Clinical Guidance

EDA. Phenotypes resulting from EDA pathogenic variants range from classic HED to nonsyndromic hypodontia. Recent investigations suggest that most EDA pathogenic variants associated with nonsyndromic hypodontia are missense variants mostly located in the region encoding the tumor necrosis factor domain. Many pathogenic variants associated with X-linked HED are thought to be loss-of-function variants including nonsense variants, insertions, and deletions that span the gene . EDAR. Variable phenotypes that range from mild to severe are associated with EDAR pathogenic variants, but genotype-phenotype correlations remain limited .

Source: GeneReviews — "Hypohidrotic Ectodermal Dysplasia"

Penetrance

Penetrance is not well described for most ectodermal dysplasias.

Source: GeneReviews — "Hypohidrotic Ectodermal Dysplasia"

Diagnostic Criteria

No guidelines regarding diagnostic criteria for hypohidrotic ectodermal dysplasia (HED) have been developed.

Suggestive Findings

HED should be suspected in an individual with:

Source: GeneReviews — "Hypohidrotic Ectodermal Dysplasia"

Differential Diagnosis

Numerous types of ectodermal dysplasia exist . Hypodontia with a vague history of heat intolerance or slight sparseness of the hair is particularly common and includes a broad differential diagnosis. The presence of onychodysplasia (inherent abnormalities of nail development) and other developmental abnormalities favor diagnoses other than hypohidrotic ectodermal dysplasia (HED). Ectodermal dysplasias that need to be considered in the differential diagnosis of HED are summarized in . Table 3. Ectodermal Dysplasias in the Differential Diagnosis of Hypohidrotic Ectodermal Dysplasia

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hypohidrotic ectodermal dysplasia (HED), the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Hypohidrotic Ectodermal Dysplasia

System/Concern | Evaluation | Comment

Hair | Assess severity of hypotrichosis. |

Skin | Assess severity of hypohidrosis incl episodes of hyperthermia. |

Dental

| Dental eval to assess jaws, alveolus, developing dentition by age 1 yr | Typically by palpating dental alveolus to establish if developing tooth buds (which manifest as bulges in alveolus) are present

Panoramic or conventional dental radiographs | As needed to determine extent of hypodontia inform treatment planning

ENT | Assess for solidified secretions in nasal aural passages. |

Eyes | Ophthalmologic eval | To assess for dry eyes due to abnormal meibomian glands

Respiratory

| Assess for recurrent pneumonia asthma related to abnormal bronchial glands. |

Genetic

counseling | By genetics professionals1 | To obtain a pedigree inform affected persons their families re nature, MOI, implications of HED to facilitate medical personal decision making

HED = hypohidrotic ectodermal dysplasia; MOI = mode of inheritance

Source: GeneReviews — "Hypohidrotic Ectodermal Dysplasia"

Clinical Guidance

Individuals with severe hypohidrosis can have marked heat intolerance; care should be taken to prevent exposure to extreme heat and the potential for febrile seizures.

Source: GeneReviews — "Hypohidrotic Ectodermal Dysplasia"

Therapies Under Investigation

A Phase II clinical trial was conducted at several US and European medical centers to investigate the use of EDI200, developed by Edimer Pharmaceuticals, Inc . The results of the study were inconclusive. EDI200 is an ectodysplasin-A1 (EDA-A1) replacement protein (Fc-EDA) that has been shown to bind specifically to the EDA-A1 receptor (EDAR) and activate the signaling pathway that leads to normal ectodermal development. EDI200 has demonstrated permanent correction of the disease manifestations in both mouse and dog models of X-linked HED, with reduction in mortality and morbidity . Postnatal administration of EDI200 did not change the HED phenotype, and a prenatal administration approach of the protein was adopted.

Source: GeneReviews — "Hypohidrotic Ectodermal Dysplasia"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in are recommended. Table 6. Recommended Surveillance for Individuals with Hypohidrotic Ectodermal Dysplasia

Source: GeneReviews — "Hypohidrotic Ectodermal Dysplasia"