Genodermatoses

Genetically inherited skin disorders

1. Presented by Dr Ravindra Mahanthi 1 st MDS Dept of Oral Pathology & Microbiology Genodermatoses

2. contents Introduction Classificati0n Ectodermal Dysplasia White Sponge Nevus Hereditary Benign Intraepithelial Dyskeratiosis Xeroderma Pigmentosum Hereditary Mucoepithelial Dysplasia Darier’s Disease Peutz-jeghers syndrome Hereditary Hemorrhagic Telangiectasia Ehlers- danlos Syndromes Tuberous Sclerosis Multiple Hamartoma Syndrome Epidermolysis Bullosa Conclusion 

3. Introduction Genodermatoses are an inherited skin disorder associated with structure and function. Several genodermatoses present with multisystem involvement lead to increased morbidity and mortality.    accompanied by various systemic manifestations.

4. Genokeratoses : Some of the systemic manifestations are characterized particularly by alterations in the normal keratinization process. These have been specifically referred to as Genokeratoses .

5. Classification There is no universally accepted classification of these dermatologic disorders. Based on etiology: Chromosomal Single gene Polygenetic

6. ECTODERMAL DYSPLASIA A group of inherited conditions in which two or more ectodermally derived anatomic structures fail to develop Classified based on clinical features Hypohydrotic ED -X linked recessive Hydrotic ED- autosomal dominant The various types of this disorder may be inherited in anyone of several genetic patterns.

7. 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

8. 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.

9. CLINICAL FEATURES: A male predominance is usually seen. (X-linked inheritance pattern). Affected individuais typically dispiay heat intolerance because of a reduced number of sweat glands . Rarely death results from the markedly elevated body temperature.

10. Fine, sparse blonde hair, Reduced density of eyebrow and eyelash hair The periocular skin may show a fine wrinkling with hyperpigmentation Midface hypoplasia resulting in protuberant lips. Xerostomia (because the salivary glands are ectodermally derived) The nails may also appear dystrophic and brittle.

11. ORAL MANIFESTATIONS: Oligodontia or hypodontia . Anodontia has also been reported, but this appears to be uncommon. Characteristically abnormal crown shapes The incisor crowns usually appear tapered, conical or pointed. The molar crowns are reduced in diameter.

12. Histologic features: shows a decreased number of sweat glands and hair follicles adnexal structures are hypoplastic and malformed Treatment : genetic counseling for parents and the patient • dental problems are managed by prosthetic replacement of dentition 

13. WHITE SPONGE NEVUS CANNON’S DISEASE; FAMILIAL WHITE FOLDED DYSPLASIA Etiology :   Autosomal dominant trait, described by cannon in 1935 Defect in normal keratinization of oral mucosa. Keratin 4 and keratin 13 is specifically expressed in the spinous layer. Mutations in either of these Keratin genes responsible for the clinical manifestations.   

14. Clinical features : Lesions appear at birth or in early age symmetric, thickened, white, corrugated or velvety diffuse plaques affect the buccal mucosa bilaterally ragged white areas which can be removed by gentle rubbing without bleeding Patients are asymptomatic  

15. Histopathologic features: Prominent hyperparakeratosis . Marked acanthosis with intracellular edema of the spinous layer. Parakeratin plugging running deep into the spinous layer.  

16. Exfoliative cytology   An eosinophilic condensation in the perinuclear region of the cells in the superficial layers of the epithelium. Tangled masses of keratin tonofilaments . Treatment and Prognosis Because this is a benign condition, no treatment is necessary . The prognosis is good.

17. HEREDITARY BENIGN INTRAEPITHELIAL DYSKERATOSIS Witkop Von Sallman Syndrome rare autosomal dominant genodermatosis affects descendants of native American, black and white people who originally lived in North Carolina . 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. 

18. Clinical features Lesions usually develop during childhood, affect oral and conjunctival mucosa. Oral lesions - similar to white sponge nevus 

19. Most interesting feature of HBID- ocular lesions, which begin to develop very early in life. Thick, opaque, gelatinous plaques affecting the bulbar conjunctiva adjacent to the cornea. Patients may experience tearing, photophobia, and itching of the eyes. Blindness may result from the induction of vascularity of the cornea.

