Oral genodermatosis

Genetically determined skin disorders are termed as genodermatoses” (geno: genetic + dermatoses: skin lesions). A genodermatoses can be defined as “a cutaneous phenotype caused by a single mutation, which may be a point mutation, deletion or a chromosomal aberration”.

Oral genodermatoses can be classified as (by Hand JL & Bork K)

  1. Genodermatoses affecting teeth and dentition:
  • Ichthyosis.
  • Sjogren-Larrson syndrome.
  • Incontinentia pigmenti.
  • Ehlers Danlos syndrome.
  • Focal dermal hypoplasia syndrome.
  • Gardner syndrome.
  • Ectodermal dysplasia.
  • Hyperimmunoglobulin E syndrome (Job syndrome).
  1. Genodermatoses affecting periodontium and gingiva:
  • Ichthyosis.
  • Sjogren-Larrson syndrome.
  • Papillon Lefevre syndrome.
  • Tuberous sclerosis.
  • Chediak-Higashi syndrome.
  • Ehlers Danlos syndrome.
  • Focal dermal hypoplasia syndrome.
  1. Genodermatoses affecting oral mucosa:
  • Darier’s disease.
  • Neurofibromatosis type 1 and 2.
  • Chediak-Higashi syndrome.
  • Ehlers Danlos syndrome.
  • Lipid proteinosis.
  • Focal dermal hypoplasia syndrome.
  • Multiple hamartoma syndrome (Cowden syndrome).
  • Pachonychia congenital.
  • Epidermolysis bullosa.
  • Multiple endocrine neoplasia syndrome.
  • White sponge nevus.
  1. Genodermatoses affecting jaw bones and facies
  • McCune-Albright syndrome.
  • Ehlers Danlos syndrome.
  • Marfan syndrome.
  • Focal dermal hypoplasia syndrome.
  • Gardner syndrome.
  • Basal cell nevus syndrome.
  • Orofacial digital syndrome type I.
  1. Genodermatoses causing pigmentation of oral mucosa
  • Carney complex.
  • Neurofibromatosis type 1 and 2.
  • Mccune-Albright syndrome.
  • Lipid proteinosis.
  • Pseudoxanthoma elasticum.
  • Peutz-Jeghers syndrome.
  • Congenital erythropoetic porphyria.
  • Hypomelanosis of ito.
  • Sturge-Weber syndrome.
  • Hereditary hemorrhagic telengiectasia syndrome.
  1. Genodermatoses with malignant potential
  • Xeroderma pigmentosum.
  • Dyskeratosis congenital.
  SNo.Oral genodermatosisMutated Gene
  1Epidermolysis bullosaKRT5/ KRT14/ COL7A1
  2IchthyosesABCA12/ FLJ39501/ FLG/ STS
  3Palmoplantar keratodermaKRT1/ KRT16/ TRPV3
  4Chédiak‑Higashi syndromeCHS1 gene   in 1q42‑43   band
  5NeurofibromatosisNF1 and NF2
  6Tuberous sclerosis complexTSC1 (9q34), TSC2 (16p13.3)
  7Gardner syndromeAPC  (5q21q22)
  8Peutz‑Jeghers syndromeSTK11
  9Dyskeratosis congenitaNOP10/ NHP2
  10Ehlers‑Danlos syndromeCOL5A1
  11Marfen syndromeFBN1
  12Cowden’s syndromePTEN (10q22‑23)
  13Apert’s syndromeC934G/ C937G

EB: Epidermolysis bullosa, PPK: Palmoplantar keratoderma, CHS: Chédiak‑Higashi syndrome, TSC: Tuberous sclerosis complex, NF: Neurofibromatosis, EDS: Ehlers‑Danlos syndrome, DKS: Dyskeratosis congenital, KRT: keratin, COL: Collagens

  • Group of heritable genetic diseases characterized by widespread blistering, scarring & milia formation caused by defects of anchoring fibrils.
  • The onset of the disease usually is at birth.
  • Dystrophic epidermolysis bullosa is characterized by flat, pink bullae of ankles, knees hands, elbows and feet in decreasing order of frequency followed by scarring & milia formation.
  • Teeth are not affected but 20% of patients manifest oral bullae and milia.
  • These milia are epidermoid cyst developing in areas of previous bulla formation
  • Autosomal dominant inherited condition characterized by gastrointestinal hamartomatous polyps and tan to dark brown or blue maculae on skin and oral mucosa.
  • Brown pigmented macules are present at birth or usually noted at early childhood.
  • Pigmented lesions are seen on skin around the lips and the vermilion zone of the lips.
  • Brown pigmented, painless patches on the buccal mucosa, tongue or labial mucosa.

Neurofibromatosis (NF) is a neurocutaneous disorder inherited as autosomal dominant trait.

