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, 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.

• 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.
• 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.
• 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.

Suggestive Findings

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, frequently the canines and first permanent molars, develop in individuals with classic HED, but tooth number and distribution are highly variable [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; however, 3D facial recognition has shown promise [Hadj-Rabia et al 2017].

Suggestive findings for X-linked HED in heterozygous females

• 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 (or likely pathogenic) variant or biallelic EDAR, EDARADD, or WNT10A pathogenic (or likely 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 (or likely pathogenic) variants confirms the diagnosis.

Mild HED

• Male proband. The diagnosis of mild HED can be established in a male proband with mild manifestations of the above characteristic features. Identification of a heterozygous EDAR, EDARADD, or WNT10A pathogenic (or likely 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 (or likely pathogenic) variant by molecular genetic testing confirms the diagnosis. The diagnosis of mild HED can also be established in a female with mild manifestations of the above characteristic features by identification of a heterozygous pathogenic (or likely pathogenic) variant in EDAR, EDARADD, or WNT10A.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

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 to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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 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 [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 the novel homozygous variant c.803+1G>A [Mégarbané et al 2008] and once with the novel homozygous missense variant 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].

Penetrance

Penetrance is not well described for most ectodermal dysplasias.

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.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hypohidrotic ectodermal dysplasia (HED), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Management of affected individuals targets the three cardinal features of HED (hypotrichosis, hypohidrosis, and hypodontia) and is directed at optimizing psychosocial development, establishing optimal oral function, and preventing hyperthermia (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 6 are recommended.

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. Testing for hypohidrosis (see Suggestive Findings) can be done in at-risk relatives of an individual with X-linked HED.

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 unaffected heterozygotes or are 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 (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 [Huttner 2014, Körber et al 2020]. Postnatal administration of EDI200 did not change the HED phenotype, and a prenatal administration approach of the protein was adopted.

Schneider et al [2018] reported successful treatment of X-linked HED via intra-amniotic administration of the recombinant protein, Fc-EDA, to two affected male twins at gestational weeks 26 and 31 and to a single affected male fetus at week 26. Postnatally, they were able to sweat normally and had not developed X-linked HED-related hyperthermia or respiratory illnesses by age 14 and 22 months. Longer-term follow up of these boys has shown continued good outcomes, although correction of the deciduous dentition was not achieved. They are predicted to have more permanent teeth than would have been expected for classic X-linked HED. An additional three male fetuses have been treated since that report through a compassionate use program [Holm Schneider, personal communication].

Subsequently, an open-label, prospective, genotype-match controlled non-randomized, multicenter, international Phase II clinical trial has begun recruiting to investigate the efficacy and safety of ER004 (previously known as EDI200) administered intra-amniotically as a prenatal treatment for males with X-linked HED. The aim of the trial is to confirm the efficacy and safety of ER004 administered intra-amniotically in a larger cohort. The target population will consist of male fetuses diagnosed with X-linked HED based on identification of a heterozygous EDA pathogenic variant in the mother and ultrasonographic identification of a significantly reduced number of fetal tooth germs, or by identification of a hemizygous EDA pathogenic variant in the fetus. The mother will receive three doses of ER004 intra-amniotically in the late second and the third trimesters of pregnancy. Efficacy and safety will be assessed in the affected males up to age six months and safety will be assessed in the mothers up to one month following delivery. In the long-term follow-up phase, efficacy and safety will be assessed in affected males up to age five years. Sweating ability of affected males will be compared to an untreated relative, when available, or to a matched control from a previous natural history study.

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.

Mode of Inheritance

Hypohidrotic ectodermal dysplasia (HED) caused by pathogenic variants in EDA is inherited in an X-linked manner.

EDAR-, EDARADD-, and WNT10A-related HED are inherited in an autosomal recessive or an autosomal dominant manner.

