Mucocutaneous Dyskeratosis with Periodontal Destruction And

Vol. 113 No. 2 February 2012

CASE REPORT Mucocutaneous dyskeratosis with periodontal destruction and premature tooth loss Michelle Agostini, DDS, PhD,a,b Renato Valiati, DDS, PhD,b Jorge Esquiche León, DDS, PhD,a Mário José Romañach, DDS, MSc,a Crispian Scully, MD, PhD,c and Oslei Paes de Almeida, DDS, PhDa University of Campinas, Piracicaba, Brazil; and University of Planalto Catarinense, Lages, Brazil; and UNIVERSITY COLLEGE LONDON AND UNIVERSITY OF BRISTOL, UNITED KINGDOM

We report the case of a 16-month-old boy who presented an exuberant erythematous gingival swelling and severe tooth mobility. Radiographic examination conﬁrmed alveolar bone loss, and gingival biopsy showed epithelium containing numerous dyskeratotic cells. Because of feeding difﬁculties, the enlarged gingival tissue and involved teeth were removed. One year later, similar problems were encountered during the eruption of the deciduous second molars. The patient also exhibited papular skin lesions. Histopathologic features on biopsies of the skin and oral lesions were similar. The oral and cutaneous lesions presented by this patient were similar to those described by From et al. in 1978 in a father and son, reported as dyskeratosis benigna intraepithelialis mucosae et cutis hereditaria—the sole report in the English language. To avoid confusion with hereditary benign intraepithelial dyskeratosis (Witkop–von Sallmann syndrome) we have renamed the condition as mucocutaneous dyskeratosis with periodontal destruction and tooth loss. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:254-259)

Dyskeratosis is characterized by premature single-cell the tooth-bearing areas, causing premature tooth loss. It is keratinization, usually caused by alterations in cellular the only dyskeratotic condition reported causing tooth desmosomal proteins or cytokeratins. Dyskeratotic loss. We describe a similar case, but without ocular in- cells are isolated round cells, with pyknotic dark-stain- volvement and with a sporadic presentation. We consider ing nuclei and clear or eosinophilic cytoplasm, seen mucocutaneous dyskeratosis with periodontal destruction mainly in the spinous layer, in areas of acantholysis or and premature tooth loss a more appropriate nomenclature in various mucocutaneous conditions, including Darier for this condition. disease, warty dyskeratoma, hereditary benign intraepithelial dyskeratosis (Witkop–von Sallmann syndrome), CASE REPORT pachyonychia congenita, and hereditary mucoepithelial A white male child aged 16 months was referred for dysplasia. Typically, the oral lesions in these disorders evaluation of a slow-growing gingival swelling and tooth show hyperkeratotic white papules or plaques, mainly mobility. The gingival swelling was first noticed when the seen on the palate, tongue, and buccal mucosa. child was 7 months old and the mandibular central incisors From et al.1 described a new entity entitled dyskeratosis were erupting. There was no consanguinity, with both parents aged 24 years old at the time of conception. The patient was benigna intraepithelialis mucosae et cutis hereditaria. That the third of 3 siblings and was delivered with no complica- report, the only one to date in the English language, tions. The patient had normal development, with no problems described a father and son who had benign intraepithelial of vision and hearing or any other ectodermal manifestations dyskeratosis affecting skin, bulbar conjunctiva, and oral or internal organ abnormalities. Height, weight, and skull mucosa. This condition differed from other dyskeratotic circumference were normal for his age. diseases, in that oral involvement was mainly restricted to Intraoral examination revealed an edematous and erythematous gingival enlargement partially or totally covering the crowns of the deciduous teeth, all of which showed grade III Supported by the State of São Paulo Research Foundation and the mobility. The gingival surface showed diffuse or punctate National Council for Scientific and Technological Development. pale-yellowish areas suggesting deposition of fibrin or keratin aDepartment of Oral Diagnosis, Piracicaba Dental School, University (Figure 1, A). Periapical radiographs showed pronounced of Campinas, Piracicaba, São Paulo, Brazil. alveolar bone resorption. b School of Dentistry, University of Planalto Catarinense, Lages, The clinical findings initially suggested a diagnosis of Santa Catarina, Brazil. Langerhans cell histiocytosis. Complete blood count was cUniversity College London and University of Bristol, UK. Received for publication Apr 24, 2011; returned for revision Jul 12, within normal limits. Incisional biopsy was performed under 2011; accepted for publication Aug 4, 2011. general anesthesia. Histopathology showed a hyperplastic © 2012 Elsevier Inc. All rights reserved. epithelium with hyperparakeratosis, acanthosis, and dyskera- 2212-4403/$ - see front matter tosis characterized by suprabasal scattered single-cell kerati- doi:10.1016/j.tripleo.2011.08.013 nization (Figure 1, B). The unusual hyperkeratosis showed

