Pediatrics

Ectodermal dysplasia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has an ectodermal dysplasia? What are the typical findings for this disease?

There are more than 200 ectodermal dysplasias, and they are defined by abnormalities in two or more ectodermal derivatives, including the skin, hair, nails, and teeth.

The most common type of ectodermal dysplasia, which accounts for 95% of cases, is X-linked ectodermal dysplasia (XLHED, also known as Christ-Siemens-Touraine syndrome).

The most common symptoms of XLHED are the following:

  • Significant decrease in sweating or hypohidrosis that can lead to heat intolerance, hyperthermia, or unexplained fevers/fevers of unknown origin in infancy that can rarely lead to febrile seizures

  • Tooth anomalies including hypodontia and conical teeth

  • Sparse hair of the scalp, eyebrows and eyelashes

Additional symptoms of XLHED typically include the following:

  • Facial features, including frontal bossing, small chin, depressed/low nasal bridge, prominent lips, periorbital/periocular wrinkling, and hyperpigmentation

  • Increased incidence of atopy, including eczema, wheezing, asthma, and food allergy

  • Dry, thin, smooth, pale skin with associated pruritus

  • Thin, slow-growing fingernails and toenails

  • Increased incidence of atopy, including eczema, wheezing, asthma, and food allergy

  • Decreased secretions with xeropthalmia, xerostomia, copious cerumen, and thick nasal secretions that lead to raspy voice, respiratory infections, and impressive thick nasal casts

  • Hyposalivation leading to dysphagia with difficulty chewing and swallowing

  • Feeding difficulties with failure to thrive

  • Neonatal diffuse erythema and scaling

What if my patient looks like he has X-linked ectodermal dysplasia but he has significant infections?

If a patient has clinical features of XLHED but has significant recurrent skin/soft tissue, pulmonary, gastrointestinal and central nervous system infections, they likely have hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID). This is a very rare type of ectodermal dysplasia that is defined by the infections and immunodeficiency, with more subtle abnormalities of the skin, hair, and nails. There is increased morbidity and mortality related to infectious complications, and stem cell transplants have been used with complications but some successes.

What if my patient has abnormalities of the skin, hair, nails and/or teeth but does not fit into X-linked ectodermal dysplasia or also has other malformations?

The second most common ectodermal dysplasia is hidrotic ectodermal dysplasias, although the incidence may be higher than appreciated since clinical findings are often subtle and limited. Affected individuals usually have normal sweating capacity and typically normal teeth, but they classically have pale, brittle, slow-growing, and wiry hair with progressive alopecia; thick, small, and discolored nails; palmoplantar hyperkeratosis; thickening and darkening of the skin at the elbows, knees, over the joints, axillae, areolae, and pubic area; clubbing of the fingers and tufting of the terminal phalanges. They can also have eye problems, speech difficulties, short stature, and thickening of the skull bones.

Complex ectodermal dysplasias involve abnormalities in the classic ectodermal structures (including the skin, hair, nails, and teeth) but also have other defects in additional ectodermal derivatives (including the central and peripheral nervous system and sensory organs), the glandular system (including the pituitary and mammary glands) as well as mesodermal structures affected by ectodermal development (including the musculoskeletal and genitourinary systems).

Ankyloblepharon-ectodermal defects–cleft/lip palate (AEC) syndrome, ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome, and focal dermal hypoplasia are all examples of complex ectodermal dysplasia syndromes.

AEC syndrome (also known as Hay-Wells syndrome) is defined by ankyloblepharon (congenital adhesions between the eyelids) and other eye findings, skin erosions especially of the scalp, pigmentary anomalies of the skin, palmoplantar erosions and hyperkeratosis, hypodontia, nail changes, hypohidrosis, cleft lip and/or palate, and rarely limb abnormalities including syndactyly.

EEC syndrome is defined by the ectrodactyly or split hand/foot malformation and the cleft lip/palate. The skin, hair, nails, and teeth can have defects but are more subtly affected. Other findings include significant eye problems, conductive hearing loss, and renal abnormalities.

