immune response to inciting factors of ANUG
are dependent on comorbidities such as HIV [38]. Studies performed that evaluated leukocyte
infection and severity of the disease. Drug sus- function found that people with ANUG had an
ceptibility of the organisms should also be moni- impaired host immune response with depressed
tored to prevent and detect resistance [33]. polymorphonuclear (PMN) cell responsiveness
in both chemotaxis and phagocytosis [39, 40].
Smoking has also been shown to contribute to
cute Necrotizing Ulcerative
A the pathogenesis of ANUG. Nicotine impairs the
Gingivitis immune response and increases release of epi-
nephrine from blood vessels. Increased epineph-
Epidemiology rine constricts blood vessels near the gingivae
contributing to aseptic necrosis of the gingival
Acute necrotizing ulcerative gingivitis (ANUG), mucosa [35].
aka Vincent infection and trench mouth, is an
uncommon periodontal disease that has been
described for hundreds of years, especially among Clinical Manifestations
military recruits. A study done in 1988 found that
the incidence of ANUG in the general population In addition to the classic gingival manifestations
was 0.6% [34]. A literature review by Wade and of ANUG, patients may also present with fetor
Kerns (1998) found that ANUG is most com- oris, lymphadenopathy, malaise, and fever [35].
mon in young adults, with varying statistics on Patients also report altered texture of the teeth,
gender preference depending on the population metallic taste, loose teeth, and ropy saliva [41].
studied. Additionally, incidence is higher among
Caucasians and smokers [35]. Other risk factors
associated with developing ANUG include poor Oral Signs and Symptoms
oral hygiene, increased psychological stress, HIV
infection, and malnutrition [34, 36]. Signs and symptoms of ANUG are primarily oral.
Lesions appear as ulcers, which may be solitary
or multiple. Ulcerations appear on the gingival
Etiopathogenesis margin and are covered with a gray pseudomem-
brane [38]. In addition to ulcers, the gingival
The pathogenesis of ANUG seems to be multi- mucosa will appear erythematous and edematous
factorial. Bacterial infection plays a role and is and will bleed easily [42] (Fig. 9.6). A scale of
highlighted by an increase in ANUG among those seven stages of the disease has been devised and
with poor oral hygiene. However, it has been dif- is described as follows: stage 1, necrosis of only
ficult to identify a causal relationship. One study the tip of the interdental papilla; stage 2, necro-
showed evidence of spirochetes in gingival tissue sis of the entire papilla; stage 3, necrosis also
by electron microscopy but did not show a causal involving the marginal gingiva; stage 4, necro-
relationship to ANUG [37]. Bacterial species sis extending into the attached gingiva; stage
176 E. W. Shelley and R. R. Torgerson
Scarlet Fever
Epidemiology
The differential diagnosis for ANUG includes Infection is initiated through direct spread of large
primary herpetic gingivostomatitis, leukemia- droplets and has an incubation period ranging
associated oral ulcers, desquamative gingivitis, from 12 h to 7 days. Development of the skin rash
mucous membrane pemphigoid, and HIV [35]. associated with scarlet fever is due to a delayed-
Additionally, ANUG may clinically resemble type hypersensitivity reaction to a pyrogenic exo-
aphthous stomatitis, erythema multiforme, trau- toxin (A, B, or C) produced by the bacteria [1].
matic ulcers, infectious mononucleosis, agran- Although antitoxin antibodies prevent recurrence
ulocytosis, secondary syphilis, and allergic of the scarlatiniform rash, the p resence of three
stomatitis [36, 43]. different types of exotoxin makes reinfection
The diagnosis of ANUG is based on the fol- with GAS possible [46].
lowing clinical criteria: (1) acute necrosis and
ulceration of the interdental papilla, (2) pain, and
(3) bleeding [45]. Clinical Manifestations
Diphtheria
Epidemiology
Epidemiology
Etiopathogenesis
New studies show that most cases of SSSS are Clinical Manifestations
caused by oxacillin-sensitive, clindamycin-resistant
strains of S. aureus [52]. Despite this fact, recom- The Ridley-Jopling classification divides lep-
mendations now are for use of penicillinase-resis- rosy into categories based on clinical mani-
tant antibiotics in combination with clindamycin as festations and bacterial load: lepromatous,
it has excellent skin penetration and inhibits toxin tuberculoid, dimorphous, and indeterminate
production [52]. Vancomycin is also commonly [56]. The WHO also developed a classification
added as it has excellent coverage for MRSA [53]. system separating the disease into paucibacil-
Temperature regulation and volume resuscitation lary and multibacillary based on the number
are an important part of supportive therapy. of skin lesions present. Lepromatous leprosy is
9 Oral Signs of Bacterial Disease 181
Fig. 9.11 Leprosy
Clinical manifestations of gingivitis and peri- Differential diagnoses include systemic diseases
odontitis are mainly oral. that have periodontal features. These include viral
infections such as herpes, lichen planus, blister-
ing disorders like pemphigus and pemphigoid,
Oral Signs and Symptoms leukemia, lymphoma, tuberculosis, Wegener’s
granulomatosis, oral cancer, and metastatic can-
Gingival discoloration and easy bleeding with cer [72]. Medications like phenytoin, calcium
or without halitosis are features of early gingi- channel blockers, and cyclosporin A may be
vitis. Eversion of the gingival margin may also associated with gingival enlargement [77].
be seen, which encourages plaque formation The diagnosis of periodontal disease is based
and trauma from ingestion of food, leading to on clinical and radiographic features. The space
more inflammation [76] (Figs. 9.12 and 9.13). between the gingiva and teeth should be 1–3 mm
If allowed to progress, periodontitis results in but will deepen as the disease progresses with
tissue destruction, recession of gums, and tooth increased loss of connective tissue and bone [78].
mobility. A serious complication of progressive
disease is abscess formation, which can be seen
in the canine, buccal, submandibular, or sublin- Treatment Recommendations
gual spaces.
Periodontal disease is preventable by adhering
to meticulous oral hygiene with both brushing
and flossing, and periodic debulking of plaque
by in-office cleanings. Minimizing risk factors
such as smoking cessation and diabetes control
are also effective. For cases of acute gingivitis,
antibiotic therapy may be used but is only useful
in combination with improvement in oral hygiene
[73]. Selected antibiotics which have been rec-
ommended include metronidazole, clindamycin,
tetracyclines, fluoroquinolones, and azithromy-
cin [73]. Antibiotics are not effective for chronic
Fig. 9.12 Plaque-induced gingivitis. (Courtesy of Dr. gingivitis or periodontitis. Tooth destruction and
Rochelle Torgerson) premature loss are permanent consequences of
chronic disease. Surgical reconstruction is the
only means of repairing gingival contours and
tooth loss.
Granuloma Inguinale
Epidemiology
Australia [79, 80]. Incidence is higher in African giva and palate and can invade underlying bone
Americans and those in lower socioeconomic causing instability of the teeth [84–86]. Ulcers
communities. of the lips may extend into the oral cavity and
cause enlargement of submental lymph nodes
[87, 88]. Progression of ulcers in the posterior
Etiopathogenesis oropharynx can cause fistulas that extend into
the neck or jaw [89].
The disease is caused by gram-negative coc-
cobacilli that reside intracellularly within
macrophages referred to as Donovan bodies. Differential Diagnosis
Transmission of the disease is not entirely under-
stood. While some consider it to be a sexually Differential diagnoses should include other
transmitted infection, the occurrence in children causes of granulomatous ulcers including cat
and nonsexually active adults continues to puzzle scratch disease, tularemia, histoplasmosis, blas-
experts [81]. The bacteria are not highly infec- tomycosis, and tuberculosis [90]. A case of oral
tious, and it generally takes multiple contacts donovanosis resembling actinomycosis has been
with an infected person for the disease to spread reported [89]. If genital ulcers are present in
[1]. Should a person become infected, however, addition to oral ulcers, one should consider the
the bacteria invade genital and mucosal tissue possibility of other sexually transmitted diseases,
where an ulcer is formed. complex aphthosis, or Behcet disease.
Definitive diagnosis can be made by identifi-
cation of Donovan bodies from a sample of the
Clinical Manifestations lesion fixed with Giemsa, Wright’s, Leishman,
or silver stain [81, 82]. Histological examina-
Initially, a painless granulomatous ulcer forms tion shows a dense inflammatory infiltrate with
on the genitalia, which may bleed easily. There marked pseudoepitheliomatous hyperplasia [81].
are four classifications of ulcers: ulcerogranu-
lomatous, hypertrophic, necrotic, and sclerotic/
cicatricial [82]. Genital and anal lesions are most Treatment Recommendations
common, but extragenital lesions and disseminated
donovanosis occur as well. Disseminated disease There are several antibiotics that are effective in
is accompanied by systemic symptoms including the treatment of donovanosis. Azithromycin and
fever, malaise, weight loss, and night sweats [80]. doxycycline are most commonly used; however,
Infection with K. granulomatis increases the ciprofloxacin and trimethoprim/sulfamethoxa-
risk of acquiring HIV. Furthermore, coinfection zole have also been used, while erythromycin can
with HIV makes the disease more difficult to be used in pregnancy. For persistent disease, an
treat resulting in persistent ulcers [80, 81]. aminoglycoside can be added [79, 91].
appears as a necrotic granuloma with ulceration Disease in the immunocompromised patient can
of the conjunctiva. Patients complain of increased be treated with macrolides, fluoroquinolones,
tear production and a foreign body sensation rifampin, or gentamicin [119].
[111]. Immunodeficient patients are at risk of
developing bacillary angiomatosis.
References
Oral Signs and Symptoms 1. Goldman L, Schafter AI, editors. Cecil medicine:
expert consult – online. Philadelphia: Elsevier Health
Sciences; 2011.
Primary CSD of the mouth and mucous mem- 2. Goldman L, Schafter AI, editors. Goldman’s Cecil
branes has been reported and appears as an medicine. 24th ed. Philadelphia: Elsevier Saunders;
oral ulcer [112, 113]. Perioral areas should be 2012.
inspected as well. Case reports have identified 3. James WD, Berger T, Elston D. Andrew’s diseases of
the skin: clinical dermatology. Philadelphia: Elsevier
patients presenting with submandibular, sub- Health Sciences; 2011.
mental, and parotid masses associated with CSD 4. Mandell GL, Bennett JE, Dolin R. Mandell, Douglas,
[114, 115]. Facial nerve palsy has been reported and Bennett’s principles and practice of infectious dis-
as a complication of CSD-induced parotid swell- eases. Philadelphia: Churchill Livingstone/Elsevier;
2010.
ing [116]. 5. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology.
UK: Elsevier Health Sciences; 2012.
6. Andreoli TE, et al. Andreoli and Carpenter’s Cecil
Differential Diagnosis essentials of medicine. Philadelphia: Elsevier Health
Sciences; 2010.
7. Schwarzenberger K, Werchniak AE, Ko CJ, editors.
The differential diagnosis of oral CSD should General dermatology. Edinburgh: Elsevier Limited;
include other zoonotic infections including tula- 2009.
remia and toxoplasmosis. A diagnosis of CSD is 8. Goering RV, Mims CA. Mims’ medical microbiology.
Philadelphia: Mosby Elsevier; 2008.
based on clinical features and can be confirmed 9. Leuci S, Martina S, Adamo D, Ruoppo E, Santarelli
by serology. Serology via indirect immunofluo- A, Sorrentino R, et al. Oral syphilis: a retrospective
rescent antibody assay can be used to establish analysis of 12 cases and a review of the literature.
a diagnosis. However, these serologic tests are Oral Dis. 2013;19(8):738–46. https://doi.org/10.1111/
odi.12058.
not always sensitive enough to detect B. henselae 10. Kent ME, Romanelli F. Reexamining syphilis: an
antibodies [117]. On histopathology of a lymph update on epidemiology, clinical manifestations, and
node biopsy, CSD is characterized by microab- management. Ann Pharmacother. 2008;42(2):226–36.
scesses with reticulohistiocytic cells [118]. The https://doi.org/10.1345/aph.1K086.
11. Drago F, Ciccarese G, Cogorno L, Tomasini CF,
presence of pleomorphic rod-shaped bacilli when Cozzani EC, Riva SF, et al. Primary syphilis of the oro-
stained with Warthin-Starry silver stain will con- pharynx: unusual location of a chancre. Int J STD AIDS.
firm the diagnosis. 2014; https://doi.org/10.1177/0956462414551235.
12. Hertel M, Matter D, Schmidt-Westhausen AM,
Bornstein MM. Oral syphilis: a series of 5 cases. J
Oral Maxillofac Surg. 2014;72(2):338–45. https://doi.
Treatment Recommendations org/10.1016/j.joms.2013.07.015.
13. Ficarra G, Carlos R. Syphilis: the renaissance of
Most antibiotics have been proven ineffective an old disease with oral implications. Head Neck
Pathol. 2009;3(3):195–206. https://doi.org/10.1007/
in the treatment of CSD; therefore, mild cases s12105-009-0127-0.
can be managed without treatment. In fact, most 14. Captline AM, White NS, Merkow LP, Snyder
cases of lymphadenopathy will resolve spontane- SP. Atrophic luetic glossitis. Report of a case. Oral
ously in 2–4 months. For the immunocompetent Surg Oral Med Oral Pathol. 1970;30(2):192–5.
https://doi.org/10.1016/0030-4220(70)90360-9.
patient with severe disease, however, azithromy- 15. Centers for Disease Control and Prevention. Sexually
cin, rifampin, ciprofloxacin, or trimethoprim-sul- transmitted diseases treatment guidelines. MMWR
famethoxazole can be tried for 5–14 days [117]. Morb Mortal Wkly Rep. 2010;59(RR-12):1–110.
188 E. W. Shelley and R. R. Torgerson
47. Habif TP. Clinical dermatology. Philadelphia: Elsevier 65. Scheepers A, Lemmer J. Erythema nodosum lepro-
Health Sciences; 2009. sum: a possible cause of oral destruction in leprosy.
48. Ferri FF. Ferri’s color atlas and text of clinical medi- Int J Lepr Other Mycobact Dis. 1992;60(4):641–3..
cine. Philadelphia: Saunders/Elsevier; 2009. doi: 1299716
49. Baren JM, Rothrock S, Brennan J, Brown L. Pediatric 66. Martinez TS, Figueira MM, Costa AV, Gonçalves
emergency medicine. Philadelphia: Elsevier Health MA, Goulart LR, Goulart IM. Oral mucosa as a
Sciences; 2007. source of Mycobacterium leprae infection and
50. Murray PR, Rosenthal KS, Pfaller MA. Medical
transmission, and implications of bacterial DNA
microbiology. Philadelphia: Elsevier Health Sciences; detection and the immunological status. Clin
2012. Microbiol Infect. 2011;17(11):1653–8. https://doi.
51. Berk DR, Bayliss SJ. MRSA, staphylococcal scalded org/10.1111/j.1469-0691.2010.03453.x.
skin syndrome, and other cutaneous bacterial emer- 67. Chimenos Kustner E, Pascual Cruz M, Pinol Dansis
gencies. Pediatr Ann. 2010;39(10):627–33. https:// C, Vinals Iglesias H, Rodríguez de Rivera Campillo
doi.org/10.3928/00904481-20100922-02. ME, López López J. Lepromatous leprosy: a review
52. Braunstein I, Wanat KA, Abuabara K, McGowan KL, and case report. Med Oral Patol Oral Cir Bucal.
Yan AC, Treat JR. Antibiotic sensitivity and resistance 2006;11(6):E474–9.
patterns in pediatric staphylococcal scalded skin syn- 68. Ishii N, Barua S, Mori S, Nagaoka Y, Suzuki K. Report
drome. Pediatr Dermatol. 2014;31(3):305–8. https:// of the tenth meeting of the WHO Technical Advisory
doi.org/10.1111/pde.12195. Group on Leprosy Control. Nihon Hansenbyo Gakkai
53. Marx J, Hockberger R, Walls R. Rosen’s emer-
Zasshi. 2010;79(1):37–42.
gency medicine – concepts and clinical practice. 69.
Chemotherapy of leprosy. Report of a WHO
Philadelphia: Elsevier Health Sciences; 2013. Study Group. World Health Organ Tech Rep Ser
54.
Global leprosy update, 2013; reducing dis- 1994;847:1–24.
ease burden. Wkly Epidemiol Rec 2014;89(36): 70. Petersen PE, Bourgeois D, Ogawa H, Estupinan-
389–400. Day S, Ndiaye C. The global burden of oral diseases
55. Cohen J, Opal SM, Powderly WG. Infectious diseases. and risks to oral health. Bull World Health Organ.
Philadelphia: Elsevier – Health Sciences Division; 2005;83(9):661–9.
2010. 71. Tomar SL, Asma S. Smoking-attributable periodon-
56. Rodrigues LC, Lockwood D. Leprosy now: epide- titis in the United States: findings from NHANES
miology, progress, challenges, and research gaps. III. National Health and Nutrition Examination
Lancet Infect Dis. 2011;11(6):464–70. https://doi. Survey. J Periodontol. 2000;71(5):743–51. https://doi.
org/10.1016/S1473-3099(11)70006-8. org/10.1902/jop.2000.71.5.743.