254 OOOO CASE REPORT Volume 113, Number 2 Agostini et al. 255

Figure. 1. A, Erythematous gingival enlargement with pale-yellowish areas, partially or totally covering the crowns of the erupted teeth, which showed severe mobility. B-D, Oral epithelium displaying pronounced single-cell keratinization in the suprabasal layers (hematoxylin-eosin [HE], B ϫ25, C ϫ200). Acantholytic cystic epithelial islands permeated by mixed inflammatory infiltrate in the connective tissue (HE, B ϫ25, D ϫ200). focal areas containing numerous dyskeratotic cells (Figure 1, became brownish. Physical examination revealed numer- C). No dysplasia was seen. In the connective tissue were ous papular skin lesions showing central keratotic plugs, islands of dyskeratotic and nondyskeratotic acantholytic epi- not exceeding 10 mm in diameter, mainly on the lower thelium permeated by a mixed inflammatory infiltrate, form- limbs, with multiple brownish macules on the back and ing pseudocystic areas containing numerous neutrophils (Fig- buttocks, probably due to postinflammatory hyperpigmen- ure 1, B and D). The focal areas of hyperkeratosis in the tation (Figure 3, A and B). Circumscribed hyperkeratotic superficial epithelium and the inflamed pseudocystic struc- palmoplantar lesions were also noted (Figure 3, D). New tures in the connective tissue probably corresponded to the lesions developed in areas of trauma, characterizing the clinical appearance of pale-yellowish areas on the gingival Koebner phenomenon, as seen on the ankle, where the skin surface. The microscopic differential diagnosis therefore in- was in contact with sandals. Panoramic radiography re- cluded a dyskeratotic mucosal or mucocutaneous disorder vealed that the anterior mandibular permanent teeth buds with oral involvement, with no definitive diagnosis. were displaced from their original position and associated Because the mother had difficulties feeding the child, all with severe alveolar bone loss and surrounding radiolucent erupted deciduous teeth and the enlarged gingival tissues areas. The second deciduous molars were “floating,” with- were removed. The resulting edentulous alveolar process out any bone support (Figure 2, B). A biopsy from a skin healed with clinically normal mucosa. lesion presented histopathologic features similar to those One year later, a similar gingival enlargement developed seen previously in the gingiva (Figure 3, C). around the deciduous second molars and an erupted lower Based on the clinical and histopathologic findings, as permanent incisor. Angular cheilitis was then also ob- well as the skin involvement, the diagnosis of mucocuta- served (Figure 2, A). The mother reported that the child neous dyskeratosis with periodontal destruction and tooth had also developed recurrent episodes of red, suppurating, loss (likely the same disease first described by From et al.1 and itching papular eruptions on the skin of the lower as dyskeratosis benigna intraepithelialis mucosae et cutis limbs, buttocks, abdomen, and back, which during healing hereditaria) was made. However, ocular involvement was ORAL AND MAXILLOFACIAL PATHOLOGY OOOO 256 Agostini et al. February 2012

Figure. 2. A, Recurrence of gingival alterations around both erupted second deciduous molars and a permanent incisor of the mandibular incisor. Angular cheilitis was also observed. B, Panoramic radiography revealed severe alveolar bone loss and radiolucent areas involving some anterior permanent tooth germs in the mandible, which were dislocated from their original position.

Figure. 3. A, Numerous papular skin lesions showing central keratotic plugs on the inferior limbs. B, Multiple brownish macules on the back and buttocks. C, Hyperparakeratosis, acanthosis, and pronounced single-cell keratinization in the epidermis (hematoxylin-eosin, ϫ200). D, Well demarcated hyperkeratosis on the plantar region. not found despite a thorough clinical evaluation and yearly edentulous subsequently appeared clinically normal (Fig- reevaluation to the age of 5 years. ure 4, B). The deciduous second molars, permanent incisors, and At the time of writing, the child was 5 years old and was affected gingival tissue (Figure 2, A) were removed and under care of a multidisciplinary team. The patient ap- subsequently the child had no further oral manifestations peared to be in good general health. The skin lesions until the eruption of the ﬁrst permanent molars, when the persist but remain under control with simple procedures to gingival enlargement again recurred (Figure 4, A). A third avoid trauma and infection. Some areas of the alveolar surgical procedure was then undertaken to remove the ridge exhibit discrete enlargements associated with erupt- gingival tissue and the associated severely mobile teeth. ing teeth, and we anticipate that, as with the eruption of the The areas of the anterior region of the jaws rendered other teeth, the clinical course and treatment are likely to OOOO CASE REPORT Volume 113, Number 2 Agostini et al. 257