X-Linked HED – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder, nor will he be hemizygous for the EDA pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a female has more than one affected child and no other affected relatives and the EDA pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a de novo EDA pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/germline mosaicism.
• Clinical examination may detect manifestations of X-linked HED in the mother; manifestations in heterozygous females are typically milder than those seen in affected males (see Clinical Description, Mild HED).
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Parents of a female proband

• A female proband may have inherited the EDA pathogenic variant from her father (who is expected to be affected) or her mother (who may be mildly affected), or the pathogenic variant may be de novo.
• Clinical examination may clarify the status of the parents. Molecular genetic testing of both parents is recommended to confirm their genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother is heterozygous for an EDA pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. 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 (see Clinical Description, Mild HED).
• If the proband represents a simplex case and the EDA pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

• If the mother of the proband has an EDA pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. 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 (see Clinical Description, Mild HED).
• If the father of the proband has an EDA pathogenic variant, he will transmit it to all his daughters and none of his sons.
• If the proband represents a simplex case and if the EDA pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a male proband. Affected males transmit the EDA pathogenic variant to all of their daughters and none of their sons.

Offspring of a female proband. Heterozygous females have a 50% chance of transmitting the EDA pathogenic variant to each child.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a pathogenic variant, the parent's family members may be at risk.

Heterozygote detection. Molecular genetic identification of female heterozygotes requires prior identification of the EDA pathogenic variant in the family.

Detection of heterozygotes based on clinical findings is often imprecise. If sweat distribution is patchy or many teeth are absent, establishing genetic status is relatively easy. Otherwise, mild manifestations in females with X-linked HED overlap with features in the general population. Hypodontia, for instance, is relatively common in the general population, and absence of one or two teeth in the mother of an affected male may be coincidental. Furthermore, there are no useful standards to judge hair density, and reports of sweat dysfunction, often judged by heat intolerance, can be inaccurate. Computerized facial recognition appears to be relatively insensitive in heterozygote detection as well.

Autosomal Recessive HED – Risk to Family Members

Parents of a proband

• The parents of a child with autosomal recessive HED are presumed to be heterozygous for a pathogenic variant in EDAR, EDARADD, or WNT10A.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EDAR, EDARADD, or WNT10A pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes may have mild features of the disorder (see Clinical Description, Mild HED), especially individuals heterozygous for a WNT10A pathogenic variant [Doolan et al 2021].

Sibs of a proband

• 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.
• Heterozygotes may have mild features of the disorder (see Clinical Description, Mild HED), especially individuals heterozygous for a WNT10A pathogenic variant [Doolan et al 2021].

Offspring of a proband. The offspring of an individual with autosomal recessive HED are obligate heterozygotes for a pathogenic variant in EDAR, EDARADD, or WNT10A.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an EDAR, EDARADD, or WNT10A pathogenic variant.

Heterozygote detection. Heterozygote detection for at-risk relatives requires prior identification of the EDAR, EDARADD, or WNT10A pathogenic variants in the family.

Autosomal Dominant HED – Risk to Family Members

Parents of a proband

• Some individuals diagnosed with autosomal dominant HED have an affected parent.
• An individual diagnosed with autosomal dominant HED may have the disorder as the result of a de novo EDAR, EDARADD, or WNT10A pathogenic variant. The proportion of probands who have a de novo pathogenic variant is unknown.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include physical examination and molecular genetic testing for the EDAR, EDARADD, or WNT10A pathogenic variant identified in the proband.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with autosomal dominant HED may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to sibs depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the EDAR, EDARADD, or WNT10A pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with autosomal dominant HED has a 50% chance of inheriting the EDAR, EDARADD, or WNT10A pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the EDAR, EDARADD, or WNT10A pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

EDA encodes ectodysplasin-A (EDA), a protein that is important for normal development of ectodermal appendages including hair, teeth, and sweat glands. EDA is important in the NFKappaB pathway, which involves numerous downstream genes involved in embryogenesis. EDA binds to the ectodysplasin-A receptor (EDAR; encoded by EDAR) activating the NFKappaB pathway. Mutated EDA is unable to bind and activate the pathway.

