Genodermatoses.

Genodermatoses are an inherited disorder, present with multisystem involvement. Help us to identify regular mutations and appalling skin diseases with recessive inheritance. Genetic heterogeneity is very common, and molecular diagnosis requires a broad effort. Recurrent mutations in unrelated families were seen in families with xeroderma, Griscelli. It seems likely that eventually oligonucleotide arrays will replace most other methods for routine mutation scanning of the more common diseases and planned sequencing will be increasingly used for rarer diseases.

Genodermatoses consign to an inherited skin disorder associated with structure and function. Several genodermatoses present with multisystem involvement lead to increased morbidity and mortality. Genetic research Center resolute on identifying the molecular basis of such outrageous skin diseases with recessive inheritance. This would help us identify regular mutations, founder effects etc., which would reduce the cost of selection patients and their carrier parents. During the years 2011–2013, 100 patients were referred to the center with Genodermatoses. The commonest group was ichthyosis, followed by epidermolysis bullosa, ectodermal dysplasia, albinism, cutis laxa, progeroid conditions, precancerous conditions xeroderma pigmentosum, Rothmund Thomson syndrome, dyskeratosis congenita. Genetic heterogeneity is very common, and molecular diagnosis requires an extensive effort. Recurrent mutations in unrelated families were seen in families with xeroderma, griscelli. Prenatal diagnosis could be provided for ichthyosis, infantile hyalinosis, and progeria.

This is the largest cohort of mutation proven patients with genodermatoses from India.[1]

Classification

Chromosomal

Single gene

Polygenetic.[2]

Ectodermal Dysplasia

Group of inherited condition. Two or more ectodermally derived anatomical structures fail to develop. Inherited one of genetic pattern, autosomal dominant, autosomal recessive, X-linked.

Hypohidrotic ectodermal dysplasia

X-linked - mapped in the proximal area of the long arm of band Xq-12-q13.1 Decreased expression of the epidermal growth factor receptor. Gene ED1 is responsible. Autosomal recessive - phenotypically indistinguishable from the X-linked form. Gene is located at dl (downless) locus.[34]

Hidrotic ectodermal dysplasia

GJB6 is the causative gene. This encodes for connexin 30. Located at pericentromeric region of chromosome 13q. For patients with cleft lip/palate-mutation PVRL 1, encoding a cell to cell adhesion molecule/herpes virus receptor. Reduction in number of, sweat gland, hair follicle, and sebaceous gland. Salivary glands may show ectasia of ducts and inflammatory changes.[5]

White sponge nevus

Defect in normal keratinization of the oral mucosa. Mutation in kerarin-4 or keratin-13. Inherited as autosomal dominant trait. High degree of penetrance and variable expressivity.[6]

Hereditary, benign, intraepithelial-dyskeratosis

Triracial isolate (native American, black and white). Autosomal dominant transmission. A segment of DNA localized at 4q35 is duplicated resulting in triple alleles for 2 linked markers suggesting that gene duplication is responsible for the disorder develop during childhood. The oral lesions are similar to those of white sponge nevus. Milder cases may exhibit the opalescent appearance of leukoedema. Superimposed candidal infection. Develop during childhood. The oral lesions are similar to those of white sponge nevus. Milder cases may exhibit the opalescent appearance of leukoedema. Superimposed candidal infection.[7]

Pachyonychia congenita

Inherited as an autosomal dominant trait. Specific mutations in the keratin 16 gene-Jadassohn–Lewandowsky type. Mutations of the keratin 17 gene are associated with the Jackso–Lawler form. The oral lesions are seen in the Jadassohn–Lawandowsky form. Whitish plaques on the mucosa of the cheeks, tongue. Marked hyperpa rakeratosts and acanthosis with perinuclear clearing of the epithelial cells. The free margins of the nails are lifted up because of an accumulation of keratinaceous material in the nail beds. Marked hyperkeratosis of the palmar and plantar surfaces, producing thick, callouslike lesions. The rest of the skin shows punctate papules, representing an abnormal accumulation of keratin in the hair follicles. Formation of painful blisters on the soles of the feet after a few minutes of walking during warm weather. Marked hyperpa rakeratosts and acanthosis with perinuclear clearing of the epithelial cells.[89]

