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

Genes

• 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.
• Although deletion/duplication analysis is available for EDAR and EDARADD, no deletions or duplications in these genes have been reported as causing HED. The utility of such testing is not known.

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

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Gene Symbol	% of HED Attributed to Mutations in This Gene	Test Method	Mutations Detected	Test Availability
EDA	~55%-60%	Sequence analysis 1, 2	Sequence variants 3	Clinical
		Duplication / deletion analysis 4, 5	Deletion / duplication of one or more exons or the whole gene
EDAR	~15%-20%	Sequence analysis	Sequence variants 3	Clinical
		Duplication / deletion analysis 5	Unknown; none reported 6
EDARADD	1%-2% 7	Sequence analysis	Sequence variants 3
		Duplication / deletion analysis 5	Unknown; none reported 6

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. 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.

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

3. 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.

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

5. 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. See array GH.

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

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

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

• If the proband's findings are classic and are consistent with X-linked inheritance (i.e., males generally more severely affected than females, no male-to-male transmission), initial testing should be for EDA mutations:
  • If the affected individual is male, sequence analysis is sufficient as it detects both sequence variants and deletions. Deletions of one or more exons or the entire gene are implied by lack of amplification; confirmation of a deletion may require deletion/duplication analysis.
  • If the affected individual is female, sequence analysis should be performed first; if no mutation is identified, deletion testing should be performed.
• If the proband's findings are classic and consistent with autosomal recessive inheritance, or mild and consistent with autosomal dominant inheritance, sequence analysis of EDAR should be performed first, followed by EDARADD if sequence analysis of EDAR does not identify causative mutation(s)
  • If molecular genetic testing of EDAR and EDARAAD do not identify causative mutations, other forms of ectodermal dysplasia should be considered (see Differential Diagnosis).

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other known phenotypes are associated with mutations in EDAR.

Mutations in EDA can be associated with isolated hypodontia [Rasool et al 2008].

A mutation in EDARADD has been associated with isolated oligodontia [Bergendal et al 2011].

Natural History

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].

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.

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.

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 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.

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 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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

• The father of an affected male is neither affected nor is he a carrier.
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• Clinical examination may detect minimal manifestations of XLHED in the mother. Molecular genetic testing is indicated.
• When an affected male represents a simplex case (male with no known family history of XLHED), several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing mutation in EDA and his mother is not a carrier.
  • His mother has a de novo disease-causing mutation in EDA, either (a) as a "germline mutation" (i.e., occurring at the time of her conception and thus present in every cell of her body); or (b) as "germline mosaicism" (i.e., occurring in a certain percentage of her germ cells only).
  • His maternal grandmother has a de novo disease-causing mutation in EDA.

Parents of a female proband

• The father of a female proband may be affected.
• The proband may have inherited the gene mutation from her mother.
• The proband may have a de novo mutation in 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 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

• 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 mutation, family members are at risk.

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. See for a list of laboratories offering DNA banking.

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. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutation(s) have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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.

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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

• 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