Figure. 4. A, Recurrence of gingival enlargement around the erupting first permanent molars. B, Normal mucosa covering the edentulous alveolar ridge in the anterior region of the mandible and the maxilla. be similar. We have examined and interviewed the other Our case was most similar to dyskeratosis benigna members of the family, and none have shown a history of intraepithelialis mucosae et cutis hereditaria,1 although similar lesions. it was neither hereditary nor showed ocular involvement, as confirmed by a rigorous ophthalmologic ex- DISCUSSION amination. The white lesions on the buccal mucosa and We present a boy diagnosed with mucocutaneous dys- palmoplantar verruca-like skin lesions reported by keratosis with periodontal destruction and premature From et al.1 were also not observed in our patient. It is tooth loss, probably a variant of the condition first possible, therefore, that our patient has an incomplete described as dyskeratosis benigna intraepithelialis mu- form of dyskeratosis benigna intraepithelialis mucosae cosae et cutis hereditaria by From, Philipsen, and Thor- 1 et cutis hereditaria or a similar but distinct disease. mann (1978). This is an exceedingly rare disorder It is interesting to note that basically the same term— characterized by mucocutaneous benign intraepithelial hereditary benign intraepithelial dyskeratosis—is used dyskeratosis and premature tooth loss. From et al.1 used for 2 different syndromes: hereditary benign intraepi- the descriptive term dyskeratosis benigna intraepithe- thelial dyskeratosis (Witkop–von Sallmann syndrome)6 lialis mucosae et cutis hereditaria, the disease affecting and dyskeratosis benigna intraepithelialis mucosae et a father and his son whose clinical and histopathologic cutis hereditaria.1 To avoid confusion and to emphasize features were not consistent with any of the known the main characteristic of this present disease, i.e., tooth mucocutaneous syndromes. Interestingly, the same pa- loss, we prefer to name this condition as mucocutane- tients described by From et al. in 19781 had been ous dyskeratosis with periodontal destruction and pre- previously reported by Hvidberg-Hansen et al. in 19742 mature tooth loss. as dyskeratotic marginal keratoconjunctivitis in hered- 1 itary periodontopathy and hyperkeratosis. They consid- Although From et al. suggested an autosomal domi- ered that the patients were affected by the Papillon- nant inheritance, our case was sporadic, with no relatives Lefèvre syndrome3 (hereditary periodontopathy and presenting similar features. Genetic studies and eventual new hyperkeratosis) and considered the ocular involvement cases reports are necessary to better elucidate this disease. as a new sign of the Papillon-Lefèvre syndrome. Nev- Mutations in the genes that codify cytokeratins, desmo- ertheless the skin involvement was dissimilar to that somal proteins, or those related to abnormal epithelial found in the Papillon-Lefèvre syndrome, in which dys- proliferation, such as those respectively associated with 10 keratosis has never been described. pachyonychia congenita, hereditary mucoepithelial 9 The first clinical sign observed in the present patient dysplasia, and hereditary benign intraepithelial dysk- 6 was edematous and erythematous gingival enlargement eratosis, need to be excluded in the pathogenesis of the associated with severe tooth mobility. Severe periodon- present disorder. Although there was no clinical evi- titis in young individuals can be a manifestation of a dences of neutrophil dysfunctions, the disease this con- range of other underlying systemic diseases, such as dition has some similarities to Papillon-Lefèvre syn- immunologic and hematologic disorders, hypophospha- drome,3 so it would be interesting to perform neutrophil tasia, Langerhans cell histiocytosis, and genetic syn- functional assays and mutation analysis of cathepsin. dromes such as Papillon-Lefèvre syndrome,4,5 which Despite the rapid and severe dental involvement, we were all excluded by the presence of numerous dysk- did not observe tooth malformation, suggesting that the eratotic cells in the gingival biopsy. Interestingly, the dyskeratotic epithelium does not influence odontogen- oral lesions were inconsistent with other well-charac- esis, and, although the panoramic radiograph showed terized dyskeratotic conditions involving the oral cavity missing developing permanent tooth buds, the possibil- (Table I). ity that they were removed during previous surgical 258 PATHOLOGY MAXILLOFACIAL AND ORAL gsiie al. et Agostini

