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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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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
, DDS, MS
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 Update: May 15, 2014.

Summary

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 pathogenic variants in EDA), two clinically similar but genetically distinct forms of HED are recognized: the clinically indistinguishable autosomal recessive form (caused by pathogenic variants in EDAR or EDARADD) and the autosomal dominant form (caused by pathogenic variants in EDAR or 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.

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 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 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 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 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.

Diagnosis

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. 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 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.
  • Between 60% and 80% of carriers display some degree of hypodontia [Cambiaghi et al 2000].

Molecular Genetic Testing

Genes

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

Clinical testing

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

Gene 1 Proportion of HED Attributed to Pathogenic Variants in This GeneTest Method
EDA~55%-60%Sequence analysis 2, 3, 4
Deletion/duplication analysis 5, 6
EDAR~15%-20%Sequence analysis 2, 3, 4
Deletion/duplication analysis 5
EDARADD1%-2% 7Sequence analysis 2, 3, 4
Deletion/duplication analysis 5, 8

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. For males affected with X-linked HED, pathogenic variants 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. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

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

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

8. 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

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having hypohidrotic ectodermal dysplasia is use of a multi-gene panel including the genes associated with the disorder and other genes of interest. See Differential Diagnosis.

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 pathogenic variants 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:

  • Asymmetric development of the alveolar ridge
  • Changes in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafter
  • Depressed nasal bridge that is obvious by early childhood
  • Decreased sebaceous secretions
  • Dry eye symptoms due to abnormal Meibomian glands [Dietz et al 2013]
  • Fragile-appearing skin
  • Lack of dermal ridges
  • Periorbital hyperpigmentation that persists
  • Recurrent pneumonia and asthma-like symptoms related to abnormal bronchial glands [Dietz et al 2013]
  • Raspy voice
  • 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 pathogenic variants range from classic HED to nonsyndromic hypodontia. Recent investigations suggest that most EDA pathogenic variants associated with nonsyndromic hypodontia are missense mutations 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 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 pathogenic variants, but genotype-phenotype correlations remain limited [Chassaing et al 2006]. The association of EDAR mutations with 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) mutation [Mégarbané et al 2008] and once with a novel homozygous missense mutation NM_022336.3: c.338G>A (p.Cys113Tyr) [Haghighi et al 2013].

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

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

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).

Management

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
  • Medical 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. There is one report of a child with HED and alopecia who was treated with topical minoxidil to the scalp with 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 esthetics 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 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.

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.

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

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

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.

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

Currently, a Phase 2 clinical trial is being conducted at several US and European medical centers to investigate the use of EDI200, developed by Edimer Pharmaceuticals, Inc [Huttner 2014]. 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 XLHED, with reduction in mortality and morbidity [Huttner 2014]. For additional information on the clinical trial click here

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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 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 molecular genetic testing.

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

Parents of a male proband

Parents of a female proband

  • The father of a female proband may be affected.
  • The proband may have inherited the pathogenic variant from her mother.
  • The proband may have de novo mutation of EDA.
  • Clinical examination may clarify the status of the parents.

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 pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant 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 pathogenic variant. The females may show minimal manifestations.

Offspring of a male proband

  • A male with XLHED will transmit the EDA pathogenic variant 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 EDA pathogenic variant to half of her children, regardless of gender. Thus, her sons are at a 50% risk of being affected and her daughters are at a 50% risk of being carriers, and as carriers may show minimal manifestations.

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 pathogenic variant, family members are at risk.

Carrier Detection

Molecular genetic testing for carrier detection of at-risk female relatives is possible if the EDA pathogenic variant 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 pathogenic variant 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 pathogenic variants 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 mutation is unknown.
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include physical examination and molecular genetic testing for the pathogenic variant 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 pathogenic variant, 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers testing for these genes or custom prenatal testing.

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 pathogenic variant(s) have been identified.

Resources

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
    Spain
    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
    Australia
    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
    Germany
    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)

129490ECTODERMAL DYSPLASIA 10A, HYPOHIDROTIC/HAIR/NAIL TYPE, AUTOSOMAL DOMINANT; ECTD10A
224900ECTODERMAL DYSPLASIA 10B, HYPOHIDROTIC/HAIR/TOOTH TYPE, AUTOSOMAL RECESSIVE; ECTD10B
300451ECTODYSPLASIN A; EDA
305100ECTODERMAL DYSPLASIA 1, HYPOHIDROTIC, X-LINKED; XHED
604095ECTODYSPLASIN A RECEPTOR; EDAR
606603EDAR-ASSOCIATED DEATH DOMAIN; EDARADD

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.

EDA

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 pathogenic variants 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. Pathogenic variants in EDA lead to ectodysplasin A molecules that are unable to regulate epithelial-mesenchyme interactions, resulting in abnormal ectodermal appendages. Several pathogenic variants 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].

EDAR

Gene structure. Human EDAR has 12 exons (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 pathogenic variants 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 (NP_071731.1).

Abnormal gene product. The defective proteins encoded by pathogenic variants 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.

EDARADD

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 an inbred 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 pathogenic variant in EDARADD, indicating that both recessive and dominant forms of HED can be caused by EDARADD pathogenic variants [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 Allelic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.424G>Ap.Glu142LysNM_080738​.3
NP_542776​.1
c.335T>Gp.Leu112Arg
c.372_377del
(402_407del) 1
p.Thr125_Val126del
(Thr135-Val136del) 1

Note on variant classification: Variants listed in the table have been provided by the authors. 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 pathogenic variants alter the charge of an amino acid in the protein, rendering it nonfunctional.

References

Literature Cited

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Chapter Notes

Acknowledgments

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

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