Hypohidrotic Ectodermal Dysplasia

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, and 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 on the basis of 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. Early dental treatment; bonding of conical shaped 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; therapeutics to maintain oral lubrication and control caries; dietary counseling for individuals with chewing and swallowing difficulties. 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. Skin care products for eczema and exposures that exacerbate dry skin.

Prevention of secondary complications: Saliva substitutes and optimal fluoride exposure may be helpful in preventing dental caries in those individuals having a marked reduction in salivary flow.

Surveillance: Dental evaluation by age one year with follow-up dental evaluations every six to 12 months.

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.

Genetic counseling.

HED is inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The majority of individuals with HED have the X-linked form. The mode of inheritance may be determined in some instances by family history and in others by molecular genetic testing. Carrier testing is possible for the X-linked and autosomal recessive forms if the pathogenic variant(s) in the family are known. Prenatal testing is possible for pregnancies at increased risk for all forms if the pathogenic variant(s) in the family are known.

Suggestive Findings

Hypohidrotic ectodermal dysplasia (HED) should be suspected in an individual with:

• Hypotrichosis (sparseness of scalp and body hair). Scalp hair has thin shafts and is lightly pigmented. Note: Hair shafts can be brittle and twisted (pili torti) or have other anomalies on microscopic analysis; however, these findings are not sufficiently sensitive to be of diagnostic benefit [Rouse et al 2004]. Secondary sexual hair (beard; axillary and pubic hair) can be normal.
• Hypohidrosis (reduced ability to sweat). Reduced ability to sweat in response to heat leads to hyperthermia:
  • The function of sweat glands may be assessed by bringing the skin into contact with an iodine solution and raising ambient temperatures to induce sweating. The iodine solution turns color when exposed to sweat and can be used to determine the amount and location of sweating.
  • The number and distribution of sweat pores can be determined by coating parts of the body (usually the hypothenar eminences of the palms) with impression materials commonly used by dentists.
  • While skin biopsies have been used to determine the distribution and morphology of sweat glands, noninvasive techniques are equally effective. Live confocal microscope imaging is able to visualize the sweat ducts on the palms [Jones et al 2013].
• Hypodontia (congenital absence of teeth):
  • An average of nine permanent teeth – typically the canines and first molars –develop in individuals with classic HED [Lexner et al 2007].
  • Teeth are often smaller than average and have an altered morphology; the anterior teeth frequently have conical crowns.
  • Dental radiographs are helpful for determining the extent of hypodontia and are useful in the diagnosis of mildly affected individuals. Taurodontism (elongation of the pulp chamber) is more common in molar teeth of individuals with HED than in unaffected individuals.

Note: Anthropometric variations (measurements of facial form and tooth size) in HED are subtle and have not proven clinically useful.

Carrier detection for X-linked HED

• Because females with X-linked HED show mosaic patterns of sweat pore function and distribution, use of an iodine solution to assess sweat gland function or impression materials to assess number and distribution of sweat pores is particularly useful.
• Between 60% and 80% of females with X-linked HED display some degree of hypodontia [Cambiaghi et al 2000].

Establishing the Diagnosis

Classic HED is often diagnosed after infancy in affected individuals with the above characteristic features of hypotrichosis, hypohidrosis, and hypodontia.

• Male proband. The diagnosis of classic HED is established in a male proband with the above characteristic features. Identification of a hemizygous EDA pathogenic variant or biallelic EDAR, EDARADD, or WNT10A pathogenic variants confirms the diagnosis.
• Female proband. The diagnosis of classic HED is established in a female proband with the above characteristic features. Identification of biallelic EDAR, EDARADD, or WNT10A pathogenic variants confirms the diagnosis.

Mild HED

• Male proband. The diagnosis of mild HED can be established in a male proband with the mild manifestations of the cardinal features. Identification of a heterozygous EDAR, EDARADD, or WNT10A pathogenic variant confirms the diagnosis.
• Female proband. The diagnosis of mild HED due to an EDA pathogenic variant can be established in a female proband with a mosaic pattern of sweat pore function and distribution, hypodontia, and a family history suggestive of X-linked HED. Identification of a heterozygous EDA pathogenic variant by molecular genetic testing confirms this diagnosis. The diagnosis of mild HED can also be established in a female with mild manifestations by identification of a heterozygous pathogenic variant in EDAR, EDARADD, or WNT10A.

Molecular testing approaches can include serial single-gene testing and a multigene panel.

Serial single-gene testing can be considered if:

• The proband's findings are classic and consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission). Sequence analysis of EDA is performed first, followed by gene-targeted deletion/duplication analysis of EDA if no pathogenic variant is found.
• The proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance. Sequence analysis of EDAR, EDARADD, and WNT10A should be performed, followed by deletion/duplication analysis if no pathogenic variant is found by sequence analysis.

If molecular genetic testing of EDA, EDAR, EDARADD, and WNT10A do not identify a pathogenic variant, other forms of ectodermal dysplasia should be considered (see Differential Diagnosis).

A multigene panel that includes EDA, EDAR, EDARADD, WNT10A, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Genotype-Phenotype Correlations

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 with most 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 [Zhang et al 2011].

EDAR. Variable phenotypes that range from mild to severe are associated with EDAR pathogenic variants, but genotype-phenotype correlations remain limited [Chassaing et al 2006]. The association of EDAR pathogenic variants and HED features along with the additional findings of amastia and palmoplantar hyperkeratosis has been reported twice, once with a novel homozygous NM_022336.3: c.803+1G>A (IVS9+1G>A) variant [Mégarbané et al 2008] and once with a novel homozygous missense variant NM_022336.3: c.338G>A (p.Cys113Tyr) [Haghighi et al 2013].