20. Histopathologic features prominent parakeratin production in addition to marked acanthosis . peculiar dyskeratotic process, similar to that of Darier’s disease, With this dyskeratotic process, an epithelial cell appears to be surrounded or engulfed by an adjacent epithelial cell, resulting in the so-called “cell- within- a- cell” phenomenon. 

21. Treatment and Prognosis Because HBID is a benign condition, no treatment is generally required or indicated for the oral lesions. If superimposed candidiasis develops ,an antifungal medication can be used. Patients with symptomatic ocular lesions should be referred to an ophthalmologist . Typically the plaques that obscure vision must be surgically excised. This procedure, however, is recognized as a temporary measure because the lesions often recur.

22. PACHYONYCHIA CONGENITA A group of rare genodermatoses Usually inherited as an autosomal dominant trait . Mutations of genes that encode for keratin 6a, 6b,16 or 17. Specific mutations in the keratin 16 gene- Jadassohn – Lewandowsky type. Mutations of the keratin 17 gene are associated with the Jackson-Lawler form.

23. Clinical features The nails are dramatically affected in most patients. The free margins of the nails are lifted up because of an accumulation of keratinaceous material in the nail beds. The oral lesions are seen in the Jadassohn–Lawandowsky form. Whitish plaques on the mucosa of the cheeks, tongue.

24. loss of fingernails.

25. Marked hyperparakeratosts and acanthosis with perinuclear clearing of the epithelial cells . Treatment and Prognosis Because the oral lesions of pachyonychia congenita show no apparent tendency for malignant transformation, no treatment is required . The nails are often lost or may need to be surgically removed because of the deformity . Patients should receive genetic counseling;

26. DYSKERATOSIS CONGENITA COLE-ENGMAN SYNDROME ZINSSER-COLE-ENGMAN SYNDROME a rare genodermatosis usually inherited as an X- linked recessive trait.  Mutations in the DKC1 gene. The mutated gene appears to disrupt the normal maintenance of telomerase.

27. Clinical features Striking male predilection. (X-linked recessive trait) 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.   

28. Hyperorthokeratosis with epithelial atrophy. As the lesions progress, epithelial dysplasia develops until frank squamous cell carcinoma evolves. Treatment and Prognosis: The discomfort of the oral lesions is managed symptomatically . A nd careful periodic oral mucosal examinations are performed to check for evidence of malignant transformation . Routine medical evaluation is warranted to monitor the patient for the development of aplastic anemia . Selected patients may be considered for allogeneic bone marrow transplantation once the aplastic anemia is identified.

29. XERODERMA PIGMENTOSUM  A rare genodermatosis in which numerous cutaneous malignancies develop at a very early age. Inherited as an autosomal recessive trait Caused by defects in the excision repair and /or post -replication repair mechanism of dna . Mutations in the epithelial cells occur, leading to the development of skin cancer.   Inability of the epithelial cells to repair ultraviolet (UV) light-induced damage. Markedly increased tendency to sunburn. 

30. Clinical features: Increased tendency to sunburn. Skin changes-atrophy, freckled pigmentation, and patchy depigmentation Early childhood-actinic keratoses develop Lesions quickly progress to squamous cell carcinoma, with basal cell carcinoma also appearing Non-melanoma skin cancer develops during the first decade of life. Melanoma- about 5% of patients, but it evolves at a later time. Oral manifestations-occur before 20 years of age- squamous cell carcinoma of the lower lip ,tip of the tongue. 

31. Histopathologic features Histopathologic features of xeroderma pigmentosum are relatively nonspecific Cutaneous premalignant lesions and malignancies that occur are microscopically indistinguishable from those observed in unaffected patients. Treatment To avoid sunlight and unfiltered fluorescent light To wear appropriate protective clothing and sunscreens Topical chemotherapeutic agents ( e.G. 5- fluorouracil) may be used to treat actinic keratoses . 

