Hypohidrotic Ectodermal Dysplasia
|HYPOHIDROTIC ECTODERMAL DYSPLASIA
|Christ-Siemens-Touraine syndrome (X-linked form)
|129490, 224900, 305100
|x-linked recessive, autosomal dominant, autosomal recessive
|EDA (300451), EDAR (604095), EDARADD (606603)
HED is the most common subtype of the ectodermal dysplasias. It is characterized by hypohidrosis (reduced or absent ability to sweat), hypodontia, hypotrichosis and distinctive facial features. Mutations in genes that encode components of the tumor necrosis factor alpha (TNFα)-related signaling pathway are causative. X-linked HED is the most prevalent subtype and associated with mutations in the EDA (ectodysplasin) gene (Xq12-q13.1); the dominant and recessive subtypes involve the EDAR (ectodysplasin receptor) (2q13) and EDARADD (ectodysplasin receptor-associated death domain) (1q42.3) genes respectively.1
Hypohidrosis is a significant feature of HED as reduced or absent eccrine glands lead to an impaired thermoregulation and hyperthermic episodes. Especially infants and children may experience extremely high fevers (up to 42°C) and febrile seizures. With age, patients learn to control their body temperature by e.g. drinking cold liquids or wetting their clothing but it is still very difficult for them, living in warm environments.2, 3
Teeth may be absent (hypodontia – mean number of missing teeth is 22), sparse, reduced in size or abnormally shaped. Common is a delayed eruption, a conical or peg shaped appearance and persistence of deciduous teeth.2 Prenatal tooth germ sonography has been shown highly specific and reliable in detecting XLHED between 18 and 28 weeks of gestation.4
The facial appearance is also characteristic with thick, prominent lips, depressed nasal bridge, frontal bossing and hypoplasia of the maxilla. Periorbital hyperpigmentation and fine wrinkling are further typical features of this disease. The facial characteristics usually become more noticeable with age.5
Nails may be dystrophic, but are normal in most patients. Hair (scalp and body) is straight, lightly pigmented / hypochromic, fine and sparse. Eyebrows are scanty or absent, whereas eyelashes may be normal, sparse or absent.6 Patients may also have chronic nasal infections with foul-smelling discharge and increased prevalence of lung infections due to diminished or absent salivary and mucous glands in the tracheal and bronchial mucosa. Dysphagia, gastro-oesophgeal reflux and constipation due to reduced/absent mucous glands intestinal may also occur. Other clinical features may include lacrimal gland atresia and photophobia, mammary gland hypoplasia (athelia, amastia) and occasional conductive hearing loss. Failure to thrive is common (about 40%) in individuals with HED.2, 3
About 80% of female carriers (x-linked HED) have dental abnormalities (e.g. absent permanent teeth, small/peg shaped teeth), two thirds have sparse/fine hair or patchy distribution of scalp/body hair and a quarter of those experience heat intolerance. Hypohidrotic areas of skin are linearly distributed along the lines of Blaschko.2, 5
Mutations in the EDA, EDAR and EDARADD genes encoding ectodysplasin, its receptor and an interacting protein have been respectively identified as the molecular cause of X-linked recessive, autosomal dominant and recessive disease forms. Ectodysplasin is a member of the TNF-related ligand family involved in the early epithelial-mesenchymal interaction that regulates ectodermal appendage formation.7
In severe cases, the diagnosis is usually made soon after birth. In milder cases, however, children may only be diagnosed clinically when teeth, nails or hair fail to develop normally. Mutation identification in the EDA or EDAR or EDARADD genes will help confirm the diagnosis and is essential for genetic counselling. Histopathologic features include absent (or sparse) eccrine glands/ducts, reduced hair follicles and sebaceous glands. Apocrine glands may be lacking, sparse or normal. A careful clinical examination helps in detecting female carriers.
Management of affected individuals requires a multi-disciplinary approach.
Thermal regulation - prevention of hyperthermia is essential. This can be achieved by avoiding heat and physical (over-)exertion, drinking cool liquids, cooling the body with wet clothing and installation of air-conditioning at home and school/work environments. Early dental restoration (bonding, overdentures, implants, bridges) is usually inevitable. Dry eyes and mouth can be treated by artificial tears and saliva or consumption of sufficient fluids. Smoky/dusty environments should be avoided and saline nose drops, home humidifier, ear lubricants, chest physiotherapy as well as topical minoxidil for alopecia are further symptomatic therapeutic options. Targeted therapies are being tested in preclinical settings. In a report about a protein replacement therapy (EDA) delivered intra-amniotically, three fetuses (from two pregnancies) were able to sweat normal at a follow-up time of 14-22 months of age.8