57. Motta AC, Komesu MC, Silva CH, Arruda D, Simão 72.
Pihlstrom BL, Michalowicz BS, Johnson
JC, Zenha EM, et al. Leprosy-specific oral lesions: a NW. Periodontal diseases. Lancet. 2005;366
report of three cases. Med Oral Pathol Oral Cir Bucal. (9499):1809–20. https://doi.org/10.1016/S0140-6736
2008;13(8):E479–82. (05)67728-8.
58. de Abreu MA, Michalany NS, Weckx LL, Neto
73. Slots J. Systemic antibiotics in periodontics. J
Pimentel DR, Hirata CH, de Avelar Alchorne Periodontol. 2004;75(11):1553–65. https://doi.org/
MM. The oral mucosa in leprosy: a clinical and 10.1902/jop.2004.75.11.1553.
histopathological study. Braz J Otorhinolaryngol. 74. Robinson PG. The significance and management
2006;72(3):312–6. of periodontal lesions in HIV infection. Oral Dis.
59. Dhawan AK, Verma P, Sharma S. Oral lesions in lep- 2002;8(Suppl 2):91–7. https://doi.org/10.1034/
rosy revisited: a case report. Am J Dermatopathol. j.1601-0825.2002.00019.x.
2012;34(6):666–7. https://doi.org/10.1097/ 75. Newman MG, et al. Carranza’s clinical periodon-
DAD.0b013e3182485bcc. tology. Philadelphia: Elsevier – Health Sciences
60. Girdhar BK, Desikan KV. A clinical study of the Division; 2014.
mouth in untreated lepromatous patients. Lepr Rev. 76. Quick CRG, et al. Essential surgery: problems, diag-
1979;50(1):25–35. nosis, and management. Philadelphia: Elsevier –
61. Bucci F Jr, Mesa M, Schwartz RA, McNeil G,
Health Sciences Division; 2013.
Lambert WC. Oral lesions in lepromatous leprosy. J 77. Marshall RI, Bartold PM. A clinical review of
Oral Med. 1987;42(1):4–6. drug-induced gingival overgrowths. Aust Dent J.
62. Scheepers A, Lemmer J, Lownie JF. Oral mani-
1999;44(4):219–32. https://doi.org/10.1111/j.1834-
festations of leprosy. Lepr Rev. 1993;64(1): 7819.1999.tb00224.x.
37–43. 78. Pihlstrom BL. Measurement of attachment level
63. Costa A, Nery J, Oliveira M, Cuzzi T, Silva M. Oral in clinical trials: probing methods. J Periodontol.
lesions in leprosy. Indian J Dermatol Venereol Leprol. 1992;63(12 Suppl):1072–7. https://doi.org/10.1902/
2003;69(6):381–5. jop.1992.63.12s.1072.
64. Swain JP, Soud A, Agarwal SK. Necrotic erythema 79. Markle W, Conti T, Kad M. Sexually transmitted
nodosum leprosum with oral mucosal involvement. diseases. Prim Care. 2013;40(3):557–87. https://doi.
Indian J Lepr. 2008;80(2):175–8. org/10.1016/j.pop.2013.05.001.
190 E. W. Shelley and R. R. Torgerson
80. Velho PE, Souza EM, Belda JW. Donovanosis. Braz J 98. Pilo P, Johansson A, Frey J. Identification of
Infect Dis. 2008;12(6):521–5. https://doi.org/10.1590/ Francisella tularensis cluster in central and western
S1413-86702008000600015. Europe. Emerg Infect Dis. 2009;15(12):2049–51.
81. O’Farrell N. Donovanosis. Sex Transm Infect.
https://doi.org/10.3201/eid1512.080805.
2002;78(6):452–7. https://doi.org/10.1136/ 99. Tularemia – United States, 2001–2010. MMWR
sti.78.6.452. Morb Mortal Wkly Rep 2013;62(47):963–6.
82. O’Farrell N, Moi H. European guideline for the
100. Senel E, Satilmis O, Acar B. Dermatologic manifes-
management of donovanosis, 2010. Int J STD tations of tularemia: a study of 151 cases in the mid-
AIDS. 2010;21(9):609–10. https://doi.org/10.1258/ Anatolian region of Turkey. Int J Dermatol. 2014;
ijsa.2010.010245. https://doi.org/10.1111/ijd.12431.
83. Rajendran R, Sivapathasundharam B. Shafer’s text- 101. Polat M, Kara SS, Tapısız A, Tezer H. Unusual pre-
book of oral pathology. Philadelphia: Elsevier/Reed sentation of oropharyngeal tularemia: a case report.
Elsevier; 2012. Vector Borne Zoonotic Dis. 2013;13(5):337–9.
84. Hanna CB, Pratt-Thomas HR. Extragenital granu-
https://doi.org/10.1089/vbz.2012.1184.
loma venereum; report of six cases of lip, oral and 102. Dentan C, Pavese P, Pelloux I, Boisset S, Brion
cutaneous involvement with review of literature. S JP, Stahl JP, et al. Treatment of tularemia in
Med J. 1948;41(9):776–82. pregnant woman. France Emerg Infect Dis.
85. Doddridge M, Muirhead R. Donovanosis of the oral 2013;19(6):996–8. https://doi.org/10.3201/eid1906.
cavity. Case report. Aust Dent J. 1994;39(4):203–5. 130138.
https://doi.org/10.1111/j.1834-7819.1994.tb04776.x. 103. Koc S, Gürbüzler L, Yaman H, Eyibilen A, Salman
86. Brain P. Granuloma inguinale with extensive oral
N, Ekici A. Tularaemia presenting as parapha-
involvement. S Afr Med J. 1951;25(33):581–2. ryngeal abscess: case presentation. J Laryngol
87. Veeranna S, Raghu TY. Oral donovanosis. Int
Otol. 2012;126(5):535–7. https://doi.org/10.1017/
J STD AIDS. 2002;13(12):855–6. https://doi. S0022215112000096.
org/10.1258/095646202321020170. 104. Dlugaiczyk J, Harrer T, Zwerina J, Traxdorf M,
88. Hart G. Donovanosis. Clin Infect Dis. 1997;25(1):24– Schwarz S, Splettstoesser W, et al. Oropharyngeal
30.. quiz 31-2 tularemia – a differential diagnosis of tonsillopha-
89. Coovadia YM, Steinberg JL, Kharsany A. Granuloma ryngitis and cervical lymphadenitis. Wien Klin
inguinale (donovanosis) of the oral cavity. A case Wochenschr. 2010;122(3–4):110–4. https://doi.
report. S Afr Med J. 1985;68(11):815–7. org/10.1007/s00508-009-1274-8.
90. Wysocki GP, Brooke RI. Oral manifestations of
105. Boisset S, Caspar Y, Sutera V, Maurin M. New
chronic granulomatous disease. Oral Surg Oral therapeutic approaches for treatment of tularaemia:
Med Oral Pathol. 1978;46(6):815–9. https://doi. a review. Front Cell Infect Microbiol. 2014;4:40.
org/10.1016/0030-4220(78)90313-4. https://doi.org/10.3389/fcimb.2014.00040.
91. Workowski KA, Berman S. Sexually transmitted dis- 106. Jackson LA, Perkins BA, Wenger JD. Cat scratch
eases treatment guidelines, 2010. MMWR Recomm disease in the United States: an analysis of
Rep. 2010;59(Rr-12):1–110. three national databases. Am J Public Health.
92. Boyce JM. Recent trends in the epidemiology
1993;83(12):1707–11.
of tularemia in the United States. J Infect Dis. 107. Dehio C. Molecular and cellular basis of barton-
1975;131(2):197–9. ella pathogenesis. Annu Rev Microbiol. 2004;58:
93. Tarnvik A, Sandstrom G, Sjostedt A. Epidemiological 365–90. https://doi.org/10.2105/AJPH.83.12.
analysis of tularemia in Sweden 1931–1993. FEMS 1707.
Immunol Med Microbiol. 1996;13(3):201–4. https:// 108. Cook GC, Zumla A. Manson’s tropical diseases.
doi.org/10.1111/j.1574-695X.1996.tb00237.x. Philadelphia: Saunders; 2009.
94. Ellis J, Oyston PC, Green M, Titball RW. Tularemia. 109. Arisoy ES, et al. Hepatosplenic cat-scratch disease
Clin Microbiol Rev. 2002;15(4):631–46. https://doi. in children: selected clinical features and treatment.
org/10.1128/CMR.15.4.631-646.2002. Clin Infect Dis. 1999;28(4):778–84.. NO DOI
95. Berdal BP, Mehl R, Meidell NK, Lorentzen-Styr AM, 110. Jacobs RF, Schutze GE. Bartonella henselae as a
Scheel O. Field investigations of tularemia in Norway. cause of prolonged fever and fever of unknown ori-
FEMS Immunol Med Microbiol. 1996;13(3): gin in children. Clin Infect Dis. 1998;26(1):80–4..
191–5. https://doi.org/10.1111/j.1574-695X.1996. NO DOI
tb00235.x. 111. Farrar J, et al. Manson’s tropical diseases: expert
96. Ohara Y, Sato T, Fujita H, Ueno T, Homma M. Clinical consult – online. UK: Elsevier Health Sciences;
manifestations of tularemia in Japan – analysis 2013.
of 1,355 cases observed between 1924 and 1987. 112. Margileth AM. Dermatologic manifesta-
Infection. 1991;19(1):14–7. https://doi.org/10.1007/ tions and update of cat scratch disease. Pediatr
BF01643750. Dermatol. 1988;5(1):1–9. https://doi.org/10.1111/
97.
Gurcan S. Epidemiology of tularemia. Balkan j.1525-1470.1988.tb00876.x.
Med J. 2014;31(1):3–10. https://doi.org/10.5152/ 113. Moriarty RA, Margileth AM. Cat scratch disease.
balkanmedj.2014.13117. Infect Dis Clin N Am. 1987;1(3):575–90.
9 Oral Signs of Bacterial Disease 191
114. Steiner M, Gould A, Wilkie W, Porter K. Cat-scratch 117. Margileth AM. Recent advances in diagnosis and
disease in the submandibular region: report of a case. treatment of cat scratch disease. Curr Infect Dis
J Oral Maxillofac Surg. 1994;52(6):614–8. https:// Rep. 2000;2(2):141–6. https://doi.org/10.1007/
doi.org/10.1016/0278-2391(94)90100-7. s11908-000-0026-8.
115. Mintz SM, Anavi Y. Cat scratch fever present- 118. Brunetti E, Fabbi M, Ferraioli G, Prati P, Filice C,
ing as a submental swelling. J Oral Maxillofac Sassera D, et al. Cat-scratch disease in Northern
Surg. 1988;46(11):1015–8. https://doi.org/10. Italy: atypical clinical manifestations in humans and
1016/0278-2391(88)90343-6. prevalence of Bartonella infection in cats. Eur J Clin
116. Premachandra DJ, Milton CM. Cat scratch disease Microbiol Infect Dis. 2013;32(4):531–4. https://doi.
in the parotid gland presenting with facial paraly- org/10.1007/s10096-012-1769-5.
sis. Br J Oral Maxillofac Surg. 1990;28(6):413–5. 119. Conrad DA. Treatment of cat-scratch disease. Curr
https://doi.org/10.1016/0266-4356(90)90042-J. Opin Pediatr. 2001;13(1):56–9.
Oral Signs of Tropical, Fungal,
and Parasitic Diseases
10
Ricardo Pérez-Alfonzo, Silvio Alencar-Marques,
Elda Giansante, and Antonio Guzmán-Fawcett
Table 10.1 Candidiasis: predisposing factors [3] membranes. The pseudomembranous form or
Physiologic factors oral thrush, easily recognized, affects 4–8% of
Pregnancy newborns. Candida vulvovaginitis, a frequent
Menopause gynecological infection, occurs more commonly
Prematurity
between 20 and 30 years of age. Candidal balani-
Drugs Diseases
Antibiotics Diabetes mellitus
tis occurs in adult and elderly men [4]. Deep and
Steroids Acquired immune systemic forms of candida are uncommon, which
deficiency syndrome may arise due to the use of intravenous catheters
(AIDS) or in intravenous drug abusers. Oral candidiasis
Immunosuppressive drugs Thyroid disease can occur in the pediatric population as well as
Oral contraceptives
adults and immunocompromised patients [1].
Local factors
pH changes in the oral and vaginal mucosa
Poor oral hygiene
Poor dentition Clinical Manifestations
Ill-fitting dentures or dental prostheses
Colonization of dental prosthesis Candidiasis can occur in a variety of clinical
Xerostomia pictures among which the most common are the
Direct contact with products high in sugars (i.e.,
localized mucocutaneous and cutaneous forms.
bakers, fruit-packers)
Finger sucking Other less common forms are chronic mucocuta-
Fingernail biting neous candidiasis and disseminated disease such
Overzealous manicures and pedicures as Candida septicemia. The course may be acute,
Factors specific for oral candidiasis subacute, or chronic. Mucosal candidiasis is clas-
Radiation therapy sified as acute and chronic (Table 10.2).
Vitamin deficiencies (B2, B3, B6, B12, C, and folic One of the more frequent presentations is
acid)
Mineral deficiencies (Ca, Fe, Zn)
intertriginous candidiasis seen interdigitally in
Malnutrition the hands, feet, or axillary, inguinal, inframam-
Inflammatory bowel disease mary, or intergluteal areas as a result of moisture
Leukemia, lymphoma, metastatic carcinomas accumulation. In the diaper area, it is usually
Addison’s disease secondary to a previous dermatitis such as an
irritant dermatitis. Neonatal candidiasis presents
as thrush or disseminated pustular or vesicular
Approximately 50% of healthy individual harbor lesions. Candida can also affect the nails, typi-
the organism, more frequently found at the pos- cally with yellow, green, or black discoloration of
terior dorsum of the tongue. It is also the primary the nail plate. Systemic candidiasis can affect any
opportunistic pathogenic yeast for humans and organ most commonly the esophagus and heart.
is highly prevalent in AIDS patients. The most Candida septicemia usually has an intestinal ori-
important pathogenic species is C. albicans, even gin, while iatrogenic candidemia is associated
though there are many others. Multiple factors with parenteral nutrition.
contribute to a shift from its saphrophitic form to
opportunistic infection, most commonly affect-
Table 10.2 Classification of oral candidiasis [2, 4]
ing the oral and genital mucous membranes [1]
Acute candidiasis
(Table 10.1).
Pseudomembranous
Atrophic
Chronic candidiasis
Epidemiology Atrophic subtype
Angular cheilitis (perlêche)
Candida causes up to 25% of the superficial Hyperplastic
mycoses involving the nails, skin, and mucous Chronic Mucocutaneous candidiasis
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 195
Pseudomembranous Candidiasis
One of the most frequent forms of candidiasis
affecting the oral mucous membranes is thrush.
It presents as creamy, fluffy plaques overlying
an erythematous mucosal area, which can be
removed with gauze (Fig. 10.1). The buccal and
labial mucosa, dorsum of the tongue, and palate
are frequently involved sites, which can cause
symptoms of dysphagia. It is the most frequent
form of candidiasis seen in newborns, infants,
elders, and immunocompromised patients
Fig. 10.3 Candidiasis in an HIV+ patient. (Courtesy of
(Figs. 10.2 and 10.3). In patients undergoing anti- J. M. Ollague, Guayaquil, Ecuador)
despite careful cleaning, becoming a reservoir for be correlated with the clinical presentation.
the microorganism. Biopsies are not usually necessary, but when
The hyperplasic forms or black hairy tongue performed, the superficial forms show filaments
(lingua villosa nigra), common in AIDS patients, and yeast within the thickened stratum corneum,
is frequently localized to the lateral borders of which is more evident with PAS or the Gomori-
the tongue, being indistinguishable from the vil- Grocott stain. In the dermis, there is mild edema.
lous hyperplasia associated with the Epstein-Barr Abscesses and a granulomatous reaction are
virus. These hyperplasic forms are rarely seen in noted with deeper involvement of the subcutis.
smokers.
Despite its name, actinomycosis is a bacterial dis- In cases of cervicofacial actinomycosis, the dif-
ease, mainly produced by Actinomyces israelii, ferential diagnosis should include mycetoma,
an anaerobic, Gram-positive, slow-growing tuberculosis scrofula, lymphomas, osteomyelitis,
saprophytic microorganism of the oral cavity. It dental fistulas, tularemia, and abscessed seba-
forms filamentous colonies, easily confused with ceous cysts. Clinical suspicion for actinomycosis
fungal structures, which can become pathogenic. is confirmed by the presence of grains. Bacterial
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 199
culture is also useful for corroborating the diag- tant to differentiate them from Nocardia grains,
nosis and identifying the causative species. which are alcohol-acid resistant as demonstrated
The characteristic, but nonspecific, sulfur with the Ziehl-Neelsen stain. Botryomycosis,
granules extruding from the fistulae can be visu- actinomycetoma, and eumycetoma also have the
alized as tiny white-yellow clumps. They can characteristic of expelling grains, with different
also be seen on direct smears or in histological staining characteristics in each case.
sections. They can measure up to 3 mm and are Cultures are helpful in establishing a diagno-
formed by compact microfilaments aggregates sis; however, they need to be grown under anaero-
with thick spikes at the periphery (Figs. 10.9 and bic conditions. In general, yellowish filamentous
10.10). When pressing them between two glass colonies can be observed in about 3–6 days. They
slides, a crunching noise is heard. It is impor- take various stains such as Gram, Giemsa, and
Grocott and are Ziehl-Neelsen negative, a distinc-
tion from Nocardia. Histopathology demonstrates
a necrotic, chronic granulomatous process with
abundant polymorphonuclear cells, foreign body
giant cells, and epithelioid cells, with yellowish
sulfur granules and filamentous Gram-positive
fungal-like pathogens. Nevertheless, the absence
of granules does not exclude the diagnosis.
