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Hypohidrotic Ectodermal Dysplasia

Synonyms: Anhidrotic Ectodermal Dysplasia, Christ-Siemens-Touraine Syndrome. Includes: Hypohidrotic Ectodermal Dysplasia, Autosomal; Hypohidrotic Ectodermal Dysplasia, X-Linked (XLHED)

, DDS, MS, , MD, and .

Author Information
Distinguished Bawden Professor, Department of Pediatric Dentistry
University of North Carolina
Chapel Hill, North Carolina
, MD
Professor of Pediatrics, Division of Genetics and Genomic Medicine
Department of Pediatrics
Washington University School of Medicine
St Louis, Missouri
Founder, National Foundation for Ectodermal Dysplasias
Mascoutah, Illinois

Initial Posting: ; Last Revision: June 13, 2013.


Disease 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 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.

Diagnosis/testing. HED can be diagnosed after infancy on the basis of physical features in most affected individuals. In addition to the most common, X-linked form (caused by mutations in EDA), two clinically similar but genetically distinct forms of HED are recognized: the clinically indistinguishable autosomal recessive form (caused by mutations in EDAR and EDARADD) and the autosomal dominant form (caused by mutations in EDAR and EDARADD), which is milder.

Management. Treatment of manifestations: Wigs are often used and special hair care formulas for sparse, dry hair may be required. During hot weather, affected individuals need access to an adequate supply of water and a cool environment (i.e., "cooling vests," air conditioning, a wet T-shirt, spray bottle of water). Early dental treatment may range from simple restorations to dentures. In children over age seven years, dental implants in the anterior portion of the mandibular arch may be beneficial to aid prosthesis retention if the child has no teeth and cannot wear a conventional removable prosthesis. Replacement of dental prostheses should be provided as needed, often every 2.5 years. 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.

Surveillance: Dental evaluations are needed every six to 12 months.

Agents/circumstances to avoid: Exposure to extreme heat.

Evaluation of relatives at risk: If the family-specific mutation(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 randomly selected individuals with HED have the X-linked form. The remaining cases have either an autosomal recessive or autosomal dominant 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 disease-causing mutation(s) in the family are known. Prenatal testing is possible for pregnancies at increased risk for all forms if the disease-causing mutation(s) in the family are known.


Clinical Diagnosis

Hypohidrotic ectodermal dysplasia (HED) can be diagnosed after infancy in most affected individuals by the presence of three cardinal features:

  • Hypotrichosis (sparseness of scalp and body hair). In addition, the scalp hair has thin shafts and is lightly pigmented. Note: Although hair shafts can be brittle and twisted (pili torti) or have other anomalies on microscopic analysis, these findings are not sufficiently sensitive to be of diagnostic benefit [Rouse et al 2004]. Secondary sexual hair (beard; axillary and pubic hair) may be more 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.
  • Hypodontia (congenital absence of teeth):
    • An average of nine permanent teeth develop in individuals with classic HED, typically the canines and first molars [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 or elongation of the pulp chamber is more common in molar teeth of individuals with HED compared with 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 carriers for 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.
  • Sixty to 80% of carriers display some degree of hypodontia [Cambiaghi et al 2000].

Molecular Genetic Testing


  • EDA is the only gene in which mutations are known to cause X-linked HED. The majority of individuals with HED have the X-linked form.
  • Mutations in EDAR and EDARADD are known to be associated with both autosomal dominant and autosomal recessive forms of HED.

Clinical testing

  • Sequence analysis of EDA cannot detect exonic, multiexonic, or whole-gene deletions in females, and additional testing using methods that detect deletions is required.
  • Deletion/duplication analysis. No deletions or duplications in EDARADD have been reported to cause HED. The utility of such testing is not known.

Table 1. Summary of Molecular Genetic Testing Used in Hypohidrotic Ectodermal Dysplasia

Gene 1% of HED Attributed to Mutations in This GeneTest MethodMutations Detected 2
EDA~55%-60%Sequence analysis 3, 4Sequence variants 5
Duplication/deletion analysis 6, 7(Multi)exonic or whole-gene deletion/duplication
EDAR~15%-20%Sequence analysisSequence variants 5
Duplication/deletion analysis 7(Multi)exonic or whole-gene deletion/duplication
EDARADD1%-2% 8Sequence analysisSequence variants 5
Duplication/deletion analysis 7Unknown; none reported 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. For males affected with X-linked HED, mutations detected include intragenic deletions. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome in affected males. Confirmation may require deletion/duplication analysis.

4. Sequence analysis of genomic DNA cannot detect deletion of an exon(s) or a whole gene on an X chromosome of carrier females.

5. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Deletion analysis is used to detect exonic deletions in females and to confirm exonic deletions in affected males.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

8. Mutations in EDARADD are likely rare and are found in only 1%-2% of HED cases [Bohring et al 2009, Cluzeau et al 2011].

9. Theoretically, method detects deletion or duplication of one or more exons or the whole gene. However, no deletions or duplications involving EDARADD as causative of HED have been reported.

Testing Strategy

To confirm/establish the diagnosis in a proband

Carrier testing for relatives at risk for X-linked HED or autosomal recessive HED requires prior identification of the disease-causing mutation(s) in the family.

Note: (1) Carriers who are heterozygotes for the autosomal recessive form are not at risk of developing the disorder. (2) Carriers who are heterozygotes for the X-linked disorder have clinical findings related to the disorder. (3) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Clinical Description

Natural History

Classic HED

Males with X-linked hypohidrotic ectodermal dysplasia (XLHED) and males and females with autosomal recessive hypohidrotic ectodermal dysplasia (ARHED) caused by EDAR or EDARADD mutations have the classic form of hypohidrotic ectodermal dysplasia (HED).

Neonates with HED may be diagnosed because of peeling skin, like that of "post-mature" babies, and periorbital hyperpigmentation. In infancy, they may be irritable because of heat intolerance; elevated body temperatures are not uncommon. More often, diagnosis is delayed until the teeth fail to erupt at the expected age (6-9 months) or the teeth that erupt are conical in shape. By this age, affected individuals may have chronic eczema and the periorbital skin may appear wrinkled.

The cardinal features of HED become obvious during childhood:

  • Thin, lightly pigmented, and slow-growing scalp hair. The apparent slow growth of the scalp hair may result from the excessive fragility of the shafts, which break easily with the usual wear and tear of childhood.
  • Greatly reduced sweat function leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature [Blüschke et al 2010, Schneider et al 2011]
  • Later-than-average appearance of only a few teeth, which are abnormally formed [Lexner et al 2008]

Other signs of classic HED include the following:

  • Periorbital hyperpigmentation that persists
  • Depressed nasal bridge (saddle nose deformity) that is obvious by early childhood
  • Decreased sebaceous secretions
  • Changes in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafter
  • Lack of dermal ridges
  • Asymmetric development of the alveolar ridge
  • Raspy voice
  • Fragile-appearing skin
  • Retruded appearance of the midface

Physical growth and psychomotor development are otherwise within normal limits.

Mild HED

Female carriers of XLHED and males and females with autosomal dominant HED (ADHED) typically have mild HED.

Female carriers of XLHED may exhibit mild manifestations of any or all the cardinal features: some sparseness of the hair, patchy distribution of sweat dysfunction, and a few small or missing teeth. They may also notice deficient milk production during nursing or have underdeveloped nipples.

Individuals with ADHED exhibit mild manifestations as described for female carriers of XLHED, without the patchy distribution of sweat dysfunction.

Genotype-Phenotype Correlations

Phenotypes resulting from EDA mutations range from classic HED to nonsyndromic hypodontia. Recent investigations suggest that most EDA mutations associated with nonsyndromic hypodontia are missense mutations with most located in the tumor necrosis factor domain. Many mutations associated with X-linked HED are thought to be loss of function mutations including nonsense mutations, insertions, and deletions that span the gene [Zhang et al 2011].

Variable phenotypes that range from mild to severe are associated with EDAR mutations, but genotype-phenotype correlations remain limited [Chassaing et al 2006].


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.


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 cases may be missed during infancy before the cardinal features become obvious.

Affected individuals have been reported in all racial and ethnic groups.

Differential Diagnosis

Numerous types of ectodermal dysplasia exist. Hypodontia with a vague history of heat intolerance or slight sparseness of the hair is a particularly common and troublesome differential diagnosis [Ho et al 1998].

The presence of onychodysplasia (inherent abnormalities of nail development) and other developmental abnormalities favor diagnoses other than hypohidrotic ectodermal dysplasia (HED).

Other types of ectodermal dysplasia that need to be considered include the following:

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to X-linked hypohidrotic ectodermal dysplasia, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

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

  • Initial evaluation of the developing dentition is 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 is recommended by one year of age.
  • Dental radiographs are essential to determining the extent of hypodontia, and are frequently taken in the toddler or child using panoramic or conventional dental radiographic techniques.
  • Genetics consultation

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.

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.


  • Dental treatment, ranging from simple restorations to dentures, must begin at an early age. Bonding of conical shaped teeth in young affected individuals improves esthetics and chewing ability.
  • Orthodontics may be necessary.
  • Dental implants in the anterior portion of the mandibular arch have proven successful only in children over age seven years [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 an 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.


  • 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.

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.


