eMedicine Specialties > Dermatology > Pediatric Diseases

Ectodermal Dysplasia

Author: Kara N Shah, MD, PhD, Assistant Professor, Department of Pediatrics and Dermatology, University of Pennsylvania School of Medicine; Attending Physician, Section of Dermatology, Division of General Pediatrics, Children's Hospital of Philadelphia
Contributor Information and Disclosures

Updated: Feb 26, 2009

Introduction

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, hair, nails, eccrine glands, and teeth. Although Thurnam published the first report of a patient with ectodermal dysplasia in 1848,¹  the term ectodermal dysplasia was not coined until 1929 by Weech.²

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) and hidrotic ectodermal dysplasia (Clouston syndrome).

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 1982,³  with additional updates in 1994 and 2001.^4,5 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).

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.⁶ 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.⁷ Other classification systems categorize the ectodermal dysplasias based on defects in cell-cell communication and signaling, adhesion, transcription regulation, or development.⁸

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; (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.

Pathophysiology

Ectodermal dysplasia results from the abnormal morphogenesis of cutaneous or oral embryonal ectoderm (ie, hair, nails, teeth, eccrine glands).

• 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.⁹
• Eccrine defects: Eccrine sweat glands may be absent or sparse and rudimentary, particularly in patients with hypohidrotic ectodermal dysplasia.^9,10
• Other secretory gland defects: Hypoplasia of the salivary 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 may occur.¹¹
• Nail dystrophy: Abnormal nail plate formation may result in brittle, thin, ridged, or grossly deformed nails.

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.

Mortality/Morbidity

Morbidity and mortality is related to the absence or dysfunction of eccrine and mucous glands. Beyond early childhood, life expectancy ranges from normal to slightly reduced.

• Intermittent hyperpyrexia may occur in infants with decreased sweating. The mortality rate approaches 30%. Recurrent high fever may also lead to seizures and neurological sequelae.
• Pharyngitis, rhinitis, cheilitis, and dysphagia may result from reduced numbers of functional mucous glands in the respiratory and gastrointestinal tracts.
• Growth failure is common.¹²
• Severe inflammatory scalp dermatitis with erosions may result in frequent infections and cause scarring alopecia in patients with AEC (Hay-Wells) syndrome and Rapp-Hodgkin syndrome.
• Patients with associated immunodeficiency are at risk for recurrent infections, which may be life threatening.

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.

Clinical

History

Individuals affected by ectodermal dysplasia have abnormalities in different ectodermal structures. Some ectodermal dysplasia types are mild, while others are devastating. Obvious manifestations of the disorders are not clinically apparent in most newborns. Dental, hair, and nail anomalies usually become evident during infancy or childhood. A family history of similar clinical features is helpful.

• Other signs and symptoms
  • Hyperthermia with fever and seizures
  • Xerophthalmia (decreased tears) and conjunctivitis¹³
  • Deficient hearing or vision
  • Xerostomia (decreased saliva)¹⁴ and frequent dental caries
  • Developmental delay or mental retardation
  • Dysphagia
  • Growth failure¹²
  • Frequent pharyngitis, otitis, and rhinitis^15,16

Physical

Clinical appearance depends on the specific anomalies associated with each disorder. General features may include the following:

• Dry, hypopigmented skin is a feature. A chronic eczematous dermatitis may be present.
• Sweating may be absent or reduced.
• Sparse, fair, brittle hair with alopecia is a feature, as are absent or diminished body hair and sparse or absent eyebrows and eyelashes.
• Nail dystrophy is a feature.
• Dental features may include hypodontia or anodontia; malformed, rudimentary, or pegged teeth; and/or enamel defects and frequent dental caries.
• Diminished lacrimation and salivation are reported.
• Dysmorphic facies is a feature.

Following are several of the well-defined ectodermal dysplasias:

• X-linked hypohidrotic ectodermal dysplasia (EDA or Christ-Siemens-Touraine syndrome) is the most common ectodermal dysplasia. Female carriers may display a blaschkoid distribution of hypohidrosis as a result of lyonization and somatic mosaicism for the abnormal X chromosome. Autosomal recessive and autosomal dominant forms of hypohidrotic ectodermal dysplasia have been reported but are rare. Intelligence is normal.
  • The typical facies, which is often not recognized until infancy, is characterized by frontal bossing; sunken cheeks; saddle nose; thick, everted lips; wrinkled, hyperpigmented periorbital skin; and large, low-set ears.
  • Dental manifestations include conical or pegged teeth, hypodontia or complete anodontia, and delayed eruption of permanent teeth.
  • Most patients have fine, sparse, lusterless, fair hair; therefore, little pigmentation in the hair shaft is observed microscopically and the medulla is often discontinuous. When medullation is present, a "bar code" appearance is often seen.
  • Onychodystrophy may occur but is not common.
  • Extensive scaling of the skin and unexplained pyrexia secondary to anhidrosis may occur in the neonatal period. The development of a chronic eczematous dermatitis is common.
  • Other common signs are short stature, eye abnormalities, decreased tearing, and photophobia.
• Hidrotic ectodermal dysplasia (Clouston syndrome) is inherited in an autosomal dominant manner; the homozygous state may be lethal. It is more common in persons of French-Canadian ancestry.^17,18,19
  • Scalp hair is very sparse, fine, and brittle and alopecia is common. Eyebrows are thinned or absent.
  • Nail dystrophy is common. Persistent paronychial infections are frequent. Polydactyly, syndactyly, and bulbous fingertips may be present.
  • Patients have normal facies, no specific dental defects, and normal sweating.
  • Other reported findings include reticulate hyperpigmentation of the knees, elbows, and fingers; palmoplantar keratoderma; and eccrine poromatosis.
• AEC (Hay-Wells) syndrome is inherited as an autosomal dominant trait of variable expressivity.²⁰
  • Scaling and erythema may be present at birth. The characteristic facies is due to ankyloblepharon (congenital adhesion of the upper and lower eyelid margins by fibrous bands); a broad nasal bridge; and a sunken, hypoplastic maxilla. Cleft palate is common; cleft lip is rare.
  • A recalcitrant, crusted, inflammatory scalp dermatitis may cause scarring alopecia.²¹  Chronic blepharitis and conjunctivitis may develop. Nails are absent or dystrophic; pegged teeth are common. Mild hypohidrosis is common. Hair may be sparse and coarse.
• EEC syndrome is inherited as an autosomal dominant trait of low penetrance and variable expressivity.²² Many sporadic cases have been reported. Ectrodactyly with tetramelic 3-4 syndactyly results in the characteristic lobster-claw deformity of the hands and feet. Hypoplastic metacarpal or metatarsal bones may be present. Cleft lip and palate create a characteristic nasal contour.
  • Other ectodermal anomalies include mild hypohidrosis; coarse, dry hair with hypotrichosis; xerostomia; dystrophic nails; dental enamel hypoplasia; and microdontia.
  • Associated defects include blepharophimosis, lacrimal duct anomalies, strabismus, deafness, choanal atresia, and abnormalities of the genitourinary tract.
• Rapp-Hodgkin ectodermal dysplasia is an autosomal dominant syndrome.²³ High forehead, narrow nose, cleft lip or palate, and maxillary hyperplasia produce a distinctive facies. Hypohidrosis is severe enough to result in heat intolerance. Dental defects include conical teeth and hypodontia. Hair is sparse, has a steel-wool texture, and may show pili torti or pili canaliculi. Many patients present with recalcitrant, inflammatory scalp dermatitis followed by scarring alopecia. Nails are narrow and dystrophic. Occasional abnormalities include deafness, eye defects, and hypospadias.

Causes

Ectodermal dysplasia results from the abnormal development of embryonic ectodermal structures. The genetic defects responsible for approximately 30 of the ectodermal dysplasias have been identified.^24,25,26

• X-linked recessive hypohidrotic ectodermal dysplasia (EDA or Christ-Siemens-Touraine syndrome) is caused by mutations in EDA, which encodes the ectodysplasin protein, a soluble ligand that activates the NF-kappaB and JNK/c-fos/c-jun signaling pathways.^27,28 Ectodysplasin is important in promoting cell survival, growth, and differentiation.
• Autosomal dominant and autosomal recessive hypohidrotic ectodermal dysplasia are caused by mutations in the DL gene, which encodes the EDA (ectodysplasin) receptor.²⁹ Autosomal recessive hypohidrotic ectodermal dysplasia may also result from mutations in the EDARADD gene, which encodes a protein that interacts with the EDA receptor.
• Hidrotic ectodermal dysplasia (Clouston syndrome), which is an autosomal dominant disorder, is caused by mutations in GJB6, which encodes connexin 30, a component of intercellular gap junctions.³⁰
• EDA-ID and OL-EDA-ID are both caused by mutations in the NEMO gene, which encodes the regulatory subunit of the inhibitor-kappa kinase complex that regulates NF-kappaB activity.^31,32,33
• AEC (Hay-Wells) syndrome, Rapp-Hodgkin syndrome, EEC syndrome, limb-mammary syndrome, split hand-split foot malformation syndrome, and acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome are all caused by mutations in the TP63 gene.^34,35 p63 is a transcription factor that regulates the activity of the tumor suppressor gene TP53.

The genetic defects underlying several other ectodermal dysplasias are also known.

• Keratitis, ichthyosis, deafness (KID) syndrome is caused by mutations in the GJB2 gene, which encodes connexin 26.³⁶
• Margarita Island ectodermal dysplasia is caused by mutations in the PVRL1 gene, which encodes nectin-1.³⁷
• Ectodermal dysplasia with skin fragility is caused by mutations in the PKP1 gene, which encodes plakophilin 1.³⁸
• Goltz syndrome (focal dermal hypoplasia) is caused by mutations in the PORCN gene.³⁹
• Naegelli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis are caused by mutations in the KRT14 gene, which encodes keratin 14.⁴⁰
• Pachyonychia congenita type I is caused by mutations in either KRT6A (keratin 6a) or KRT16 (keratin 16), while pachyonychia congenita type II is caused by mutations in either KRT6B (keratin 6b) or KRT17 (keratin 17).
• Ellis-van Creveld syndrome is cause by mutations in EVC or EVC2.^41,42,43

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