Treatment Recommendations
Fig. 10.9 Actinomycosis:
microscopic examination
of a grain showing
microfilaments clumped
together with thick spikes
at the periphery
200 R. Pérez-Alfonzo et al.
Fig. 10.10 Actinomyco-
sis: basophilic grains in
a hematoxylin-eosin
stain, high magnification
is determined by the clinical response. In cases and in Asia. In the USA, it has a high incidence
of allergy, resistance or intolerance to penicillin in the Ohio and Mississippi River valleys. It can
treatment with amoxicillin/clavulanate or trim- also be acquired when visiting caves, mines, and
ethoprim/sulfamethoxazole can be considered. abandoned buildings, where bats and bat drop-
Debridement and surgical draining of the lesions pings are frequent. The feces of different birds
are recommended. such as hens, turkeys, gooses, doves, and star-
lings can also carry this pathogen.
Histoplasmosis
Clinical Manifestations
Etiopathogenesis
Histoplasmosis characteristically arises from the
Histoplasmosis is a deep systemic mycosis pro- inhalation of spores. In highly immunosuppressed
duced by Histoplasma capsulatum within the patients, cutaneous infection is possible, but very
Ascomycota phylum, which enters through respi- rare. In most immunocompetent individuals, the
ratory pathways followed by possible oral, pha- infection is asymptomatic; however, it can cause
ryngeal involvement or potential spread to other mild respiratory symptoms. In isolated cases,
organs [2]. it can present with symptoms and radiological
imaging findings similar to pulmonary tubercu-
losis later evolving into a disseminated infection.
Epidemiology However, in 1% of patients, the infection runs
a severe course with remarkable pulmonary or
Histoplasmosis constitutes the most frequent extrapulmonary manifestations. Histoplasmosis is
pulmonary mycosis worldwide. It is an opportu- an AIDS-defining opportunistic disease; therefore,
nistic infection more commonly seen in HIV and the diagnostic work-up should include a complete
immunosuppressed patients. laboratory investigation including serologies to
It is prevalent in tropical climates particularly exclude HIV infection. HIV-infected patients are
in South America, Central and Southern Africa, particularly susceptible to histoplasmosis such
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 201
Treatment Recommendations
Epidemiology
Itraconazole and amphotericin B (liposomal
and deoxycholate) are effective therapies for The incidence of mucormycosis is expected to
histoplasmosis. For chronic pulmonary involve- increase worldwide given the higher prevalence
ment and mild-to-moderate disease itraconazole, of predisposing factors. The mortality rate of
200 mg three times daily for 3 days followed mucormycosis has been cited as 40% despite
by itraconazole 200 mg once or twice daily aggressive surgical and antifungal therapy.
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 203
Fig. 10.16 Mucormycosis: Patient with Non-Hodgkin’s Fig. 10.17 Mucormycosis affecting the palate. (Courtesy
lymphoma on immunosuppressive therapy. (Courtesy of of A. Bonifaz, Mexico DF, Mexico)
E. Cavallera, Z. Rivera, A.M. Pulido, Caracas, Venezuela)
involvement occurred as the initial manifestation
in most cases (n = 16). In three cases, the initial
Patients with malignancies and hematopoietic lesion presented as a palatal ulcer. All patients
stem cell transplant patients have mortality rates received amphotericin B desoxycholate com-
up to 65% and 90%, respectively [22–24]. bined with itraconazole in four cases and fluco-
nazole in four other cases. Four cases were also
subjected to surgical intervention. Clinical and
Clinical Manifestations mycological cure was achieved in only four cases
(19%) [22].
The infection usually compromises the nasal In children, the rhinocerebral form is the main
cavity and can by contiguity affect the paranasal clinical presentation, followed by the primary
sinuses, palate, and buccal mucosa (Fig. 10.17). cutaneous and the pulmonary types. Predisposing
It has two clinical forms: primary and second- factors such as DM and hematologic disease are
ary cutaneous zygomycosis. The primary form similar to those seen in adults [26].
has an overall good prognosis characteristi-
cally appearing as necrotic lesions after a trau-
matic injury. By contrast, the secondary form Differential Diagnosis
has a poor prognosis and starts as a fistula with
necrotic tissue, generally as an extension of rhi- The diagnosis of mucormycosis is established
nocerebral involvement [25]. based on clinical presentation and histopatho-
The possible clinical manifestations of mucor- logical features showing vascular invasion by
mycosis include rhinocerebral invasion and pul- hyphae leading to thrombosis and tissue necrosis
monary, cutaneous, and gastric disseminated as the hallmark of the disease better demonstrated
disease [20, 21]. The original clinical description with the silver stain. The inflammatory response
of the rhinocerebral type of mucormycosis is of is sparse, and edema and necrosis are conspicu-
oral/palatal necrosis. Bonifaz et al. presented 21 ous. Samples must be sent for culture in order
mucormycosis cases with palatal involvement to identify the species and confirm the clinical
(18.75%), from a total of 112 cases screened. All diagnosis. Radiological imaging is important in
but one were associated with diabetic ketoacido- cases with facial involvement in order to evaluate
sis (5 patients had type 1 DM and 15 had type the extent of the disease and possible intracranial
2 DM). The rhinocerebral clinical presentation involvement [27]. Early clinical recognition and
was observed in 19 cases (90%), while in 2 cases prompt therapy are crucial to preventing fatal
there was disseminated disease. Nasal mucosal outcomes.
204 R. Pérez-Alfonzo et al.
Differential Diagnosis
Treatment Recommendations
Fig. 10.24 Paracoccidi-
oidomycosis: micro-
scopic examination with
KOH showing multiple
buds attached to a
mother cell
Fig. 10.25 Paracoccidioi-
domycosis: histopathology
with Grocott silver stain
mia, hypomagnesemia, and renal tubular acidosis presence of comorbidities, as well as treatment.
[40]. Amphotericin lipid complex 3.0–4.0 mg/kg/ Usually, there is a marked clinical improvement
day for 15 days followed by itraconazole 200– after 1 or 2 months of treatment with healing of
400 mg/day can be an option for severe cases mucosal and cutaneous lesions. Nevertheless,
[21]. Fluconazole 800 mg per day is an alterna- patients must be advised that healing of mucosal
tive treatment regimen for patients with neuro- or cutaneous lesions is not an indicator of com-
logical involvement [21]. plete irradication of the disease. Complete cure is
The clinical prognosis in paracoccidioido- recognized when there are no more clinical signs
mycosis depends on the severity of the disease, of the disease, radiologic examination shows sta-
208 R. Pérez-Alfonzo et al.
bilization of pulmonary disease, and serological ease. Cutaneous blastomycosis is the main extra-
testing remains negative [41]. pulmonary form; it can occur in 40% of cases
and is divided in primary and secondary cuta-
neous forms. The primary cutaneous form arises
Blastomycosis from inoculation of the fungus through skin
trauma causing a chancre or nodular lesions with
Subacute or chronic mycosis is caused by a lymphangitis or adenitis similar to sporotricho-
dimorphic fungus called Blastomyces dermatiti- sis. The secondary form arises from hematoge-
dis (B. dermatitidis). It is characterized by granu- nous and lymphatic dissemination. Localization
lomatous suppurative lesions affecting the lungs, to the face, particularly the nose, is very charac-
skin, and bones. teristic. The initial papular and nodular lesions
eventually form abscesses, ulcers, and verrucous
lesions [42].
Etiopathogenesis
Epidemiology
Differential Diagnosis
The most important endemic focus of blastomy-
cosis is found in the USA and Canada, located in Blastomycosis is one of the great mimickers in
the areas bordering the Great Lakes, St. Lawrence medicine: verrucous cutaneous blastomyco-
River, and the Ohio and Mississippi river valleys. sis resembles malignancy and mass-like lung
Small foci have also been found in Mexico, opacities due to B. dermatitidis are often con-
Central America, and Africa. B. dermatitidis has fused with cancer. Blastomycosis may be clini-
been isolated in damp soil and can affect animals cally indistinguishable from tuberculosis and
such as horses, beavers, and especially dogs. Men paracoccidioidomycosis.
are affected more often than women and children The diagnosis of blastomycosis is frequently
because they are more likely to participate in delayed due to its clinical presentation, which
activities that put them at risk for exposure to the can be similar to more common clinical entities,
organism [2]. most notably squamous cell carcinoma. A sub-
stantial portion of cases (42%) present without
clinical or radiological evidence of pulmonary
Clinical Manifestations infection [42]. Sputum, pus, or wound exudates
can be examined with potassium hydroxide,
Blastomycosis can affect the pulmonary, genito- which reveals the mono-gemmating blastoco-
urinary, cutaneous, musculoskeletal, and central nidia, with thick birefringent walls. Gemmation
nervous system in addition to disseminated dis- is very useful for differentiating the disease
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 209
Clinical Manifestations
have pathognomonic findings on imaging studies other systemic endemic mycoses, primary coc-
requiring biopsy of pulmonary tissue to establish cidioidomycosis is a consequence of inhaling the
the diagnosis. fungus [65–67]. Clinical pulmonary manifesta-
Cutaneous or mucosal lesions can be diag- tions following infection will vary depending on
nosed by histopathological examination, which the extent of infection and the immune status of
is enhanced by stains such as mucicarmine, PAS, the host. Overt disease can involve almost every
or alcian blue. Sabouraud’s dextrose agar or other organ system; however, pulmonary disease is the
enriched media containing antibacterial antibiot- most common clinical manifestation [65–67].
ics without cycloheximide are preferred media. The infection is a consequence of inhalation
The culture should be incubated at 30 °C with of arthroconidia, which results in asymptomatic,
growth observed within 2–7 days. After an isolate mild, or severe febrile respiratory illness [68]. The
has been established as Cryptococcus, the distinc- Coccidioides spp. is considered one of the most
tion between C. neoformans and C.gattii can be virulent among the etiologic agents of systemic
made using canavanine-glycine-bromothymol- mycosis. Inhalation of a few conidia can lead to
blue (CGB) agar [53, 64]. After 1–5 days, the C. infection in a normal healthy host. Accidental
gattii turns the CGB medium from yellow green inhalation of conidia from Coccidioides culture
to blue, and the C. neoformans does not [53, 64]. is also a risk to laboratory workers and students
This is a very sensitive and specific method to [67]. There is no racial, sex, or age difference in
identify the Cryptococcus species. Nevertheless, susceptibility to primary pulmonary infection;
molecular methods can be used with similar sen- however, a study in Kern County, California, done
sitivity and specificity. The serodiagnosis uses in 1995–1996 observed that independent risk fac-
a latex agglutination kit devised to detect the tors for severe pulmonary disease included DM,
polysaccharide capsule antigen with a sensitivity recent history of cigarette smoking, low income,
above 90% [64]. and older age [69]. Independent risk factors for
disseminated disease include black race, low
income, and pregnancy as well as immunocom-
Treatment Recommendations promised patients [69, 70]. Other studies have
reported that African Americans, Hispanics,
The strategies to treat the various clinical sub- Asians, and American Indians have a higher rate
types of cryptococcosis are beyond the scope of extrapulmonary disease than Caucasians [71].
of this chapter and are very well presented and
discussed in the Clinical Practice Guidelines for
the Management of Cryptococcal Disease, which Epidemiology
is periodically updated [49]. For those patients
with localized skin or mucosal disease for whom Coccidioidomycosis is endemic in specific areas
CNS, pulmonary, or disseminated disease has of the USA, Mexico, and Central and South
been ruled out, treatment options are fluconazole America with a geographical distribution in
400 mg per day or itraconazole 200 mg per day semiarid or desert-like regions [65–67]. In the
for 6–12 months [49]. USA, the southwestern region of the country is
the most important endemic area particularly
the San Joaquin Valley and Southern California,
Coccidioidomycosis Arizona, Nevada, Utah, and New Mexico [65,
67]. The incidence of coccidioidomycosis is
Etiopathogenesis growing in all endemic areas. In the USA, the
incidence of coccidioidomycosis infection in
Coccidioidomycosis is a systemic mycosis caused endemic areas has considerably increased from
by the dimorphic fungus Coccidioides immitis 5.3 cases in 1998 to 42.6 cases per 100,000 popu-
or Coccidioides posadasii [65, 66]. Similar to lation in 2011. Primary coccidioidal pneumonia
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 213
accounts for 15–29% of all cases among patients CT or MRI do not have specific pathognomonic
with community-acquired pneumonia in Arizona findings. Therefore, establishing a diagnosis will
[72]. Coccidioidomycosis can be considered an require a culture or biopsy. On histopathological
occupational hazard particularly in individu- examination, a purulent or granulomatous reac-
als who do agricultural work and construction, tion is observed. Spherules with endospores in
which has a higher risk of infection [65]. different stages of development and released
endospores are frequently found in the cytoplasm
of histiocytes, giant cells, or free in the tissue.
Clinical Manifestations Visual inspection of gross clinical specimens can
be of great diagnostic value, as mature spherules
The majority of those exposed to the disease are large and easily observed. Fresh tissue cul-
experience asymptomatic pulmonary infec- tures can be performed using routine laboratory
tion. Typically, prior exposure does not lead to media at room temperature. However, because
residual scarring in the lungs. In these instances, of risk of contamination, precautionary measures
a positive coccidioidin skin test can confirm pre- need to be taken in handling Coccidioides [67].
vious infection. Symptomatic pulmonary disease
manifests 1–4 weeks following exposure. Most
patients are febrile, and while chest pain is com- Treatment Recommendations
mon, cough is less often observed as compared
to other pulmonary infections [68]. Other pos- Amphotericin B in its different forms, itracon-
sible symptoms are anorexia, malaise, myalgia, azole, and fluconazole are the most useful and
and backaches. Erythema nodosum and ery- frequently used treatments. Posaconazole and
thema multiforme are common cutaneous mani- voriconazole can be administered as salvage
festations associated with pulmonary primary therapy. Immunosuppressed patients, pregnant
infection [68, 71]. The symptoms of pulmonary women, and elderly patients will require special
infection usually subside after 2 or 3 weeks but attention [67, 76].
can progress to the development of cavitary dis-
ease, coccidioidomas, or progressive pulmonary
disease. Disseminated disease occurring within Parasitic Diseases
the 1st weeks of primary disease is a predictor
of a poor outcome. Single organ involvement is Leishmaniasis
not infrequent in which case lesions affecting the
eyes, bones, urogenital tract, or skin may be the Leishmaniasis is found worldwide; it is one of
only manifestation of the disease. Oral lesions the most frequent tropical diseases constituting
tend to be extremely rare and most often occur a significant public health problem in more than
in immunosuppressed patients with disseminated 88 countries. Leishmaniasis found in Central and
disease or occasionally as a solitary lesion affect- South America has a more aggressive behavior
ing the tongue [73–75]. and can affect the mucous membranes leading
to a clinical form referred to as mucocutaneous
leishmaniasis (MCL). Depending on the parasite
Differential Diagnosis species and the cell-mediated immune response
of the patient, it can appear in four different
In endemic areas, primary pulmonary coccidioi- clinical forms: localized cutaneous, disseminated
domycosis is an important consideration in the cutaneous, mucocutaneous, and the visceral form
setting of community-acquired pulmonary infec- (aka Kala Azar). Typically, an indolent ulcerated
tion. Chronic pulmonary disease must be dif- erythematous nodule arises after an insect bite,
ferentiated from tuberculosis, malignancy, and more frequently affecting the lower limbs or the
other systemic mycoses. Imaging studies such as head and neck [77].
214 R. Pérez-Alfonzo et al.
Etiopathogenesis
Cutaneous leishmaniasis (CL) is primarily a (Fig. 10.27). These forms have a variable pre-
disease of the Near East (Oriental Sore) and sentation with nasal-labial edema in some
the Mediterranean area. In Central and South cases, which can later affect the nasal septum
America and Africa, it is frequent to find both and palate leading to perforation and disfiguring
cutaneous and mucocutaneous forms of the lesions of the centrofacial region (Figs. 10.28,
disease. In developed countries, its increased 10.29, and 10.30). Mucous membrane involve-
frequency is associated with leisure travel to ment usually occurs due to hematogenous or
endemic areas, immunosuppressive therapy, and lymphatic spread or via proximity with a local-
the HIV/AIDS population. ized cutaneous lesion.
