Dental Science - Review Article

Genodermatoses

N. Aravindha Babu, E. Rajesh, Jayasri Krupaa, G. Gnananandar

Department of ABSTRACT Oral pathology and Microbiology, Sree Genodermatoses are an inherited disorder, present with multisystem involvement. Help us to identify regular Balaji Dental College mutations and appalling diseases with recessive inheritance. Genetic heterogeneity is very common, and and Hospital, Bharath molecular diagnosis requires a broad effort. Recurrent mutations in unrelated families were seen in families University, Chennai, with xeroderma, Griscelli. It seems likely that eventually oligonucleotide arrays will replace most other methods Tamil Nadu, India for routine mutation scanning of the more common diseases and planned sequencing will be increasingly used for rarer diseases. Address for correspondence: Dr. G. Gnananandar, E-mail: gnanam.anu.rg@ gmail.com KEY WORDS: Benign, dyskeratosis congenital, , Ehlers–Danlos syndrome, epidermolysis

Received : 31-10-14 bullosa, hereditary, hidrotic ectodermal dysplasia, hypohidrotic ectodermal dysplasia, , Review completed : 31-10-14 intraepithelial-dyskeratosis, keratosis follicularis, multiple hamartoma syndrome, pachyonychia congenital, Accepted : 09-11-14 Peutz–Jeghers syndrome, tuberous sclerosis, Warty dyskeratoma, white sponge ,

enodermatoses consign to an inherited skin disorder associated Classification G with structure and function. Several genodermatoses present with multisystem involvement lead to increased morbidity and • Chromosomal mortality. Genetic research Center resolute on identifying the • Single gene molecular basis of such outrageous skin diseases with recessive • Polygenetic.[2] inheritance. This would help us identify regular mutations, founder effects etc., which would reduce the cost of selection Ectodermal Dysplasia patients and their carrier parents. During the years 2011–2013, 100 patients were referred to the center with Genodermatoses. Group of inherited condition. Two or more ectodermally The commonest group was , followed by epidermolysis derived anatomical structures fail to develop. Inherited one bullosa, ectodermal dysplasia, albinism, cutis laxa, progeroid of genetic pattern, autosomal dominant, autosomal recessive, conditions, precancerous conditions xeroderma pigmentosum, X‑linked. Rothmund Thomson syndrome, . Genetic heterogeneity is very common, and molecular diagnosis requires Hypohidrotic ectodermal dysplasia an extensive effort. Recurrent mutations in unrelated families were seen in families with xeroderma, griscelli. Prenatal diagnosis X‑linked ‑ mapped in the proximal area of the long arm of could be provided for ichthyosis, infantile hyalinosis, and progeria. band Xq‑12‑q13.1 Decreased expression of the epidermal growth factor receptor. Gene ED1 is responsible. Autosomal This is the largest cohort of mutation proven patients with recessive ‑ phenotypically indistinguishable from the X‑linked genodermatoses from India.[1] form. Gene is located at dl (downless) locus.[3,4]

Access this article online Quick Response Code: Hidrotic ectodermal dysplasia Website: www.jpbsonline.org GJB6 is the causative gene. This encodes for 30. Located at pericentromeric region of chromosome 13q. For DOI: patients with cleft lip/palate‑mutation PVRL 1, encoding a 10.4103/0975-7406.155903 cell to cell adhesion molecule/herpes virus receptor. Reduction in number of, sweat gland, hair follicle, and sebaceous gland.

How to cite this article: Babu NA, Rajesh E, Krupaa J, Gnananandar G. Genodermatoses. J Pharm Bioall Sci 2015;7:S203-6.

