Hypohidrotic Ectodermal Dysplasia

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

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. 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 and pubic hair) is 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)

  • Usually only five to seven teeth, typically the canines and first molars, develop.

  • Teeth are smaller than average and have conical crowns.

  • Dental radiographs are essential to determine the extent of hypodontia and are useful in the diagnosis of mildly affected 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.

• Carriers frequently will also display some degree of hypodontia [Cambiaghi et al 2000].

Molecular Genetic Testing

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.—ED.

Genes

• EDA is the only gene known to be associated with X-linked HED. Ninety-five percent of individuals with HED have the X-linked form.

• The genes EDAR and EDARADD are known to be associated with both autosomal dominant and autosomal recessive forms of HED. Mutations in these genes account for 5% of HED.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing

• Carrier testing for X-linked HED and autosomal recessive HED

• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• Sequence analysis

  • EDA. In males with X-linked HED, direct sequencing of the eight exons with flanking intron sequences of ectodysplasin-A using genomic DNA identifies about 95% of mutations, including missense and nonsense mutations and deletions.

  • EDAR. Sequence analysis of the EDAR coding region is available on a clinical basis.

Duplication/deletion testing. Sequence analysis of EDA cannot detect certain types of deletion mutations in females. Therefore, specialized testing to identify a deletion is necessary if the female being tested has: (1) clinical findings suggesting that she is a carrier but (2) either (a) no affected male relatives or (b) no affected male relatives who have undergone molecular genetic testing.

Molecular genetic testing: Research

• Direct DNA. Molecular genetic testing of the EDARADD gene is available on a research basis only.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Hypohidrotic Ectodermal Dysplasia

Test Method	Mutations Detected	Mutation Detection Rate	Test Availability
Sequence analysis	EDA sequence variants	~95% of mutations in males affected with X-Linked HED 1	Clinical
Duplication/deletion testing 2	EDA deletions	Unknown
Sequence analysis	EDAR sequence variants	Unknown	Clinical
Direct DNA	EDARADD sequence variants	Unknown	Research only

1. Includes deletions
2. Detects deletions in females

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

Testing Strategy for 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.

  • If the affected individual is female, sequence analysis should be performed first; if no mutation is identified, deletion testing should be performed next.

• If the proband's findings are classic and consistent with autosomal recessive inheritance or mild and consistent with autosomal dominant inheritance, initial testing should be for EDAR mutations.

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in EDA, EDAR, or EDARADD.

Natural History

Genotype-Phenotype Correlations

No correlations exist between physical features and the gene involved or the specific mutations observed within a given gene. 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 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 at Initial Diagnosis to Establish the Extent of Disease

Initial evaluation includes review of family and medical history and careful examination of the affected individual and potential carriers for clinical manifestations of hypohydrotic ectodermal dysplasia (HED).

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.

Panoramic or conventional dental radiographs, essential to determining the extent of hypodontia, are frequently taken in the toddler/child using panoramic or conventional dental radiographs.

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 hyperthemia.

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 "cooling vests," air conditioning, a wet T-shirt, and/or a spray bottle of water.

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 only have proven successful for use in children over age seven years.

• Children with HED typically need to have their dental prostheses replaced every 2.5 years.

• Dental implants in adults can support an esthetic and functional dentition.

• 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.

• Skin care products are useful for management of eczema and rashes and for dry skin associated with certain outdoor exposures like swimming.

Surveillance

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.

Testing of Relatives at Risk

Evaluation of potential female carriers should be considered when an X-linked mode of inheritance appears likely or clinical features are consistent with HED.

Therapies Under Investigation

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

Mode of Inheritance

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

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 is not affected and is not 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 the EDA gene and his mother is not a carrier.

  • His mother has a de novo disease-causing mutation in the EDA gene, 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 the EDA gene.

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 new mutation in the EDA gene.

• Clinical examination may clarify the status of the parents.

Sibs of a proband

• The risk to sibs depends upon 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 for the general population because the risk of 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 but 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. The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected or to have a disease-causing mutation, family members are at risk.

Carrier Detection

• Molecular genetic testing for carrier detection of at-risk female relatives is available on a clinical basis after the EDA mutation has been identified in the proband.

• 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 the EDAR gene.

• 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. Each sib of an obligate heterozygote is at a 50% risk of being a heterozygote.

Carrier Detection

Carrier detection by molecular genetic testing is available to at-risk family members after the disease-causing EDAR mutations have been identified in the proband.

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 the EDAR gene identified in the proband. If the testing yields normal results, the possibility of a mutation in the EDARADD gene still exists; testing for EDARADD is available on a research basis only.

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 upon 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 EDAR or EDARADD allele to each child.

Other family members of a proband. The risk to other family members depends upon the status of the proband's parents. If a parent is found to be affected or to have a disease-causing allele, family members are at risk.

Related Genetic Counseling Issues

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.

DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

XLHED. Prenatal testing is possible for pregnancies of women who are carrier if the EDA mutation has been identified. The usual procedure is to determine the sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15-18 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 for ADHED or ARHED is possible by analyzing of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing EDAR allele(s) of an affected family member must be identified before prenatal testing can be performed.

Requests for prenatal testing for conditions such as HED that 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, careful discussion of these issues is appropriate.

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

Molecular Genetic Pathogenesis

The molecular pathogenesis of hypohydrotic 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

Normal allelic variants: EDA comprises 12 exons, eight of which encode the transmembrane protein ectodysplasin-A [Kere et al 1996, Srivastava et al 1997, Bayes et al 1998, Ferguson et al 1998, Monreal et al 1998].

Pathologic allelic variants: More than 60 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.

Abnormal gene product: Mutations in EDA lead to ectodysplasin A molecules that are unable to regulate epithelial-mesenchyme interactions, leading to abnormal ectodermal appendages. Several mutations in the EDA gene 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

Normal allelic variants: The human EDAR gene as 12 exons. EDAR is homologous to the mouse downless gene.

Pathologic allelic variants: Several mutations have been identified in the EDAR gene, including deletions and transitions [Shimomura et al 2004, Chassaing et al 2006]. Those responsible for autosomal recessive HED exhibit loss of function, while those responsible for autosomal dominant HED exhibit a dominant-negative effect. At least two of the dominant-negative mutations are not associated with the HED phenotype.

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.

Abnormal gene product: The defective proteins encoded by mutations in EDAR are unable to bind with ectodysplasin.

EDARADD

Normal allelic variants: The human EDARADD gene has two isoforms, each with six exons encoding 205 and 215 amino acid proteins. EDARADD is homologous to the mouse crinkled gene.

Pathologic allelic variants: A transition at nucleotide 424 of the EDARADD gene, leading to a glutamate-to-lysine (p.E142K) amino acid substitution in the encoded protein, has been identified [Headon et al 2001].

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: The EDARADD mutation alters the charge of an amino acid in the resultant gene, rendering it incapable of performing its function.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Suggested Readings

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

• 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