Pemphigus Vulgaris: The Eyes Have It Saba Merchant and Michael Weinstein Pediatrics 2003;112;183

The online version of this article, along with updated information and services, is located on the World Wide Web at:
http://pediatrics.aappublications.org/content/112/1/183.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2003 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on January 31, 2012

EXPERIENCE AND REASONBriefly Recorded

In Medicine one must pay attention not to plausible theorizing but to experience and reason together. . . . I agree that theorizing is to be approved, provided that it is based on facts, and systematically makes its deductions from what is observed. . . . But conclusions drawn from unaided reason can hardly be serviceable; only those drawn from observed fact. Hippocrates: Precepts. (Short communications of factual material are published here. Comments and criticisms appear as letters to the Editor.)

Pemphigus Vulgaris: The Eyes Have It

ABSTRACT. Pemphigus vulgaris is a potentially fatal autoimmune blistering disease that is rare in childhood. We report 2 recent cases seen contemporaneously in adolescents who presented with chronic oral mucosal lesions and conjunctivitis. The previously unemphasized ocular manifestations are described and the importance of a biopsy in establishing the diagnosis in instances of unexplained chronic mucositis is stressed. Pediatrics 2003;112:183185; pemphigus, conjunctivitis.
ABBREVIATIONS. PV, pemphigus vulgaris; IgG, immunoglobulin G; IV, intravenous.

emphigus, derived from the Greek word meaning bubble or blister, refers to a group of uncommon autoimmune skin conditions characterized by blistering of the skin and mucous membranes. Before immunosuppressive therapy, pemphigus was usually fatal. Pemphigus is rare in childhood, and the diagnosis is usually not considered at the time signs first develop. We describe 2 adolescents with pemphigus vulgaris (PV) who presented with chronic mucositis and had conjunctival involvement before the development of cutaneous lesions, a feature unemphasized in the pediatric age group.
CASE REPORTS

acuity was normal. Three superficial erosions not previously noticed by the patient, measuring 0.5 to 0.8 cm in diameter, were seen on the trunk and scalp. An area of skin erosion was also seen on the corona of the penis. No vesicles or bullae were present. Laboratory investigations revealed a hemoglobin of 157 g/L, white blood cell count of 11.6 109/ L (5.35 109 /L polymorphonuclear leukocytes, 1.74 109 /L eosinophils) and a normal platelet count. The erythrocyte sedimentation rate was 9 mm/ hour. Urinalysis, serum electrolytes, renal function tests, and transaminases were normal. Serology for antinuclear factor was negative. Viral studies of the oral lesions were negative for herpes simplex virus by polymerase chain reaction. Total parenteral nutrition was provided because of severe dysphagia, and an intravenous (IV) morphine infusion was required for analgesia. Biopsy of one of the skin erosions was performed, demonstrating suprabasal and intraepidermal acantholysis with the formation of an intraepidermal, suprabasal vesicle. Immunofluorescence demonstrated intercellular deposition of immunoglobulin G (IgG) and C3, and serology for antidesmoglein 3 was positive by indirect immunofluorescence. The clinical, biopsy, and serologic findings were diagnostic of PV. Treatment with IV methylprednisolone (1 mg/kg/d) was administered for 2 weeks followed by prednisone 40 mg twice daily taken with calcium and vitamin D supplementation. Gradual improvement occurred over 3 weeks. One month after beginning treatment, all manifestations had resolved except for a persistent ulcerative throat lesion. Azathioprine was begun at 3 months as an adjunctive and steroidsparing therapy.