Table I. Comparative characteristics of dyskeratotic diseases of the skin and/or mucosa and the present case Premature Skin Oral mucosa tooth loss Eye Nail Microscopic features Hereditary benign intraepithelial No White opalescent and spongy No Perilimbic gelatinous No “Cell-within-a-cell” dyskeratotic dyskeratosis (Witkop–von lesions plaques pattern (spinous layer); Sallmann)6 hyperkeratosis; acanthosis Kyrle disease7 Papules with central keratin No No Xerophthalmia; No Dyskeratosis (basal layer); plugs pseudopterygium; parakeratotic invaginated plug palpebral adhesions; ectropion Darier-White disease8 Warty papules and plaques Multiple white and red No Asymptomatic Plate anomalies (V notch); Dyskeratosis (corps ronds and papules (hard palate, peripheral corneal longitudinal white or red grains); acantholysis gingivae) opacities streaks Hereditary mucoepithelial Follicular keratosis Chronic nonpainful erythema No Recurrent keratitis; No Dyskeratosis (spinous layer); dysplasia9 (hard palate, gingivae, nystagmus; cataract; vacuolization tongue); fissured tongue corneal opacities Pachyonychia congenita10 Palmoplantar keratoderma; White plaque lesions (tongue No No Dystrophy Dyskeratosis (spinous layer); follicular keratosis; and buccal mucosae) vacuolization hyperhidrosis Dyskeratosis benigna Keratotic papules (body Edematous and erythematous Yes Keratoconjunctivitis; No Dyskeratosis (suprabasal layers); intraepithelialis mucosae et and limbs); palmoplantar gingival enlargement; bilateral corneal hyperparakeratosis; acanthosis cutis hereditaria1 circumscribed severe tooth mobility; maculation hyperkeratosis and alveolar bone resorption; verruca-like lesions; angular cheilitis; white Koebner phenomenon lesions (buccal mucosae) Present case Keratotic papules (body Edematous and erythematous Yes No No Dyskeratosis (suprabasal layers); and limbs); palmoplantar gingival enlargement; hyperparakeratosis; acanthosis circumscribed severe tooth mobility; hyperkeratosis; Koebner alveolar bone resorption; phenomenon angular cheilitis eray2012 February OOOO OOOO CASE REPORT Volume 113, Number 2 Agostini et al. 259 procedures cannot be excluded. The dyskeratotic epi- Systemic conditions associated with periodontitis in childhood thelium is probably very susceptible to trauma, permit- and adolescence. A review of diagnostic possibilities. Med Oral ting bacterial invasion, resulting in intense inflamma- Patol Oral Cir Bucal 2005;10:142-50. 5. Hicks J, Flaitz CM. Langerhans cell histiocytosis: current in- tion, and dyskeratotic epithelial proliferation, leading to sights in a molecular age with emphasis on clinical oral and 1 bone resorption and tooth loss. From et al. interpreted maxillofacial pathology practice. Oral Surg Oral Med Oral the “monstruous gingival swelling” observed during Pathol Oral Radiol Endod 2005;100:S42-66. tooth eruption in their patients as a reactive feature, 6. Baroni A, Palla M, Aiello FS, Ruocco E, Faccenda F, Vozza A, suggesting that it resulted from masticatory trauma, an et al. Hereditary benign intraepithelial dyskeratosis: case report. Int J Dermatol 2009;48:627-9. analogous reaction to the Koebner phenomenon of the 7. McKee PH, Calonje E, Grantner SR. Granulomatous, necrobiotic skin. We think that the exacerbated gingival swelling is and perforating dermatoses. Hyperkeratosis follicularis et para- a consequence of the presence of pseudocysts contain- follicularis in cutem penetrans. In: McKee PH, Calonje E, Grant- ing acantholytic dyskeratotic cells, associated with in- ner SR, editors. Pathology of the skin with clinical correlations. tense inflammatory infiltrate in the gingival connective Edinburgh, UK: Elsevier Mosby; 2005. p. 335-37. 8. Frezzini C, Cedro M, Leao JC, Porter S. Darier disease affecting tissue. Further studies are necessary to elucidate if these the gingival and oral mucosal surfaces. Oral Surg Oral Med Oral pseudocystic areas are derived from the surface epithe- Pathol Oral Radiol Endod 2006;102:e29-33. lium or from the odontogenic epithelial rests affected 9. Boralevi F, Haftek M, Vabres P, Lepreux S, Goizet C, Leaute- by local masticatory trauma. Labreze C, et al. Hereditary mucoepithelial dysplasia: clinical, No serious complications are anticipated, and we ultrastructural and genetic study of eight patients and literature review. Br J Dermatol 2005;153:310-8. think that, with good multidisciplinary care, affected 10. Leachman SA, Kaspar RL, Fleckman P, Florell SR, Smith FJ, patients can lead a normal life. McLean WH, et al. Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc 2005; REFERENCES 10:3-17. 1. From E, Philipsen HP, Thormann J. Dyskeratosis benigna intraepithelialis mucosae et cutis hereditaria. A report of this disorder Reprint requests: in father and son. J Cutan Pathol 1978;5:105-15. 2. Hvidberg-Hansen J, Larsen FE, Kleener J. Dyskeratotic marginal Michelle Agostini keratoconjunctivitis in hereditary periodontopathy and hyperker- Departamento de Diagnóstico Oral atosis. 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