32. Hereditary Mucoepithelial Dysplasia Rare disorder autosomal dominant trait Mucosal cells do not develop in a normal fashion – hence the name dysplasia No increased risk of malignancy

33. Clinical features Both cutaneous and mucosal abnormalities present Sparse, coarse hair with non scarring alopecia Ocular lesions- Photophobia,cataracts,ker atitis,nystagmus,impaired vision Rough ,dry skin,prominent perineal rashes appearing in infancy Pulmonary complications- recurrent pneumonia, cavitations of lung parenchyma 

34. Oral manifestations striking , well demarkated fiery red erythema of hard palate Attached gingiva , tongue mucosa-Less involved Mucosal alterations typically asymptomatic Nasal,conjunctival,vaginal cervical,urethral mucosa involved 

35. Histopathology Shows epithelium with minimal keratinisation and disorganized maturisation pattern Relatively high N/C ratio of epithelial cells No significant nuclear or cellular pleomorphism Cytoplasmic vacuolations seen as grey inclusions, more in cytologic smears Ultrastructurally , lesional cells have reduced no. of desmosomes and gap junctions 

36. DARIER’S DISEASE   KERATOSIS FOLLICULARIS ,DYSKERATOSIS FOLLICULARIS; DARIER-WHITE DISEASE.  Uncommon genodermatosis Striking skin involvement and relatively subtle oral mucosal lesions. Inherited as an autosomal dominant trait mutations in atp2a2 gene lack of cohesion among the surface epithelial cell characterizes this disease Mutation of a gene that encodes an intracellular calcium pump- cause for abnormal desmosomal organization in the affected epithelial cells. 

37. Clinical features Erythematous , pruritic , papules on skin of trunk and the scalp Develop during the second decade of life Accumulation of keratin, producing a rough texture A foul odor may be present as a result of bacterial degradation of the keratin Palms and soles often exhibit pits and keratoses Nails show longitudinal lines, ridges, or painful splits and sub ungual keratosis

38. oral lesions Asymptomatic , discovered on routine examination. consist of multiple, normal- colored or white, flat topped papules result in a cobblestone mucosal appearance affect the hard palate and alveolar mucosa buccal mucosa or tongue may be involved palatal lesions may resemble inflammatory papillary hyperplasia or nicotine stomatitis  

39. Histopathologic features Shows a dyskeratotic process Characterized by central keratin plug that overlies epithelium exhibiting a suprabasilar cleft. Intraepithelial clefting phenomenon, known as acantholysis . Rete ridges appear narrow, elongated, and “test tube” shaped. Epithelium reveals varying numbers of two types of dyskeratotic cells, Corps ronds (round bodies) or grains (resemble cereal grains).

40. Treatment and Prognosis the condition is not premalignant or otherwise life threatening, genetic counseling is appropriate. Photosensitive patients should use a sunscreen , and all patients should minimize unnecessary exposure to hot environments. For relatively mild cases, keratolytic agents may be the only treatment required. For more severely affected patients, systemic retinoids are often beneficial

41. PEUTZ-JEGHERS SYNDROME relatively rare but well recognized condition, having a prevalence of approximately 1 in 20,000 births . The syndrome is generally inherited as a n autosomal dominant trait , although 35 % of cases represent new mutations . Mutation of a gene known as LKBI, which encodes for a serine / threonine kinase .

42. Clinical Features Usually develop early in childhood and 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. The intestinal polyps (The jejunum and ileum are most commonly affected.) Gastrointestinal adenocarcinoma develops in 2 % to 3% of affected patients.

43. O ral lesions essentially represent an extension of the perioral freckling. These 1- to 4-mm brown to blue-gray macules primarily affect the vermilion zone, the labial and buccal mucosa , and the tongue and are seen in more than 90 % of these patients. The number of lesions and the extent of involvement can vary markedly from patient to patient

44. Histopathologic Features Slight acanthosis of the epithelium with elongation of the rete ridges. No apparent increase in melanocyte number is detected by electron microscopy. But the dendritic processes of the melanocytes are elongated. Furthermore the melanin pigment appears to be Retained in the melanocytes rather than being transferred to adjacent keratinocytes .

45. Treatment and Prognosis Patients with Peutz-Jeghers syndrome should be monitored for development of intussusception or tumor formation . Genetic counseling is also appropriate.