Case 2
A 16-year-old previously healthy girl of African descent was admitted to hospital in June 2001 because of a 3-month history of painful oral ulcers that led to dysphagia precipitating a 9-kg weight loss and bilateral nonpurulent conjunctivitis. The sores began in the throat with progressive involvement of the lips, tongue, and buccal mucosa. She was unsuccessfully treated with 3 courses of oral antibiotics. There was no history of fever, joint pain, diarrhea, or exposure to medications. Physical examination revealed bilateral conjunctival injection, and corneal ulcers were detected on slit lamp examination. Erosions were noted on the tongue, palate, and buccal mucosa. There were crusted lesions on the chest, shoulder, and thighs. Biopsy of 1 of the skin lesions was performed, demonstrating intraepidermal bulla, spongiosis, and acantholysis. Serology was positive for circulating pemphigus autoantibodies in a dilution of 1:320. Immunofluorescence studies demonstrated IgG and complement deposition in the intercellular spaces in the epidermis. The clinical, biopsy, and serologic findings were diagnostic of PV. She was treated with IV fluids and morphine for analgesia. IV methylprednisolone (1 mg/kg/d) was administered for 4 days, followed by prednisone (2 mg/kg/d).

Case 1
A 15-year-old previously healthy boy of Pakistani descent was admitted to hospital in May 2001 because of a 2-month history of painful oral ulcers and conjunctivitis. The sores were noted to begin in the throat with progressive involvement of the lips, tongue, and buccal mucosa. He had no improvement after several courses of antibiotics prescribed by his family physician. Conjunctival injection with profuse watery discharge and photophobia began soon after the oral involvement, and the patient was ultimately admitted to the hospital because of severe dysphagia that precipitated a 5-kg weight loss. There was no history of fever, joint pain, abdominal pain, diarrhea, noticeable skin lesions, or exposure to medications before the onset of the lesions. Physical examination revealed an unwell-looking boy. There were widespread erosions of the lips, gingiva, tongue, and buccal mucosa (Fig 1). Ophthalmologic examination revealed conjunctivitis. No uveitis was detected on slit-lamp examination, and visual

DISCUSSION

Received for publication Oct 30, 2002; accepted Jan 31, 2003. Address correspondence to Michael Weinstein, MD, Division of Paediatric Medicine, Hospital for Sick Children, 555 University Ave, Toronto, Canada, M5G 1X8. E-mail: michael.weinstein@sickkids.ca PEDIATRICS (ISSN 0031 4005). Copyright 2003 by the American Academy of Pediatrics.

Pemphigus is caused by the formation of pathogenic autoantibodies directed against desmosomal proteins that act as intercellular adhesion molecules, leading to acantholysis or separation of epidermal cells from each other.1 Different forms of pemphigus occur, depending on the type of desmoglein attacked and the subsequent level of epidermis affected. PV is
183

PEDIATRICS Vol. 112 No. 1 July 2003 Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on January 31, 2012

Fig 1. Photograph demonstrating extensive ulceration of the lips and oral mucosa.

the most common form and presents with oral lesions and flaccid cutaneous blisters that may exhibit a Nikolsky sign, a separation of the epithelium with tangential pressure on the skin surface. Pemphigus foliaceous, a more benign form of the disease, involves the more superficial levels of the epidermis, presents with crusting skin lesions of the face, scalp, and upper trunk and rarely involves the mucous membranes. Desmoglein 3, present only in the deep epidermis, is affected in PV. Desmoglein 1, present throughout the epidermis, is the adhesion molecule affected in pemphigus foliaceous, and it is felt that the normal presence of desmoglein 3 in the deep epidermis compensates for the loss of desmoglein 1 in this condition and prevents deep skin and mucosal blistering.2 A paraneoplastic variant of the condition may occur, most commonly with lymphatic malignancies,3 and drug-precipitated forms (eg, penicillamine) have been reported. A transient neonatal form can occur in infants of affected mothers.4 Ocular manifestations may precede oral or skin lesions by several days to months. The characteristic ocular finding is conjunctivitis with hyperemia and mucoid discharge. Conjunctival blisters, erosions, and synechiae are rare, although conjunctival biopsies may demonstrate similar histopathologic and direct immunofluorescence findings to skin biopsies.5 The eye symptoms generally improve with the institution of systemic therapy, and long-term sequelae are uncommon.5 The few documented cases of ocular involvement in PV are in adults. To the best of our knowledge, ocular findings in pediatric PV have not been reported in the literature. Pemphigus has a worldwide distribution but is more common among people of Ashkenazi Jewish