Dyskeratosis congenita

Inherited as an X-linked recessive trait. Striking male predilection. Autosomal dominant and autosomal recessive forms are less common. Mutations in the DKC1 gene. The mutated gene appears to disrupt the normal maintenance of telomerase. Skin hyper pigmentation develops, affecting the face, neck, and upper chest. Dysplastic changes of the nails intraorally, the tongue and buccal mucosa develop bullae; these are followed by erosions and eventually leukoplakic lesions. The leukoplakic lesions are considered to be premalignant. Thrombocytopenia is usually the first hematologic problem that develops. Followed by anemia. Ultimately aplastic anemia develops. Hyperorthokeratosis with epithelial atrophy. As the lesions progress, epithelial dysplasia develops until frank squamous cell carcinoma evolves.[10]

Xeroderma pigmentosum

Inherited as an autosomal recessive trait. Caused by one of the several defects in the excision repair and/or postreplication repair mechanism of DNA. Inability of the epithelial cells to repair ultraviolet (UV) light-induced damage. Markedly increased tendency to sunburn. Atrophy, freckled pigmentation, and patchy depigmentation, soon follow. In early childhood, actinic keratoses begin developing. These lesions quickly progress to squamous cell carcinoma.

Basal cell carcinoma, melanoma and nonmelanoma skin cancer also develops occur before 20 years of age. Development of squamous cell carcinoma of the lower lip and the tip of the tongue Nonspecific Cutaneous premalignant lesions and malignancies that occur are microscopically indistinguishable from those observed in unaffected patients.[11]

Incontinentia pigmenti

Inherited as an X-linked dominant trait. Single unpaired gene 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 stage - vesiculobullous lesions appear on the skin of the trunk and limbs. Spontaneous resolution occurs within 4 months. Verrucous stage - verrucous cutaneous plaques develop, affecting the limbs. These clear by 6 months of age. Hyper pigmentation stage - macular, brown skin lesions appear, characterized by a strange swirling pattern. Atrophy and depigmentation stage - atrophy and depigmentation of the skin ultimately occur.

Central nervous system abnormalities mental retardation, seizure disorders, motor difficulties, strabismus, cataracts, retinal vascular abnormalities, optic nerve atrophy oligodontia (hypodontia), delayed eruption, hypoplasia of the teeth. The teeth are small and cone-shaped, both the primary and permanent dentitions are affected. Histopathology; vesicular stage - intraepithelial clefts filled with eosinophils are observed. Verrucous stage - hyperkeratosis, acanthosis, and papillomatosis are noted. Hyperpigmentation stage - shows numerous melanin-containing macrophages (melanin incontinence) in the subepithelial connective tissue.[12]

Keratosis follicularis

Autosomal dominant, a high degree of penetrance and variable expressivity. Mutation of the gene that encodes an intracellular calcium pump (ATP2A2 located at 12th chromosome). Suprabasal clefting and several “corps ronds” clinical features common in childhood, numerous erythematous, often pruritic, papules on the skin, common on scalp and trunk, accumulation of keratin, produce rough texture. Foul odor is due to bacterial degradation of keratin, Palm and sole exhibits pits and keratosis. Nails show longitudinal lines, ridges or painful splits. Become worse during the summer either due to the sensitivity to UV light or increased sweating that causes more epithelial clefting, cobble stone.[13]

Warty dyskeratoma

Histopathologically identical to Darier's disease. Hence, the lesion has been termed isolated Darier's disease. Cause-unknown. Appears as a solitary, asymptomatic, umbilicated papule on the skin. Intraoral lesion also develops in patients older than age 40. The intraoral warty dyskeratoma appears as a pink or white, umbilicated papule located on the keratinized mucosa, especially the hard palate, and the alveolar ridge. Dyskeratosis and a supra basilar cleft. Formation of corps ronds and grains is not a prominent feature.[14]

Peutz–Jeghers syndrome

Inherited as an autosomal dominant trait. 35% of cases represent new mutations. Mutation of a gene known as LKB1/STK11, which encodes for a serine/threonine kinase. Characterized by freckle like lesions of the hands, perioral skin, and oral mucosa in conjunction with intestinal polyposis.

Clinical features

Involve the periorificial areas (e.g. mouth, nose, anus, genital region). The lesions resemble freckles, but they do not wax and wane with sun exposure as do true freckles. The intestinal polyps, generally considered to be hamartomatous growths. Gastrointestinal adenocarcinoma develops in 2–3% of affected patients. The oral lesions essentially represent an extension of the perioral freckling. These 1–4-mm brown to blue-gray macules. Primarily affect the vermilion zone, the labial and buccal mucosa, and the tongue.[14]

Histopathology

Microscopic evaluation of the pigmented cutaneous lesions shows Slight acanthosis of the epithelium with elongation of the rete ridges. No apparent increase in melanocyte number is detected by electron microscopy.