EDAR contains a single transmembrane domain with type 1 membrane topology. The protein probably functions as a multimeric receptor and is related to the TNFR family. Mutated EDAR is unable to bind with ectodysplasin. EDAR variants causing autosomal recessive hypohidrotic ectodermal dysplasia (HED) exhibit loss of function, while those associated with autosomal dominant HED exhibit a dominant-negative effect [Valcuende-Cavero et al 2008]. At least two of the dominant-negative pathogenic variants are not associated with the HED phenotype.

The protein encoded by EDARADD is similar to the death domain, MyD88, a cytoplasmic transducer of Toll/interleukin receptor signaling [Headon et al 2001]. It also contains a Traf-binding consensus sequence. It is coexpressed with tumor necrosis factor receptor superfamily member EDAR in epithelial cells during the formation of hair follicles and teeth. It interacts with the death domain of EDAR and links the receptor to signaling pathways downstream. EDARADD pathogenic variants alter the charge of an amino acid in the protein, usually rendering it unable to interact with EDAR. In one family with autosomal dominant HED, a novel missense variant did not interfere with interaction between EDAR and EDARADD proteins but still led to impaired activation of NFKappaB signaling [Wohlfart et al 2016, Asano et al 2021].

WNT10A encodes a peptide containing two N-linked glycosylation sites and residues conserved among WNTs. The protein contains two domains, a signal peptide and the Wnt domain, and encodes a secreted signaling molecule that is involved in several developmental processes, such as regulation of cell fate and patterning during embryogenesis. WNT10A and WNT10B are highly expressed in embryonic skin as well as the placodes involved in follicle morphogenesis. WNT10A is also very important for normal dentinogenesis and tooth morphogenesis.

Mechanism of disease causation. Depending on the specific variant and resulting protein, the mechanism of disease can be loss of function or a dominant-negative effect. EDA pathogenic variants are loss of function. Pathogenic variants in WNT10A appear to cause changes in protein folding or stabilization causing a loss of function [Zeng et al 2021]. EDARADD pathogenic variants can result in a dominant-negative effect or loss of function depending on the variant [Asano et al 2021].

Gene-specific laboratory considerations: EDARADD. EDARADD has two isoforms, each w/6 exons encoding 205 & 215 amino acid proteins (NM_080738.3 and NM_145861.2, respectively).

Author Notes

J Timothy Wright DDS, MS
UNC Adams School of Dentistry

Dorothy K Grange, MD
Washington University Physicians
Washington University School of Medicine in St Louis

Mary Fete
National Foundation Ectodermal Dysplasias

Acknowledgments

Thanks to the National Foundation for Ectodermal Dysplasias (Mary Fete, Executive Director).

Author History

Mary Fete, MSN, RN, CCM (2017-present)
Dorothy K Grange, MD (2006-present)
Ronald J Jorgenson, DDS, PhD; former President, Applied Genetics, Austin, Texas (2002-2006)
Mary K Richter; National Foundation for Ectodermal Dysplasias (2006-2017)
J Timothy Wright, DDS, MS (2006-present)

Revision History

• 27 October 2022 (sw) Comprehensive update posted live
• 1 June 2017 (sw) Comprehensive update posted live
• 15 May 2014 (me) Comprehensive update posted live
• 13 June 2013 (aa) Revision: EDAR deletion reported
• 29 December 2011 (me) Comprehensive update posted live
• 23 July 2009 (me) Comprehensive update posted live
• 16 November 2006 (me) Comprehensive update posted live
• 28 April 2003 (me) Review posted live
• 23 October 2002 (rj) Original submission