Subsequent to the bite of an infected vector, a Mucosal involvement varies between 1% and
nodule or an erythematous plaque with variable 7% of cutaneous leishmaniasis cases primarily
degrees of induration with subsequent ulceration due to infection with the Leishmania (Viannia)
develops at the site. brazilensis complex. Mucosal involvement may
Cutaneous leishmaniasis produced by occur months or years after the cutaneous lesion
Leishmania tropica, characteristic of the so- has healed, independent of whether or not it was
called Old World Leishmaniasis, tends to be treated or arise spontaneously.
limited. Mucocutaneous leishmaniasis can Nasal mucosal lesions initially appear with
compromise the nasal and labial mucosa symptoms of nasal obstruction, rhinorrhea often
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 215
MCL patients [81]. The presence of oral lesions tuberculous, and histoplasmosis. Another impor-
was associated with involvement of the nasal, tant differential diagnosis is midline destruc-
pharyngeal, and laryngeal mucous membranes, tive disease such as Wegener’s granulomatosis,
poor host response, and an indicator of treatment vasculitis, and natural killer/T cell lymphoma
resistant disease [81]. Oral lesions affecting the (NKTCL) [87].
labial mucosa, tongue, and hard and soft palate
have been reported, which can present as labial or
gingival hypertrophy, swelling or ulcerations of Treatment Recommendations
the tongue or palate with a cobblestone appear-
ance, and vegetating tumors of the hard pal- The role of therapy in cutaneous leishmani-
ate [79–84]. In immunocompromised patients, asis is unclear since most cutaneous forms heal
the oral mucosa is the second most frequently spontaneously with or without scarring. Various
affected site of the head and neck region [82]. treatments have been used for the treatment of
MCL [77] (Table 10.4). Antimonials, especially
meglumine antimoniate, are the most effective
Differential Diagnosis treatment with a high cure rate. They can be
administered intralesionally in localized cutane-
A definitive diagnosis is reached by visualiza- ous forms or intramuscularly at 20 mg/kg/d for
tion of the Leishmania amastigote parasite within 20 consecutive days in disseminated cutaneous
tissue macrophages. The biopsy should be taken forms, or patients at risk for mucosal involve-
from the active border of the lesion, and, if pos- ment. Unfortunately, this drug has a high risk of
sible, long-standing lesions should be avoided. untoward side effects such as myalgias, fever,
Tissue biopsy or aspiration material should be headaches, and, less frequently, renal, hepatic,
used to prepare Giemsa stained slides for micro- pancreatic, and hematologic toxicity. Serum
scopic examination to confirm the presence of the sodium and potassium levels should be checked
amastigote parasite [85]. Tissue cultures can also since hypokalemia can occur with increased risk
facilitate diagnosis. of cardiac arrhythmias [88, 89].
Species identification is critical in order to deter- Oral miltefosine 50 mg three times per daily
mine the expected clinical course, prognosis, and for 28 days is effective in the treatment of vis-
choice of treatment. PCR analysis can also be used ceral leishmaniasis caused by L. donovani. There
to establish the diagnosis and determine the specific are multiple reports of its effectiveness in cuta-
Leishmania species involved [77]. Other methods neous leishmaniasis, cases resistant to antimo-
that can be used to confirm the diagnosis include nial treatment, and in instances of intolerance to
immunohistochemistry using Leishmania-specific antimonials due to side effects. It has also been
monoclonal antibodies, immunofluorescence, ani- used successfully in the treatment of Leishmania
mal inoculation, and serologic assay. Montenegro’s major, Leishmania donovani, Leishmania brasil-
skin test can also be helpful; however, it cannot dis- iensis, and Leishmania mexicana. However, gas-
tinguish between past and active infection, which is trointestinal side effects may limit its use [84,
important particularly in endemic areas [86]. 90, 91]. Some reports warn that although dif-
The differential diagnosis of leishmaniasis fuse cutaneous leishmaniasis responds to milt-
includes paracoccidioidomycosis, cutaneous efosine, relapse may occur with discontinuation
[92]. Liposomal amphotericin B is an alterna- of endemic syphilis, like that of yaws and
tive therapy for MCL in South America particu- pinta, is associated with poor hygiene. Despite
larly in cases due to Leishmania braziliensis and extensive eradication campaigns, yaws remains
Leishmania guyanensis. widespread in the tropics predominantly affect-
Immunotherapy with IFN, 5% imiquimod, ing children living in certain tropical regions.
or topical granulocyte-macrophage colony- It is endemic in parts of West Africa, Southeast
stimulating factor as an adjunct to antimonial Asia, and the Pacific. Pinta remains endemic in
treatment was helpful in some series. Effective Central and South America, and endemic syph-
vaccination has been reported in patients with ilis is present in certain regions of the Middle
severe MCL and early diffuse CL by injecting East [101–104]. With increasing worldwide
killed Leishmania braziliensis promastigotes travel, the diagnosis of the non-venereal trepo-
together with viable bacillus Calmette-Guerin nematoses must be considered in appropriate
[93, 94]. The potential of daylight-activated pho- clinical situations.
todynamic therapy for treating localized forms of
cutaneous leishmaniasis, in the setting of limited
resources, could be a promising therapy [95]. Clinical Manifestations
Yaws
Etiopathogenesis
Yaws is caused by Treponema pallidum ssp.
The genus Treponema contains both pathogenic pertenue, a gram-negative spirochete closely
and nonpathogenic species. Human pathogens related to Treponema pallidum ssp. pallidum, the
cause four treponematoses: venereal syphilis (T. agent of venereal syphilis. The primary lesion is
pallidum subsp. pallidum) and the endemic (non- found at the site of cutaneous inoculation as an
venereal) treponematoses, yaws (T. pallidum erythematous papule or group of papules or nod-
subsp. pertenue), endemic syphilis (T. pallidum ules known as mother yaw or raspberry. Lesions
subsp. endemicum), and pinta (T. carateum) [98, enlarge and ulcerate exuding a serous fluid rich
100]. Non-pathogenic treponemes can be part of in treponemes. These lesions heal spontaneously
the normal intestinal, oral, or genital flora. within one to several months, leaving an atro-
phic, depressed scar. Months after inoculation,
the treponemes disseminate, a widespread rash
Epidemiology develops, and secondary lesions quite similar
to the mother yaw develop. Crops of lesions
The endemic treponemal diseases are highly develop initially on the face and later spread
contagious. Transmission occurs through non- to the trunk and arms. Lesions of the palms
sexual human-to-human contact. Transmission and soles are characteristic, as is the case with
218 R. Pérez-Alfonzo et al.
Etiopathogenesis
of mucormycosis: from bench to bedside. Clin Infect on the Southeast of Brazil. Am J Trop Med Hyg.
Dis. 2009;48:1743–51. 2011;85:546–50.
21. Marques SA. Fungal infections of the mucous mem- 36. Marques SA. Paracoccidioidomycosis: epidemiologi-
brane. Dermatol Ther. 2010;23:244–51. cal, clinical, diagnostic and treatment up-dating. An
22. Bonifaz A, Macias B, Paredes-Farreira F, Arias P, Bras Dermatol. 2013;88:700–11.
Ponce RM, Araiza J. Palatal zygomycosis: experience 37. Franco M, Montenegro MR, Mendes RP, Marques
of 21 cases. Oral Dis. 2008;14:569–74. SA, Dillon N, Mota NGS. Paracoccidioidomycosis: a
23. Kontoyiannis DP, Wessel VC, Bodey GP, Rolston
recently proposed classification of its clinical forms.
KV. Zygomycosis in the 1990s in a tertiary-care can- Rev Soc Bras Med Trop. 1987;20:129–32.
cer center. Clin Infect Dis. 2000;30:851–6. 38. Marques SA, Cortez DB, Lastória JC, Camargo RMP,
24. Marr KA, Carter RA, Crippa F, Wald A, Corey
Marques MEA. Paracoccidioidomycosis: frequency,
L. Epidemiology and outcome of mould infections morphology and pathogenesis of tegumentary lesions.
in hematopoietic stem cell transplant recipients. Clin An Bras Dermatol. 2007;82:411–7.
Infect Dis. 2002;34:909–17. 39.
Queiroz-Telles F, Goldani LZ, Schlamm HT,
25. Bonifaz A, Vázquez-González D, Tirado-Sánchez A, Goodrich JM, Espinel-Ingroff A, Shikanai-Yasuda
Ponce-Olivera RM. Cutaneous zygomycosis. Clin MA. An open-label comparative pilot study of oral
Dermatol. 2012;30:413–9. voriconazole and itraconazole for long-term treat-
26. Bonifaz A, Tirado-Sánchez A, Calderón L, Romero- ment of paracoccidioidomycosis. Clin Infect Dis.
Cabello R, Kassack J, Ponce RM, et al. Mucormycosis 2007;45:1462–9.
in children: a study of 22 cases in a Mexican hospital. 40. Peçanha PM, Souza S, Falqueto A, Grão-Veloso TR,
Mycoses. 2014;57(Suppl 3):79–84. Lírio LV, Ferreira CUG Jr, et al. Amphotericin B lipid
27. Ameen M, Arenas R, Martinez-Luna E, Reyes M, complex in the treatment of severe paracoccidioi-
Zacarias R. The emergence of mucormycosis as an domycosis: a case series. Int J Antimicrob Agents.
important opportunistic fungal infection: five cases 2016;48:428–30.
presenting to a tertiary referral center for mycology. 41. Shikanai-Yasuda MA, TellesFilho FQ, Mendes RP,
Int J Dermatol. 2007;46:380–4. Colombo AL, Moretti ML. Grupo de Consultores
28. Reed G, Ibrahim A, Edwards J Jr. Deferasirox, an do Consenso em Paracoccidiodomicose. Consenso
iron-chelating agent, as salvage therapy for rhinocer- em paracoccidioidomicose. Rev Soc Bras Med Trop.
ebral mucormycosis. Antimicrob Agents Chemother. 2006;39:297–310.
2006;50:3968–9. 42. Saccente M, Woods GL. Clinical and labora-
29. Bagagli E, Theodoro RC, Bosco SM, McEwen JG. tory update on blastomycosis. Clin Microbiol Rev.
Paracoccidioidesbrasiliensis: phylogenetic and 2010;23:367–81.
ecological aspects. Mycopathologia. 2008;165: 43. Rucci J, Eisinger G, Miranda-Gomez G, Nguyen
197–207. J. Blastomycosis of the head and neck. Am J
30. Matute DR, McEwen JG, Puccia R, Montes BA, San- Otolaryngol. 2014;35:390–5.
Blas G, Bagagli E, et al. Cryptic speciation and recom- 44. Kruse AL, Zwahlen RA, Bredell MG, Gengler C,
bination in the fungus Paracoccidioidesbrasiliensis Dannemann C, Grätz KW. Primary blastomycosis of
as revealed by gene genealogies. Mol Biol Evol. oral cavity. J Craniofac Surg. 2010;21:121–3.
2006;23:65–73. 45. Fanucci E, Nezzo M, Neroni L, Montesani L Jr, Ottria
31. Matute DR, Sepulveda VE, Quesada LM, Goldman L, Gargari M. Diagnosis and treatment of paranasal
GH, Taylor JW, Restrepo A, et al. Microsatellite sinus fungus ball of odontogenic origin: case report.
analysis of three phylogenetic species of Oral Implantol (Rome). 2014;6(3):63–6.
Paracoccidioidesbrasiliensis. J Clin Microbiol. 46. Grosjean P, Weber R. Fungus balls of the parana-
2006;44:2153–7. sal sinuses: a review. Eur Arch Otorhinolaryngol.
32. Teixeira MM, Theodoro RC, de Carvalho MJ,
2007;264:461–70.
Fernandes L, Paes HC, Hahn RC. Phylogenetic 47. Ganesh P, Nagarjuna M, Shetty S, Kumar P, Bhat V,
analysis reveals a high level of speciation in the Salins PC. Invasive aspergillosis presenting as swell-
Paracoccidioides genus. Mol Phylogenet Evol. ing of the buccal mucosa in an immunocompetent
2009;52:273–83. individual. Oral Surg Oral Med Oral Pathol Oral
33. Theodoro RC, Teixeira Mde M, Felipe MS, Paduan Radiol. 2015;119:e60–4.
Kdos S, Ribolla PM, San-Blas G, et al. Genus 48. MacDougall L, Fyfe M, Romney M, Starr M,
Paracoccidioides: species recognition and biogeo- Galanis E. Risk factors for Cryptococcus gattii infec-
graphic aspects. PLoSOne. 2012;7:e37694. tion, British Columbia. Canada Emerg Infect Dis.
34. Turissini DA, Gomez OM, Teixeira MM, McEwen 2011;17:193–9.
JG, Matute DR. Species boundaries in the human 49. Perfect JR, Dismukes WE, Dromer F, Goldman
pathogen Paracoccidioides. Fungal Genet Biol. DL, Graybill JR, Hamill RJ, et al. Clinical prac-
2017;106:9–25. tice guidelines for the management of crypto-
35. Bellissimo-Rodrigues F, Machado AA, Martinez
coccal disease: 2010 update by the infectious
R. Paracoccidioidomycosis epidemiological features diseases society of America. Clin Infect Dis. 2010;50:
of a 1,000-cases series from a hyperendemic area 291–322.
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 223
Report of a case involving the palate. Report of a case 96. Marks M, Solomon AW, Mabey DC. Endemic
involving the palate. Oral Dis. 2002;8:59–61. Treponemal disease. Trans R Soc Trop Med Hyg.
83. Passi D, Sharma S, Dutta, S, Gupta C. Localized 2014;108:601–7.
leishmaniasis of oral mucosa: Report of an unusual 97. Koff AB, Rosen T. Non venereal treponemato-
clinicopathological entity. Hindawi Publishing ses: yaws, endemic syphilis, and pinta. J Am Acad
Corporation. Case Reports in Dentistry. 2014;753149. Dermatol. 1993;29:519–35.
https://doi.org/10.1155/2014/753149. 98. Antal GM, Lukehart SA, Meheus AZ. The endemic
84.
Kassam K, Davidson R, Tadrous PJ, Kumar treponematoses. Microbes Infect. 2002;4:83–94.
M. Lingual Leishmaniasis presenting to maxillofacial 99. Giacani L, Lukehart SA. The endemic treponemato-
surgery in UK with successful treatment with miltefo- ses. Clin Microbiol Rev. 2014;27:89–115.
sine. Case Rep Med. 2013;2013:975131. 100. Radolf JD. Treponema. In: Baron S, editor. Medical
85. Daneshbod Y, Oryan A, Davarmanesh M, Shirian
microbiology. 4th ed. Galveston: University of Texas
S, Negahban S, Aledavood A, et al. Clinical, histo- Medical Branch at Galveston; 1996. Chapter 36.
pathologic, and cytologic diagnosis of mucosal leish- 101. Marks M, Mitjà O, Solomon AW, Asiedu KB, Mabey
maniasis and literature review. Arch Pathol Lab Med. DC. Yaws. Br Med Bull. 2015;113:91–100.
2011;135:478–82. 102. Marks M, Lebari D, Solomon AW, Higgins SP. Yaws.
86. Almeida TF, da Silveira EM, Dos Santos CR, León Int J STD AIDS. 2015;26:696–703.
JE, Mesquita AT. Exclusive primary lesion of oral 103. Mitjà O, Asiedu K, Mabey D. Yaws. Lancet.
leishmaniasis with Immunohistochemical diagnosis. 2013;381:763–73.
Head Neck Pathol. 2016;10:533–7. 104. Kazadi WM, Asiedu KB, Agana N, Mitjà
87. Crovetto-Martínez R, Aguirre-Urizar JM, Orte-Aldea O. Epidemiology of yaws: an update. Clin
C, Araluce-Iturbe I, Whyte-Orozco J, Crovetto-De Epidemiol. 2014;6:119–28.
la Torre MA. Mucocutaneous leishmaniasis must 105. Mitjà O, Hays R, Ipai A, Penias M, Paru R, Fagaho
be included in the differential diagnosis of mid- D, et al. Single-dose azithromycin versus benzathine-
line destructive disease: two case reports. Oral Surg benzylpenicillin for treatment of yaws in children in
Oral Med Oral Pathol Oral Radiol. 2015;119(1): Papua New Guinea: an open-label, non-inferiority,
e20–6. randomised trial. Lancet. 2012;379:342–7.
88. Minodier P, Parola P. Cutaneous leishmaniasis treat- 106. Kwakye-Maclean C, Agana N, Gyapong J, Nortey
ment. Travel Med Infect Dis. 2007;5:150–8. P, Adu-Sarkodie Y, Aryee E, et al. A single dose
89. Amato VS, Tuon FF, Siqueira AM, Nicodemo AC, oral azithromycin versus intramuscular benzathine
Neto VA. Treatment of mucosal leishmaniasis in Latin penicillin for the treatment of yaws-a randomized
America: systematic review. Am J Trop Med Hyg. non inferiority trial in Ghana. PLoS Negl Trop Dis.
2007;77:266–74. 2017;11(1):e0005154.
90. Zerpa O, Blanco B, Kannee C, Ulrich M, Sindermann 107. Fegan D, Glennon MJ, Kool J, Taleo F. Tropical
H, Engel J, Convit J. Treatment of diffuse cutaneous leg ulcers in children: more than yaws. Trop Dr.
leishmaniasis with miltefosine: a case report. Int J 2016;46:90–3.
Dermatol. 2006;45:751–3. 108. Rivera-Olivero IA, Guevara A, Escalona A, Oliver
91. Vélez I, López L, Sánchez X, Mestra L, Rojas C, M, Pérez-Alfonzo R, Piquero J, et al. Soft-tissue
Rodriguez E. Efficacy of miltefosine for the treatment infections due to non-tuberculous mycobacteria fol-
of American cutaneous leishmaniasis. Am J Trop Med lowing mesotherapy. What is the price of beauty.