Inherited as an autosomal dominant trait. Mutation of either one of two different genes at two separate loci is responsible for the condition. Hereditary hemorrhagic telangiectasia (HHT) 1 is caused by a mutation of the endoglin gene on chromosome 9. Whereas active in receptor-like kinase-1 mutation produces HHT2. The proteins produced by these genes may play a role in blood vessel wall integrity with both types of HHT, numerous vascular hamartomas develop affecting the skin and mucosa. Patients affected with HHT 1 tend to have more pulmonary involvement. Whereas those with HHT 2 generally have milder disease of later onset.

Frequent episodes of epistaxis. Telangiectasias of the mucosa and skin. Arteriovenous malformation involving the lungs, liver or CNS.

Oral manifestations

These telangiectatic vessels are most frequently found on the vermilion zone of the lips, tongue, and buccal mucosa. Although any oral mucosal site may be affected. Superficially located collection of thin walled vascular spaces.[15]

Ehlers–Danlos syndrome

A group of inherited connective tissue disorders. Problems are usually attributed to the production of abnormal collagen, the protein that is the main structural component of the connective tissue. The production of collagen necessitates many bio-chemical steps that are controlled by several genes. Potential exists for anyone of these genes to mutate producing selective defects in collagen synthesis.[16]

Tuberous sclerosis

Classically characterized by mental retardation, seizure disorders and angiofibromas of the skin. Inherited as an autosomal dominant trait. Sporadic and new mutation are also there. These mutations involve either one of two recentiy described genes. Tuberous sclerosis complex (TSC)-1 (found on chromosome 9) more commonly, TSC-2 (found on chromosome 16).

Clinical features facial angiofibromas, ungual or periungual fibromas, hypomelanotic maculcs (three or more), shagreen patch, CNS hamartomas, cardiac rhabdomyoma, renal angiomyolipoma, multiple retinal nodular hamartomas, minor features - Multiple, randomly distributed enamel pits gingival fibromas, bone “cysts” (actually fibrous pro liferations, multiple renal cysts, hamartomatous rectal polyps, histopathology - Enlarged gingiva shows nonspecific fibrous hyperplasia. Radiolucent jaw lesions consist of dense fibrous connective tissue that resembles desmoplastic fibroma.[17]

Multiple hamartoma syndrome

Inherited as an autosomal dominant trait showing a high degree of penctrance and a range of expressivity. The gene responsible for this disorder has been mapped to chromosome 10, mutation of the pten (phosphatase and tensin homolog deleted on chromosome 10) gene has been implicated in its pathogenesis.

Clinical features - Cutaneous manifestations are present in almost all patients. The majority of the skin lesions appear as multiple, small (<1 mm) papules, primarily on the facial skin, especially around the mouth, nose, and ears. Other commonly noted skin lesions are acral keratosis. Cutaneous hemangiomas, xanthomas, and lipomas have also been described. Oral manifestation oral lesions usually consist of multiple papules affecting the gingivae, dorsal tongue, and buccal mucosa. Other possible oral findings include a high arched palate, periodontitis, and extensive dental caries.[18]

Epidermolysis bullosa

Specific defect in the attachment mechanisms of the epithelial cells.

Classification: (1) Simplex (2) Junctional (3) Dystrophic specific mutations in the genes encoding keratin 5 and keratin-14 have been identified as being responsible for most of the simplex types. Mutations in the genetic codes for laminin-5, type XVII collagen and alpha-6 bete-4 integrin have been documented for the junctional types. Dystrophic types appear to be caused by mutations in the genes responsible for type VII collagen production.

Clinical features

Dystrophic type - The initial lesions are vesicles or bullae. The bullae rupture, resulting in erosions or ulcerations that ultimately heal with scarring. Appendages such as finger nails may be lost. The oral manifestations are typically mild, with some gingival erythema and tenderness.

Histopathology - The simplex form shows intraepithelial clefting by light microscopy. Juntional and dystrophic forms show subepithelial clefting. Electron microscopic examination, which is still considered the diagnostic “gold standard.” Clefting at the level of the lamina lucida of the basement membrane in the junctional forms. Below the lamina densa of the basement membrane in the dystrophic forms.[19]

Conclusion

The genetic mysteries underlying several common genodermatoses solved by gene identification strategies. Some innovative methods need to be elucidated at the molecular level. It seems likely that eventually oligonucleotide arrays will replace most other methods for routine mutation scanning of the more common diseases and automated sequencing will be increasingly used for rarer diseases. In India, we are yet to crack the genetic puzzle of most genodermatoses. Our population being genetically diverse, consent the organization of an local mutation database of these conditions before assays can be designed for diagnostic work.