46. Hereditary Hemorrhagic Telangiectasia OSLER-WEBER-RENDU SYNDROME  Uncommon mucocutaneous disorder Inherited as an autosomal dominant trait HHTI -caused by a mutation of endoglin gene on chromosome 9 HHT2- ALK-1 ( activin receptor-like kinase-1) mutation HHT1 -more pulmonary involvement, HHT2 -milder disease of later onset.

47. Clinical features Diagnosed initially because of epistaxis . Nasal and oropharyngeal mucosa exhibit numerous scattered red papules Small collections of dilated capillaries ( telangiectasias ) close to the surface of the mucosa. Found on the vermilion zone of the lips, tongue, buccal mucosa Lesions distributed throughout the gastrointestinal mucosa, the genitourinary mucosa, conjunctival mucosa Chronic iron-deficiency anemia Arteriovenous fistulas in the lungs, liver, or brain Predisposition to brain abscess 

48. 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.

49. Histopathologic features a superficially located collection of thin-walled vascular spaces that contain erythrocytes. Treatment and Prognosis For mild cases of HHT. no treatment may be required. Moderate cases may be managed by selective cryosurgery or electrocautery of the most bothersome of the telangiectatic vessels. More severely affected patients. particularly those troubled by repeated episodes of epistaxis may require a surgical procedure at the nasal septum( septal dermoplasty ).  

50. EHLERS-DANLOS SYNDROMES A group of heterogeneous inherited connective tissue disorders Problems attributed to the production of abnormal collagen. 

51. Types of EHLERS-DANLOS SYNDROMES

52. Inherited as an autosomal dominant trait Defects of type I,III and V collagen Hyper elasticity of the skin and cutaneous fragility Vascular type of ehlers-danlos ( ecchymotic type)- extensive bruising that occurs with everyday trauma Ehlers- danlos syndrome (type VIII) -dental manifestations as a hallmark feature Marked periodontal disease activity at a relatively early age

53. unusual healing response occurs with relatively minor injury to the skin termed papyraceous scarring (resembles crumpled cigarette paper)

54. oral manifestations Include the ability of 50% of these patients to touch the tip of their nose with their tongue ( gorlin sign) Easy bruising and bleeding during minor manipulations of the oral mucosa Oral mucosal friability is present Tendency for recurrent subluxation of TMJ 

55. Treatment and Prognosis the various types of this syndrome show a variety of inheritance patterns, So an accurate diagnosis is required so that appropriate genetic counseling can be provided.

56. TUBEROUS SCLEROSIS EPILOIA; BOURNEVILLE-PRINGLE SYNDROME Uncommon syndrome Classically characterized by mental retardation, seizure disorders, and angiofibromas of the skin. Inherited as an autosomal dominant trait Two thirds of the cases are sporadic 

57. Facial angiofibromas appear as multiple, smooth-surfaced papules and occur primarily in the nasolabial fold area. Similar lesions, called ungula or periungual fibromas , are seen around or under the margins of the nails. Two other characteristic skin lesions are Connective tissue hamartomas – shagreen patches Ovoid areas of hypopigmentation - ashleaf spots.

58. CNS manifestations include seizure disorders and mental retardation rare tumor of the heart muscle- cardiac rhabdomyoma hamartomatous proliferations in the CNS develop into the potato-like growths “tubers” seen at autopsy. angiomyolipoma -Another hamartomatous type of growth related to this disorder occurs primarily in the kidney.

59. Oral manifestations Include developmental enamel pitting on the facial aspect of the anterior permanent dentition Fibrous papules seen on the anterior gingival mucosa Lips, buccal mucosa, palate, and tongue may be involved Radiolucencies of the jaws that represent dense fibrous connective tissue proliferations 

60. Radiologic features- radio lucent jaw lesions consist of dense fibrous connective tissue -resembles desmoplastic fibroma or simple type of central odontogenic fibroma . 

61. Histopathologic features: Shows a nonspecific fibrous hyperplasia. A benign aggregation of delicate fibrous connective tissue Characterized by plump, uniformly spaced fibroblasts with numerous interspersed thin-walled vascular channels  Treatment and prognosis The management of the seizure disorder with anticonvulsant agents. Periodic mri of the head may be done to screen for intra cranial lesions, whereas ultrasound evaluation is performed for evaluation of kidney involvement.