Journal of Pharmacy and Bioallied Sciences April 2015 Vol 7 Supplement 1 S203  Babu, et al.: Genodermatoses

Salivary glands may show ectasia of ducts and inflammatory Xeroderma pigmentosum changes.[5] Inherited as an autosomal recessive trait. Caused by one of the White sponge nevus several defects in the excision repair and/or postreplication repair mechanism of DNA. Inability of the epithelial cells to repair Defect in normal keratinization of the oral mucosa. Mutation in (UV) light‑induced damage. Markedly increased kerarin‑4 or keratin‑13. Inherited as autosomal dominant trait. tendency to . Atrophy, freckled pigmentation, and High degree of penetrance and variable expressivity.[6] patchy depigmentation, soon follow. In early childhood, actinic keratoses begin developing. These lesions quickly progress to Hereditary, benign, intraepithelial‑dyskeratosis squamous cell carcinoma.

Triracial isolate (native American, black and white). Autosomal Basal cell carcinoma, melanoma and nonmelanoma skin cancer dominant transmission. A segment of DNA localized at 4q35 also develops occur before 20 years of age. Development of is duplicated resulting in triple alleles for 2 linked markers squamous cell carcinoma of the lower lip and the tip of the suggesting that gene duplication is responsible for the disorder tongue Nonspecific Cutaneous premalignant lesions and develop during childhood. The oral lesions are similar to those malignancies that occur are microscopically indistinguishable of white sponge nevus. Milder cases may exhibit the opalescent from those observed in unaffected patients.[11] appearance of leukoedema. Superimposed candidal infection. Develop during childhood. The oral lesions are similar to Incontinentia pigmenti those of white sponge nevus. Milder cases may exhibit the opalescent appearance of leukoedema. Superimposed candidal Inherited as an X‑linked dominant trait. Single unpaired gene infection.[7] on the X‑chromosome being lethal for most males. Affected patients show chromosomal instability. Primarily affecting the skin, eyes and central nervous system (CNS), as well as oral structures. Begin in the first few weeks of infancy vesicular Inherited as an autosomal dominant trait. Specific stage ‑ vesiculobullous lesions appear on the skin of the trunk mutations in the keratin 16 gene‑Jadassohn–Lewandowsky and limbs. Spontaneous resolution occurs within 4 months. type. Mutations of the keratin 17 gene are associated with Verrucous stage ‑ verrucous cutaneous plaques develop, the Jackson–Lawler form. The oral lesions are seen in the affecting the limbs. These clear by 6 months of age. Hyper Jadassohn–Lawandowsky form. Whitish plaques on the pigmentation stage ‑ macular, brown skin lesions appear, mucosa of the cheeks, tongue. Marked hyperpa rakeratosts characterized by a strange swirling pattern. Atrophy and and acanthosis with perinuclear clearing of the epithelial depigmentation stage ‑ atrophy and depigmentation of the cells. The free margins of the nails are lifted up because of skin ultimately occur. an accumulation of keratinaceous material in the nail beds. Marked of the palmar and plantar surfaces, Central nervous system abnormalities mental retardation, producing thick, callouslike lesions. The rest of the skin shows seizure disorders, motor difficulties, strabismus, cataracts, punctate papules, representing an abnormal accumulation of retinal vascular abnormalities, optic nerve atrophy keratin in the hair follicles. Formation of painful blisters on oligodontia (hypodontia), delayed eruption, hypoplasia of the the soles of the feet after a few minutes of walking during teeth. The teeth are small and cone‑shaped, both the primary warm weather. Marked hyperpa rakeratosts and acanthosis and permanent dentitions are affected. Histopathology; with perinuclear clearing of the epithelial cells.[8,9] vesicular stage ‑ intraepithelial clefts filled with eosinophils are observed. Verrucous stage ‑ hyperkeratosis, acanthosis, and Dyskeratosis congenita papillomatosis are noted. Hyperpigmentation stage ‑ shows numerous melanin‑containing (melanin Inherited as an X‑linked recessive trait. Striking male incontinence) in the subepithelial connective tissue.[12] predilection. Autosomal dominant and autosomal recessive forms are less common. Mutations in the DKC1 gene. The Keratosis follicularis mutated gene appears to disrupt the normal maintenance of telomerase. Skin hyper pigmentation develops, affecting the Autosomal dominant, a high degree of penetrance and variable face, neck, and upper chest. Dysplastic changes of the nails expressivity. Mutation of the gene that encodes an intracellular intraorally, the tongue and buccal mucosa develop bullae; these calcium pump (ATP2A2 located at 12th chromosome). are followed by erosions and eventually leukoplakic lesions. Suprabasal clefting and several “corps ronds” clinical features The leukoplakic lesions are considered to be premalignant. common in childhood, numerous erythematous, often pruritic, Thrombocytopenia is usually the first hematologic problem papules on the skin, common on scalp and trunk, accumulation that develops. Followed by anemia. Ultimately aplastic anemia of keratin, produce rough texture. Foul odor is due to bacterial develops. Hyperorthokeratosis with epithelial atrophy. As degradation of keratin, Palm and sole exhibits pits and keratosis. the lesions progress, epithelial dysplasia develops until frank Nails show longitudinal lines, ridges or painful splits. Become squamous cell carcinoma evolves.[10] worse during the summer either due to the sensitivity to UV

