Dermatology

Anhidrotic (hypohidrotic) ectodermal dysplasia

Hypohidrotic Ectodermal Dysplasia

Other synonyms include anhidrotic ectodermal dysplasia, Christ-Siemens-Touraine syndrome, and ectodermal dysplasia 1.

OMIM codes for hypohidrotic ectodermal dysplasia: X linked (#305100), autosomal recessive (#224900), autosomal dominant (#129490)

Are You Confident of the Diagnosis?

Hypohidrotic ectodermal dysplasia (HED) is the most correct term for this inherited condition. Other synonyms include anhidrotic ectodermal dysplasia, but this is a misnomer, as affected individuals are typically able to sweat to some degree.

  • What to be alert for in the history

Sweating is greatly diminished. An infantile history of unexplained fevers is usually reported. Often affected toddlers lay on the floor in an attempt to cool themselves.

Overheating can manifest with symptoms of irritability, erythema of the ears, headache, dizziness, weakness, fatigue, nausea, vomiting and muscle cramps.

Diagnosis is most often made with the eruption of conical teeth which may be delayed beyond 15 months of age. Hypodontia is also appreciated on imaging at this age (Figure 1).

Figure 1.

This child with HED has hypodontia with conical teeth, which is often the clinical finding that leads to the diagnosis. (Courtesy of National Foundation for Ectodermal Dysplasias)

  • Characteristic findings on physical examination

Affected newborns may be born with diffuse, scaling, erythematous skin similar to a collodian membrane. Classic facial features include frontal bossing, prominent supraorbital ridge, small chin, low, depressed nasal bridge, and prominent lips (Figure 2). Periorbital and perioral wrinkling and hyperpigmentation are obvious features . White facial papules described as sebaceous hyperplasia can also be seen as can hypotrichosis with thin, light, slow-growing hair on the scalp and also thin, sparse eyebrows and eyelashes. (Figure 3).

Figure 2.

These three unrelated males with HED have characteristic features of the syndrome, including hypotrichosis, perioral hyperpigmentation, and saddle nose. (Courtesy of National Foundation for Ectodermal Dysplasias)

Figure 3.

The mother is a carrier of the mutation for HED and her son is classically affected in an X-linked fashion. (Courtesy of National Foundation for Ectodermal Dysplasias)

Secondary sexual hair is typically normal. Nails are most often normal but can be thin or spoon shaped. The skin may be thin, smooth and dry.

  • Expected results of diagnostic studies

Decreased sweat port counts and flattened epidermal ridges are noted on confocal microscopy. Diminished sweating is noted on starch iodide palmar impressions and with pilocarpine iontophoresis. A trichogram may reveal variable hair shaft thickness, trichorrhexis nodosa and pili torti. Lack of eccrine structures on skin biopsy may be observed

Genetic testing for mutations of EDA (X-linked), EDAR, autosomal recessive/autosomal dominant (AR/AD), and EDAR-ADD (AR/AD) is also commercially available

  • Diagnosis confirmation

Diagnosis is typically based on the constellation of classic clinical features. Genetic testing can help confirm a diagnosis in question

The differential diagnosis includes ichthyosis; the neonatal finding of diffuse scaly erythema can be mistaken for an inherited ichthyosis. Ichthyotic disorders present with a true collodian membrane while hypohidrotic ectodermal dysplasia may mimic this finding with a pseudo-collodian membrane.

Hypohidrotic ectodermal dysplasia with immune deficiency caused by mutations in the NEMO gene presents with similar but more subtle clinical findings but can be distinguished by the multiple severe infections that develop due to the underlying immunodeficiency.

Who is at Risk for Developing this Disease?

The prevalence of HED is 1:10,000.It does not appear to have a racial or ethnic predilection.

Ninety-five percent of hypohidrotic ectodermal dysplasia cases are inherited as an X-linked recessive disorder. Therefore, the disease is only fully manifest in affected males and female carriers are more mildly affected. All daughters born to an affected male will be a carrier. None of the sons of an affected male will be affected. Each child of a carrier female has a 50% possibility of inheriting the mutation.

Equal incidence in males and females is noted in the rare autosomal dominant or autosomal recessive cases reported.

What is the Cause of the Disease?

  • Etiology

Hypohidrotic ectodermal dysplasia is a genetically inherited disorder. Mutations in the causative gene are typically inherited from an affected parent but a spontaneous mutation can also occur.

  • Pathophysiology

Mutations in the causative gene are responsible for the manifestations of the disorder. Mutations in the ectodysplasin signaling pathway are seen in those affected with hypohidrotic ectodermal dysplasia. X-linked cases are due to a mutation in the gene encoding ectodysplasin (EDA1) on chromosome Xq12-13.1.

Autosomal dominant and autosomal recessive cases are due to mutations in the gene for ectodysplasin receptor (EDAR) on chromosome 2q11-q13 or EDAR-associated death domain (EDAR-ADD) on chromosome 1q42.4-q43. The NEMO gene is implicated for HED-ID.