62. MULTIPLE HAMARTOMA SYNDROME COWDEN SYNDROME A rare condition has important implications for the affected patient Malignancies develop in a high percentage of these individuals. Inherited as autosomal dominant Mutation of the pten (phosphate and tensin homolog deleted on chromosome 10) gene

63. Cutaneous manifestations develop during the second decade of life skin lesions appear as multiple, small papules, primarily on the facial skin, especially around the mouth, nose, and ears Microscopically these papules represent hair follicle hamartomas - trichilemmomas acral keratosis - a warty appearing growth that develops on the dorsal surface of the hand palmoplantar keratosis - a prominent callus like lesion on the palms or soles.

64. Diagnosis The diagnosis is based on the finding of two of the following three signs: Multiple facial trichilemmomas Multiple oral papules Acral keratoses A positive family history is also helpful in confirming the diagnosis.

65. Histopathologic features H istopathologic features of the oral lesions are rather nonspecific, essentially representing fibroepithelial hyperplasia Other lesions associated with this syndrome have their own characteristic histopathologic findings, depending on the hamartomatous or neoplastic tissue origin. 

66. oral lesionsoral lesions Mutiple papules affecting the gingiva , dorsal tongue, and buccal mucosa. Other oral findings - higharched palate, periodontitis , Extensive dental caries  Treatment and Prognosis: Some investigators recommend bilateral prophylactic mastectomies as early as the third decade of life for female patients because of the associated increased risk of breast cancer.

67. EPIDERMOLYSIS BULLOSA A heterogeneous group of inherited blistering mucocutaneous disorders. A specific defect in the attachment mechanisms of the epithelial cells, either to each other or to the underlying connective tissue. Depending on the defective mechanism of cellular cohesion, there are four broad categories: EB Simplex- Keratin 5,14 EB Junctional - α3, β3,r2 EB Dystrophic -Oral lesions are most common, type VIII collagen EB Hemidesmosome - plectin,type XVII collagen, α6β38

68. Clinical features Dystrophic forms of epidermolysis bullosa -an autosomal dominant Initial lesions are vesicles or bullae Seen early in life and develop on areas exposed to low-grade, chronic trauma, such as the knuckles or knees. The bullae rupture, resulting in erosions or ulcerations that ultimately heal with scarring. Appendages such as fingernails may be lost. 

69. Generalized recessive dystrophic epidermolysis bullosa represents one of the more debilitating forms of the disease. Vesicles and bullae form with even minor trauma. Hand function is often greatly diminished resulting in fusion of the fingers into a mitten like deformity. Bulla and vesicle formation is induced by virtually any food having some degree of texture. Even with a soft diet, the repeated cycles of scarring often result in microstomia and ankyloglossia . Carious destruction of the dentition at an early age is common 

70. oral manifestations Typically mild Gingival erythema and tenderness Gingival recession and reduction in the depth of the buccal vestibule.  

71. Histopathologic features Features of epidermolysis bullosa vary with the type being examined Simplex form shows intraepithelial clefting by light microscopy. Junctional and dystrophic forms show subeptithelial clefting . Electron microscopy-reveals 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 dystrophic forms.

72. Treatment and prognosis: Treatment of epidermolysis bullosa varies with the type. For milder cases no treatment other than local wound care may be needed. Sterile drainage of larger blisters and the use of topical antibiotics. For the more severe cases Intensive management with oral antibiotics may be necessary if cellulitis develops Despite intensive medical care, some patients die as a result of infectious complications.

73. Conclusion  The genetic mysteries underlying several common genodermatoses solved by gene identification strategies. Some innovative methods need to be elucidated at the molecular level. The study of dermatoses affecting oral cavity is important because of the role which the dentist plays in the diagnosis, and treatment of these lesions. It is especially important for the dentist to recognize dermatoses that exhibit concomitant lesions of the oral mucous membrane. The dentist should be familiar with them so that he may either institute appropriate treatment or refer the patient to the proper therapist.

74. REFFERENCES Neville, Oral and Maxillofacial Pathology, First south asia edition. Shafer`s textbook of oral pathology 6 th edition . Gnananandar G, Rajesh E, Babu N, Krupaa J. Genodermatoses . Journal of Pharmacy and Bioallied Sciences. 2015;7(5):205.