DiagnosisClinical DiagnosisThe diagnosis of hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome) should be considered after infancy in individuals with the following: Nail dystrophy (malformed, thickened, small nails).This is an essential feature of the syndrome. In approximately 30% of affected persons, nail dystrophy may be the only obvious finding during the physical examination at a specific time. Hypotrichosis (partial or total alopecia). The scalp hair is sparse, pale, fine, and brittle. It may be completely absent. The eyebrows are sparse or absent. The eyelashes are short and sparse. Axillary and pubic hair is sparse or absent. Palmoplantar hyperkeratosis (hyperkeratosis of the palms and soles). This is a common but not universal finding. Molecular Genetic TestingGene. GJB6, encoding gap junction protein β6 (connexin-30), is the only gene currently known to be associated with hidrotic ectodermal dysplasia 2 [Kibar et al 1996, Kibar et al 1999, Kibar et al 2000, Lamartine et al 2000, Smith et al 2002]. Clinical testing Targeted mutation analysis. Four GJB6 disease-causing GJB6 mutations (p.Gly11Arg, p.Ala88Val, p.Val37Glu, p.Asp50Asn) have been identified to date [Lamartine et al 2000, Smith et al 2002, Zhang et al 2003, Baris et al 2008]. p.Gly11Arg, found among individuals of French, French-Canadian, African, Spanish, Scottish-Irish, and Chinese origin p.Ala88Val, found among individuals of Indian, Malaysian, and Welsh origin p.Val37Glu, found in a simplex case (i.e., a single affected individual in a family) of Scottish origin p.Asp50Asn, found among individuals of Ashkenazi Jewish origin Sequence analysis. Sequence analysis of the coding region is used when targeted mutation analysis does not detect one of the four known mutations [Lamartine et al 2000]. All individuals with a classic HED2 phenotype have identifiable mutations. Table 1. Summary of Molecular Genetic Testing Used in Hidrotic Ectodermal Dysplasia 2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ¹ Test AvailabilityGJB6Targeted mutation analysisp.Gly11Arg, p.Ala88Val, p.Val37Glu, p.Asp50Asn100%Clinical Sequence analysisSequence variants ^{2100%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband Initial molecular genetic testing should be targeted mutation analysis for one of the four mutations in GJB6, starting with the most frequent mutation found in the ethnic origin of the individual. If targeted mutation analysis for the four known mutations does not identify a mutation, sequence analysis should be performed. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersOther phenotypes associated with mutations in GJB6:Nonsyndromic hearing loss (NSHL) DFNA3 (OMIM 601544). The GJB6 mutation p.Thr5Met is associated with DFNA3 [Grifa et al 1999]. Persons with DFNA3 develop hearing impairment in childhood [Denoyelle et al 1998]. High frequencies are more severely affected than low frequencies, resulting in a downsloping mild- or moderate-to-profound audiometric pattern. The hearing loss is moderate to severe. Inheritance is autosomal dominant. DFNB1 (OMIM 220290). The GJB6 mutation del(GJB6-D13S1830) is associated with DFNB1 [del Castillo et al 2003]. DFNB1 is also associated with mutations in GJB2. Approximately 98% of individuals with DFNB1 have two identifiable GJB2 mutations. Approximately 2% of individuals with DFNB1 have one identifiable GJB2 mutation and a large deletion that includes a portion of GJB6 (i.e., they are double heterozygotes). The DFNB1-associated GJB6 mutation is a large deletion that involves most of GJB6 and a large portion of the upstream region. Whether this deletion affects transcription of GJB2 or represents an example of digenic inheritance at the DFNB1 locus has not been determined. Inheritance is autosomal recessive. Keratitis-ichthyosis-deafness (KID) syndrome (OMIM 148210). Jan et al [2004] reported a boy age six years with erythrokeratoderma and some similarities to KID syndrome.}

Natural HistoryHidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome) is characterized by dystrophy of the nails, alopecia (partial or total), hyperpigmentation of the skin (especially over the joints), palmoplantar hyperkeratosis, and clubbing of the fingers. Sweat glands, sebaceous glands, and teeth are normal. The clinical manifestations are highly variable even within the same family.HED2 can be characterized by dysplastic nails and sparse scalp hair early in life. During childhood, palmoplantar keratoderma may develop.In infancy, the scalp hair is wiry, brittle, patchy, and pale. Progressive hair loss may lead to total alopecia, usually by puberty. Hair in other parts of the body may also be affected.In early childhood, the nails may be milky white. They gradually become dystrophic, thick, short, and distally separated from the nail bed. Nail growth is slow.Palmoplantar keratoderma increases in severity with age. Teeth and ability to sweat are normal, as are physical growth and psychomotor development.

Genotype-Phenotype CorrelationsAlthough most GJB6 mutations cause the clinical presentations typical of HED2 with involvement of the hair, the nails, and the palmoplantar skin, the p.Gly11Arg and p.Ala88Val mutations can be associated with a clinical picture similar to that of pachyonychia congenita [van Steensel et al 2003] (see Differential Diagnosis).In one Chinese family, hidrotic ectodermal dysplasia 2 caused by the p.Gly11Arg mutation involved only hair and nails [Chen et al 2010].