Focal dermal hypoplasia (also known as Goltz syndrome) is defined by Blaschko linear pigmentary changes with skin atrophy, telangiectasias, and superficial fat herniations as well as papillomas, dysplastic nails, hypotrichosis, hypodontia, eye anomalies, skeletal abnormalities (including microcephaly, facial asymmetry, and short stature), gastrointestinal and genitourinary malformations, and rarely mental retardation.

What other disease/condition shares some of these symptoms?

XLHED can mimic an inherited ichthyotic condition during the neonatal period because of the scaly erythroderma that can be mistaken for a collodian membrane. HED-ID also has features similar to XLHED but is distinguished by severe, life-threatening infections.

Hidrotic ectodermal dysplasia shares symptoms and findings with Unna-Thost keratoderma because of the palmoplantar keratoderma, with pachyonychia congenita because of the severe nail dystrophy and focal palmoplantar hyperkeratosis, and with dyskeratosis congenita because of the nail dystrophy, palmoplantar hyperkeratosis, and reticulated pigmentary abnormalities.

AEC syndrome can be mistaken for epidermolysis bullosa because of the neonatal skin erosions, for an ichthyotic disorder because of the neonatal erythroderma, and for EEC because of the clefting.

EEC syndrome can be mistaken for the limb-mammary syndrome because of the limb defects and for AEC syndrome because of the clefting and occasional limb defects.

Goltz syndrome can be considered in the differential diagnosis of incontinentia pigmenti because of the streaky skin changes, of Rothmond-Thomson syndrome because of the telangectasias and skin atrophy, and of nevus sebaceous syndrome because of fat herniations, papillomas, and skeletal abnormalities.

What caused this disease to develop at this time?

The ectodermal dysplasias are a group of genetically inherited diseases. The majority of patients have a known family history, and the mutation is genetically transmitted by a defined inheritance pattern. Disease-causing spontaneous mutations can also occur.

HED is typically X-linked recessive but has rarely been reported to be autosomal dominant or autosomal recessive.

HED-ID is typically X-linked recessive but can be autosomal dominant or autosomal recessive.

Hidrotic ectodermal dysplasia is autosomal dominant.

AEC and EEC syndromes are autosomal dominant.

Goltz syndrome is X-linked dominant and is sporadic in 95% of cases.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Diagnosis is typically based on clinical features.

Diagnostic study findings in XLHED that can be helpful in establishing the diagnosis when clinical exam findings are subtle or the diagnosis is in question can include the following:

  • Decreased sweat duct counts and flattened epidermal ridges noted on confocal microscopy

  • Diminished sweating noted on starch iodide palmar impressions, which can produce widely variable results, or with pilocarpine iontophoresis, which more reliably reveals quantifiably reduced or absent sweat volumes in those with XLHED

  • Hair shaft analysis by light microscopy may reveal variable hair shaft thickness, trichorrhexis nodosa, and pili torti, but results can vary widely, whereas phototrichogram more reliably reveals fewer terminal hairs with decreased thickness along with fewer follicular units with fewer hairs per unit in affected individuals.

  • Lack of eccrine structures on skin biopsy of the palm and scalp may be observed.

  • Genetic testing for the causative mutations of ectodysplasin (EDA [X-linked]), ectodysplasin A receptor (EDAR) (autosomal recessive/autosomal dominant), and ectodysplasin A receptor– associated death domain (EDAR-ADD) (autosomal recessive/autosomal dominant) is also commercially available (www.genetests.org).

  • Sweat pore counts, starch iodide palmar impressions, and trichograms are all nonspecific with low sensitivity and specificity. Skin biopsy specimens, especially of the scalp or palm, that lack eccrine structures are diagnostic of HED. The presence of eccrine structures on skin biopsy can be seen in HED, but their presence suggests the patient does not have HED. Mutation detection frequency for EDA, which is the causative mutation in 95% of XLHED cases, is approximately 95% and is considered the gold standard for confirming a diagnosis.

Would imaging studies be helpful? If so, which ones?