WNT10A. Variable phenotypes are reported in individuals with pathogenic variants in WNT10A. Homozygosity for the common c.321C>A (p.Cys107Ter) nonsense variant may be identified more frequently in individuals with severe manifestations, including odonto-onycho-dermal dysplasia [Krøigård et al 2016]. WNT10A pathogenic variants may also be found in individuals with abnormal dentition in association with additional mild ectodermal symptoms or with selective tooth agenesis [Mues et al 2014, Bergendal et al 2016]. Individuals with WNT10A variants are more likely than those with other forms of HED to have missing fingernails and toenails at birth. Also unlike other forms of HED, the deciduous dentition may be almost completely present but with abnormally shaped teeth, while there is often severe hypodontia of the adult dentition. There may be hyperhidrosis involving the palms and soles with decreased sweating on the rest of the body.

Nomenclature

Historically, the term "anhidrotic" has been defined as the inability to perspire; "hypohidrotic" suggests impairment in the ability to perspire. Because most individuals with HED have at least a limited ability to perspire, the term "hypohidrotic" more accurately reflects the condition.

Prevalence

Although not specifically known, it is estimated that at least one in 5,000-10,000 newborns has HED. This is probably an underestimate of the prevalence, as many individuals may be missed during infancy before the cardinal features become obvious.

Affected individuals from all racial and ethnic groups have been reported [Fete et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hypohidrotic ectodermal dysplasia (HED), the following evaluations are recommended:

• Initial evaluation of the developing dentition, typically accomplished by palpating the dental alveolus of the infant/toddler to establish if developing tooth buds (which manifest as bulges in alveolus) are present. A dental evaluation by age one year is recommended.
• Dental radiographs, essential to determining the extent of hypodontia and frequently taken in the toddler or child using panoramic or conventional dental radiographic techniques
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management of affected individuals targets the three cardinal features and is directed at optimizing psychosocial development, establishing optimal oral function, and preventing hyperthermia.

Hypotrichosis. Wigs or special hair care formulas and techniques to manage sparse, dry hair may be useful. One report describes a child with HED and alopecia who was treated with topical minoxidil to the scalp and had resultant hair growth [Lee et al 2013].

Hypohidrosis. During hot weather, affected individuals must have access to an adequate supply of water and a cool environment, which may mean air conditioning, a wet T-shirt, and/or a spray bottle of water. Some individuals may benefit from "cooling vests."

Affected individuals learn to control their exposure to heat and to minimize its consequences, but special situations may arise in which intervention by physicians and families is helpful. For example, a physician may have to prescribe an air conditioner before a school district complies, or parents may have to advocate for children who need to carry liquids into areas where they are prohibited.

Hypodontia

• Dental treatment, ranging from simple restorations to dentures, must begin at an early age. Bonding of conical shaped teeth in young affected individuals improves aesthetics and chewing ability.
• Orthodontics may be necessary.
• Dental implants in the anterior portion of the mandibular arch have proven successful only in children age seven years and older [Kramer et al 2007, Stanford et al 2008].
• Children with HED typically need to have their dental prostheses replaced every 2.5 years.
• Dental implants in adults can support aesthetic and functional dentition.
• Hyposalivation is present in some individuals, predisposing them to dental caries and the need for therapeutics directed at maintaining oral lubrication and caries control.
• Dietary counseling may be helpful for those individuals who have trouble chewing and swallowing despite adequate dental care.

Other

• Regular visits with an ENT physician may be necessary for management of the nasal and aural concretions. Commonly, nasal and aural concretions must be removed with suction devices or forceps and recommendations made about humidification of the ambient air to prevent their formation [Mehta et al 2007].
• Skin care products are useful for management of eczema and rashes and for dry skin associated with certain outdoor exposures like swimming.
• Lubrication eye drops can be helpful for dry eyes.

Prevention of Secondary Complications

Saliva substitutes and optimal fluoride exposure may be helpful in preventing dental caries in those individuals having a marked reduction in salivary flow. Other dental caries preventive approaches such as pit and fissure sealants can be beneficial as well.

Surveillance

The first dental visit should occur by age one year to monitor tooth and maxillary/mandibular development and for anticipatory guidance for parents. The developing dentition should be evaluated every six to 12 months to monitor existing treatments and to provide continued interventions as needed.

Agents/Circumstances to Avoid

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.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic, at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and treatment and, importantly, measures to avoid hyperthermia.

Evaluations can include:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Targeted history, physical examination, and dental examination for the features of HED if the pathogenic variant(s) in the family are not known. A sweat test can be done in at-risk relatives of an individual with XLHED.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Optimal prenatal nutrition is recommended for mothers who are carriers of or affected with HED. Affected women at risk for hyperthermia should take extra care not to become overheated during pregnancy. There are no other special recommendations for pregnancy management.

Some women may have difficulty breastfeeding their infants because of hypoplasia of the mammary glands.

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 [Huttner 2014]. The results of the study were inconclusive. EDI200 is an ectodysplasin-A1 (EDA-A1) replacement protein 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 hypohidrotic ectodermal dysplasia, with reduction in mortality and morbidity [Huttner 2014]. For additional information on the clinical trial click here

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.