Literature Cited

• Arte S, Parmanen S, Pirinen S, Alaluusua S, Nieminen P. Candidate gene analysis of tooth agenesis identifies novel mutations in six genes and suggests significant role for WNT and EDA signaling and allele combinations. PLoS One. 2013;8:e73705. [PMC free article: PMC3750013] [PubMed: 23991204]
• Asano N, Yasuno S, Hayashi R, Shimomura Y. Characterization of EDARADD gene mutations responsible for hypohidrotic ectodermal dysplasia. J Dermatol. 2021;48:1533–41. [PubMed: 34219261]
• Bergendal B, Norderyd J, Zhou X, Klar J, Dahl N. Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency. BMC Med Genet. 2016;17:88. [PMC free article: PMC5122154] [PubMed: 27881089]
• Blüschke G, Nüsken KD, Schneider H. Prevalence and prevention of severe complications of hypohidrotic ectodermal dysplasia in infancy. Early Hum Dev. 2010;86:397–9. [PubMed: 20682465]
• Cambiaghi S, Restano L, Paakkonen K, Caputo R, Kere J. Clinical findings in mosaic carriers of hypohidrotic ectodermal dysplasia. Arch Dermatol. 2000;136:217–24. [PubMed: 10677098]
• Chassaing N, Bourthoumieu S, Cossee M, Calvas P, Vincent MC. Mutations in EDAR account for one-quarter of non-ED1-related hypohidrotic ectodermal dysplasia. Hum Mutat. 2006;27:255–9. [PubMed: 16435307]
• Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, Bal E, Chassaing N, Vincent MC, Viot G, Clauss F, Manière MC, Toupenay S, Le Merrer M, Lyonnet S, Cormier-Daire V, Amiel J, Faivre L, de Prost Y, Munnich A, Bonnefont JP, Bodemer C, Smahi A. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat. 2011;32:70–2. [PubMed: 20979233]
• Cluzeau C, Marrakchi S, Picard C, Munnich A, Smahi A, Turki H. First homozygous large deletion in EDARADD gene associated with a severe form of anhidrotic ectodermal dysplasia. J Eur Acad Dermatol Venereol. 2019;33:e55–e57. [PubMed: 30022538]
• Dietz J, Kaercher T, Schneider AT, Zimmermann T, Huttner K, Johnson R, Schneider H. Early respiratory and ocular involvement in X-linked hypohidrotic ectodermal dysplasia. Eur J Pediatr. 2013;172:1023–31. [PubMed: 23553579]
• Doolan BJ, Onoufriadis A, Kantaputra P, McGrath JA. WNT10A, dermatology and dentistry. Br J Dermatol. 2021;185:1105–11. [PubMed: 34184264]
• Hadj-Rabia S, Schneider H, Navarro E, Klein O, Kirby N, Huttner K, Wolf L, Orin M, Wohlfart S, Bodemer C, Grange DK. Automatic recognition of the XLHED phenotype from facial images. Am J Med Genet A. 2017;173:2408–14. [PubMed: 28691769]
• Haghighi A, Nikuei P, Haghighi-Kakhki H, Saleh-Gohari N, Baghestani S, Krawitz PM, Hecht J, Mundlos S. Whole-exome sequencing identifies a novel missense mutation in EDAR causing autosomal recessive hypohidrotic ectodermal dysplasia with bilateral amastia and palmoplantar hyperkeratosis. Br J Dermatol. 2013;168:1353–6. [PubMed: 23210707]
• Headon DJ, Emmal SA, Ferguson BM, Tucker AS, Justice MJ, Sharpe PT, Zonana J, Overbeek PA. Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature. 2001;414:913–6. [PubMed: 11780064]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Huttner K. Future developments in XLHED treatment approaches. Am J Med Genet. 2014;164A:2433–6. [PubMed: 24678015]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
