Pediatric Dermatology Vol. 26 No.

2 176179, 2009

Dyskeratosis Congenita Report of a Case with Emphasis on Gingival Aspects

Silvia V. Lourenc o, D.D.S., Ph.D.,* Paula A. Boggio, M.D., Fernando A. Fezzi, D.D.S., o, D.D.S., and Marcello Menta S. Nico, M.D., Ph.D. Alexandre L. Sebastia
*Department of General Pathology, Dental School, University of Sao Paulo, Sao Paulo, Brazil, Department of Dermatology, Hospital das Clnicas, Medical School, University of Sao Paulo, Sao Paulo, Brazil

Abstract: A case of dyskeratosis congenita (DC) of an 11-year-old male is reported. He presented with the characteristic clinical triad of reticular pigmentation of the skin, dystrophic nails and oral lesions, and up to the present he had not developed hematological compromise. Oral lesions consisted of extensive tongue erosions and keratosis, and exuberant gingivitis associated. Appropriate periodontal treatment was performed with discrete improvement only. We emphasize that severe gingival inammation, although infrequent, may represent an alteration specic to DC and therefore should be considered as an additional sign of this syndrome.

Dyskeratosis congenita (DC) is a rare inherited disorder with variable mode of inheritance, which mainly involves ectodermal derived tissues. It was rst described by Zinsser in 1910 and later redened by Engman and Cole (1). It is characterized by the dermatologic triad of reticulated skin pigmentation, mucosal lesions, and nail dystrophy. Several associated abnormalities are reported in DC, as well as predisposition to malignancy (13). Complications include bone marrow failure of unclear physiopathology and malignant neoplasms, which constitute the primary cause of death in the second and third decades of life (13). We herein report a case of DC of an 11-year-old male, who presented the typical dermatologic features of the disease. Additionally, a severe gingivitis was detected and that may constitute a rare and probably underreported oral nding related to this condition.
Address correspondence to Dr. Silvia Vanessa Lourenc o, D.D.S., Ph.D., Faculdade de Odontologia da Universidade de Sa o Paulo, Disciplina de Patologia Geral, Av Prof Lineu Prestes, 2227, ria, Sa CEP: 05508-000, Cidade Universita o Paulo, SP-Brazil, or e-mail: sloducca@usp.br. DOI: 10.1111/j.1525-1470.2009.00878.x

CASE REPORT An 11-year-old Afro-Brazilian man was referred with a 2-year history of a painful plaque on the tongue. Oral examination showed a keratotic, atrophic, and partially eroded plaque extending form the dorsum to the right lateral border of the tongue (Fig. 1). Physical examination revealed subtle reticulated hyperpigmented macules with mild atrophy, symmetrically distributed on eyelids, face (Fig. 2A), neck (Fig. 2B), upper chest, extensor aspects of the arms, axilla, and penis and groin (Fig. 2C). Severe 20-nail-dystrophy was also observed (Fig. 3). Both skin and nail lesions appeared approximately at 7 years of age. Personal data was otherwise irrelevant, and familiar history was noncontributory (examination of his parents revealed no abnormalities). A biopsy specimen from the tongue lesion revealed moderate

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Figure 1. Eritroleukoplakic plaque on the dorsum of the tongue.

Figure 3. Severe ngernails dystrophy.

epithelial dysplasia (Figs. 4A and B). A diagnosis of DC was rendered with the compilation of dermatological and oral signs. During follow-up he developed severe edema and erythema of the upper and lower gingivae, associated with erosion and hypertrophy (Fig. 5A). Biopsy from aected gingiva was performed, which showed nonspecic diuse chronic inammation (Fig. 5B). Appropriate periodontal treatment was initiated with only slight improvement after several sessions. Hematological evaluation of the patient revealed mild anemia with macrocytosis and poikylocytosis on peripheral smear. A bone marrow aspirate and biopsy were performed and a hypercellular marrow with diminished granulocyte erythroblast relationship was

detected. Relative hypocellularity of granulocytic series with larger granulocytes, and absolute and relative hypercellularity of erythroid series with macroerythroblasts, some of them showing karyolysis and karyorrhexis were also seen. Remaining cellular series as well as interstitial elements presented no abnormalities. The patient persisted under continuous surveillance, and as a moderate pancytopenia was recently detected, bone marrow transplantation was scheduled. DISCUSSION Dyskeratosis congenita, also known as ZinsserEngman-Cole syndrome, is an inherited severe multisystemic disorder that mainly aects tissues of

2A
Figure 2. Reticulated pigmented macules on eyelids and cheeks (A), neck (B), and penis and groin (C).

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Figure 4. Tongue epithelial moderate dysplasia. HematoxylinEosin, original magnication 40 (A), and 100 (B).