 S204 Journal of Pharmacy and Bioallied Sciences April 2015 Vol 7 Supplement 1 Babu, et al.: Genodermatoses light or increased sweating that causes more epithelial clefting, Oral manifestations cobble stone.[13] These telangiectatic vessels are most frequently found on the Warty dyskeratoma vermilion zone of the lips, tongue, and buccal mucosa. Although any oral mucosal site may be affected. Superficially located Histopathologically identical to Darier’s disease. Hence, the collection of thin walled vascular spaces.[15] lesion has been termed isolated Darier’s disease. Cause‑unknown. Appears as a solitary, asymptomatic, umbilicated papule on the skin. Ehlers–Danlos syndrome Intraoral lesion also develops in patients older than age 40. The intraoral warty dyskeratoma appears as a pink or white, umbilicated A group of inherited connective tissue disorders. Problems are papule located on the keratinized mucosa, especially the hard usually attributed to the production of abnormal collagen, palate, and the alveolar ridge. Dyskeratosis and a supra basilar cleft. the protein that is the main structural component of the Formation of corps ronds and grains is not a prominent feature.[14] connective tissue. The production of collagen necessitates many bio‑chemical steps that are controlled by several genes. Peutz–Jeghers syndrome Potential exists for anyone of these genes to mutate producing selective defects in collagen synthesis.[16] Inherited as an autosomal dominant trait. 35% of cases represent new mutations. Mutation of a gene known as LKB1/STK11, Tuberous sclerosis which encodes for a serine/threonine kinase. Characterized by freckle like lesions of the hands, perioral skin, and oral mucosa Classically characterized by mental retardation, seizure in conjunction with intestinal polyposis. disorders and angiofibromas of the skin. Inherited as an autosomal dominant trait. Sporadic and new mutation are Clinical features also there. These mutations involve either one of two recentiy described genes. Tuberous sclerosis complex (TSC)‑1 (found Involve the periorificial areas (e.g. mouth, nose, anus, genital on chromosome 9) more commonly, TSC‑2 (found on region). The lesions resemble freckles, but they do not wax chromosome 16). and wane with sun exposure as do true freckles. The intestinal polyps, generally considered to be hamartomatous growths. Clinical features facial angiofibromas, ungual or periungual Gastrointestinal adenocarcinoma develops in 2–3% of affected fibromas, hypomelanotic maculcs (three or more), shagreen patients. The oral lesions essentially represent an extension patch, CNS hamartomas, cardiac rhabdomyoma, renal of the perioral freckling. These 1–4‑mm brown to blue‑gray angiomyolipoma, multiple retinal nodular hamartomas, macules. Primarily affect the vermilion zone, the labial and minor features ‑ Multiple, randomly distributed enamel buccal mucosa, and the tongue.[14] pits gingival fibromas, bone “cysts” (actually fibrous pro liferations, multiple renal cysts, hamartomatous rectal Histopathology polyps, histopathology ‑ Enlarged gingiva shows nonspecific fibrous hyperplasia.Radiolucent jaw lesions consist of dense Microscopic evaluation of the pigmented cutaneous lesions fibrous connective tissue that resembles desmoplastic shows Slight acanthosis of the epithelium with elongation of fibroma.[17] the rete ridges. No apparent increase in melanocyte number is detected by electron microscopy. Multiple hamartoma syndrome