• Jones KB, Goodwin AF, Landan M, Seidel K, Tran DK, Hogue J, Chavez M, Fete M, Yu W, Hussein T, Johnson R, Huttner K, Jheon AH, Klein OD. Characterization of X-linked hypohidrotic ectodermal dysplasia (XL-HED) hair and sweat gland phenotypes using phototrichogram analysis and live confocal imaging. Am J Med Genet A. 2013;161A:1585–93. [PMC free article: PMC4414120] [PubMed: 23687000]
• Körber I, Klein OD, Morhart P, Faschingbauer F, Grange DK, Clarke A, Bodemer C, Maitz S, Huttner K, Kirby N, Durand C, Schneider H. Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects. Br J Clin Pharmacol. 2020;86:2063–9. [PMC free article: PMC7495278] [PubMed: 32250462]
• Kramer FJ, Baethge C, Tschernitschek H. Implants in children with ectodermal dysplasia: a case report and literature review. Clin Oral Implants Res. 2007;18:140–6. [PubMed: 17224035]
• Krøigård AB, Clemmensen O, Gjørup H, Hertz JM, Bygum A. Odonto-onycho-dermal dysplasia in a patient homozygous for a WNT10A nonsense mutation and mild manifestations of ectodermal dysplasia in carriers of the mutation. BMC Dermatol. 2016;16:3. [PMC free article: PMC4785680] [PubMed: 26964878]
• Lee HE, Chang IK, Im M, Seo YJ, Lee JH, Lee Y. Topical minoxidil treatment for congenital alopecia in hypohidrotic ectodermal dysplasia. J Am Acad Dermatol. 2013;68:e139–40. [PubMed: 23522427]
• Lévy J, Capri Y, Rachid M, Dupont C, Vermeesch JR, Devriendt K, Verloes A, Tabet AC, Bailleul-Forestier I. LEF1 haploinsufficiency causes ectodermal dysplasia. Clin Genet. 2020;97:595–600. [PubMed: 32022899]
• Lexner MO, Bardow A, Hertz JM, Nielsen LA, Kreiborg S. Anomalies of tooth formation in hypohidrotic ectodermal dysplasia. Int J Paediatr Dent. 2007;17:10–8. [PubMed: 17181574]
• Lexner MO, Bardow A, Juncker I, Jensen LG, Almer L, Kreiborg S, Hertz JM. X-linked hypohidrotic ectodermal dysplasia. Genetic and dental findings in 67 Danish patients from 19 families. Clin Genet. 2008;74:252–9. [PubMed: 18510547]
• Mégarbané H, Cluzeau C, Bodemer C, Fraïtag S, Chababi-Atallah M, Mégarbané A, Smahi A. Unusual presentation of a severe autosomal recessive anhydrotic ectodermal dysplasia with a novel mutation in the EDAR gene. Am J Med Genet A. 2008;146A:2657–62. [PubMed: 18816645]
• Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet. 1999;22:366–9. [PubMed: 10431241]
• Monreal AW, Zonana J, Ferguson B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet. 1998;63:380–9. [PMC free article: PMC1377324] [PubMed: 9683615]
• Mues G, Bonds J, Xiang L, Vieira AR, Seymen F, Klein O, D’Souza RN. The WNT10A gene in ectodermal dysplasias and selective tooth agenesis. Am J Med Genet. 2014;164A:2455–60. [PMC free article: PMC4167166] [PubMed: 24700731]
• Plaisancié J, Bailleul-Forestier I, Gaston V, Vaysse F, Lacombe D, Holder-Espinasse M, Abramowicz M, Coubes C, Plessis G, Faivre L, Demeer B, Vincent-Delorme C, Dollfus H, Sigaudy S, Guillén-Navarro E, Verloes A, Jonveaux P, Martin-Coignard D, Colin E, Bieth E, Calvas P, Chassaing N. Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia. Am J Med Genet A. 2013;161A:671–8. [PubMed: 23401279]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rouse C, Siegfried E, Breer W, Nahass G. Hair and sweat glands in families with hypohidrotic ectodermal dysplasia: further characterization. Arch Dermatol. 2004;140:850–5. [PubMed: 15262696]