Figure 5. Erythema and edema of upper gingiva (A), and nonspecic chronic inammatory inltrate on gingival biopsy (HematoxylinEosin, original magnication 40) (B).

ectodermal origin (1). It is an extremely rare conditionwith an estimated prevalence under one per million, widely distributed, and aecting all races (24). Three dierent modes of inheritance are currently recognized: recessive X-link DC (OMIM 305000) autosomal dominant DC (OMIM 127550) and autosomal dominant DC (OMIM 224230). Most reported cases correspond to recessive X-link transmission, generally aecting men (5). Dyskeratosis congenita pathogenesis is linked to an impairment of telomerase maintenance. Telomeres are specialized nucleoprotein structures at the end of chromosomes that protect end-to-end chromosome fusion. Telomeres get shorter with each cell division because DNA polymerase-I cannot copy the extreme end of a DNA strand, therefore when telomeres get critically short, cell death occurs. Telomerase activity counteracts the continuous telomere shortening caused by cell replication. Telomerase activity is not observed after birth in most somatic cells. In contrast, germ cells, stem cells, activated T-cells, monocytes, and notably most cancer cells express telomerase activity, but only in germ cells

and cancer cells is telomerase activity sucient to prevent telomere shortening (5). Mutations in three genes have been identied in patients with DC-DKC1, TERC, and TERT. The products of these genes, dyskerin encoded by DKCI, the RNA component of telomerase, TERC, and the catalytic component of telomerase, TERT, form the catalytically active telomerase. DKC1 maps to the X-chromosome. Mutations in this gene cause X-linked DC in all male members of aected families and carrier state in females. In families with DC because of TERC or TERT gene mutations the disease usually follows an autosomal dominant pattern of inheritance. Patients with the autosomal dominant form typically present with milder disease and the onset of their manifestations is often later in life (5). Despite genetic heterogeneity, DC phenotypes are usually similar. Nevertheless, some data suggest a milder clinical course, with late diagnosis and a lesser incidence of aplastic anemia in patients with autosomal dominant inheritance (13). In the present case X-linked recessive inheritance is likely, as there is no

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other family member aected and familial consanguinity was denied. Dyskeratosis congenita rst signs are detected between the ages of 5 to 12 years with dermatologic alterations. The triad of reticulated skin pigmentation, mucosal lesions, and nail dystrophy typically characterizes the syndrome. A lacy reticulated brown pigmentation sometimes with superimposed discrete atrophy and telangiectases (leading to a poikilodermatous aspect) overlying the skin of face, neck, chest, proximal limbs and intertriginous areas, is frequently the rst sign of DC. Nail compromise, ranging from mild dystrophy to petirigum or anonichya, is generally present concurrently (14). Mucosal alterations occur simultaneously with oral cavity compromise being a rule. Initial lesions are recurrent vesicles and erosions, followed by white keratotic patches that evolve to erythroplakia with recurrent episodes of ulceration. Although oral lesions can occur at dierent sites, the dorsum of the tongue is the site more frequently aected (3,4,6,7). Ulceration without tendency to heal, inltration or progressive enlargement of oral mucosal lesions must be suspicious of evolution into a squamous cell carcinoma (SCC). The case reported herein presented with the complete triad of DC, referring the rst signs as skin and nail alterations at the age of 7 years and posterior development of leukoplakia of the tongue at 9, without complication up to date. Less common oral ndings in DC include diuse mucosal pigmentation and gingival compromisewith bleeding, recession, with or without inammation (6,7). Severe gingivitis, as observed in our patient, is an extremely infrequent occurrence in DC that should probably be recognized as specic to the disease. This manifestation was reported by some authors as a condition that resembled juvenile periodontitis (6,7). The absence of improvement after periodontal treatment supports this hypothesis. Dental ndings on DC comprise of caries formation, hypondontia, hypocalcication, thin enamel structure, increased mobility and loss of teeth elements, short blunted roots, taurodontism, destruction of alveolar margins and severe alveolar bone loss resembling juvenile periodontitis, but these were not present in our patient (6,7). Systemic manifestations of DC (a few of which seem to be regarded to ectodermal defect) are present with variable frequency, and consist of growth and mental retardation, deafness, transparent tympanic membranes, lacrimal duct obstruction, conjunctivitis, blepharitis, palmoplantar hyperkeratosis and hyperhidrosis, urethral anomalies, esophageal stenosis, choanal atresia, hepatic abnormalities, frontal lobes atrophy, extensive intracranial calcications, hypogonadism, osteoporosis,

avascular necrosis of bone and immunological disturbances (1,69). Multidisciplinary evaluation of our patient did not detect any of these alterations. Approaching the second or third decades of life almost 50% of DC patients will develop bone marrow failure, manifesting as aplastic anemia or pancytopenia (14). Therefore, every DC patient should be under continuous hematological surveillance that allows, as in the present case, an early diagnosis and introduction of specic therapy for bone marrow failure. An increased incidence of malignancies constitutes another constant feature of DC, being cutaneous or mucosal SCC, esophageal and pancreatic carcinomas and Hodgkin lymphoma the most frequent tumors associated with the syndrome. Squamous cell carcinomas often develop on previously aected mucosal areas, between the third and fth decades, so permanent monitoring is highly recommended (4,9,10). Complications of bone marrow insuciency, together with malignancies are the principal cause of death in DC patients, which occurs at an average age of 23.6 to 30 years (2,10). AKNOWLEDGMENT The study was supported by FAPESP grant 02 02676-7. REFERENCES
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