Clinical characteristics: Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

Diagnosis/testing: Classic HED can be diagnosed after infancy based on physical features in most affected individuals. Identification of a hemizygous EDA pathogenic variant in an affected male or biallelic EDAR, EDARADD, or WNT10A pathogenic variants in an affected male or female confirms the diagnosis.

The diagnosis of mild HED is established in a female by identification of a heterozygous EDA, EDAR, EDARADD, or WNT10A pathogenic variant. The diagnosis of mild HED is established in a male by identification of a heterozygous EDAR, EDARADD, or WNT10A pathogenic variant.

Management: Treatment of manifestations: Wigs or special hair care formulas for sparse, dry hair may be useful. Access to an adequate water supply and a cool environment during hot weather. Skin care products for eczema and exposures that exacerbate dry skin. Early dental treatment; bonding of conical teeth; orthodontics as necessary; dental implants in the anterior portion of the mandibular arch in older children; replacement of dental prostheses as needed, often every 2.5 years; dental implants in adults; dietary counseling for individuals with chewing and swallowing difficulties; therapeutics to maintain oral lubrication and control caries; fluoride treatment to prevent caries. Nasal and aural concretions may be removed with suction devices or forceps as needed by an otolaryngologist. Prevention of nasal concretions through humidification of ambient air is helpful. Lubrication eye drops. Management of recurrent respiratory infections and asthma per primary care provider with referral to allergist and/or pulmonologist as needed.

Surveillance: Dental evaluation by age one year with follow-up dental evaluations every six to 12 months. Assess for skin, hair, ophthalmologic, and respiratory manifestations annually and/or as needed. Assess for abnormal nasal and aural secretions annually and/or as needed.

Agents/circumstances to avoid: Exposure to extreme heat.

Evaluation of relatives at risk: If the family-specific pathogenic variant(s) are known, molecular genetic testing of at-risk relatives should be offered to permit early diagnosis and treatment, especially to avoid hyperthermia.

Pregnancy management: Optimal prenatal nutrition for mothers who are unaffected heterozygotes or those who are affected with HED. Affected women at risk for hyperthermia should not become overheated during pregnancy.

Genetic counseling: EDA-related HED is inherited in an X-linked manner. EDAR-, EDARADD-, and WNT10A-related HED are inherited in an autosomal recessive or an autosomal dominant manner.

1. X-linked HED. If the mother of a proband is heterozygous for an EDA pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. If the father of the proband has an EDA pathogenic variant, he will transmit it to all his daughters and none of his sons. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may show manifestations of ectodermal dysplasia. Molecular genetic identification of female heterozygotes requires prior identification of the EDA pathogenic variant in the family.

2. Autosomal recessive HED. The parents of a child with autosomal recessive HED are presumed to be heterozygous for a pathogenic variant in EDAR, EDARADD, or WNT10A. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygote detection for at-risk relatives requires prior identification of the EDAR, EDARADD, or WNT10A pathogenic variants in the family.

3. Autosomal dominant HED. Some individuals diagnosed with autosomal dominant HED have an affected parent. Each child of an individual with autosomal dominant HED has a 50% chance of inheriting the EDAR, EDARADD, or WNT10A pathogenic variant.

Once the EDA, EDAR, EDARADD, or WNT10A pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for HED are possible.