The first dental visit should occur by one year of age 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

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

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 with risk of hyperthermia should take extra care to not 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

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hypohidrotic ectodermal dysplasia (HED) is inherited in an autosomal dominant, autosomal recessive, or X-linked manner.

Evaluation of the proband includes review of family history and careful examination of family members to identify clinical manifestations of hypohidrotic ectodermal dysplasia (HED).The mode of inheritance may be determined by family history and/or by molecular genetic testing.

Risk to Family Members — X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED)

Parents of a male proband

Parents of a female proband

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • If the mother is a carrier, the chance of transmitting the EDA mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and may show minimal manifestations.
  • If the mother is not a carrier, the risk to sibs is low but greater than that of the general population because the risk for germline mosaicism in mothers is not known.
  • If the father is affected, none of the male sibs and all of the female sibs will inherit the mutation. The females may show minimal manifestations.

Offspring of a male proband

  • A male with XLHED will transmit the disease-causing EDA allele to all of his daughters and none of his sons.
  • The daughters will be obligate carriers and may show minimal manifestations.

Offspring of a female proband. A female with XLHED will transmit the disease-causing EDA allele to half of her children, regardless of gender. Thus, her sons have a 50% risk of being affected and her daughters have a 50% risk of being carriers, who may show minimal manifestations.

Other family members of a proband

Carrier Detection

Molecular genetic testing for carrier detection of at-risk female relatives is possible if the EDA disease-causing mutation in the family is known.

Detection of carriers on the basis of clinical findings is often imprecise. If sweat distribution is patchy or many teeth are absent, establishing carrier status is relatively easy. Otherwise, mild manifestations 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, are notoriously inaccurate.

Risk to Family Members — Autosomal Recessive Hypohidrotic Ectodermal Dysplasia (ARHED)

Parents of a proband

  • The parents are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation in EDAR or EDARADD
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. All of the offspring are obligate heterozygotes.

Other family members of a proband. Each sib of an obligate heterozygote is at a 50% risk of being a heterozygote.

Carrier Detection

Carrier detection by molecular genetic testing is possible for at-risk family members if the disease-causing mutations have been identified in the family.

Risk to Family Members — Autosomal Dominant Hypohidrotic Ectodermal Dysplasia (ADHED)

Parents of a proband

  • Some individuals diagnosed with ADHED have an affected parent.
  • A proband with ADHED may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical examination and molecular genetic testing for the mutation in EDAR or EDARADD identified in the proband.

Note: Although individuals diagnosed with ADHED may have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the proband's parent.
  • If one of the proband's parents is affected, the risk to the sibs is 50%.

Offspring of a proband. Individuals with ADHED have a 50% chance of transmitting the mutant allele to each child.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a disease-causing allele, his or her family members are 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, clarification of carrier status, and discussion of the availability of prenatal 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 carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

XLHED. Prenatal testing for pregnancies at increased risk is possible if the EDA mutation in the family is known. The usual procedure is to determine the sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.

ARHED/ADHED. If the disease-causing mutation(s) have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like HED) are treatable and do not affect intellect are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Asociación de Afectados por Displasia Ectodérmica
    Consumer health-oriented organization for Spain.
    C Poet Andres Bolarín
    2-3º Dcha.
    Murcia 30011
    Phone: 968 350 026
    Email: info@displasiaectodermica.org
  • Ectodermal Dysplasia Society
    108 Charlton Lane
    Cheltenham Gloucestershire GL53 9EA
    United Kingdom
    Phone: 01242 261332
    Email: diana@ectodermaldysplasia.org
  • Medline Plus
  • National Foundation for Ectodermal Dysplasias (NFED)
    410 East Main Street
    PO Box 114
    Mascoutah IL 62258-0114
    Phone: 618-566-2020
    Fax: 618-566-4718
    Email: info@nfed.org
  • National Library of Medicine Genetics Home Reference
  • ozED- Australian Ectodermal Dysplasia Support Group Inc.
    PO Box 472
    Aspley Queensland 4034
    Phone: 03 9778 8026; 61 3 9755 5626
  • Selbsthilfegruppe Ektodermale Dysplasie e.V.
    Consumer health-oriented organization for Germany, Austria, and Switzerland
    Landhausweg 3
    Aichtal D-72631
    Phone: 0 71 27 96 96 91
    Fax: 0 71 27 96 96 92
    Email: Burk-Aichtal@t-online.de
  • Ectodermal Dysplasias International Registry
    National Foundation for Ectodermal Dysplasias
    410 East Main Street
    Mascoutah IL 62258
    Phone: 618-566-2020
    Fax: 618-566-4718
    Email: info@nfed.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hypohidrotic Ectodermal Dysplasia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hypohidrotic Ectodermal Dysplasia (View All in OMIM)


Molecular Genetic Pathogenesis

The molecular pathogenesis of hypohidrotic ectodermal dysplasia (HED) is poorly understood. The gene responsible for X-linked HED, EDA, produces ectodysplasin-A, a protein that is important for normal development of ectodermal appendages including hair, teeth, and sweat glands. Evidence is accumulating that ectodysplasin-A is important in several pathways that involve ectodermal-mesodermal interactions during embryogenesis. Defects in the molecular structure of ectodysplasin-A may inhibit the action of enzymes necessary for normal development of the ectoderm and/or its interaction with the underlying mesoderm.