and Mediterranean descent, affects both sexes equally, and has a mean age of onset in the sixth decade of life. Pemphigus is rare in childhood, and the diagnosis is usually not considered at the time signs first develop. Conditions that are commonly first considered include Stevens-Johnson syndrome, aphthous stomatitis, herpes simplex virus infection, impetigo, contact dermatitis, and Behcets disease. Other autoimmune disorders characterized by chronic oral mucositis include lichen planus, pemphigoid, linear immunoglobulin A disease, and epidermolysis bullosa acquisita. The diagnosis of PV and the differentiation between it and other similar processes requires a biopsy of perilesional skin or oral mucosa. Immunoglobulin (usually IgG) and sometimes complement is detected by direct immunofluorescence in the intercellular spaces of the epidermis. Circulating autoantibodies can also be detected by indirect immunofluorescence testing of patients serum. The mainstay of treatment of PV is systemic steroid therapy in high doses (1 6 mg/kg/d). Adjuvant therapies have included azathioprine, cyclosporine, cyclophosphamide, methotrexate, dapsone, mycophenolate mofetil, plasmapheresis, and IV immune globulin.6 The course of PV in childhood is similar to that observed in adults and does not follow a more benign course as originally considered.7,8 Pemphigus is very uncommon in the pediatric population. These cases highlight the need to consider PV in children and adolescents with chronic mucositis without another obvious cause, the fact that PV may present with oral and conjunctival involvement before or without cutaneous signs, and the importance of a

184

EXPERIENCE AND REASON Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on January 31, 2012

biopsy in establishing the diagnosis in cases of unexplained chronic mucositis.

Saba Merchant, MD Department of Paediatrics Hospital for Sick Children University of Toronto Toronto, Canada M5G 1X8 Michael Weinstein, MD Division of Paediatric Medicine Hospital for Sick Children University of Toronto Toronto, Canada M5G 1X8 REFERENCES
1. Edelson RL. Pemphigus decoding the cellular language of cutaneous autoimmunity. N Engl J Med. 2000;343:60 61 2. Wu H, Hong Wang Z, Yan, A, et al. Protection against pemphigus foliaceous by desmoglein 3 in neonates. N Engl J Med. 2000;343:3135 3. Nousari HC, Deterding R, Wojtczack H, et al. The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med. 1999;340: 1406 1410 4. Merlob P, Metzker A, Hazaz B, Rogovin H, Reisner SH. Neonatal pemphigus vulgaris. Pediatrics. 1986;78:11021105 5. Hodak E, Kremer I. Conjunctival involvement in pemphigus vulgaris: a clinical, histopathological and immunofluorescence study. Br J Dermatol. 1990;123:1520 6. Jun H, Antaya RJ. Pemphigus vulgaris in an adolescent. Curr Opin Pediatr. 2002;14:426 428 7. Jordon RE, Ihrig JJ, Perry HO. Childhood pemphigus vulgaris. Arch Dermatol. 1969;99:176 180 8. Lehman R, Landau JW, Newcomer VD. Pemphigus vulgaris in a 12year-old boy. J Pediatr. 1965;67:264 269