A panoramic radiograph or dental films can confirm the presence of hypodontia and tooth malformations.

Confirming the diagnosis

The diagnosis is typically based on the classic clinical presentation. Infants with XLHED often escape diagnosis unless there is a family history. Affected infants classically have a history of unexplained fevers and neonatal erythroderma, which can look similar to a "postmature" baby or be mistaken for a collodian membrane.

The findings in a newborn can be subtle but include the classic facial features with frontal bossing, low nasal bridge, small chin, prominent lips, and periocular hyperpigmentation. Diagnosis is more easily made during the toddler years when conical teeth erupt. Toddlers may be noted to lay on cool surfaces or the floor in an attempt to cool themselves.

Hypohidrosis is typically not perceived until early childhood. In later childhood, affected children often complain about feeling overheated and can have symptoms of overheating, including irritability, erythema of the ears, headache, dizziness, weakness, fatigue, nausea, vomiting, and muscle cramps.

If the diagnosis in is question, confirmatory genetic testing is available but rarely necessary.

If you are able to confirm that the patient has X-linked ectodermal dysplasia, what treatment should be initiated?

Cooling techniques to reduce elevated body temperature are key. Avoiding or appropriately managing situations with intense physical activity (i.e., sports) or exposure to high ambient temperatures is important, especially in infancy, childhood, and in the elderly. Specific cooling techniques include seeking shade; using umbrellas; carrying damp washcloths or towels in a small cooler with ice; using moistened bandanas around the head, neck, or wrists; wearing dampened clothing; applying chilled emollients, water from misting water bottles, and air from battery-powered handheld fans; consuming cool drinks; using cooling vests; and seeking air-conditioned environments.

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

Symptomatic treatment is warranted for the skin findings and comorbid diseases.

Dental referral is warranted in all cases. Early dental evaluation and treatment is important and helps with language development, mastication, and cosmesis and is recommended every 6-12 months. Dentures in childhood and orthodontia or dental implants are options for treatment in older individuals. Other specialty consultations, including periodontics, are warranted based on individual symptoms.

Atopic dermatitis can be appropriately managed with bland emollients, topical steroids, topical immunomodulators, and antihistamines prescribed by a dermatologist.

Potential increased risk of melanoma has been reported, so an annual full-body skin examination is also advised.

Dry eyes and thick nasal secretions can be treated with saline sprays. Ophthalmologic and otolaryngologic consultation 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.

There is currently no available therapy that leads to cure of HED; however, EDI200 is a ectodysplasin-A1 (EDA-A1) recombinant replacement protein being developed by Edimer that is in FDA-approved Phase II trials and is being administered to males in the newborn period to hopefully mitigate some of the symptoms of the condition. For more information, please visit clinicaltrials.gov with identifier NCT01775462.

Affected individuals and families should also be referred to their national patient advocacy groups (i.e., The National Foundation for Ectodermal Dysplasias, www.nfed.org) for further education and support.

What are the adverse effects associated with each treatment option?

Most of the treatments and therapies for XLED are for symptomatic relief and are well tolerated.

What are the possible outcomes of X-linked ectodermal dysplasia?

XLHED is caused by mutations in the DNA. Therefore, the disease manifestations are genetically determined. There are no current curative treatments for this condition; clinical trials of a replacement protein to correct the findings of the condition are ongoing, but presently, the findings are permanent and passed on to the offspring of affected individuals, with the inheritance pattern based on the the specific familial mode of inheritance.

Mortality in the first 3 years of life is as high as 13% resulting from complications of hyperthermia, failure to thrive, and respiratory infections. Otherwise, life expectancy is normal.

Stressing the importance of multidisciplinary care and follow-up is essential for optimal management.

What causes this disease and how frequent is it?

Epidemiology:

XLHED has an estimated incidence of 1/10,000. It is a genetically inherited disease. Ninety-five percent of cases are X-linked recessive; therefore, the disease is only fully manifested in affected male patients, 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 female carrier has a 50% of inheriting the mutation.

