Clinical Diagnosis

The 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 Testing

Gene. 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 2

View in own window

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
GJB6	Targeted mutation analysis	p.Gly11Arg, p.Ala88Val, p.Val37Glu, p.Asp50Asn	100%	Clinical
	Sequence analysis	Sequence variants 2	100%

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. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 Strategy

To 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.

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

Other 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 six-year-old boy with erythrokeratoderma and some similarities to KID syndrome.

Natural History

Hidrotic 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 Correlations

Although 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].

Penetrance

Penetrance is likely 100% [Author, personal observation].

Anticipation

Anticipation is not noted in HED2.

Nomenclature

When referring to HED2 (Clouston syndrome), the nonspecific term 'hidrotic ectodermal dysplasia' should not be used, as other forms of ectodermal dysplasia are associated with normal sweating.

Prevalence

HED2 is relatively common in the French-Canadian population of southwest Quebec [Kibar et al 2000]. However, this condition has also been reported in the US, particularly in Vermont, upstate New York, and Louisiana among communities of French-Canadian origin, as well as among populations of African, Chinese, French, Indian, Irish, Malaysian, Scottish, Spanish, and Ashkenazi Jewish origin [Radhakrishna et al 1997, Taylor et al 1998, Kibar et al 2000, Zhang et al 2003, Baris et al 2008]

Evaluations Following Initial Diagnosis

To 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 Manifestations

Dystrophic 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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

Hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals with HED2 have an affected parent and a family history of other affected individuals in the same or previous generations.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing.
• A proband with HED2 may have the disorder as a result of a de novo gene mutation. The exact proportion of such cases is unknown but presumed to be very low.
  • A de novo mutation (p.Val37Glu) has been reported [Smith et al 2002]
  • Baris et al [2008] reported a proband and his mother who were clinically affected and harbored a p.Asp50Asn mutation. The mother’s parents were not affected and did not have the mutation.

Note: Although almost all individuals diagnosed with HED2 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected and a disease-causing mutation cannot be detected in DNA extracted from the leukocytes of either parent, the risk to sibs of the proband is low.
• If a disease-causing mutation in the proband cannot be detected in the DNA of either parent, the two possible explanations are either germline mosaicism in a parent or a de novo mutation in the proband. The risk to the sibs of the proband depends on the probability of germline mosaicism in a parent of the proband and the rate of spontaneous mutation of GJB6. Rare instances of germline mosaicism and de novo mutations have been reported in other disorders. In both hypothetical instances, the risk that a sib will be affected would be significantly below 1%.

Offspring of a proband. Each child of an individual affected with HED2, irrespective of gender, has a 50% chance of inheriting the mutation and being affected.

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, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk 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 or at risk.

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

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele 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 such as HED2 are not common. Differences in perspective may exist among medical professionals and within 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 has 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).