There are two distinct types:

  1. Neurofibromatosis 1 (NF1)
  • Also known as von Recklinghausen disease.
  • Characterized by the presence of multiple café-au-lait spots defined as oval shaped light brown patches greater than 0.5cm in diameter, multiple cutaneous neurofibromas (tumours on, under, or hanging off the skin), axillary or inguinal freckling, Lisch nodules (tiny tumours on the iris of the eye).
  1. Neurofibromatosis 2 (NF2)
  • Also known as bilateral acoustic neurofibromatosis.
  • Characterized by bilateral vestibular schwannomas involving the superior vestibular branch of the eighth cranial nerve and lesions on the brain and spinal cord.
  • Tumours of the auditory nerves that lead to hearing loss, is usually the first symptom of the disease.
  • Soft tissue neurofibromas are discrete with overlying normal mucosa having varying colour ranging from normal mucosal colour to red or sometimes yellow.
  • Located in the cheek, palate, tongue, floor of the mouth and lips.
  • The tongue most commonly affected site.
  • Superficial neurofibromas of tongue gives fissured appearance.
  • Deep seated tumors give an appearance of macroglossia.
  • Also occur on the gingival and buccal mucous membrane.
  • Tumor within the periodontal membrane lead to the migration of teeth.
  • Neurofibromas of jaw appear as radiolucent areas on radiographic examination.

Rare autosomal dominant genetic disorders associated with neoplasm and malignancy of endocrine gland.

Two main types of MEN have been identified.

  1. MEN- I is characterized by the combination of tumors of the pituitary glands, islets of pancreas and hyperparathyroidism.
  2. MEN-II is characterized by the combination of multiple pheochromocytomas and medullary thyroid carcinomas.

MEN -II is sub divided into two phenotypes: IIA and IIB. MEN-IIB is distinguished from other MEN syndromes because of its association with physical characteristics other than the endocrine findings like- thickened corneal nerves, a ‘wide-eyed’ facies, Marfanoid body habitus with joint laxity and mucosal neuromas. It is also known as Mucosal Neuroma Syndrome or Wagen-Mann Froboese Syndrome.

  • Oral submucosal neurofibromas produce characteristic diffuse or nodular swellings in the oral cavity known as “multiple mucosal neuroma syndrome’’. It is the first clue to the syndrome at early age.
  • Mucosal neuromas may be found on the dorsal surface of tongue, palate, buccal mucosa and pharynx.
  • The tongue neurofibromas appears crenated or notched.
  • Pedunculate symmetric nodules on the buccal mucosa behind each lip commissure have been described as pebbly or blubbery.
  • The palate may be high and arched.

All of the findings in MEN IIB are generally thought of as asymptomatic and benign.

  • Cowden syndrome a rare genodermotosis also called “Cowden’s disease” and “Multiple Hamartoma Syndrome”.
  • It is an autosomal dominant inherited disorder characterized by multiple tumor-like growths called hamartomas arising from all germ layers and an increased risk of cancer of breast, thyroid, endometrium, and renal system.
  • Oral hamartomas occur mainly on gingiva, buccal and palatal mucosa.
  • The oropharynx, larynx and nasal mucosa may also be involved.
  • Typical appearance of mulitiple, coalescent, flat topped mucosal papules has been described as cobblestone-like.
  • Rare heritable neurocutaneous disorder characterized by disorders of skin, ocular, bones, nervous system, genitourinary and cardiovascular systems.
  • The condition causes an unusual skeletal abnormalities and a higher risk of skin cancers.

Multiple jaw cysts, odontogenic keratocyst and osseous anomalies like cleft palate. Cleft palate and jaw cysts can lead to abnormal tooth development or jaw fractures.

Gardner’s syndrome is a rare autosomal dominant genetic disease characterized by intestinal polyposis, sebaceous cysts and multiple jaw osteomas. It is associated with other skin cysts like epidermoid and desmoid cysts, eye abnormality like congenital hypertrophy of the retinal pigmented epithelium and malignancies like papillary thyroid carcinomas, and adenocarcinomas and also dental abnormalities.

  • Bone islands represent a focus of mature compact bone in the alveolar portions of the jaws radiographically without evidence of bone expansion.
  • Multiple supernumerary and unerupted teeth occur in the incisor, cuspid and bicuspid regions, while the molar areas are rarely affected.
  • Supernumerary teeth are usually peg shaped or otherwise misshapen. Odontomas are the compound type and occur in the same distribution as the supernumerary teeth.
  • Osteomas, which cause a focal expansion of the surface of the jaw bone, can be felt through the skin or oral mucosa.
  • Characterized by classic triad of dystrophy of the nails, lacy reticular cutaneous pigmentation and oral leukoplakia.
  • High tendency for malignancies and progressive bone marrow failure.
  • Mucosal leukoplakias in any mucosa but most frequently in oral mucosa, typically involve the lingual mucosa, buccal mucosa, palate and tongue.
  • The leukoplakia may become verrucous, and ulceration may occur.
  • Periodontal disease, increased dental caries, thin enamel and hypodontia.
  • It is a group of inherited disorders of connective tissue which supports the skin, bone, blood vessels and many other organs of the body.
  • Ehlers- Danlos syndrome is caused by a defect in the synthesis of collagen (Type I or III).
  1. A.   The major signs and symptoms include:

    ·         Loose, hyper mobility of joints that is prone to sprains, dislocation, sub luxation and hyperextension.  

