Clinical characteristics.

Hidrotic ectodermal dysplasia 2, or Clouston syndrome (referred to as HED2 throughout this GeneReview) is characterized by a triad of major clinical features including partial-to-complete alopecia, nail dystrophy, and palmoplantar hyperkeratosis. Sweating is preserved and there are usually no dental anomalies.

Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is fine, sparse, and brittle. Progressive hair loss may lead to total alopecia by puberty. The nails may be milky white in early childhood; they gradually become dystrophic, thick, and distally separated from the nail bed. Palmoplantar keratoderma may develop during childhood and increases in severity with age. Associated features may include cutaneous hyperpigmentation (particularly over the joints) and finger clubbing. The clinical manifestations are highly variable even within the same family.

Diagnosis/testing.

The diagnosis of HED2 is established in a proband with suggestive findings and a heterozygous pathogenic variant in GJB6 identified by molecular genetic testing. Targeted analysis for the four most common GJB6 pathogenic variants detects pathogenic variants in approximately 100% of affected individuals.

Management.

Treatment of manifestations: Special hair care products to help manage dry and sparse hair; wigs; artificial nails; emollients and keratolytics to relieve palmoplantar hyperkeratosis.

Genetic counseling.

HED2 is inherited in an autosomal dominant manner. Most individuals with HED2 have an affected parent; de novo pathogenic variants have also been reported. Offspring of affected individuals have a 50% chance of inheriting the pathogenic variant and being affected. Once the causative GJB6 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for HED2 are possible.

Suggestive Findings

Hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome) should be considered after infancy in individuals with the following clinical features:

• Nail dystrophy (malformed, thickened, small nails); 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, or 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); a common but not universal finding

Establishing the Diagnosis

The molecular diagnosis of HED2 is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in GJB6 identified by molecular genetic testing (see Table 1).

Note: Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous GJB6 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with ectodermal dysplasia are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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.

To date, more than 150 individuals with HED2 have been identified [Lamartine et al 2000a, Lamartine et al 2000b, Smith et al 2002, van Steensel et al 2003, Zhang et al 2003, Baris et al 2008, Chen et al 2010, Marakhonov et al 2012, Fujimoto et al 2013, Mousumi et al 2013, Sugiura et al 2013, Hu et al 2015, Agarwal et al 2016, Odell et al 2016, Pietrzak et al 2016, Yang et al 2016, Cammarata-Scalisi et al 2019, Khatter et al 2019, Shi et al 2019, Sukakul et al 2019, Zhan et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

Hair. In infancy, the scalp hair is fine, wiry, brittle, patchy, and pale. Progressive hair loss may lead to total alopecia, usually by puberty, although alopecia totalis in infancy has also been reported. Eyebrows, eyelashes, and pubic and axillary hair are also typically sparse or absent.

Nails. In early childhood, the nails may be milky white. They gradually become dystrophic, thick, short, and distally separated from the nail bed. There may be vertical ridging (onychorrhexis), triangular nail plates, or absent nails. Nail growth is slow.

Skin. Palmoplantar keratoderma, which is absent in some pedigrees, increases in severity with age; when present, onset is from early childhood to adolescence. Changes are usually diffuse with or without a cobblestone appearance; in some individuals the keratoderma is more focal. There may be associated skin thickening and hyperpigmentation on the knuckles, knees, and elbows.

Teeth and ability to sweat are normal, as are physical growth and psychomotor development.

Genotype-Phenotype Correlations

Whereas most GJB6 pathogenic variants cause the clinical presentations typical of HED2 (i.e., with involvement of the hair, nails, and palmoplantar skin), the p.Gly11Arg and p.Ala88Val pathogenic variants can be associated with a clinical picture similar to that of pachyonychia congenita [van Steensel et al 2003] (see Differential Diagnosis).

In some families, HED2 caused by the p.Gly11Arg pathogenic variant involved only hair and nails [Chen et al 2010, Hu et al 2015, Khatter et al 2019].

Penetrance

Penetrance is high [Hayflick et al 1996] – likely 100% [Author, personal observation].

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]. The condition has also been reported in the US, particularly in Vermont, upstate New York, and Louisiana among communities of French-Canadian ancestry as well as among populations of African, Chinese, French, Indian, Thai, Irish, Malaysian, Scottish, Spanish, and Ashkenazi Jewish ancestry [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 and needs in an individual diagnosed with hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Evaluation of Relatives at Risk

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

Pregnancy Management

Tretinoin and minoxidil should be avoided in pregnancy.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with HED2 have an affected parent and a family history of other affected individuals in the same or previous generations.
• A proband with HED2 may have the disorder as the result of a de novo GJB6 pathogenic variant [Smith et al 2002, Baris et al 2008]. The exact proportion of individuals with HED2 resulting from a de novo pathogenic variant is unknown but presumed to be low.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant (i.e., a proband who appears to be the only affected family member).
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with HED2 may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (physical examination and molecular genetic testing for the pathogenic variant identified in the proband) have demonstrated that neither parent has manifestations of the disorder or is heterozygous for the pathogenic variant.

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 and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the GJB6 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the GJB6 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for HED2 because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with HED2 has a 50% chance of inheriting the GJB6 pathogenic variant and being affected.

Other family members The risk to other family members depends on the status of the proband's parents: if a parent has the GJB6 pathogenic variant, the parent's family members are at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the GJB6 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for HED2 are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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.

Mechanism of disease causation. The presence of the mutated protein may lead to a defect in trafficking of other gap junction protein subunits, since their oligomerization is complete upon entry into the Golgi apparatus [Evans et al 1999, van Steensel 2004]. Several pathogenic variants in genes encoding related gap junction proteins result in mistrafficking of the protein [Common et al 2002]. The association of HED2 with four different pathogenic variants in GJB6 supports this idea. In that case, the pathogenic variants of GJB6 should interfere with its incorporation into the gap junction. To date, this hypothesis has not been experimentally validated [van Steensel 2004]. However, evidence was provided that GJB6 could be a transcriptional target gene of p63, elucidating further the process of the development of the skin and the morphogenesis of its appendages [Fujimoto et al 2013].

Cancer and Benign Tumors

Certain GJB6 variants associated with HED2 have been identified in eccrine syringofibroadenomas, a rare benign neoplasm derived from acrosyringium cells of the eccrine sudoriferous glands [Andrade et al 2014]. Syringofibrocarcinoma has been reported in an individual with Clouston syndrome and represents malignant transformation of eccrine syringofibroadenomas. This tumor arose on the foot and was managed surgically. Screening skin examinations should therefore be considered for individuals with Clouston syndrome [Odell et al 2016].

Author History

Danielle Greenblatt, MB ChB, FRCP (2020-present)

Vazken M Der Kaloustian, MD; McGill University (2005-2020)

Jemima Mellerio, BSc, MB BS, MD, FRCP (2020-present)

Revision History

• 15 October 2020 (sw) Comprehensive update posted live
• 22 January 2015 (me) Comprehensive update posted live
• 3 February 2011 (me) Comprehensive update posted live
• 7 August 2007 (me) Comprehensive update posted live
• 25 April 2005 (me) Review posted live
• 23 November 2004 (vdk) Original submission

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