Systemic Implications and Complications

The inability to perspire can cause hyperthermia, which may lead to febrile seizures and neurologic damage. Decreased secretions can also lead to xerostomia, xerophthalmia, thick nasal secretions, excessive cerumen, hoarse voice, respiratory infections, and dysphagia.

Feeding issues, weight deficits and failure to thrive can be seen in affected infants and children. An increased incidence of atopy is also noted in affected individuals, including eczema, wheezing, asthma, food allergy and abnormal immunoglobulin production, in particular elevated IgE levels related to atopic diathesis and also a decreased delayed hypersensitivity to DNCB.

Mortality in the first three years of life is as high as 13% due to complications of hyperthermia, failure to thrive, and respiratory infections. Otherwise, life expectancy is normal.

Treatment Options

Cooling techniques to reduce elevated body temperature are key. Avoiding or appropriately managing situations with intense physical activity (ie sports) or when exposed to high ambient temperatures is important, especially in infancy, childhood and in the elderly.

Specific cooling techniques include seeking shade, using umbrellas, carrying damp washclothes or towels in a small cooler with ice, use of moistened bandanas around the head, neck or wrists, wearing dampened clothing, application of chilled emollients, misting water bottles, battery powered handheld fans, consuming cool drinks, use of cooling vests and air conditioned environments.

Since this condition affects multiple body systems, multidisciplinary care is advised for treatment of the various manifestations.

There is no currently available therapy that leads to cure of hypohidrotic ectodermal dysplasia.

Promising animal models in mice and dogs with gestational and postnatal administration of a synthetic recombinant EDA-A1 protein led to phenotypic rescue, including normalization of hair, teeth, lacrimation and improved sweating as well as decreased respiratory infections. EDI200 is currently being developed with the hope of human trials in XLHED in the near future.

Optimal Therapeutic Approach for this Disease

Symptomatic treatment is warranted for the skin findings and co-morbid diseases. Dental referral is warranted in all cases. Other specialty consultations are warranted based on individual symptoms.

Atopic dermatitis can be appropriately managed with topical steroids, topical immunomodulators and antihistamines by a dermatologist. Potential increased risk of melanoma has been reported, so an annual full body skin examination is also advised.

Early dental evaluation and treatment is important and helps with language development, mastication, and cosmesis. Dentures in childhood and orthodontia or dental implants are options for treatment in older individuals.

Dry eyes and thick nasal secretions can be treated with saline sprays. Consultation with ophthalmology and otolaryngology may be warranted.

Hearing and speech evaluations are recommended in affected children.

Asthma and recurrent respiratory infections should be treated appropriately and referral to a pulmonologist may be warranted.

Xerostomia can be treated with saliva substitutes or sialagogues.

Weight deficits can be managed by high caloric diets. Gastroenterology or nutrition consultation may be indicated in cases of failure to thrive.

Genetics evaluation can be helpful in coordination of care, genetic counseling and molecular testing.

Patient Management

Education of the patient and family regarding the condition is necessary. Patients should be instructed regarding the signs of overheating. They should be encouraged to modify their activities when necessary and to be aware of their body's limitations when at risk for hyperthermia.

Cooling techniques should also be discussed and readily implemented by the patients and families when warranted.

The importance of recognizing and promptly treating hyperthermia, failure to thrive and respiratory infections in affected infants and toddlers should be stressed as these issues can lead to mortality. Multidisciplinary care is important in this condition and follow-up with multiple specialists may be required.

Families should be referred to the appropriate national patient advocacy groups (ie The National Foundation for Ectodermal Dysplasias) for further education and support. Encourage affected individuals and families to enroll in the national registry at https://nfed.patientcrossroads.org/

Unusual Clinical Scenarios to Consider in Patient Management

Affected individuals should be encouraged to lead full lives with lifestyle modifications required only as necessary. Affected children and adolescents should be encouraged to participate in water-based sports as an ideal option but can also fully participate in all sports with precautions. Letters from the physician may need to be written to schools, teachers, and coaches to educate them about the need and importance of activity modifications, signs of overheating and cooling techniques.

Visits to zoos and amusement parks are advised on cloudy days. Letters from the physician to amusement parks administration can help prevent affected individuals from waiting in long lines in the sun to reduce risk of overheating.

Ability to sweat is reported by some affected adults to improve with age. Common medical conditions and illnesses also occur in affected individuals and not every symptom will be associated with or explained by the patient's ectodermal dysplasia.

Early dental treatment optimizes the chance that young children will be compliant with wearing dentures. Avoid tooth extraction to preserve the alveolar ridge. Dental treatment and surgeries may be able to be covered by medical insurance in affected individuals.

Thick secretions can lead to impressive nasal casts.

There is no optimal treatment for the periorbital/perioral wrinkling and long-term use of topical steroids to manage this condition should be avoided. Topical immunomodulators, topical keratolytics and topical vitamin D analogues are also uniformly ineffective for treatment.

You must be a registered member of Clinical Advisor to post a comment.
close

Next Article in Dermatology

Sign Up for Free e-newsletters