Inherited as an autosomal dominant trait. Mutation of either Inherited as an autosomal dominant trait showing a high one of two different genes at two separate loci is responsible for degree of penctrance and a range of expressivity. The gene the condition. Hereditary hemorrhagic telangiectasia (HHT) 1 responsible for this disorder has been mapped to chromosome is caused by a mutation of the endoglin gene on chromosome 10, mutation of the pten (phosphatase and tensin homolog 9. Whereas active in receptor‑like kinase‑1 mutation produces deleted on chromosome 10) gene has been implicated in its HHT2. The proteins produced by these genes may play a role pathogenesis. in blood vessel wall integrity with both types of HHT, numerous vascular hamartomas develop affecting the skin and mucosa. Clinical features ‑ Cutaneous manifestations are present in Patients affected with HHT 1 tend to have more pulmonary almost all patients. The majority of the skin lesions appear as involvement. Whereas those with HHT 2 generally have milder multiple, small (<1 mm) papules, primarily on the facial skin, disease of later onset. especially around the mouth, nose, and ears. Other commonly noted skin lesions are acral keratosis. Cutaneous hemangiomas, Clinical features xanthomas, and lipomas have also been described. Oral manifestation oral lesions usually consist of multiple papules Frequent episodes of epistaxis. Telangiectasias of the mucosa affecting the gingivae, dorsal tongue, and buccal mucosa. Other and skin. Arteriovenous malformation involving the , possible oral findings include a high arched palate, periodontitis, liver or CNS. and extensive dental caries.[18]

Journal of Pharmacy and Bioallied Sciences April 2015 Vol 7 Supplement 1 S205  Babu, et al.: Genodermatoses