Literature Cited

1. Baris HN, Zlotogorski A, Peretz-Amit G, Doviner V, Shohat M, Reznik-Wolf H, Pras E. A novel GJB6 missense mutation in hidrotic ectodermal dysplasia 2 (Clouston syndrome) broadens its genotypic basis. Br J Dermatol. 2008;159:1373–8. [PubMed: 18717672]
2. Chen N, Xu C, Han B, Wang ZY, Song YL, Li S, Zhang RL, Pan CM, Zhang L. G11R mutation in GJB6 gene causes hidrotic ectodermal dysplasia involving only hair and nails in a Chinese family. J Dermatol. 2010;37:559–61. [PubMed: 20536673]
3. Common JE, Becker D, Di WL, Leigh IM, O'Toole EA, Kelsell DP. Functional studies of human skin disease and deafness-associated connexin 30 mutations. Biochem Biophys Res Commun. 2002;298:651–6. [PubMed: 12419304]
4. del Castillo I, Moreno-Pelayo MA, Del Castillo FJ, Brownstein Z, Marlin S, Adina Q, Cockburn DJ, Pandya A, Siemering KR, Chamberlin GP, Ballana E, Wuyts W, Maciel-Guerra AT, Alvarez A, Villamar M, Shohat M, Abeliovich D, Dahl HH, Estivill X, Gasparini P, Hutchin T, Nance WE, Sartorato EL, Smith RJ, Van Camp G, Avraham KB, Petit C, Moreno F. Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study. Am J Hum Genet. 2003;73:1452–8. [PMC free article: PMC1180408] [PubMed: 14571368]
5. Denoyelle F, Lina-Granade G, Plauchu H, Bruzzone R, Chaib H, Levi-Acobas F, Weil D, Petit C. Connexin 26 gene linked to a dominant deafness. Nature. 1998;393:319–20. [PubMed: 9620796]
6. Evans WH, Ahmad S, Diez J, George CH, Kendall JM, Martin PE. Trafficking pathways leading to the formation of gap junctions. Novartis Found Symp. 1999;219:44–54. [PubMed: 10207897]
7. Grifa A, Wagner CA, D'Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, Rabionet R, Arbones M, Monica MD, Estivill X, Zelante L, Lang F, Gasparini P. Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat Genet. 1999;23:16–8. [PubMed: 10471490]
8. Jan AY, Amin S, Ratajczak P, Richard G, Sybert VP. Genetic heterogeneity of KID syndrome: identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol. 2004;122:1108–13. [PubMed: 15140211]
9. Kibar Z, Der Kaloustian VM, Brais B, Hani V, Fraser FC, Rouleau GA. The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q. Hum Mol Genet. 1996;5:543–7. [PubMed: 8845850]
10. Kibar Z, Dube MP, Powell J, McCuaig C, Hayflick SJ, Zonana J, Hovnanian A, Radhakrishna U, Antonarakis SE, Benohanian A, Sheeran AD, Stephan ML, Gosselin R, Kelsell DP, Christianson AL, Fraser FC, Der Kaloustian VM, Rouleau GA. Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping. Eur J Hum Genet. 2000;8:372–80. [PubMed: 10854098]
11. Kibar Z, Lafreniere RG, Chakravarti A, Wang JC, Chevrette M, Der Kaloustian VM, Rouleau GA. A radiation hybrid map of 48 loci including the clouston hidrotic ectodermal dysplasia locus in the pericentromeric region of chromosome 13q. Genomics. 1999;56:127–30. [PubMed: 10036193]
12. Lamartine J. Towards a new classification of ectodermal dysplasias. Clin Exp Dermatol. 2003;28:351–5. [PubMed: 12823289]
13. Lamartine J, Munhoz Essenfelder G, Kibar Z, Lanneluc I, Callouet E, Laoudj D, Lemaître G, Hand C, Hayflick SJ, Zonana J, Antonarakis S, Radhakrishna U, Kelsell DP, Christianson AL, Pitaval A, Der Kaloustian V, Fraser C, Blanchet-Bardon C, Rouleau GA, Waksman G. Mutations in GJB6 cause hidrotic ectodermal dysplasia. Nat Genet. 2000;26:142–4. [PubMed: 11017065]
14. Megarbane A, Noujeim Z, Fabre M, Der Kaloustian VM. New form of hidrotic ectodermal dysplasia in a Lebanese family. Am J Med Genet. 1998;75:196–9. [PubMed: 9450885]
15. Melkote S, Dhurat RS, Palav A, Jerajani HR. Alopecia in congenital hidrotic ectodermal dysplasia responding to treatment with a combination of topical minoxidil and tretinoin. Int J Dermatol. 2009;48:184–85. [PubMed: 19200200]
16. Naeem M, Wajid M, Lee K, Leal SM, Ahmad W. A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type. J Med Genet. 2006;43:274–9. [PMC free article: PMC2563238] [PubMed: 16525032]
17. Radhakrishna U, Blouin JL, Mehenni H, Mehta TY, Sheth FJ, Sheth JJ, Solanki JV, Antonarakis SE. The gene for autosomal dominant hidrotic ectodermal dysplasia (Clouston syndrome) in a large Indian family maps to the 13q11-q12.1 pericentromeric region. Am J Med Genet. 1997;71:80–6. [PubMed: 9215774]
18. Rafiq MA, Faiyaz-Ul-Haque M, Ud Din MA, Malik S, Sohail M, Anwar M, Haque S, Paterson AD, Tsui LC, Ahmad W. A novel locus of ectodermal dysplasia maps to chromosome 10q24.32-q25.1. J Invest Dermatol. 2005;124:338–42. [PubMed: 15675952]
19. Smith FJ, Morley SM, McLean WH. A novel connexin 30 mutation in Clouston syndrome. J Invest Dermatol. 2002;118:530–2. [PubMed: 11874494]
20. Taylor TD, Hayflick SJ, McKinnon W, Guttmacher AE, Hovnanian A, Litt M, Zonana J. Confirmation of linkage of Clouston syndrome (hidrotic ectodermal dysplasia) to 13q11-q12.1 with evidence for multiple independent mutations. J Invest Dermatol. 1998;111:83–5. [PubMed: 9665391]
21. van Steensel MA, Jonkman MF, van Geel M, Steijlen PM, McLean WH, Smith FJ. Clouston syndrome can mimic pachyonychia congenita. J Invest Dermatol. 2003;121:1035–8. [PubMed: 14708603]
22. van Steensel MA, Steijlen PM, Bladergroen RS, Hoefsloot EH, van Ravenswaaij-Arts CM, van Geel M. A phenotype resembling the Clouston syndrome with deafness is associated with a novel missense GJB2 mutation. J Invest Dermatol. 2004;123:291–3. [PubMed: 15245427]
23. van Steensel MA. Gap junction diseases of the skin. Am J Med Genet. 2004;131C:12–9. [PubMed: 15468169]
24. Zhang XJ, Chen JJ, Yang S, Cui Y, Xiong XY, He PP, Dong PL, Xu SJ, Li YB, Zhou Q, Wang Y, Huang W. A mutation in the connexin 30 gene in Chinese Han patients with hidrotic ectodermal dysplasia. J Dermatol Sci. 2003;32:11–7. [PubMed: 12788524]

Revision History

• 3 February 2011 (me) Comprehensive update posted live
• 7 August 2007 (me) Comprehensive update posted site
• 25 April 2005 (me) Review posted to live Web site
• 23 November 2004 (vdk) Original submission