Gene structure. EDA comprises 12 exons, eight of which encode the transmembrane protein ectodysplasin-A [Bayes et al 1998, Ferguson et al 1998, Monreal et al 1998] (Reference sequence NM_001399.4). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Numerous mutations have been identified in EDA, including nucleotide substitutions (missense, nonsense, and splicing), small deletions and insertions, and gross deletions [Visinoni et al 2003, Hsu et al 2004].

Normal gene product. Ectodysplasin-A has 391 amino acid residues with a short collagenous domain (Gly-X-Y) that is homologous to the protein in the tabby mouse. Ezer et al [1999] demonstrated that ectodysplasin-A is a trimeric type II protein that colocalizes with cytoskeletal structures at the lateral and apical surfaces of cells, suggesting that it is a novel member of the tumor necrosis factor (TNF)-related ligand family that plays a role in early epithelial-mesenchyme interactions. Several isoforms of ectodysplasin are expressed in keratinocytes, hair follicles, and sweat glands. (Reference sequence NP_001390.1)

Abnormal gene product. Mutations in EDA lead to ectodysplasin A molecules that are unable to regulate epithelial-mesenchyme interactions, resulting in abnormal ectodermal appendages. Several mutations in EDA produce ectodysplasin A molecules that resist cleavage by furin and are consequently unable to be converted to their active forms and mediate the cell-to-cell signaling that regulates morphogenesis of ectodermal appendages [Chen et al 2001].


Gene structure. Human EDAR has 12 exons (Reference sequence NM_022336.3). EDAR is orthologous to the mouse downless gene. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Several mutations have been identified in EDAR, including deletions, transitions, and a gross deletion [Shimomura et al 2004, Chassaing et al 2006, Mégarbané et al 2008, van der Hout et al 2008, Monreal et al 1999].

Normal gene product. EDAR encodes a 448-amino acid protein that 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. It forms a ligand-receptor pair with ectodysplasin (Reference sequence NP_071731.1).

Abnormal gene product. The defective proteins encoded by mutations in EDAR are unable to bind with ectodysplasin. Those responsible for autosomal recessive HED exhibit loss of function, while those responsible for autosomal dominant HED exhibit a dominant negative effect [Valcuende-Cavero et al 2008]. At least two of the dominant negative mutations are not associated with the HED phenotype.


Gene structure. Human EDARADD has two isoforms, each with six exons encoding 205 and 215 amino acid proteins (NM_080738.3 and NM_145861.2, respectively). EDARADD is homologous to the mouse crinkled gene. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. A transition at nucleotide 424 of EDARADD, leading to a glutamine-to-lysine (p.Glu142Lys) amino acid substitution in the encoded protein, has been identified in a consanguineous family with autosomal recessive HED [Headon et al 2001]. Another family with autosomal dominant HED has been found to have a heterozygous c.335T>G mutation in EDARADD, indicating that both recessive and dominant forms of HED can be caused by EDARADD mutations [Bal et al 2007]. A homozygous 6-bp in-frame deletion (c.402-407del, p.Thr135-Val136del) has also been reported in a patient with HED [Chassaing et al 2010].

Table 2. Selected EDARADD Pathogenic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
(402_407del) 1
(Thr135-Val136del) 1

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Numbering according to the longer transcript variant and protein isoform (NM_145861​.2; NP_665860​.2).

Normal gene product. 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.

Abnormal gene product. EDARADD mutations alter the charge of an amino acid in the resultant gene, rendering it incapable of performing its function.


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Literature Cited

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Chapter Notes


Ronald J Jorgenson, DDS, PhD

National Foundation for Ectodermal Dysplasias

Author History

Dorothy K Grange, MD (2006-present)
Ronald J Jorgenson, DDS, PhD; former President, Applied Genetics, Austin, TX (2002-2006)
Mary K Richter (2006-present)
J Timothy Wright, DDS, MS (2006-present)

Revision History

  • 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 to live Web site
  • 28 April 2003 (me) Review posted to live Web site
  • 23 October 2002 (rj) Original submission
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