• Schneider H, Faschingbauer F, Schuepbach-Mallepell S, Körber I, Wohlfart S, Dick A, Wahlbuhl M, Kowalczyk-Quintas C, Vigolo M, Kirby N, Tannert C, Rompel O, Rascher W, Beckmann MW, Schneider P. Prenatal correction of X-linked hypohidrotic ectodermal dysplasia. N Engl J Med. 2018;378:1604–10. [PubMed: 29694819]
• Schneider H, Hammersen J, Preisler-Adams S, Huttner K, Rascher W, Bohring A. Sweating ability and genotype in individuals with X-linked hypohidrotic ectodermal dysplasia. J Med Genet. 2011;48:426–32. [PubMed: 21357618]
• Stanford CM, Guckes A, Fete M, Srun S, Richter MK. Perceptions of outcomes of implant therapy in patients with ectodermal dysplasia syndromes. Int J Prosthodont. 2008;21:195–200. [PubMed: 18548955]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. PMID. [PMC free article: PMC7497289] [PubMed: 32596782]
• Valcuende-Cavero F, Martinez F, Pérez-Pastor G, Oltra S, Ferrer I, Tomás-Cabedo G, Moreno-Presmanes M. Autosomal-dominant hypohidrotic ectodermal dysplasia caused by a novel mutation. J Eur Acad Dermatol Venereol. 2008;22:1508–10. [PubMed: 18384562]
• van der Hout AH, Oudesluijs GG, Venema A, Verheij JB, Mol BG, Rump P, Brunner HG, Vos YJ, van Essen AJ. Mutation screening of the ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia. Eur J Hum Genet. 2008;16:673–9. [PubMed: 18231121]
• Wisniewski SA, Trzeciak WH. A rare heterozygous TRAF6 variant is associated with hypohidrotic ectodermal dysplasia. Br J Dermatol. 2012;166:1353–6. [PubMed: 22296312]
• Wohlfart S, Meiller R, Hammersen J, Park J, Menzel-Severing J, Melichar VO, Huttner K, Johnson R, Porte F, Schneider H. Natural history of X-linked hypohidrotic ectodermal dysplasia: a 5-year follow-up study. Orphanet J Rare Dis. 2020;15:7. [PMC free article: PMC6954509] [PubMed: 31924237]
• Wohlfart S, Söder S, Smahi A, Schneider H. A novel missense mutation in the gene EDARADD associated with an unusual phenotype of hypohidrotic ectodermal dysplasia. Am J Med Genet. 2016;170A:249–53. [PubMed: 26440664]
• Wright JT, Fete M, Schneider H, Zinser M, Koster MI, Clarke AJ, Hadj-Rabia S, Tadini G, Pagnan N, Visinoni AF, Bergendal B, Abbott B, Fete T, Stanford C, Butcher C, D'Souza RN, Sybert VP, Morasso MI. Ectodermal dysplasias: classification and organization by phenotype, genotype and molecular pathway. Am J Med Genet A. 2019;179:442–7. [PMC free article: PMC6421567] [PubMed: 30703280]
• Yu M, Fan Z, Wong SW, Sun K, Zhang L, Liu H, Feng H, Liu Y, Han D. Lrp6 dynamic expression in tooth development and mutations in oligodontia. J Dent Res. 2021;100:415–22. [PubMed: 33164649]
• Zeng Y, Baugh E, Akyalcin S, Letra A. Functional effects of WNT10A rare variants associated with tooth agenesis. J Dent Res. 2021;100:302–9. [PubMed: 33034246]
• Zhang J, Han D, Song S, Wang Y, Zhao H, Pan S, Bai B, Feng H. Correlation between the phenotypes and genotypes of X-linked hypohidrotic ectodermal dysplasia and non-syndromic hypodontia caused by ectodysplasin-A mutations. Eur J Med Genet. 2011;54:e377–82. [PubMed: 21457804]
• Zhou M, Zhang H, Camhi H, Seymen F, Koruyucu M, Kasimoglu Y, Kim JW, Kim-Berman H, Yuson NMR, Benke PJ, Wu Y, Wang F, Zhu Y, Simmer JP, Hu JC. Analyses of oligodontia phenotypes and genetic etiologies. Int J Oral Sci. 2021;13:32. [PMC free article: PMC8484616] [PubMed: 34593752]