Ectodermal Dysplasia

Updated: Feb 24, 2016
  • Author: Kara N Shah, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

The ectodermal dysplasias (EDs) comprise a large, heterogeneous group of inherited disorders that are defined by primary defects in the development of 2 or more tissues derived from embryonic ectoderm. The tissues primarily involved are the skin and its appendages (hair follicles, eccrine glands, sebaceous glands, and, nails) and teeth. Although Thurnam published the first report of a patient with ectodermal dysplasia in 1848, the term ectodermal dysplasia was not coined until 1929 by Weech. [1]

The ectodermal dysplasias are congenital, diffuse, and nonprogressive. To date, more than 192 distinct disorders have been described. The most common ectodermal dysplasias are X-linked recessive hypohidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome), as shown in the image below, and hidrotic ectodermal dysplasia (Clouston syndrome).

A newborn boy with anhidrotic/hypohidrotic ectoder A newborn boy with anhidrotic/hypohidrotic ectodermal dysplasia syndrome showing generalized fine scaling and a history of intermittent fever.

Current classification of ectodermal dysplasias is based on clinical features. Pure ectodermal dysplasias are manifested by defects in ectodermal structures alone, while ectodermal dysplasia syndromes are defined by the combination of ectodermal defects in association with other anomalies.

Freire-Maia and Pinheiro proposed the first classification system of the ectodermal dysplasias in 1982, [2] with additional updates in 1994 and 2001. [3, 4] Their original classification system stratified the ectodermal dysplasias into different subgroups according to the presence or absence of (1) hair anomalies or trichodysplasias, (2) dental abnormalities, (3) nail abnormalities or onychodysplasias, and (4) eccrine gland dysfunction or dyshidrosis.

Overall, the ectodermal dysplasias were classified into either group A disorders, which were manifested by defects in at least 2 of the 4 classic ectodermal structures as defined above, with or without other defects, and group B disorders, which were manifested by a defect in one classic ectodermal structure (1-4 from above) in combination with (5) a defect in one other ectodermal structure (ie, ears, lips, dermatoglyphics). Eleven group A subgroups were defined, each with a distinct combination of 2 or more ectodermal defects (eg, 2-4, 1-2-3, 1-2-3-4 from above). The group B disorders were indicated as 1-5, 2-5, 3-5, or 4-5 (from above). Visinoni tabulated a summary of the 186 defined ectodermal dysplasia syndromes classified as group A in 2009. [5]  This classification was revised in 2014 to include 163 defined ectodermal dysplasia syndromes. [6]

With the recent identification of the causative genetic defect for a number of the ectodermal dysplasias, newer classification systems have been devised. In 2003, Lamartine reclassified the ectodermal dysplasias into the following 4 functional groups based on the underlying pathophysiologic defect: (1) cell-to-cell communication and signaling, (2) adhesion, (3) development, and (4) other. [7] Similarly, in 2001, Priolo and Laganà reclassified the ectodermal dysplasias into 2 main functional groups: (1) defects in developmental regulation/epithelial-mesenchymal interaction and (2) defects in cytoskeleton maintenance and cell stability. [8] Other classification systems categorize the ectodermal dysplasias based on defects in cell-cell communication and signaling, adhesion, transcription regulation, or development. [9]

Several ectodermal dysplasia syndromes may manifest in association with midfacial defects, mainly cleft lip, cleft palate, or both. The 3 most commonly recognized entities are (1) ectodermal dysplasia, ectrodactyly, and clefting (EEC) syndrome [10] ; (2) Hay-Wells syndrome or ankyloblepharon, ectodermal dysplasia, and cleft lip/palate (AEC) syndrome; and (3) Rapp-Hodgkin syndrome, all of which are caused by mutations in the TP63 gene. See the images below.