    ·         Early onset of osteoarthritis, easy bruising, dysautonomia (a disorder of the autonomic nervous system) typically accompanied by valvular heart disease.

    ·         Flat feet, vulnerability to chest and sinus infections.

  2. Vascular type of Ehlers-Danlos syndrome is associated with fragile blood vessels, includes tearing of the intestine, bleeding and rupture of the uterus (womb) during pregnancy. Velvety-smooth skin, abnormal wound healing and easy scar formation, low muscle tone and muscle weakness, myalgia and arthralgia.

It consists of extra-oral and intra-oral manifestations.

A.   Extra-oral manifestations:

  •  Slender and asymmetric face, retrognathia, scars on the chin and forehead, repeated dislocations of TMJ.
  • The area around the eye includes hypertelorism, epicanthus (a vertical fold of the skin on either side of the nose, sometimes covering the inner canthus), strabismus (abnormal alignment of eyes), narrow nasal bridge, shaggy hair, and sagging of the skin.

B.   Intra-oral manifestations:

  • High arched palate, crowding of teeth, highly fragile mucosa (similar to the patients’ skin), which is easily ruptured when dental instruments touch them and sutures do not remain in place, usually bruising is evident on the oral mucosa.

Marfan’s syndrome is a heritable genetic disorder of the connective tissue that involves ocular, skeletal, and cardiovascular systems

  • Patient tend to be unusually tall, thin built with long limbs and long, thin spidery fingers.
  • Spine curves on one side called scoliosis.
  • Complications include defects of the heart valves and aorta, aortic aueurysms and mitral valve prolapse and left ventricular dysfunction. Syndrome also affects the lungs, eyes, dural sac surrounding the spinal cord, the skeleton and the hard palate.
  • Jaw bones present retrognathia, deep narrow palate leading to crowding of teeth.
  • Angle’s Class II molar relationship and lack of space for all of the dental structures which is caused by palatal position of upper laterals in relation to the centrals.
  • Root deformity, abnormal pulp shape, and pulpal inclusions.

It is a rare autosomal dominant genetic disorder that leads to abnormal blood vessel formation which affects the skin, mucous membranes, and often organs such as the lungs, liver, spleen and brain, characterized by small and large arteriovenous malformations that become more prominent with age.

  • Punctate, spider like or nodular lesions found on buccal mucosa, tongue, lips, palate and gingiva.
  • Colour may vary from bright red to purple, but in oral mucosa usually cherry red.
  • White sponge nevus (WSN) is an autosomal dominant skin disorder first described by Hyde in 1909 and formally identified by Cannon in 1935.
  • This condition is attributed to a defect in the normal keratinization (keratin 4 and keratin 13, which are specifically expressed in the spinous cell layer of the oral mucosa).
  • Lesions usually appear at birth or in early childhood, but sometimes the condition develops during adolescence.
  • The lesions consist of symmetric, thickened, white, corrugated or velvety, diffuse plaques.
  • Buccal mucosa is the most frequently affected, followed by the labial and gingival mucosa, and the floor of the mouth.
  • Extra-oral mucosal sites, such as the nasal, esophageal, laryngeal, and anogenital mucosa, appear to be less commonly affected.
  • Patients are usually asymptomatic.
  • The white color does not diminish when the tissue is stretched in any mucosal site.
  • Leukoedema was first described by Sandstead and Lowe in 1953.
  • Leukoedema term is due to lesion’s white appearance “Leuko” and histological findings of “Intracellular-Edema”.
  • Found in buccal mucosa bilaterally.
  • It usually has a faint, white, diffuse, and filmy appearance, with numerous surface folds resulting in wrinkling of the mucosa.
  • It cannot be scraped off, and it disappears or fades upon stretching the mucosa.
  • Microscopic examination reveals thickening of the epithelium, with significant intracellular edema of the stratum spinosum.
  • PreNatal Diagnosis (PND) may be chosen to assess the high risk for severe cases of genodermatoses. Estimation of genetic risk should be highly accurate.
  • Genetic counselling is the process of advice where the patient or family is given information on the type of inheritance, risk of occurrence, prognosis of a disease, prevention and treatment.
  • Genetic counselling should be carefully done for patients and their families and they should be provided with accurate information on the diseases based on the ethical considerations.
  • There are no specific effective treatments for genodermatoses. Causative genes are identified and are targeted by gene replacement therapy and gene expression inhibition therapy.
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