Dysplasie, ektodermale hypohidrotische
Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder of ectoderm development characterized by malformation of ectodermal structures such as skin, hair, teeth and sweat glands. It comprises three clinically almost indistinguishable subtypes with impaired sweating as the key symptom: Christ-Siemens-Touraine (CST) syndrome (X-linked), autosomal recessive (AR), and autosomal dominant (AD) HED, as well as a fourth rare subtype with immunodeficiency as the key symptom (HED with immunodeficiency) (see these terms).
HED has a prevalence of approximately 1/15,000. CST syndrome is the most frequent sub-type (80% of cases) with an incidence in males of 1/50,000 to 1/100,000 births.
HED is characterized by a triad of signs comprising sparse hair (atrichosis/hypotrichosis), abnormal (e.g. conical) or missing teeth (anodontia/hypodontia), and decreased or absent sudation due to a lack of sweat glands (anhidrosis/hypohidrosis) which leads to heat intolerance and may cause recurrent, potentially life-threatening hyperthermic episodes. The skin is thin, dry and eczematous with regional hyperkeratosis. Most of the patients suffer from dry eye problems (e.g. chronic conjunctivitis, blepharitis), nasopharyngeal dryness and asthma-like symptoms. HED is associated with typical facial features such as a protruding forehead, sparse and fine eyebrows and eyelashes, wrinkles under the eyes, characteristic periorbital hyperpigmentation, a saddle-bridged nose, and hypoplasia of the mandible. Hair pigmentation is often absent or light. Failure to thrive may be observed. The AD and AR forms affect both sexes equally. In the X-linked form, female carriers can be asymptomatic or have a milder phenotype that may include oligodontia, conical incisors, hypotrichosis and moderate hypohidrosis.
HED is due to mutations in genes of the ectodysplasin/NF-κB pathway, necessary for the correct development of several ectodermal structures. Mutations in EDA (Xq12-q13.1), encoding the epithelial morphogen ectodysplasin-A of the tumor necrosis factor family, cause the CST syndrome. Mutations in EDAR (2q13), encoding the Ectodysplasin-A receptor, or EDARADD(1q42.3), encoding the EDAR-associated death domain (EDARADD) protein, cause both AR and AD HED. IKBKG (Xq28) mutations cause HED with immunodeficiency. WNT10A, TRAF6, NFKBIA or EDA2R mutations may be responsible for some HED cases.
The diagnosis is often established after hyperthermic episodes or with delayed teeth eruption. Lack of sweat glands can be evidenced by a skin biopsy or non-invasively by confocal microscopy or graphite prints of feet/hands. Sweat gland function can be assessed by quantifying pilocarpine-induced sweat production. Diagnosis is confirmed by genetic testing.
Differential diagnoses include other types of ED like odonto-onycho-dermal dysplasia and certain forms of ichthyosis (see these terms).
Uncontrolled exposure to heat must be avoided. Continuous monitoring of body temperature is required for babies placed in an incubator. Older children should adopt physical cooling measures, e.g. frequent consumption of cool liquids, wetting the clothes or wearing special cooling vests/caps. Early dental treatment aims at restoring function and improving the appearance of the teeth. Orthodontic treatment often comprises bone grafting or sinus-lift procedures followed by placement of dental implants supporting dental prostheses. HED with immunodeficiency requires immune-based therapies plus aggressive management of infections or hematopoietic stem cell transplantation.
If the disease is not diagnosed early enough in infancy, hyperthermia may lead to brain damage and eventually death. With early diagnosis and adequate management, most patients have a normal life expectancy.
Quelle: Orphanet: an online rare disease and orphan drug data base. Copyright, INSERM 1997. Available on http://www.orpha.net. Accessed 10.04.2014
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