Ectodermal dysplasia, ectrodactyly, and clefting s Ectodermal dysplasia, ectrodactyly, and clefting syndrome. Light-colored hair and scalp and earlobe defects are observed. Cleft lip and palate results in a characteristic nasal contour.
Ectrodactyly observed in an individual with ectode Ectrodactyly observed in an individual with ectodermal dysplasia, ectrodactyly, and clefting syndrome.
Typical cleft lip/palate and maxillary hyperplasia Typical cleft lip/palate and maxillary hyperplasia in a patient with Rapp-Hodgkin syndrome.
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Pathophysiology

Ectodermal dysplasia results from the abnormal morphogenesis of cutaneous or oral embryonal ectoderm (ie, hair, nails, teeth, eccrine glands). In some forms, mesodermal abnormalities are also present. Characteristic features include the following:

  • Hair defects: A reduction in the number of hair follicles in conjunction with structural hair shaft abnormalities may be seen. Structural hair shaft abnormalities may result from aberrations in hair bulb formation and include longitudinal grooving, hair shaft torsion, and cuticle ruffling. Hair bulbs may be distorted, bifid, or small. [11]
  • Eccrine defects: Eccrine sweat glands may be absent or sparse and rudimentary, particularly in patients with hypohidrotic ectodermal dysplasia. [11, 12]
  • Other secretory gland defects: Hypoplasia of the salivary, sebaceous, and lacrimal glands may occur. In some patients, mucous glands may be absent in the upper respiratory tract and in the bronchi, esophagus, and duodenum.
  • Dental defects: Abnormal morphogenesis or absence of teeth as well as enamel defects may occur. [13]
  • Nail dystrophy: Abnormal nail plate formation may result in brittle, thin, ridged, or grossly deformed nails.

Although few ectodermal dysplasia syndromes have a known genetic etiology, the number of ectodermal dysplasia syndromes with an identifiable genetic basis is increasing. In 2009, 64 genes and 3 chromosomal loci were associated with 62 ectodermal dysplasias. [5]

Key transcription factors and intracellular signaling pathways that have been implicated in the ectodermal dysplasias include the tumor necrosis factor (TNF)-like/TNV receptor signaling pathway, which involves ectodysplasin (EDA), the EDR receptor (EDAR), the EDAR-associated death domain (EDARADD); the WNT signaling pathway; the NF-kB signally pathway, which involves the NF-kB essential modulator (NEMO); and the transcription factor p63. [14]

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Epidemiology

Frequency

United States

The frequency of the different ectodermal dysplasias in a given population is highly variable. The prevalence of hypohidrotic ectodermal dysplasia, the most common variant, is estimated to be 1 case per 100,000 births.

International

Collectively, the prevalence of ectodermal dysplasia is estimated at 7 cases per 10,000 births.

Race

The ectodermal dysplasias have been reported most often in whites, but they have also been observed in persons of other races. Hidrotic ectodermal dysplasia has been reported in an extensive kindred of French-Canadian origin.

Sex

X-linked recessive hypohidrotic ectodermal dysplasia has full expression only in males. Female carriers outnumber affected men, but females show little or no signs of the condition. X-linked recessive anhidrotic ectodermal dysplasia (EDA) with immunodeficiency (EDA-ID) and the X-linked recessive syndrome of osteopetrosis, lymphedema, EDA, and immunodeficiency (OL-EDA-ID) are also seen exclusively in males. The remaining ectodermal dysplasias have no sexual predilection.

Age

Clinical recognition of ectodermal dysplasia varies from birth to childhood depending on the severity of symptoms and the recognition of associated complications. Many patients are not diagnosed until infancy or childhood, when dental anomalies, nail abnormalities, or alopecia become apparent.

AEC or Hay-Wells syndrome may manifest at birth as ankyloblepharon in association chronic scalp erosions. Hypohidrotic ectodermal dysplasia may manifest as scaling and erythema at birth. EEC syndrome and other related ectrodactyly syndromes (eg, acro-dermato-ungual-lacrimal-tooth [ADULT] syndrome and limb-mammary syndrome) are usually recognized at birth as a result of the characteristic limb deformities. Patients with anhidrosis or hypohidrosis may present in early infancy with recurrent episodes of hyperpyrexia.

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