Hyg. 2010;83:351–6. Enferm Infecc Microbiol Clin. 2006;24:302–6.
92. Zerpa O, Ulrich M, Blanco B, Polegre M, Avila
109. Torres-Coy JA, Rodríguez-Castillo BA, Pérez-
A, Matos N, et al. Diffuse cutaneous leishmani- Alfonzo R, DE Waard JH. Source inves-
asis responds to miltefosine but then relapses. Br J tigation of two outbreaks of skin and soft
Dermatol. 2007;156:1328–35. tissue infection by Mycobacterium abscessus subsp.
93. Convit J, Ulrich M, Zerpa O, Borges R, Aranzazu N, abscessus in Venezuela. Epidemiol Infect. 2016;144:
Valera M, et al. Immunotherapy of american cutaneous 1117–20.
leishmaniasis in Venezuela during the period 1990– 110. Peralta G, Tobin-D'Angelo M, Parham A, Edison L,
99. Trans R Soc Trop Med Hyg. 2003;97(4):469–72. Lorentzson L, Smith C, et al. Notes from the field:
94. Convit J, Ulrich M, Polegre MA, Avila A, Rodríguez Mycobacterium abscessus infections among patients
N, Mazzedo MI, et al. Therapy of Venezuelan patients of a pediatric dentistry practice – Georgia, 2015.
with severe mucocutaneous or early lesions of diffuse MMWR Morb Mortal Wkly Rep. 2016;65:355–6.
cutaneous leishmaniasis with a vaccine containing 111. Lange CG, Woolley IJ, Brodt RH. Disseminated
pasteurized Leishmania promastigotes and bacil- mycobacterium avium-intracellulare complex
lus Calmette-Guerin: preliminary report. Mem Inst (MAC) infection in the era of effective antiretrovi-
Oswaldo Cruz. 2004;99:57–62. ral therapy: is prophylaxis still indicated? Drugs.
95. Ameen M. The potential of daylight-activated photo- 2004;64:679–92.
dynamic therapy for treating localized forms of cuta- 112. Safraneck TJ, Jarvis WR, Carson LA, Cusick LB,
neous leishmaniasis in resource-limited settings. Br J Bland LA, Swenson JM, Silcox VA. Myobacterirum
Dermatol. 2015;172:1192–3. chelonae wound infections after plastic surgery
10 Oral Signs of Tropical, Fungal, and Parasitic Diseases 225
employing contaminated gentian violet skin-mark- masses in children: investigation and conservative
ing solution. N Engl J Med. 1987;317:197–201. management. J Laryngol Otol. 1995;109:525–30.
113. Murillo J, Torres J, Bofill L, Ríos-Fabra A, Irausquin 117. Berkovic J, Vanchiere JA, Gungor A. Non tubercu-
E, Istúriz R, et al. Skin and wound infection by lous mycobacterial lesion of the parotid gland and
rapidly growing mycobacteria: an unexpected facial skin in a 4 year old girl: a proposed treatment
complication of liposuction and liposculpture. The strategy. Am J Otolaryngol. 2016;37:89–94.
Venezuelan Collaborative Infectious and Tropical 118. Bonali M, Mattioli F, Alicandri-Ciufelli M,
Diseases Study Group. Arch Dermatol. 2000;136: Presutti L. Atypical mycobacteriosis involving
1347–52. parotid and para-retropharyngeal spaces. Eur Arch
114. Robinson P, Farthing P, Scott GM, Bennett JH. Oral Otorhinolaryngol. 2016;273:4031–3.
Mycobacterium avium complex infection in a 119. Yamanaka T, Okamoto H, Hosoi H. Non-tuberculous
patient with HIV-related disease. A case report. mycobacterial infection of the parotid gland in an
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. immunocompetent elderly patient. BMJ Case Rep.
1996;81:177–9. 2013;16:2013.
115. Alagarswamy RK, Halfpenny W, Thiruchelvam JK, 120. Motswaledi MH, Khammissa RA, Jadwat Y, Lemmer
Mohamid W. Rare presentation of Mycobacterium J, Feller L. Oral sarcoidosis: a case report and review
avium-intracellulare infection. Br J Oral Maxillofac of the literature. Aust Dent J. 2014;59:389–94.
Surg. 2007;45:670–2. 121. Sharma P, Saxena S, Aggarwal P, Reddy
116. Cox HJ, Brightwell AP, Riordan T. Non-tuberculous V. Tuberculosis of odontogenic cyst. Indian J Tuberc.
mycobacterial infections presenting as salivary gland 2013;60:50–4.
Oral Signs of Genetic Disease
11
Julio C. Sartori-Valinotti and Jennifer L. Hand
Etiopathogenesis
Etiopathogenesis
Fig. 11.4 Follicular hyperkeratosis over the extensor
PC is an autosomal dominant disorder. Keratins elbow in a young man with pachyonychia congenita
are structural proteins usually expressed in pairs
[15]. The keratin pair K6b/K17 is expressed in
nails and the palmoplantar surface. Mutations in Oral Signs and Symptoms
either of these keratins cause PC type 2. Mutations
in either K16 or K6a cause PC type 1 [15]. The Oral lesions of PC are white, opaque thickenings
genes for keratin 6a and 6b are on chromosome 12, in small areas of the tongue or buccal mucosa
and the genes for keratin 16 and 17 are on chromo- (Fig. 11.5) or confluently covering the entire sur-
some 17. A clinical genetic test is available. face of the tongue, lips, and cheeks [14], with the
tongue being the most common location [16].
Oral leukokeratosis is seen in 70% of patients
Clinical Manifestations with genetically confirmed PC [17]. Onset at
birth has been reported in 54% of patients [17]
In PC type 1 (aka Jadassohn-Lewandowsky syn- and may represent the earliest manifestation of
drome), hyperkeratosis of the palms, soles, knees, the disease. It can also be exacerbated by or inter-
and elbows, follicular hyperkeratosis (Fig. 11.4), fere with breastfeeding [18]. The oral plaques
and hyperhidrosis of the hands and feet are asso- can be painful as a result of trauma due to food
ciated features. Oral leukokeratosis may be mild intake or entirely painless [18–20]. Involvement
or absent in PC type 2 (aka Jackson-Lawler syn- of the oropharynx may create a hoarse voice.
drome), which is associated with natal teeth, Histologic examination demonstrates acanthosis,
milder keratoderma, epidermal cysts, and steato- marked hyperkeratosis, and absence of the granu-
cysts. Oral leukokeratosis may be found but is lar layer. Malignant transformation of the leuko-
less marked than in PC type 1 [15]. keratosis has not been reported [14].
230 J. C. Sartori-Valinotti and J. L. Hand
Dyskeratosis Congenita
Epidemiology
Etiopathogenesis
Fig. 11.5 Leukokeratosis over the lateral tongue in a All forms of the disease are caused by a disorder in
young girl with pachyonychia congenita telomere maintenance and feature short telomeres.
Multiple genes with different mechanisms of inher-
Fifteen percent of patients with keratin 17 itance have been described. The most common
mutations have “natal teeth” compared to only type, X-linked DC, is caused by a mutation in
3% of patients with keratin 6a mutation and none DKC1, which encodes dyskerin, on chromosome
with keratin 6b or 16 [17]. Natal teeth are either Xq28. Autosomal dominant DC is due to heterozy-
soft or crumbly and rapidly lost or normal gous mutations in either TERT or TERC. Autosomal
appearing and persistent until permanent tooth recessive DC is caused by homozygous or com-
eruption [16]. Angular cheilitis and median pound heterozygous mutation in NOLA2, TCAB1,
rhomboid glossitis have been described in RTEL1, and TERT genes [25–27].
patients with PC [18, 21].
Clinical Manifestations
Differential Diagnosis
Typically, DC presents with a triad of reticulated
Oral leukokeratosis in PC can be mistaken for hyperpigmentation of the skin (usually neck and
white sponge nevus, oral leukoplakia, hairy chest), dystrophy of the nails, and oral leukopla-
tongue, and oral candidiasis [20]. Oral leuko- kia. In addition, patients have a predisposition to
keratosis is often misdiagnosed as thrush but hematologic abnormalities and bone marrow
does not improve with antifungal therapy. failure [28, 29]. Bone marrow failure is the chief
Interestingly, superinfection with C. albicans cause of early death. New treatments are under
has been described [14, 22]. In a patient reported development, but currently no treatments are
by Hannaford and Stapleton [22], lesions did not found to be uniformly effective in all patients
respond to anti-candidal treatment despite a pos- [28]. Patients with DC are also predisposed to
itive culture. pulmonary complications and malignancy.
Oral rehabilitation to eliminate the possibility of Oral leukoplakia is a diagnostic feature of this
chronic trauma to the oral mucosa may be accom- disorder and usually appears early in life in asso-
plished with the use of a well-designed prosthesis ciation with skin hyperpigmentation [29]. In a
or intraoral devices [20]. Systemic retinoids may cohort of 17 patients with DC, oral leukoplakia
lead to improvement of oral leukoplakia [23]. was noted in 65% of patients. Other findings
However, the development of side effects limits included decreased root/crown ratio and mild
its use in patients with PC [24]. taurodontism [30]. Leukoplakia is generally
11 Oral Signs of Genetic Disease 231
Differential Diagnosis
Treatment Recommendations
Rothmund-Thomson Syndrome
Epidemiology
Differential Diagnosis
Differential Diagnosis
Fig. 11.9 Telangiectasias of the lip in a man with heredi- In the setting of mucosal telangiectasias in a
tary hemorrhagic telangiectasia patient with a history of epistaxis, multiple cuta-
neous telangiectasias, and a positive family his-
not been elucidated. HHT5 is caused by hetero- tory, the diagnosis should be straightforward.
zygous mutation in the GDF2 gene (also known However, for atypical presentations, a high index
as BMP9) on chromosome 10q11 [49]. In addi- of suspicion is needed. Patients with hereditary
tion, mutations in SMAD4 on chromosome benign telangiectasia develop cutaneous plaque-
18q21 cause a form of HHT called juvenile pol- like, arborizing, radiating, or punctate telangiec-
yposis/hereditary hemorrhagic telangiectasia tasias beginning in childhood. However, there are
syndrome [50]. no mucosal or systemic vascular lesions [56].
HHT is characterized by multiple small and Patients should be educated on the importance of
large arteriovenous malformations that become avoiding oral trauma to prevent hemorrhage.
more prominent with age. The most common Vascular malformations are amenable to treat-
areas of involvement include the mucous mem- ment with sclerotherapy which obviates the need
branes, skin (Fig. 11.9), gastrointestinal tract, for more invasive surgical procedures and
liver, brain, and lung. Bleeding may cause sud- reduces the risk for postsurgical complications
den and devastating consequences. The earliest [52]. Nd:YAG laser has also been successfully
manifestation of the disease is epistaxis during used in the management of oral hemorrhage sec-
childhood [47]. ondary to telangiectasias [57]. Some authors
advocate the use of prophylactic antibiotics
before oral procedures using the same guidelines
Oral Signs and Symptoms as for patients at high risk of bacterial endocardi-
tis [55].
Oral lesions may be punctate, spider-like, or nod-
ular and can be found on the buccal mucosa,
tongue, lips, palate, and gingivae [51]. Punctate Hermansky-Pudlak Syndrome
telangiectasias on the tip of the tongue may be
the first sign to present in childhood. More lesions Epidemiology
usually develop after puberty. Color may vary
from bright red to purple [4] but in the oral Overall, the prevalence of Hermansky-Pudlak
mucosa is usually cherry red [51]. Presentation of syndrome (HPS) is very low with approximately
HHT as oral vascular malformations, hemor- 0.15 cases per 100,000 births. However, in Puerto
234 J. C. Sartori-Valinotti and J. L. Hand
Rico HPS likely represents the most frequent of this possibility, especially when practicing in
single-gene disorder. It is also prevalent in a vil- areas of high prevalence. Dental care practice
lage of canton Valais, Switzerland [58]. In Puerto recommendations including the use of protec-
Rico, the carrier frequency is estimated to be 1 in tive UV glasses, as to avoid excessive glare
21 [59]. from dental light, to administration of blood
derivatives to assist with hemostasis are avail-
able [64].
Etiopathogenesis
One of the most striking findings of the disease is The reported prevalence of Peutz-Jeghers syn-
the self-mutilating behavior with biting of the fin- drome (PJS) is 2.2 cases per 100,000 births [1].
gers and lips. The median age of onset is 2 years
when eruption of the primary dentition is almost
complete. The sites more frequently affected are Etiopathogenesis
the lower lip, inner cheeks, and tongue [67, 68].
The disorder is due to mutations in the serine/
threonine kinase, STK11, gene located at chro-
Differential Diagnosis mosomal locus 19p13 [73]. It is estimated that in
50% of cases, the condition is inherited from a
Self-injury with involvement of the oral and parent, and in 50% of cases, the condition is the
perioral regions and the hands may be seen in result of a new or de novo mutation [73]. A clini-
a variety of neurological disorders (congenital, cal genetic test is currently available for PJS.
posttraumatic, and degenerative), congenital
insensitivity pain with anhidrosis, and mental
retardation [69, 70]. Limeres et al. proposed that Clinical Manifestations
the pattern of oral self-injury is not disease spe-
cific [68]. As such, the diagnosis relies on other PJS is a genetic condition characterized by gas-
condition-specific findings, which are usually trointestinal polyposis and tan to dark brown or
apparent before self-mutilation ensues. Classic blue macules on the skin and oral mucosa
LNS features near complete absence of resid- (Figs. 11.10 and 11.11) [74]. Diagnosis is based
ual HPRT activity (less than 1.5%), whereas
patients with Kelley-Seegmiller syndrome have
a residual enzyme activity of at least 8%. The
latter group of patients develops gout after
puberty. Up to 25% of patients may have mild
neurologic abnormalities but no self-injurious
behavior [71].
Treatment Recommendations
Treatment Recommendations
The pigmented macules are usually present at birth PXE is an autosomal recessive condition due to
or are first noted in early childhood [74]. The mac- mutations in the ATP-binding cassette, subfamily
ules are usually found on the lips, buccal mucosa, C, member 6 (ABCC6) gene. ABCC6 belongs to
and perioral skin. In the mouth, they may also be the multidrug resistance-associated protein
found on the palate and tongue. On the skin, distri- (MRP) subfamily of ATP-binding cassette (ABC)
bution may include the face, dorsum of the hands, transmembrane transporters [80].
feet, fingers, eyes, umbilicus, and anus. Macules
may be found in a periorificial distribution around
the eyes in some patients. Skin macules are reported Clinical Manifestations
to fade with age, but the macules involving the oral
mucosa tend to be persistent [74]. The hallmark of the disease is the accumulation
of fragmented and calcified elastic fibers in the
skin, blood vessel walls, and Bruch’s membrane
Differential Diagnosis in the eye resulting in soft, ivory-colored papules
in a reticular pattern on the neck and intertriginous
Lentigines with a distribution similar to that of areas, as well as coronary artery occlusive disease,
PJS are found in Bandler syndrome and Laugier- gastrointestinal hemorrhage, and retinal angioid
Hunziker syndrome. Periorificial pigmented mac- streaks and choroidal neovascularizations [80].
ules are seen in Carney Complex. Centrofacial Carriers of heterozygous mutations in ABCC6
lentiginosis and inherited patterned lentigino- gene may present with partial manifestations of the
sis feature lentigines on the lips. Patients with disease.
11 Oral Signs of Genetic Disease 237
Epidemiology
Treatment Recommendations
atic and first noted at birth or in early childhood. sion protein that antagonizes the WNT signaling
The labial and gingival mucosa, the floor of the pathway [94]. It is inherited in an autosomal
mouth, or the entire oral cavity may be involved. dominant fashion.
While the lesions are painless, patients complain
of an altered texture of the mucosa or that the
lesions are cosmetically unappealing [89]. Clinical Manifestations
OI is characterized by varying degrees of bone Early institution of treatment will ensure good
fragility and low bone mass leading to multiple occlusion, adequate mandibular and maxillary
240 J. C. Sartori-Valinotti and J. L. Hand
Clinical Manifestations
faces of the central and lateral incisors and 12q23-q24.1. The SERCA2b pump specifically
canine teeth [145]. The prevalence of enamel maintains low cytosolic Ca(2+) concentrations
pits in patients with TS is thought to range by actively transporting Ca(2+) from the cytosol
from 48% to 100% [145, 149]. Smaller pits into the sarco/endoplasmic reticulum lumen of
can be better appreciated using dental plaque- keratinocytes [153, 154]. Gene penetrance may
disclosing stain on the surfaces of the teeth. be complete by age 10, but expressivity is vari-
Electron microscopy can also be used, once a able [155].
tooth has been extracted. Enamel pits may be
found on the teeth of otherwise healthy patients
but are usually fewer and less obvious. A study Clinical Manifestations
by Flanagan et al. [149] found that the major-
ity of patients with TSC had greater than 14 Disease onset is usually between the ages of
pits per person, whereas the majority of normal 6 and 20 years. The characteristic skin find-
controls had less than 6 pits per person. ings are brown, warty, hyperkeratotic, 2–4 mm
papules with predilection for the seborrheic
areas (scalp, forehead, trunk, and intertrigi-
Differential Diagnosis nous regions). Acral involvement is almost
universal (96% of patients) with palmar kera-
Oral fibromas can be misdiagnosed as fibrous totic plaques, palmoplantar pits, and acrokera-
hyperplasias, focal papillomas, hemangiomas, tosis verruciformis-like lesions on the dorsal
lymphangiomas, or lipomas [150]. hands [156]. The hyperkeratotic plaques are
often malodorous and moderately pruritic.
