DiagnosisClinical DiagnosisHypohidrotic 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 HEDBecause 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 TestingGenesEDA 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 testingSequence 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 DysplasiaView in own windowGene ^{1% of HED Attributed to Mutations in This GeneTest MethodMutations Detected 2Test AvailabilityEDA~55%-60%Sequence analysis 3,4Sequence variants 5ClinicalDuplication / deletion analysis 6,7Deletion / duplication of one or more exons or the whole geneEDAR~15%-20%Sequence analysisSequence variants 5ClinicalDuplication / deletion analysis 7Deletion / duplication of one or more exons or the whole geneEDARADD1%-2% 8Sequence analysisSequence variants 5Duplication / deletion analysis 7Unknown; none reported 91. 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.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 StrategyTo confirm/establish the diagnosis in a probandIf 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.Genetically Related (Allelic) DisordersNo 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 HistoryClassic HEDMales 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 persistsDepressed nasal bridge (saddle nose deformity) that is obvious by early childhoodDecreased sebaceous secretionsChanges in nasal secretions from concretions (solidified secretions in the nasal and aural passages) in early infancy to large mucous clots thereafterLack of dermal ridgesAsymmetric development of the alveolar ridgeRaspy voiceFragile-appearing skinRetruded appearance of the midfacePhysical growth and psychomotor development are otherwise within normal limits.Mild HEDFemale 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 CorrelationsPhenotypes 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].

Differential DiagnosisNumerous 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:Schopf-Schulz-Passarge syndrome and odonto-onycho-dermal dysplasia syndrome, associated with mutations in WNT10A [Mégarbané et al 2004, Adaimy et al 2007, Castori et al 2008, Nagy et al 2010, Castori et al 2011]Witkop tooth and nail syndromeTricho-dento-osseous syndromeHED with immunodeficiency caused by mutations in NEMO, the gene encoding the protein nuclear factor kappa-B (NF-kappa-B) essential modulator [Zonana et al 2000, Doffinger et al 2001, Carrol et al 2003]Ectodermal dysplasia, anhidrotic, with T-cell immunodeficiency caused by mutations in NFKBIA [Lopez-Granados et al 2008]Note to clinicians: For a patient-specific ‘simultaneous consult’ related to X-linked hypohidrotic ectodermal dysplasia, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 consultationTreatment of ManifestationsManagement 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.HypodontiaDental 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.OtherRegular 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 ComplicationsSaliva substitutes and optimal fluoride exposure may be helpful in preventing dental caries in those individuals having a marked reduction in salivary flow.SurveillanceThe 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 AvoidIndividuals 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 RiskIf 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 InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDEDAXq13​.1Ectodysplasin-AEDA @ LOVDEDAEDAR2q12​.3Tumor necrosis factor receptor superfamily member EDAREDAR homepage - Mendelian genesEDAREDARADD1q42-q43Ectodysplasin-A receptor-associated adapter proteinEDARADD homepage - Mendelian genesEDARADDData 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) View in own window 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; EDARADDMolecular Genetic PathogenesisThe 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.EDANormal allelic variants. 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)Pathologic 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].EDARNormal allelic variants. Human EDAR has 12 exons (Reference sequence NM_022336.3). EDAR is orthologous to the mouse downless gene.Pathologic 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. EDARADDNormal allelic variants. 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.Pathologic 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 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 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference Sequencesc.424G>Ap.Glu142LysNM_080738​.3
NP_542776​.1c.335T>Gp.Leu112Argc.372_377del
(402_407del) ^{1p.Thr125_Val126del
(Thr135-Val136del) 1See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).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.}