Autosomal dominant and autosomal recessive cases are rarely reported and have an equal male to female incidence.

There are no apparent racial or ethnic predilections.

How do these pathogens/genes/exposures cause the disease?

Etiology: Hypohidrotic ectodermal dysplasia is a genetically inherited disorder. Mutations in the causative gene are typically inherited from an affected parent, but 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 XLHED. 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.

Other clinical manifestations that might help with diagnosis and management.

The following are unique management issues to consider for patients affected by XLHED:

  • 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.

  • 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 keratolyticagents, and topical vitamin D analogues are also uniformly ineffective for treatment.

What complications might you expect from the disease or treatment of the disease?

The inability to perspire can cause hyperthermia that 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. Symptomatic treatments are well-tolerated with limited complications.

There is no therapeutic cure for XLHED at this time, but clinical trials of a replacement protein administered in the newborn period are underway.

Are additional laboratory studies available; even some that are not widely available?

The following studies are rarely performed in the clinical setting and are typically used for research purposes:

  • Direct observation of epidermal ridge and sweat ducts on the fingertip using a stereomicroscope

  • Standard fingerprinting to assess for loss of epidermal ridge clarity

  • Sweat pore counts using application of 5% phthaladehyde to the fingertip

  • Sweat pore counts on Permlastic impressions from the fingertips

  • Identification of sweat pores and skin temperature patterns on whole-body thermography

  • Starch iodine sweat pattern testing

  • Phototrichogram to assess the number and character of the hair and follicular units

  • Skin biopsy of the palm or scalp to assess for reduced number of eccrine structures

How can X-linked ectodermal dysplasia be prevented?

At this time, the disease cannot be prevented in individuals with a disease-causing mutation.

What is the evidence?

Bluschke, G, Nusken, KD, Schneider, H. "Prevalence and prevention of severe complications of hypohidrotic ectodermal dysplasia in infancy". Early Hum Dev. vol. 86. 2010. pp. 397-9.

Burger, K, Schneider, AT, Wohlfart, S. "Genotype-phenotype correlation in boys with X-linked hypohidrotic ectodermal dysplasia". Am Med Genet A. 2014.

Casal, MR, Lewis, JR, Mauldin, EA. "Significant correction of disease after postnatal administration of recombinant ectodysplasin A in canine x-linked ectodermal dysplasia". Am J Hum Genet. vol. 81. 2007. pp. 1050-6.

Hobkirk, JA, Nohl, F, Bergendal, B. "The management of ectodermal dysplasia and severe hypodontia. International conference statements". J Oral Rehabil. vol. 33. 2006. pp. 634-7.

Irvine, AD, Harper, J, Orange, A, Prose, NS. "Ectodermal dysplasias". Textbook of Pediatric Dermatology. Wiley-Blackwell. 2006.

Rouse, C, Siegfried, E, Breer, W. "Hair and sweat glands in families with hypohidrotic ectodermal dysplasia: further characterization". Arch Dermatol. vol. 140. 2004. pp. 850-5.

Salinas, CF, Jorgenson, RJ, Wright, JT. "2008 International conference on ectodermal dysplasias classification: conference report". Am J Med Genet Part A. vol. 149A. 2009. pp. 1958-69.

Shah, KN. "Ectodermal dysplasia". http://emedicine.medscape.com/article/1110595-overview..

Visinoni, AF, Lisboa-Costa, T, Pagnan, NAB. "Ectodermal dysplasias: clinical and molecular review". Am J Med Genet Part A. vol. 149A. 2009. pp. 1980-2002.

Wright, JT, Grange, DK, Richter, MK. "Hypohidrotic ectodermal dysplasia. GeneReviews". http://www.ncbi.nlm.nih.gov/books/NBK1112/..

Ongoing controversies regarding etiology, diagnosis, treatment

There are no ongoing controversies, but there is ongoing research regarding a potential disease-modifying treatment for XLHED.

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 in Phase II trials and is being administered to newborn males in the first two weeks fo life. For more information, please visit clinicaltrials.gov with identifier NCT01775462.

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