Nail changes include longitudinal erythro- and
Treatment Recommendations leukonychia, distal V-shaped notching, longi-
tudinal fissuring and ridging, and subungual
Oral fibromas may interfere with oral hygiene. hyperkeratotic fragments [157]. Interestingly,
As such, education on oral hygiene and dietary several neuropsychiatric conditions have
habits, fluoride therapy, and frequent in-office been documented in a subset of patients with
cleanings are advisable [151]. Surgical resection DD. Mild mental retardation, seizures, schizo-
of the most prominent ones could be considered phrenia, bipolar disorder, major depression,
on an individual basis. and suicidal attempts have been reported [156,
158, 159].
Darier Disease
Oral Signs and Symptoms
Epidemiology
The incidence of oral lesions in DD varies
Darier disease (DD) has an estimated prevalence between 15% (24/163) [156] and 50% (12/24)
of 1 in 55,000. Disease onset is usually before the [160]. Lesions are painless, whitish, coalescing
third decade of life [152]. papules, primarily present on the palate (most
common location), followed by the gingiva, oral
mucosa, and tongue [160]. The severity of oral
Etiopathogenesis involvement seems to mirror that of cutaneous
disease. Parotid gland swelling has also been
DD, an autosomal dominant disorder, results described but only in patients with concomitant
from a heterozygous mutation in the ATP2A2 oral involvement [160]. Most recently, esopha-
gene, which encodes the sarcoplasmic reticulum geal affliction, including carcinoma, has been
Ca(2+)-ATPase-2 (SERCA2), on chromosome noted [161, 162].
11 Oral Signs of Genetic Disease 243
Ehlers-Danlos Syndrome
Oral Signs and Symptoms
Epidemiology
About 50% of EDS patients are able to touch
The prevalence of Ehlers-Danlos syndrome their nasal tip with their tongue compared to 10%
(EDS) is approximately 1 in 5000–10,000. There of the general population, the so-called Gorlin’s
is no racial predilection [163]. sign. Absence of the inferior labial frenulum has
a 100% sensitivity, whereas absence of the lin-
gual frenulum has a 100% specificity for the EDS
Etiopathogenesis types I, II, and III [164].
The most comprehensive review on the oral
Mutations in collagen and collagen-processing manifestations of EDS is by Abel and Carrasco
enzymes are responsible for the various pheno- [163]. Patients may present with periodontal
types of the disease. EDS types 1 and 2 are caused disease with early-onset periodontitis, gingival
by mutations in either the collagen alpha-1(V) fibrinoid deposits, and bleeding as well as
gene (COL5A1) on chromosome 9q34 or the col- increased tooth mobility, congenital absence of
lagen alpha-2(V) gene (COL5A2) on chromo- teeth, and supernumerary teeth. Teeth can be
some 2q31. EDS type 3 is caused by mutation in small, irregularly placed with short, malformed,
the tenascin-XB or COL3A1 genes. Mutations in or dilacerated roots. Enamel hypoplasia and
COL3A1 genes are also responsible for EDS dentin structural irregularities are also observed
type 4. EDS type 6 is due to mutations in lysyl and may render teeth prone to dental caries
hydroxylase (PLOD1) on chromosome 1. Lastly, [165]. Hemorrhagic bulla of the oral mucosa as
mutations in COL1A1, COL1A2, and procolla- an early manifestation of EDS type 4 (vascular
gen protease ADAMTS2 cause EDS type 7A, 7B, type) has been reported [166]. KCOTs can be
and 7C, respectively [163]. EDS can be inherited found in association with supernumerary teeth
in an autosomal or recessive fashion. [167]. Patients with EDS type 4 may also expe-
rience tooth loss following orthodontic treat-
ment due to severe destruction of the periodontal
Clinical Manifestations support [168].
Hypermobility of the temporomandibular
EDS is a group of connective tissue disorders joint (TMJ) is a frequent sign [169] as is pain in
with shared features including skin hyperextensi- the masticatory muscles upon mouth opening.
244 J. C. Sartori-Valinotti and J. L. Hand
11. Doruk C, Bicakci AA, Babacan H. Orthodontic and erase component NHP2 cause the premature ageing
orthopedic treatment of a patient with incontinentia syndrome dyskeratosis congenita. Proc Natl Acad Sci
pigmenti. Angle Orthod. 2003;73(6):763–8. U S A. 2008;105(23):8073–8.
12. Yamashiro T, Nakagawa K, Takada K. Case report: 28. Dokal I. Dyskeratosis congenita: recent advances
orthodontic treatment of dental problems in inconti- and future directions. J Pediatr Hematol Oncol.
nentia pigmenti. Angle Orthod. 1998;68(3):281–4. 1999;21(5):344–50.
13. McLean WH, Hansen CD, Eliason MJ, Smith FJ. The 29. Solder B, Weiss M, Jäger A, Belohradsky BH.
phenotypic and molecular genetic features of pachyo- Dyskeratosis congenita: multisystemic disorder with
nychia congenita. J Invest Dermatol. 2011;131(5): special consideration of immunologic aspects. A review
1015–7. of the literature. Clin Pediatr. 1998;37(9):521–30.
14.
Dahl PR, Daoud MS, Su WP. Jadassohn- 30. Atkinson JC, Harvey KE, Domingo DL, Trujillo
Lewandowski syndrome (pachyonychia congenita). MI, Guadagnini JP, Gollins S, et al. Oral and den-
Semin Dermatol. 1995;14(2):129–34. tal phenotype of dyskeratosis congenita. Oral Dis.
15. Smith FJ, Coleman CM, Bayoumy NM, Tenconi R, 2008;14(5):419–27.
Nelson J, David A, et al. Novel keratin 17 mutations 31. Fernandez Garcia MS, Teruya-Feldstein J. The diag-
in pachyonychia congenita type 2. J Invest Dermatol. nosis and treatment of dyskeratosis congenita: a
2001;116(5):806–8. review. J Blood Med. 2014;5:157–67.
16. Shah S, Boen M, Kenner-Bell B, Schwartz M, 32. Yavuzyilmaz E, Yamalik N, Yetgin S, Kansu O. Oral-
Rademaker A, Paller AS. Pachyonychia congenita dental findings in dyskeratosis congenita. J Oral
in pediatric patients: natural history, features, and Pathol Med. 1992;21(6):280–4.
impact. JAMA Dermatol. 2014;150(2):146–53. 33. Vohra F, Al-Kheraif AA, Qadri T, Hassan MI, Ahmed
17. Eliason MJ, Leachman SA, Feng BJ, Schwartz ME, A, Warnakulasuriya S, et al. Efficacy of photodynamic
Hansen CD. A review of the clinical phenotype of therapy in the management of oral premalignant
254 patients with genetically confirmed pachyo- lesions. A systematic review. Photodiagn Photodyn
nychia congenita. J Am Acad Dermatol. 2012;67(4): Ther. 2015;12(1):150–9.
680–6. 34. Tambuwala A, Sangle A, Khan A, Sayed A. Excision
18. Leachman SA, Kaspar RL, Fleckman P, Florell SR, of oral leukoplakia by CO2 lasers versus traditional
Smith FJ, McLean WH, et al. Clinical and patho- scalpel: a comparative study. J Maxillofac Oral Surg.
logical features of pachyonychia congenita. J Investig 2014;13(3):320–7.
Dermatol Symp Proc. 2005;10(1):3–17. 35. Kitao S, Shimamoto A, Goto M, Miller RW, Smithson
19. Su WP, Chun SI, Hammond DE, Gordon H.
WA, Lindor NM, et al. Mutations in RECQL4 cause
Pachyonychia congenita: a clinical study of 12 a subset of cases of Rothmund-Thomson syndrome.
cases and review of the literature. Pediatr Dermatol. Nat Genet. 1999;22(1):82–4.
1990;7(1):33–8. 36. Mann MB, Hodges CA, Barnes E, Vogel H, Hassold
20. da Silva Santos PS, Mannarino F, Lellis RF, Osório TJ, Luo G. Defective sister-chromatid cohesion, aneu-
LH. Oral manifestations of pachyonychia congenita. ploidy and cancer predisposition in a mouse model of
Dermatol Online J. 2010;16(10):3. type II Rothmund-Thomson syndrome. Hum Mol
21. Karen JK, Schaffer JV. Pachyonychia congenita asso- Genet. 2005;14(6):813–25.
ciated with median rhomboid glossitis. Dermatol 37. Simon T, Kohlhase J, Wilhelm C, Kochanek M, De
Online J. 2007;13(1):21. Carolis B, Berthold F. Multiple malignant diseases
22. Hannaford RS, Stapleton K. Pachyonychia congenita in a patient with Rothmund-Thomson syndrome with
tarda. Australas J Dermatol. 2000;41(3):175–7. RECQL4 mutations: case report and literature review.
23. Rondon Lugo AJ. Congenital pachyonychia treated Am J Med Genet A. 2010;152A(6):1575–9.
by oral retinoid. Med Cutanea Ibero-Lat-Am. 38. Pujol LA, Erickson RP, Heidenreich RA, Cunniff
1982;10(6):395–8. C. Variable presentation of Rothmund-Thomson syn-
24. Gruber R, Edlinger M, Kaspar RL, Hansen CD,
drome. Am J Med Genet. 2000;95(3):204–7.
Leachman S, Milstone LM, et al. An appraisal of oral 39. Wang LL, Levy ML, Lewis RA, Chintagumpala MM,
retinoids in the treatment of pachyonychia congenita. Lev D, Rogers M, et al. Clinical manifestations in a
J Am Acad Dermatol. 2012;66(6):e193–9. cohort of 41 Rothmund-Thomson syndrome patients.
25.
Kirwan M, Dokal I. Dyskeratosis congenita: Am J Med Genet. 2001;102(1):11–7.
a genetic disorder of many faces. Clin Genet. 40. Thomson MS. Poikiloderma congenitale: two cases
2008;73(2):103–12. for diagnosis. Proc R Soc Med. 1936;29(5):453–5.
26. Lamm N, Ordan E, Shponkin R, Richler C, Aker 41. Kraus BS, Gottlieb MA, Meliton HR. The denti-
M, Tzfati Y. Diminished telomeric 3′ overhangs are tion in Rothmund’s syndrome. J Am Dent Assoc.
associated with telomere dysfunction in Hoyeraal- 1970;81(4):895–915.
Hreidarsson syndrome. PLoS One. 2009;4(5): 42. Starr DG, McClure JP, Connor JM. Non-
e5666. dermatological complications and genetic aspects
27. Vulliamy T, Beswick R, Kirwan M, Marrone A,
of the Rothmund-Thomson syndrome. Clin Genet.
Digweed M, Walne A, et al. Mutations in the telom- 1985;27(1):102–4.
248 J. C. Sartori-Valinotti and J. L. Hand
43. Haytac MC, Oztunç H, Mete UO, Kaya M. Rothmund- of epistaxis and oral hemorrhage by Nd-Yag laser.
Thomson syndrome: a case report. Oral Surg Oral Minerva Stomatol. 1998;47(6):283–6.
Med Oral Pathol Oral Radiol Endod. 2002;94(4): 58. Schallreuter KU, Frenk E, Wolfe LS, Witkop CJ,
479–84. Wood JM. Hermansky-Pudlak syndrome in a Swiss
44. Roinioti TD, Stefanopoulos PK. Short root anomaly population. Dermatology. 1993;187(4):248–56.
associated with Rothmund-Thomson syndrome. 59.
Wildenberg SC, Oetting WS, Almodóvar C,
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Krumwiede M, White JG, King RA. A gene causing
2007;103(1):e19–22. Hermansky-Pudlak syndrome in a Puerto Rican popu-
45.
Kant SG, Baraitser M, Milla PJ, Winter lation maps to chromosome 10q2. Am J Hum Genet.
RM. Rapadilino syndrome – a non-Finnish case. Clin 1995;57(4):755–65.
Dysmorphol. 1998;7(2):135–8. 60. Oh J, Bailin T, Fukai K, Feng GH, Ho L, Mao JI, et al.
46. Vargas FR, de Almeida JC, Llerena Júnior JC,
Positional cloning of a gene for Hermansky-Pudlak
Reis DF. Rapadilino syndrome. Am J Med Genet. syndrome, a disorder of cytoplasmic organelles. Nat
1992;44(6):716–9. Genet. 1996;14(3):300–6.
47. Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff 61. Oh J, Ho L, Ala-Mello S, Amato D, Armstrong L,
UW, McDonald J, Proctor DD, et al. International Bellucci S, et al. Mutation analysis of patients with
guidelines for the diagnosis and management of Hermansky-Pudlak syndrome: a frameshift hot spot in
hereditary haemorrhagic telangiectasia. J Med Genet. the HPS gene and apparent locus heterogeneity. Am J
2011;48(2):73–87. Hum Genet. 1998;62(3):593–8.
48. McDonald JE, Miller FJ, Hallam SE, Nelson L,
62. Kinnear PE, Tuddenham EG. Albinism with haemor-
Marchuk DA, Ward KJ. Clinical manifestations in a rhagic diathesis: Hermansky-Pudlak syndrome. Br J
large hereditary hemorrhagic telangiectasia (HHT) Ophthalmol. 1985;69(12):904–8.
type 2 kindred. Am J Med Genet. 2000;93(4): 63. Theuring F, Fiedler J. Fatal bleeding following tooth
320–7. extraction. Hermansky-Pudlak-syndrome. Dtsch
49. Wooderchak-Donahue WL, McDonald J, O’Fallon B, Stomatol. 1973;23(1):52–5.
Upton PD, Li W, Roman BL, et al. BMP9 mutations 64. Feliciano NZ, Rivera E, Agrait E, Rodriguez
cause a vascular-anomaly syndrome with phenotypic K. Hermansky-Pudlak syndrome: dental management
overlap with hereditary hemorrhagic telangiectasia. considerations. J Dent Child. 2006;73(1):51–6.
Am J Hum Genet. 2013;93(3):530–7. 65. Valera MC, Kemoun P, Cousty S, Sie P, Payrastre
50. Schwenter F, Faughnan ME, Gradinger AB, Berk T, B. Inherited platelet disorders and oral health. J Oral
Gryfe R, Pollett A, et al. Juvenile polyposis, heredi- Pathol Med. 2013;42(2):115–24.
tary hemorrhagic telangiectasia, and early onset 66. Keebaugh AC, Sullivan RT, Thomas JW. Gene dupli-
colorectal cancer in patients with SMAD4 mutation. cation and inactivation in the HPRT gene family.
J Gastroenterol. 2012;47(7):795–804. Genomics. 2007;89(1):134–42.
51. Austin GB, Quart AM, Novak B. Hereditary hemor- 67. Torres RJ, Puig JG. Hypoxanthine-guanine phospho-
rhagic telangiectasia with oral manifestations. Report ribosyltransferase (HPRT) deficiency: Lesch-Nyhan
of periodontal treatment in two cases. Oral Surg Oral syndrome. Orphanet J Rare Dis. 2007;2:48.
Med Oral Pathol. 1981;51(3):245–51. 68. Limeres J, Feijoo JF, Baluja F, Seoane JM, Diniz M,
52. Hopp RN, de Siqueira DC, Sena-Filho M, Jorge
Diz P. Oral self-injury: an update. Dent Traumatol.
J. Oral vascular malformation in a patient with heredi- 2013;29(1):8–14.
tary hemorrhagic telangiectasia: a case report. Spec 69. Bodner L, Woldenberg Y, Pinsk V, Levy J. Orofacial
Care Dent. 2013;33(3):150–3. manifestations of congenital insensitivity to pain with
53. Haitjema TJ, van Snippenburg R, Disch FJ, Overtoom anhidrosis: a report of 24 cases. ASDC J Dent Child.
TT, Westermann CJ. Recurrent epistaxis: sometimes 2002;69(3):293–6.. 235
Rendu-Osler-Weber disease. Ned Tijdschr Geneeskd. 70. Rojahn J. Self-injurious and stereotypic behavior
1996;140(44):2157–60. of noninstitutionalized mentally retarded people:
54. Mylona E, Vadala C, Papastamopoulos V, Skoutelis prevalence and classification. Am J Ment Defic.
A. Brain abscess caused by Enterococcus faecalis 1986;91(3):268–76.
following a dental procedure in a patient with heredi- 71. Brunner J, Lotschutz D. Kelley-Seegmiller syndrome.
tary hemorrhagic telangiectasia. J Clin Microbiol. Klin Padiatr. 2008;220(1):21–3.
2012;50(5):1807–9. 72. Cusumano FJ, Penna KJ, Panossian G. Prevention
55. Corre P, Perret C, Isidor B, Khonsari RH. A brain of self-mutilation in patients with Lesch-Nyhan
abscess following dental extractions in a patient with syndrome: review of literature. ASDC J Dent Child.
hereditary hemorrhagic telangiectasia. Br J Oral 2001;68(3):175–8.