Epidermolysis bullosa 3. Mortier K, Wackens G. Ectodermal Dysplasia anhidrotic. Orphanet Encyclopedia 2004. Available from: http://www.orpha.net/data/patho/ GB/uk-ectodermal-dysplasia-anhidrotic.pdf. [Last accessed on 2014 Specific defect in the attachment mechanisms of the epithelial Sep 15]. cells. 4. Shah KN, Elston DM, editor. Ectodermal Dysplasia. EMedicine from WebMD: New York (NY), USA; 2014. Availble from: http://www. emedicine.com/derm/topic114.htm. [Last updated on 2014 Feb 14]. Classification: (1) Simplex (2) Junctional (3) Dystrophic specific 5. Fraser FC, Der Kaloustian VM. A man, a syndrome, a gene: Clouston's mutations in the genes encoding keratin 5 and keratin‑14 have hidrotic ectodermal dysplasia (HED). Am J Med Genet 2001;102:164- been identified as being responsible for most of the simplex 168. types. Mutations in the genetic codes for laminin‑5, type XVII 6. William DJ, Timothy GB, Armstrong CW, Jenkins SR, Kaufman L, Kerkering TM, et al. Andrews’ Diseases of the Skin: collagen and alpha‑6 bete‑4 integrin have been documented for Clinical Dermatology. Philadelphia: Saunders Elsevier; 2006. p. 807. the junctional types. Dystrophic types appear to be caused by 7. Jham BC, Mesquita RA, Aguiar MC, Carmo MA. Hereditary benign mutations in the genes responsible for type VII collagen production. intraepithelial dyskeratosis. J Oral Pathol Med 2007;36:55‑7. 8. Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia, PA: Saunders Clinical features Elsevier; 2009. p. 253. 9. Leachman SA, Kaspar RL, Fleckman P, Florell SR, Smith FJ, Dystrophic type ‑ The initial lesions are vesicles or bullae. McLean WH, et al. Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc 2005;10:3‑17. The bullae rupture, resulting in erosions or ulcerations that 10. Sinha S, Trivedi V, Krishna A, Rao N. Dyskeratosis ultimately heal with scarring. Appendages such as finger nails congenita‑ management and review of complications: A case report. may be lost. The oral manifestations are typically mild, with Oman Med J 2013;28:281‑4. 11. Masutani C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, some gingival erythema and tenderness. et al. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature 1999;399:700‑4. Histopathology ‑ The simplex form shows intraepithelial 12. Ehrenreich M, Tarlow MM, Godlewska‑Janusz E, Schwartz RA. clefting by light microscopy. Juntional and dystrophic forms Incontinentia pigmenti (Bloch‑Sulzberger syndrome): A systemic disorder. Cutis 2007;79:355‑62. show subepithelial clefting. Electron microscopic examination, 13. Hwang S, Schwartz RA. : A common follicular which is still considered the diagnostic “gold standard.” Clefting hyperkeratosis. Cutis 2008;82:177‑80. at the level of the lamina lucida of the basement membrane in 14. Diallo M, Cribier B, Scrivener Y. Warty dyskeratoma: Infundibular the junctional forms. Below the lamina densa of the basement histogenesis. Anatomoclinical study of 43 cases. Ann Dermatol [19] Venereol 2007;134:633‑6. membrane in the dystrophic forms. 15. Mehenni H, Blouin JL, Radhakrishna U, Bhardwaj SS, Bhardwaj K, Dixit VB, et al. Peutz‑Jeghers syndrome: Confirmation of linkage to Conclusion chromosome 19p13.3 and identification of a potential second locus, on 19q13.4. Am J Hum Genet 1997;61:1327‑34. 16. Rombaut L, Malfait F, De Wandele I, Cools A, Thijs Y, De Paepe A, The genetic mysteries underlying several common genodermatoses et al. Medication, surgery, and physiotherapy among patients with solved by gene identification strategies. Some innovative methods the type of Ehlers‑Danlos syndrome. Arch Phys Med need to be elucidated at the molecular level. It seems likely Rehabil 2011;92:1106‑12. 17. Agrawal S, Fulton AB. Ophthalmic manifestations. In: Kwiatkowski DJ, that eventually oligonucleotide arrays will replace most other Whittemore VH, Thiele EA, editors. Tuberous Sclerosis Complex: methods for routine mutation scanning of the more common Genes, Clinical Features, and Therapeutics. Weinheim: Wiley‑VCH; diseases and automated sequencing will be increasingly used for 2010. p. 271‑84. 18. Marsh DJ, Coulon V, Lunetta KL, Rocca‑Serra P, Dahia PL, Zheng Z, rarer diseases. In India, we are yet to crack the genetic puzzle of et al. Mutation spectrum and genotype‑phenotype analyses in most genodermatoses. Our population being genetically diverse, Cowden disease and Bannayan‑Zonana syndrome, two hamartoma consent the organization of an local mutation database of these syndromes with germline PTEN mutation. Hum Mol Genet conditions before assays can be designed for diagnostic work. 1998;7:507‑15. 19. Fine JD, Bauer EA, Gedde‑Dahl T. Inherited : Definition and historical overview. In: Fine JD, Bauer EA, McGuire J, References Moshell A, editors. Epidermolysis Bullosa: Clinical, Epidemiologic, and Laboratory Advances, and the Findings of the National 1. Hiremagalore RN, Nizamabad N, Kamasamudram V. Molecular Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins University diagnostics in genodermatoses – Simplified. Indian J Dermatol Press; 1999. p. 1‑19. Venereol Leprol 2008;74:8‑14. 2. William J, Timothy B, Dirk E. Andrews’ Diseases of the Skin: Clinical Source of Support: Nil, Conflict of Interest: None declared. Dermatology. 10th ed. Philadelphia: Saunders Elsevier; 2005.

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