Differential DiagnosisVarious types of hidrotic ectodermal dysplasia exist, and it is likely that new types will be described [Megarbane et al 1998, Lamartine 2003, van Steensel et al 2004]. Hidrotic ectodermal dysplasia 2 (HED2) must be differentiated from the following ectodermal dysplasias that can affect nails and hair. Ability to sweat and oligodontia in these disorders are variable. Hypotrichosis-deafness syndrome Pachyonychia congenita type 1 (PC-1), characterized by hypertrophic nail dystrophy, focal palmoplantar keratoderma, blistering oral leukokeratosis, palmoplantar hyperhidrosis, and follicular keratoses on the trunk and extremities. The two keratin genes known to be associated with PC-1 are KRT6A (encoding keratin, type II cytoskeletal 6A) and KRT16 (encoding keratin, type I cytoskeletal 16). Autosomal dominant and autosomal recessive forms of hypohidrotic ectodermal dysplasia (HED), characterized by sparseness of scalp and body hair, hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth) evident in 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, later than average. Three clinically similar but genetically distinct forms of HED exist. The X-linked recessive (caused by mutation in EDA) and autosomal recessive forms (EDAR and EDARADD) are indistinguishable; the autosomal dominant form (EDAR and EDARADD) is milder in expression. In rare cases, HED2 can mimic certain aspects of KID syndrome, with an erythrokeratoderma and sensorineural deafness [Jan et al 2004].A novel missense mutation of GJB2 associated with thin hair, deafness, and nail dystrophy resembles HED2 with deafness [van Steensel et al 2004]. Rafiq et al [2005] studied an autosomal recessive form of ectodermal dysplasia (ED) in 13 individuals over six generations from an inbred Pakistani family. The clinical features include severely dystrophic nails and thin scalp hair, fine eyebrows and eyelashes, and thin body hair. Linkage analysis mapped the ED-related gene on chromosome 10q24.32-q25.1 at a 3.92 cM interval flanked by markers D10S1710 and D10S1741 [Rafiq et al 2005].Naeem et al [2006] described a form of ED in a large consanguineous Pakistani kindred with multiple affected individuals. DNA analysis revealed a homozygous missense mutation of the keratin gene (KRTHB5), in the hair matrix and cuticle.Isolated nail dystrophy can also be a finding of Darier's disease and acquired disorders such as lichen planus and psoriasis. Associated symptoms and history should allow easy differentiation. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, 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 hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome), a thorough examination of the nails, hair, and skin is recommended.Treatment of ManifestationsDystrophic nails. Artificial nails may improve the appearance of the hands/feet, and may be especially helpful to young girls and women. Hypotrichosis. No special pharmaceutical agent is available to improve hair growth. Alopecia was found to respond to treatment with a combination of topical minoxidil and tretinoin in an individual with probable congenital hidrotic ectodermal dysplasia [Melkote et al 2009]. The individual’s clinical findings were compatible with the clinical diagnosis of HED2; however, the diagnosis was not confirmed with molecular genetic testing. The authors also noted that the efficacy and safety of long-term treatment need to be explored further.Special hair care products may help to manage dry and sparse hair. In many cases, wigs are helpful. Palmoplantar hyperkeratosis. Skin emollients may help relieve palmoplantar hyperkeratosis. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.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. Hidrotic Ectodermal Dysplasia 2: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGJB613q12​.11Gap junction beta-6 proteinDeafness Gene Mutation Database
The Connexin-deafness homepage
Hereditary Hearing Loss Homepage
CCHMC - Human Genetics Mutation DatabaseGJB6Data 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 Hidrotic Ectodermal Dysplasia 2 (View All in OMIM) View in own window 129500CLOUSTON SYNDROME 604418GAP JUNCTION PROTEIN, BETA-6; GJB6Normal allelic variants. GJB6 has one exon, which is not interrupted by introns. Pathologic allelic variants. Four GJB6 mutations are associated with hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome). Lamartine et al [2000] found a 31G>A transition in GJB6 leading to a p.Gly11Arg missense mutation. They also found a 263C>T transition leading to a p.Ala88Val missense mutation. Smith et al [2002] reported a novel mutation p.Val37Glu within the first transmembrane domain of connexin-30 (gap junction beta-6 protein). The amino acid substitution arose from a heterozygous 110T-to-A transversion in GJB6 [Smith et al 2002]. Baris et al [2008] reported another novel mutation p.Asp50Asn resulting from a G>A transition affecting the E1 first extracellular loop of the connexin 30 molecule. Two other GJB6 mutations are responsible for nonsyndromic sensorineural hearing loss. Table 2. Selected GJB6 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReferencesc.31G>Ap.Gly11ArgLamartine et al [2000]
Smith et al [2002]
Baris et al [2008]c.263C>Tp.Ala88Valc.110T>Ap.Val37Gluc.148G>Ap.Asp50AsnSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. Gap junction beta-6 protein comprises 261 amino acids and four transmembrane domains, two extracellular domains, and three cytoplasmic domains including the amino- and carboxy-terminal regions. Gap junction beta-6 protein, with five other similar subunits, forms a gap junction channel, the connexon, which mediates the direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. GJB6 is expressed most abundantly in brain and skin. Abnormal gene product. The presence of the mutated connexin protein may possibly lead to a defect in trafficking of other connexins, since their oligomerization is complete upon entry into the Golgi apparatus [Evans et al 1999, van Steensel 2004]. Several mutations in connexin genes affect trafficking of the protein [Common et al 2002]. The association of HED2 with three different mutations in GJB6 supports this idea. In that case, the mutations of GJB6 should interfere with its incorporation into the gap junction. So far, this hypothesis has not been experimentally validated [van Steensel 2004].