Maxillofac Surg. 2011;49(5):e9–11. 73. Amos CI, Bali D, Thiel TJ, Anderson JP, Gourley I,
56. Brancati F, Valente EM, Tadini G, Caputo V, Di
Frazier ML, et al. Fine mapping of a genetic locus for
Benedetto A, Gelmetti C, et al. Autosomal dominant Peutz-Jeghers syndrome on chromosome 19p. Cancer
hereditary benign telangiectasia maps to the CMC1 Res. 1997;57(17):3653–6.
locus for capillary malformation on chromosome 74. Kitagawa S, Townsend BL, Hebert AA. Peutz-Jeghers
5q14. J Med Genet. 2003;40(11):849–53. syndrome. Dermatol Clin. 1995;13(1):127–33.
57. Galletta A, Amato G. Hereditary hemorrhagic telan- 75. Boardman LA, Thibodeau SN, Schaid DJ, Lindor
giectasia (Osler-Rendu-Weber disease) management NM, McDonnell SK, Burgart LJ, et al. Increased risk
11 Oral Signs of Genetic Disease 249
for cancer in patients with the Peutz-Jeghers syn- of oral white sponge nevus occurring in a patient
drome. Ann Intern Med. 1998;128(11):896–9. with systemic lupus erythematosus. Int J Dermatol.
76. Li Y, Tong X, Yang J, Yang L, Tao J, Tu Y. Q-switched 2006;45(9):1130–1.
alexandrite laser treatment of facial and labial lentigines 92. Satriano RA, Errichetti E, Baroni A. White sponge
associated with Peutz-Jeghers syndrome. Photodermatol nevus treated with chlorhexidine. J Dermatol.
Photoimmunol Photomed. 2012;28(4):196–9. 2012;39(8):742–3.
77. Xi Z, Hui Q, Zhong L. Q-switched alexandrite laser 93. Dufrasne L, Magremanne M, Parent D, Evrard
treatment of oral labial lentigines in Chinese sub- L. Current therapeutic approach of the white sponge
jects with Peutz-Jeghers syndrome. Dermatol Surg. naevus of the oral cavity. Bull Group Int Rech Sci
2009;35(7):1084–8. Stomatol Odontol. 2011;50(1):1–5.
78. Chang CJ, Nelson JS. Q-switched ruby laser treat- 94. Kinzler KW, Nilbert MC, Su LK, Vogelstein B,
ment of mucocutaneous melanosis associated with Bryan TM, Levy DB, et al. Identification of FAP
Peutz-Jeghers syndrome. Ann Plast Surg. 1996;36(4): locus genes from chromosome 5q21. Science.
394–7. 1991;253(5020):661–5.
79. Finger RP, Charbel Issa P, Ladewig MS, Götting C, 95. Petersen GM, Slack J, Nakamura Y. Screening guide-
Szliska C, Scholl HP, et al. Pseudoxanthoma elasti- lines and premorbid diagnosis of familial adeno-
cum: genetics, clinical manifestations and therapeutic matous polyposis using linkage. Gastroenterology.
approaches. Surv Ophthalmol. 2009;54(2):272–85. 1991;100(6):1658–64.
80. Bergen AA, Plomp AS, Schuurman EJ, Terry S,
96. Traboulsi EI, Maumenee IH, Krush AJ, Giardiello
Breuning M, Dauwerse H, et al. Mutations in ABCC6 FM, Levin LS, Hamilton SR. Pigmented ocular
cause pseudoxanthoma elasticum. Nat Genet. fundus lesions in the inherited gastrointestinal pol-
2000;25(2):228–31. yposis syndromes and in hereditary nonpolyposis
81. Spinzi G, Strocchi E, Imperiali G, Sangiovanni
colorectal cancer. Ophthalmology. 1988;95(7):
A, Terruzzi V, Minoli G. Pseudoxanthoma elasti- 964–9.
cum: a rare cause of gastrointestinal bleeding. Am J 97. Jagelman DG. Extracolonic manifestations of famil-
Gastroenterol. 1996;91(8):1631–4. ial polyposis coli. Semin Surg Oncol. 1987;3(2):
82. Goette DK, Carpenter WM. The mucocutaneous
88–91.
marker of pseudoxanthoma elasticum. Oral Surg Oral 98. Fader M, Kline SN, Spatz SS, Zubrow HJ. Gardner’s
Med Oral Pathol. 1981;51(1):68–72. syndrome (intestinal polyposis, osteomas, sebaceous
83. Sayin MO, Atilla AO, Esenlik E, Ozen T, Karahan cysts) and a new dental discovery. Oral Surg Oral
N. Oligodontia in pseudoxanthoma elasticum. Oral Med Pathol. 1962;15:153–72.
Surg Oral Med Oral Pathol Oral Radiol Endod. 99. Ida M, Nakamura T, Utsunomiya J. Osteomatous
2007;103(5):e60–4. changes and tooth abnormalities found in the jaw
84. Utani A, Tanioka M, Yamamoto Y, Taki R, Araki E, of patients with adenomatosis coli. Oral Surg
Tamura H, et al. Relationship between the distribu- Oral Med Pathol. 1962;15:153–72.. 1981. 52(1):
tion of pseudoxanthoma elasticum skin and mucous 2–11
membrane lesions and cardiovascular involvement. J 100. Kubo K, Miyatani H, Takenoshita Y, Abe K, Oka M,
Dermatol. 2010;37(2):130–6. Iida M, et al. Widespread radiopacity of jaw bones in
85. Sherer DW, Sapadin AN, Lebwohl MG. Pseudoxanthoma familial adenomatosis coli. J Craniomaxillofac Surg.
elasticum: an update. Dermatology. 1999;199(1):3–7. 1989;17(8):350–3.
86. Shibuya Y, Zhang J, Yokoo S, Umeda M, Komori 101. Wijn MA, Keller JJ, Giardiello FM, Brand HS. Oral
T. Constitutional mutation of keratin 13 gene in familial and maxillofacial manifestations of familial adeno-
white sponge nevus. Oral Surg Oral Med Oral Pathol matous polyposis. Oral Dis. 2007;13(4):360–5.
Oral Radiol Endod. 2003;96(5):561–5. 102. Lew D, DeWitt A, Hicks RJ, Cavalcanti
87. Rugg EL, McLean WH, Allison WE, Lunny DP,
MG. Osteomas of the condyle associated with
Macleod RI, Felix DH, et al. A mutation in the muco- Gardner’s syndrome causing limited mandibular
sal keratin K4 is associated with oral white sponge movement. J Oral Maxillofac Surg. 1999;57(8):
nevus. Nat Genet. 1995;11(4):450–2. 1004–9.
88. Richard G, De Laurenzi V, Didona B, Bale SJ,
103. Jones EL, Cornell WP. Gardner’s syndrome; review
Compton JG. Keratin 13 point mutation underlies the of the literature and report on a family. Arch Surg.
hereditary mucosal epithelial disorder white sponge 1966;92(2):287–300.
nevus. Nat Genet. 1995;11(4):453–5. 104. Payne M, Anderson JA, Cook J. Gardner’s syn-
89. Lamey PJ, Bolas A, Napier SS, Darwazeh AM,
drome – a case report. Br Dent J. 2002;193(7):
Macdonald DG. Oral white sponge naevus: 383–4.
response to antibiotic therapy. Clin Exp Dermatol. 105. Wijn MA, Keller JJ, Brand HS. Oral and maxillofa-
1998;23(2):59–63. cial manifestations of familial adenomatosis polypo-
90. Otobe IF, de Sousa SO, Matthews RW, Migliari sis. Gardner’s syndrome. Ned Tijdschr Tandheelkd.
DA. White sponge naevus: improvement with tetra- 2005;112(9):340–4.
cycline mouth rinse: report of four cases. Clin Exp 106. Boffano P, Bosco GF, Gerbino G. The surgical
Dermatol. 2007;32(6):749–51. management of oral and maxillofacial manifesta-
91. Otobe IF, de Sousa SO, Migliari DA, Matthews tions of Gardner syndrome. J Oral Maxillofac Surg.
RW. Successful treatment with topical tetracycline 2010;68(10):2549–54.
250 J. C. Sartori-Valinotti and J. L. Hand
107. Stevenson DA, Carey JC, Byrne JL, 123. Smith MJ, Beetz C, Williams SG, Bhaskar SS,
Srisukhumbowornchai S, Feldkamp ML. Analysis O’Sullivan J, Anderson B, et al. Germline muta-
of skeletal dysplasias in the Utah population. Am J tions in SUFU cause Gorlin syndrome-associated
Med Genet A. 2012;158A(5):1046–54. childhood medulloblastoma and redefine the risk
108. Stoll C, Dott B, Roth MP, Alembik Y. Birth preva- associated with PTCH1 mutations. J Clin Oncol.
lence rates of skeletal dysplasias. Clin Genet. 2014;32(36):4155–61.
1989;35(2):88–92. 124. Fujii K, Miyashita T. Gorlin syndrome (nevoid basal
109. Harrington J, Sochett E, Howard A. Update on the cell carcinoma syndrome): update and literature
evaluation and treatment of osteogenesis imperfecta. review. Pediatr Int. 2014;56(5):667–74.
Pediatr Clin N Am. 2014;61(6):1243–57. 125. Kimonis VE, Goldstein AM, Pastakia B, Yang ML,
110. Bodian DL, Chan TF, Poon A, Schwarze U, Yang K, Kase R, DiGiovanna JJ, et al. Clinical manifesta-
Byers PH, et al. Mutation and polymorphism spec- tions in 105 persons with nevoid basal cell carci-
trum in osteogenesis imperfecta type II: implications noma syndrome. Am J Med Genet. 1997;69(3):
for genotype-phenotype relationships. Hum Mol 299–308.
Genet. 2009;18(3):463–71. 126. Levine DJ, Robertson DB, Varma VA. Familial
111. Paterson CR, Monk EA, McAllion SJ. How common subconjunctival epithelial cysts associated with
is hearing impairment in osteogenesis imperfecta? J the nevoid basal cell carcinoma syndrome. Arch
Laryngol Otol. 2001;115(4):280–2. Dermatol. 1987;123(1):23–4.
112. Bonita RE, Cohen IS, Berko BA. Valvular heart dis- 127. Gorlin RJ, Goltz RW. Multiple nevoid basal-cell
ease in osteogenesis imperfecta: presentation of a epithelioma, jaw cysts and bifid rib. A syndrome. N
case and review of the literature. Echocardiography. Engl J Med. 1960;262:908–12.
2010;27(1):69–73. 128. Evans DG, Sims DG, Donnai D. Family implica-
113. Charnas LR, Marini JC. Communicating hydro- tions of neonatal Gorlin’s syndrome. Arch Dis Child.
cephalus, basilar invagination, and other neurologic 1991;66(10. Spec No):1162–3.
features in osteogenesis imperfecta. Neurology. 129. Lile HA, Rogers JF, Gerald B. The basal cell nevus
1993;43(12):2603–8. syndrome. Am J Roentgenol Radium Ther Nucl
114. O’Connell AC, Marini JC. Evaluation of oral prob- Med. 1968;103(1):214–7.
lems in an osteogenesis imperfecta population. Oral 130. Wright JM, Odell EW, Speight PM, Takata
Surg Oral Med Oral Pathol Oral Radiol Endod. T. Odontogenic tumors, WHO 2005: where do we
1999;87(2):189–96. go from here? Head Neck Pathol. 2014;8(4):373–82.
115. Majorana A, Bardellini E, Brunelli PC, Lacaita M, 131. Lo Muzio L, Nocini P, Bucci P, Pannone G, Consolo
Cazzolla AP, Favia G. Dentinogenesis imperfecta U, Procaccini M. Early diagnosis of nevoid basal
in children with osteogenesis imperfecta: a clini- cell carcinoma syndrome. J Am Dent Assoc.
cal and ultrastructural study. Int J Paediatr Dent. 1999;130(5):669–74.
2010;20(2):112–8. 132. Brannon RB. The odontogenic keratocyst. A clini-
116. Barron MJ, McDonnell ST, Mackie I, Dixon MJ. copathologic study of 312 cases. Part I. Clinical
Hereditary dentine disorders: dentinogenesis imper- features. Oral Surg Oral Med Oral Pathol.
fecta and dentine dysplasia. Orphanet J Rare Dis. 1976;42(1):54–72.
2008;3:31. 133. Habibi A, Saghravanian N, Habibi M, Mellati
117. Abukabbos H, Al-Sineedi F. Clinical manifestations E, Habibi M. Keratocystic odontogenic tumor: a
and dental management of dentinogenesis imper- 10-year retrospective study of 83 cases in an Iranian
fecta associated with osteogenesis imperfecta: case population. J Oral Sci. 2007;49(3):229–35.
report. Saudi Dent J. 2013;25(4):159–65. 134. Evans DG, Ladusans EJ, Rimmer S, Burnell LD,
118. Sapir S, Shapira J. Dentinogenesis imperfecta: an early Thakker N, Farndon PA. Complications of the nae-
treatment strategy. Pediatr Dent. 2001;23(3):232–7. void basal cell carcinoma syndrome: results of a pop-
119. Mars M, Smith BG. Dentinogenesis imperfecta. An ulation based study. J Med Genet. 1993;30(6):460–4.
integrated conservative approach to treatment. Br 135. Kimonis VE, Singh KE, Zhong R, Pastakia B,
Dent J. 1982;152(1):15–8. Digiovanna JJ, Bale SJ. Clinical and radiologi-
120. Bencharit S, Border MB, Mack CR, Byrd WC, cal features in young individuals with nevoid
Wright JT. Full-mouth rehabilitation for a patient basal cell carcinoma syndrome. Genet Med.
with dentinogenesis imperfecta: a clinical report. J 2013;15(1):79–83.
Oral Implantol. 2014;40(5):593–600. 136. Leonardi R, Sorge G, Caltabino M. Bilateral hyper-
121. Evans DG, Howard E, Giblin C, Clancy T, Spencer plasia of the mandibular coronoid processes associ-
H, Huson SM, et al. Birth incidence and prevalence ated with the nevoid basal cell carcinoma syndrome
of tumor-prone syndromes: estimates from a UK in an Italian boy. Br Dent J. 2001;190(7):349–50.
family genetic register service. Am J Med Genet A. 137. Roopak B, Singh M, Shah A, Patel G. Keratocystic
2010;152A(2):327–32. odontogenic tumor: treatment modalities: study of 3
122. Shanley S, Ratcliffe J, Hockey A, Haan E, Oley C, cases. Niger J Clin Pract. 2014;17(3):378–83.
Ravine D, et al. Nevoid basal cell carcinoma syn- 138. Sembronio S, Albiero AM, Zerman N, Costa F, Politi
drome: review of 118 affected individuals. Am J M. Endoscopically assisted enucleation and curet-
Med Genet. 1994;50(3):282–90. tage of large mandibular odontogenic keratocyst.
11 Oral Signs of Genetic Disease 251
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 155. Munro CS. The phenotype of Darier’s disease: pen-
2009;107(2):193–6. etrance and expressivity in adults and children. Br J
139. Terranova F, Trevisiol L, Nocini PF, Bissolotti G, Bondì Dermatol. 1992;127(2):126–30.
V, De Santis D, Bertossi D, D’agostino A. Keratocyst, 156. Burge SM, Wilkinson JD. Darier-White disease: a
conservative treatment: case report. Minerva Stomatol. review of the clinical features in 163 patients. J Am
2013;62(8 Suppl 1):71–8. Epub 2013 Aug 1. Acad Dermatol. 1992;27(1):40–50.
140. Nakayama T, Otori N, Asaka D, Okushi T, Haruna 157. Burge S. Darier’s disease – the clinical fea-
S. Endoscopic modified medial maxillectomy tures and pathogenesis. Clin Exp Dermatol.
for odontogenic cysts and tumours. Rhinology. 1994;19(3):193–205.
2014;52(4):376–80. 158. Craddock N, Dawson E, Burge S, Parfitt L, Mant
141. Gene Reviews. Nevoid basal cell carcinoma syn- B, Roberts Q, et al. The gene for Darier’s disease
drome. 2013. 12/08/2014. Available from: http:// maps to chromosome 12q23-q24.1. Hum Mol Genet.
www.ncbi.nlm.nih.gov/books/NBK1151/. 1993;2(11):1941–3.
142. Hallett L, Foster T, Liu Z, Blieden M, Valentim 159. Gordon-Smith K, Jones LA, Burge SM, Munro
J. Burden of disease and unmet needs in tuber- CS, Tavadia S, Craddock N. The neuropsychiat-
ous sclerosis complex with neurological manifes- ric phenotype in Darier disease. Br J Dermatol.
tations: systematic review. Curr Med Res Opin. 2010;163(3):515–22.
2011;27(8):1571–83. 160. Macleod RI, Munro CS. The incidence and distribu-
143. Osborne JP, Fryer A, Webb D. Epidemiology of tuber- tion of oral lesions in patients with Darier’s disease.
ous sclerosis. Ann N Y Acad Sci. 1991;615:125–7. Br Dent J. 1991;171(5):133–6.