metaphyses are particularly concerning and are strongly associated with child abuse.1,2 When abuse is suspected, the radiographic skeletal survey is recommended for global imaging.3 The role of imaging, however, is to not only identify the extent of physical injury but also to assess all imaging findings that suggest alternative diagnoses.3 In addition to radiographic studies, history and clinical findings are also important. There are childhood disorders in which metabolic bone disease occurs and can lead to bone fractures. Numerous studies have shown that bone disease is a well-known complication in children with biliary atresia. Radiographic findings in this population include osteopenia, rickets, and/or fractures. We report 3 cases of infants with biliary atresia who came to the emergency department (ED) for apparent bone pain. When multiple fractures were seen on radiographic studies, the Child Protective Services (CPS) team in the ED investigated the caretakers for possible child abuse.
CASE REPORTS Case 1
A 4-month-old black girl with biliary atresia underwent a hepatic portoenterostomy and received a short course of steroids. She was brought to the ED 1 month later for irritability and left arm pain. Radiographic study of the left humerus revealed a fracture proximally. She underwent a skeletal survey which, in addition to the humeral fracture, revealed generalized osteopenia with fracture of bilateral scapulae and fracture of the right distal radius and ulna (Fig 1). The types and numbers of fractures were thought highly suspicious for nonaccidental trauma. The family was immediately evaluated by the CPS team in the ED. Subsequent to the CPS evaluation, blood analyses revealed hypocalcemia (ionized calcium: 0.7 mmol/L; total calcium: 5.7 mg/dL). The 25-OH vitamin D level was below normal despite the patient being supplemented with 10 times the recommended daily allowance for vitamin D. She was admitted to the hospital for intravenous calcium. The orthopedic team recommended splinting of left upper extremity. The patient was discharged from the hospital with 1,25 (OH)2D (Rocaltrol) and a calcium carbonate supplement in addition to her previous medications.

Fractures in Biliary Atresia Misinterpreted as Child Abuse

ABSTRACT. Bone fractures in children without a history of injury are highly suspicious for child abuse. Biliary atresia is a disorder associated with metabolic bone disease, and there are numerous reports of osteopenia, rickets, and/or fractures in this population. We report 3 cases of children with biliary atresia who had bony fractures as well as osteopenia whose caretakers were investigated for child abuse. Pediatricians should be aware of an increased incidence of fractures and overall prevalence of bone disease in this population. Pediatrics 2003; 112:185188; biliary atresia, osteopenia, fractures, abuse.
ABBREVIATIONS. ED, emergency department; CPS, Child Protective Services.

Case 2
A 14-month-old black girl with biliary atresia underwent a hepatic portoenterostomy. Approximately 9 months after surgery she was brought to the ED after falling downstairs and refusing to bear weight on her left leg. Radiographic studies revealed osteopenia and buckle fractures of the distal left tibia and fibula (Fig 2). A metaphyseal corner-type fracture in the medial femoral metaphysis was also seen. This type of fracture is frequently seen in nonaccidental trauma. The radiologist referred the patient back to the ED where the family was investigated by CPS for possible child abuse. No blood chemistries were performed at the time. The patient had been receiving 8 times the recommended daily allowance for vitamin D supplementation and previous blood analyses had revealed normal 25-OH vitamin D and total calcium levels.

one fractures in young children without a history of injury are considered highly suspicious for nonaccidental trauma. In children 1 year of age, long bone fractures especially involving the
Received for publication Nov 15, 2002; accepted Feb 6, 2003. Reprints requests to (P.A.D.) Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Childrens Center, 600 N Wolfe St, Brady 320, Baltimore, MD 21287. E-mail: tderusso@jhmi.edu PEDIATRICS (ISSN 0031 4005). Copyright 2003 by the American Academy of Pediatrics.

Case 3
An 18-month-old black girl with biliary atresia underwent a hepatic portoenterostomy and was residing in a convalescent hospital for children. She was referred to the ED for leg pain resulting in nonweight bearing that was noted shortly after a phlebotomist had held her by the ankles to draw blood from her foot. Radiographic studies revealed fractures in the distal metaphyses of both tibias and fibulas that were already healing (Fig 3). Severe osteopenia with abnormal modeling consistent with long-standing chronic liver disease was also reported. Blood analyses were not

EXPERIENCE AND REASON Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on January 31, 2012

185

Pemphigus Vulgaris: The Eyes Have It Saba Merchant and Michael Weinstein Pediatrics 2003;112;183
Updated Information & Services References including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/112/1/183.full.ht ml This article cites 8 articles, 2 of which can be accessed free at: http://pediatrics.aappublications.org/content/112/1/183.full.ht ml#ref-list-1 This article, along with others on similar topics, appears in the following collection(s): Allergy & Dermatology http://pediatrics.aappublications.org/cgi/collection/allergy_an d_dermatology Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

Subspecialty Collections

Permissions & Licensing

Reprints

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2003 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Indonesia:AAP Sponsored on January 31, 2012