144. Curatolo P, Bombardieri R, Jozwiak S. Tuberous 161. Thiagarajan MK, Narasimhan M, Sankarasubra-
sclerosis. Lancet. 2008;372(9639):657–68. manian A. Darier disease with oral and esopha-
145. Cutando A, Gil JA, Lopez J. Oral health manage- geal involvement: a case report. Indian J Dent Res.
ment implications in patients with tuberous scle- 2011;22(6):843–6.
rosis. Oral Surg Oral Med Oral Pathol Oral Radiol 162. Shimizu H, Tan Kinoshita MT, Suzuki H. Darier’s
Endod. 2000;90(4):430–5. disease with esophageal carcinoma. Eur J Dermatol.
146. Gomez MR. History of the tuberous sclerosis com- 2000;10(6):470–2.
plex. Brain Dev. 1995;17(Suppl):55–7. 163. Abel MD, Carrasco LR. Ehlers-Danlos syndrome:
147. Teng JM, Cowen EW, Wataya-Kaneda M, Gosnell classifications, oral manifestations, and dental con-
ES, Witman PM, Hebert AA, et al. Dermatologic and siderations. Oral Surg Oral Med Oral Pathol Oral
dental aspects of the 2012 International Tuberous Radiol Endod. 2006;102(5):582–90.
Sclerosis Complex Consensus Statements. JAMA 164. De Felice C, Toti P, Di Maggio G, Parrini S,
Dermatol. 2014;150(10):1095–101. Bagnoli F. Absence of the inferior labial and lin-
148. Tillman HH, De Caro F. Tuberous sclerosis. Oral gual frenula in Ehlers-Danlos syndrome. Lancet.
Surg Oral Med Oral Pathol. 1991;71(3):301–2. 2001;357(9267):1500–2.
149. Flanagan N, O’Connor WJ, McCartan B, Miller S, 165. Majorana A, Facchetti F. The orodental findings in
McMenamin J, Watson R. Developmental enamel the Ehlers-Danlos syndrome. A report of 2 clinical
defects in tuberous sclerosis: a clinical genetic cases. Minerva Stomatol. 1992;41(3):127–33.
marker? J Med Genet. 1997;34(8):637–9. 166. Colebatch AN, Shaw EC, Foulds NC, Davidson
150. Valerio RA, de Queiroz AM, Romualdo PC, BK. Hemorrhagic bullae of the oral mucosa as an
Brentegani LG, de Paula-Silva FW. Mucocele and early manifestation of vascular-type ehlers-danlos
fibroma: treatment and clinical features for differen- syndrome. J Clin Rheumatol. 2011;17(7):383–4.
tial diagnosis. Braz Dent J. 2013;24(5):537–41. 167. Ferreira O Jr, Cardoso CL, Capelozza AL, Yaedú RY,
151. Ammari MM, Ribeiro de Souza IP, Maia LC, Primo da Costa AR. Odontogenic keratocyst and multiple
LG. Oral findings in a family with tuberous sclerosis supernumerary teeth in a patient with Ehlers-Danlos
complex. Spec Care Dent. 2014. [Epub ahead of print]. syndrome – a case report and review of the literature.
152. Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen Quintessence Int. 2008;39(3):251–6.
N, Burge S, Monk S, et al. Mutations in ATP2A2, 168. Badauy CM, Gomes SS, Sant’Ana Filho M,
encoding a Ca2+ pump, cause Darier disease. Nat Chies JA. Ehlers-Danlos syndrome (EDS) type
Genet. 1999;21(3):271–7. IV: review of the literature. Clin Oral Investig.
153. MacLennan DH, Brandl CJ, Korczak B, Green 2007;11(3):183–7.
NM. Amino-acid sequence of a Ca2+ + Mg2+- 169. Letourneau Y, Perusse R, Buithieu H. Oral mani-
dependent ATPase from rabbit muscle sarcoplasmic festations of Ehlers-Danlos syndrome. J Can Dent
reticulum, deduced from its complementary DNA Assoc. 2001;67(6):330–4.
sequence. Nature. 1985;316(6030):696–700. 170. Hagberg C, Korpe L, Berglund B. Temporomandibular
154. Ruiz-Perez VL, Carter SA, Healy E, Todd C, Rees joint problems and self-registration of mandibular
JL, Steijlen PM, et al. ATP2A2 mutations in Darier’s opening capacity among adults with Ehlers-Danlos
disease: variant cutaneous phenotypes are associated syndrome. A questionnaire study. Orthod Craniofac
with missense mutations, but neuropsychiatric fea- Res. 2004;7(1):40–6.
tures are independent of mutation class. Hum Mol 171. Norton LA, Assael LA. Orthodontic and temporo-
Genet. 1999;8(9):1621–30. mandibular joint considerations in treatment of
252 J. C. Sartori-Valinotti and J. L. Hand
patients with Ehlers-Danlos syndrome. Am J Orthod noma: a case-control analysis. Cancer Epidemiol
Dentofac Orthop. 1997;111(1):75–84. Biomark Prev. 2006;15(12):2526–32.
172. Sherman SL, Allen EG, Bean LH, Freeman 186. Anttinen A, Koulu L, Nikoskelainen E, Portin R,
SB. Epidemiology of Down syndrome. Ment Retard Kurki T, Erkinjuntti M, et al. Neurological symp-
Dev Disabil Res Rev. 2007;13(3):221–7. toms and natural course of xeroderma pigmentosum.
173. Sekerci AE, Cantekin K, Aydinbelge M, Ucar Fİ. Brain. 2008;131(Pt 8):1979–89.
Prevalence of dental anomalies in the permanent 187. Wayli HA. Xeroderma pigmentosum and its dental
dentition of children with Down syndrome. J Dent implications. Eur J Dent. 2015;9(1):145–8.
Child. 2014;81(2):78–83. 188. Lopes-Cardoso C, Paes da Silva Ramos Fernandes
174. Abeleira MT, Outumuro M, Ramos I, Limeres LM, Ferreira-Rocha J, Teixeira-Soares C, Antônio-
J, Diniz M, Diz P. Dimensions of central inci- Barreto J, Humberto-Damante J. Xeroderma
sors, canines, and first molars in subjects with Pigmentosum – a case report with oral implications.
Down syndrome measured on cone-beam com- J Clin Exp Dent. 2012;4(4):e248–51.
puted tomographs. Am J Orthod Dentofac Orthop. 189. Gorlin RJ, Sedano H, Anderson VE. The syndrome
2014;146(6):765–75. of palmar-plantar hyperkeratosis and premature
175. Oredugba FA, Eigbobo JO, Temisanren OT. Tooth periodontal destruction of the teeth. A clinical and
crown dimensions in a selected population of genetic analysis of the Papillon-Lefevre syndrome. J
Nigerians with Down syndrome. West Afr J Med. Pediatr. 1964;65:895–908.
2014;33(2):146–50. 190. Cury VF, Costa JE, Gomez RS, Boson WL, Loures
176. Rao D, Hegde S, Naik S, Shetty P. Malocclusion in CG, De ML. A novel mutation of the cathepsin C
individuals with mental subnormality – a review. gene in Papillon-Lefevre syndrome. J Periodontol.
Oral Health Dent Manag. 2014;13(3):786–91. 2002;73(3):307–12.
177. de Miguel-Diez J, Villa-Asensi JR, Alvarez-Sala 191. Zhang Y, Lundgren T, Renvert S, Tatakis DN, Firatli
JL. Prevalence of sleep-disordered breathing in chil- E, Uygur C, et al. Evidence of a founder effect for
dren with Down syndrome: polygraphic findings in four cathepsin C gene mutations in Papillon-Lefevre
108 children. Sleep. 2003;26(8):1006–9. syndrome patients. J Med Genet. 2001;38(2):
178. Guimaraes CV, Donnelly LF, Shott SR, Amin RS, 96–101.
Kalra M. Relative rather than absolute macroglossia 192. Wiebe CB, Häkkinen L, Putnins EE, Walsh P,
in patients with Down syndrome: implications for Larjava HS. Successful periodontal maintenance
treatment of obstructive sleep apnea. Pediatr Radiol. of a case with Papillon-Lefevre syndrome: 12-year
2008;38(10):1062–7. follow-up and review of the literature. J Periodontol.
179. Anuthama K, Prasad H, Ramani P, Premkumar 2001;72(6):824–30.
P, Natesan A, Sherlin HJ. Genetic alterations in 193. Ragunatha S, Ramesh M, Anupama P, Kapoor M,
syndromes with oral manifestations. Dent Res J. Bhat M. Papillon-Lefevre syndrome with homozy-
2013;10(6):713–22. gous nonsense mutation of cathepsin C gene present-
180. Al-Sufyani GA, Al-Maweri SA, Al-Ghashm AA, ing with late-onset periodontitis. Pediatr Dermatol.
Al-Soneidar WA. Oral hygiene and gingival health 2015;32(2):292–4.
status of children with Down syndrome in Yemen: 194. Eick S, Puklo M, Adamowicz K, Kantyka T,
a cross-sectional study. J Int Soc Prevent Commun Hiemstra P, Stennicke H, et al. Lack of cathelicidin
Dent. 2014;4(2):82–6. processing in Papillon-Lefevre syndrome patients
181. Chin CJ, Khami MM, Husein M. A general reveals essential role of LL-37 in periodontal
review of the otolaryngologic manifestations of homeostasis. Orphanet J Rare Dis. 2014;9:148.
Down syndrome. Int J Pediatr Otorhinolaryngol. 195. Hart TC, Hart PS, Michalec MD, Zhang Y, Firatli
2014;78(6):899–904. E, Van Dyke TE, et al. Haim-Munk syndrome and
182. Ribeiro CG, Siqueira AF, Bez L, Cardoso AC, Papillon-Lefevre syndrome are allelic mutations in
Ferreira CF. Dental implant rehabilitation of a cathepsin C. J Med Genet. 2000;37(2):88–94.
patient with Down syndrome: a case report. J Oral 196. Ahmed B. Prosthodontic rehabilitation of Papillon-
Implantol. 2011;37(4):481–7. Lefevre syndrome. J Coll Phys Surg Pak JCPSP.
183. Lehmann AR, McGibbon D, Stefanini M. Xeroderma 2014;24(Suppl 2):S132–4.
pigmentosum. Orphanet J Rare Dis. 2011;6:70. 197. Nickles K, Schacher B, Ratka-Krüger P, Krebs
184. Kraemer KH, Lee MM, Andrews AD, Lambert M, Eickholz P. Long-term results after treatment
WC. The role of sunlight and DNA repair in mela- of periodontitis in patients with Papillon-Lefevre
noma and nonmelanoma skin cancer. The xero- syndrome: success and failure. J Clin Periodontol.
derma pigmentosum paradigm. Arch Dermatol. 2013;40(8):789–98.
1994;130(8):1018–21. 198. Sarma N, Ghosh C, Kar S, Bazmi BA. Low-dose
185. Li C, Hu Z, Liu Z, Wang LE, Strom SS, Gershenwald acitretin in Papillon-Lefevre syndrome: treatment
JE, et al. Polymorphisms in the DNA repair genes and 1-year follow-up. Dermatol Ther. 2015;28(1):
XPC, XPD, and XPG and risk of cutaneous mela- 28–31.
Index
A treatment recommendations, 48
Acid reflux, 21 Adrenal insufficiency, 45
Acrodermatitis enteropathica (AE), 78, 79 etiopathogenesis of, 46
Actinomycosis, 199, 200 Advanced oral hairy leukoplakia, 157
Actinomyces israeli, 198 Age-related sicca syndrome, 94
clinical manifestations, 198 AIDS-associated lymphoma, 27
differential diagnosis, 198, 199 ALA synthase-2 (ALAS 2), 57
epidemiology, 198 Alcoholics, 72
etiopathogenesis, 198 Alezzandrini syndrome, 136
histopathology, 199 Amyloidosis, 29, 56
treatment, 199 chronic ulceration and macroglossia in, 56
Acute atrophic candidiasis, 195, 196 clinical manifestations, 31, 56
Acute gonococcal urethritis in men, 172 differential diagnosis, 31, 32, 57
Acute leukemias, 25 epidemiology, 56
Acute lymphocytic leukemia (ALL), 25 etiopathogenesis, 31, 56
Acute myelogenous leukemia (AML), 25, 26 oral signs and symptoms, 31, 56
Acute necrotizing ulcerative gingitivis (ANUG), 176 treatment recommendations, 32, 57
antibacterial therapy, 176 Anemia, 19
diagnosis, 176 Aneurin. See Thiamine
differential diagnosis, 176 Angina bullosa haemorrhagica (ABH)
epidemiology, 175 clinical manifestations, 135
etiopathogenesis, 175 differential diagnosis, 135
excessive corticosteroids, 175 epidemiology, 135
gingival manifestations, 175 etiopathogenesis, 135
leukocyte function, 175 oral signs and symptoms, 135
norepinephrine, 175 treatment recommendations, 135
oral hygiene, 175, 176 Angular cheilitis/perleche, 67, 72, 78, 79, 195, 197
oral penicillin V and metronidazole, 176 and median rhomboid glossitis, 230
psychological stress and impaired immune function, predisposing factors, 196
175 Angular stomatitis, 67
signs and symptoms, 175 Antimalarials, 104
smoking, 175 Antimicrobials, 13
spirochetes in gingival tissue, 175 Aphthous ulcers, 16, 157, 158
stages, 175, 176 Aphthous-like ulcers, 17
tetracycline, 176 Arthralgias, 92, 106
Addison’s disease, 45 Arthritis, 99
clinical features of, 47 Ascorbic acid, 74
clinical manifestations, 46 Aspergillosis
differential diagnosis, 47, 48 amphotericin B, 210
epidemiology, 45 clinical manifestations, 209
etiopathogenesis, 45 differential diagnosis, 210
oral pigmentation in, 47 epidemiology, 209
oral signs and symptoms, 46 etiopathogenesis, 209
R clinical manifestations, 92
Rachitic rosary, 76 differential diagnosis, 94, 95
RAPADILINO syndrome, 232 epidemiology, 91–93
Raynaud’s phenomenon, 100, 101, 103 etiopathogenesis, 92
Recurrent aphthous stomatitis (RAS), 29, 68, 81, 82 non-visceral manifestations, 92, 93
Recurrent gingivitis, 29 oral signs and symptoms, 93, 94
Recurrent herpes labialis (RHL), 149 treatment, 95, 96
Recurrent intraoral herpes (RIH), 149 visceral manifestations, 93
Red blood cell disorders, 33 Small aphthous ulcerations, 70
Renal involvement, MCTD, 103 Splenic sequestration, 34
Reticular oral lichen planus, 122 Squamous cell carcinoma, 205
Rheumatic fever, 178 Staphylococcal scalded skin syndrome (SSSS)
Rheumatoid arthritis (RA), 98 bullous variants, 180
Riboflavin deficiency, 69 clindamycin-resistant strains, 180
Ridley-Jopling classification, leprosy, 180 clinical manifestations, 179, 180
Rituximab, 96, 115, 119, 121 diagnosis, 180
Root, 3, 4 differential diagnosis, 180
Rothmund-Thompson syndrome (RTS), 232 epidemiology, 179
clinical manifestations, 232 etiopathogenesis, 179
dental malformations, 232 hyperemia, 180
differential diagnosis, 232 oral involvement, 180
epidemiology, 231 oxacillin-sensitive, 180
etiopathogenesis, 231 penicillinase-resistant antibiotics, 180
treatment, 232 temperature regulation and volume resuscitation, 180
Rubella, 161 vancomycin, 180
Stevens-Johnson syndrome
clinical manifestations, 126
S differential diagnosis, 127
Salivary gland disease with xerostomia, 158, 159 epidemiology, 126
Salivary glands, oral cavity, 4 etiopathogenesis, 126
Scarlet fever, 177 oral signs and symptoms, 126, 127
allergic drug reaction, 177 treatment recommendations, 127, 128
antistreptolysin O titers, 177 String of pearls, 131
circumoral pallor, 176 Subacute/chronic mycosis, 208
clinical signs, 177 Sublingual gland, 4
differential diagnosis, 177 Submandibular ducts, 12
enlarged uvula and tonsils with erythema, 177 Submandibular gland, 4
epidemiology, 176 Sulcular gingiva lines, 3
etiopathogenesis, 176 Sulcus terminalis, 2
incidence, 176 Suprabasal acantholysis, 116
by Pastia’s lines, 176 Syphilis
penicillin, 177 antiretroviral therapy, 169
treatment, 177 blistering mucositis, 170
Sclerosis, 101 cardiovascular involvement, 170
Scrotal dermatitis, 69 CDC guidelines, 172
Scurvy, 73, 74 clinical manifestations, 170
Seborrheic dermatitis-like rash, 69 congenital, 171
Serositis, 99 dark field microscopy/serologic testing, 169
Severe congenital neutropenia (SCN), 28 diagnosis, 170
Severity of Illness Score for Toxic Epidermal Necrolysis differential diagnosis, 171, 172
(SCORTEN), 127 epidemiology, 169
Sickle cell disease (SCD) etiopathogenesis, 169, 170
clinical manifestations, 39 gummas, 170
differential diagnosis, 40 histopathological examination, 171
epidemiology, 39 necrosis of dorsum of tongue, 170
etiopathogenesis, 39 nonspecific ulcers, 170
oral signs and symptoms, 40 penicillin G, 172
treatment recommendations, 40 primary, 170
Sickle cell trait (SCT), 39 safety, sex practices, 169
Sjögren’s syndrome (SS) secondary, 170, 171
Index 265