Commonly referred to as “Clouston Syndrome” or Connexin 30
Facts
- What does GJB6 stand for? Gap junction beta 6 gene.1
- What does the GJB6 gene do? Encodes the gap junction protein connexin 30.1
- What happens when GJB6 becomes mutated? Hair loss, nail changes, and thickened skin of the palms and soles.1
- Clinical significance of mutation? Cellular hyperproliferation & hyperkeratotic lesions along with other traits in most phenotypes.1
About GJB6-pEDD or Clouston syndrome
Skin disease caused by GJB6 mutations is known as hidrotic ectodermal dysplasia (HED) or Clouston syndrome.1 Clouston syndrome is a rare, genetic disease that is found among families worldwide and occurs in approximately 1 per 500,000 live births.3,4 The disease is passed down from a parent to their offspring in an autosomal dominant inheritance pattern.1 This means that it only takes one copy of the mutated GJB6 gene from one parent to cause Clouston syndrome. The parent who has Clouston syndrome has a 50% chance of passing the mutated GJB6 gene in each pregnancy. A diagnosis of Clouston syndrome is sometimes delayed due to milder symptoms in young patients as well as a wide variety of phenotypes among patients with the disease.1 There have also been several families that have Clouston syndrome, but were previously diagnosed with pachyonychia congenita. For these reasons, genetic testing is emphasized and necessary to determine whether an individual with symptoms of Clouston syndrome is caused by a mutation in the GJB6 gene.2
Symptoms of GJB6
Major features of Clouston syndrome include hair loss, nail abnormalities, and palmoplantar hyperkeratosis. Nail dystrophy and sparse hair are typically noted during early infancy, while palmoplantar keratosis presents in childhood.4 The hair loss among affected individuals ranges from partial to complete hair loss. Additionally, individuals may have sparse, short, or absent eyebrows and eyelashes.1 Individuals with Clouston syndrome that have nail dystrophy typically have nails that are thickened, ridged, and hyperconvex.1 Palmoplantar keratosis is a term used to describe thickening of the skin on the palms of the hands and soles of the feet. The severity of palmoplantar keratosis varies among individuals with Clouston syndrome and tends to increase with age.1,4
IPCRR Data for GJB6
Thirty two individuals fully enrolled in the International Pachyonychia Congenita Research Registry (IPCRR) were found not to have PC but instead carry a mutation in GJB6 gene. Sixteen are in the United States, and five are in the Netherlands. The rest of the families and individuals are located in Poland, Sweden, Australia, Croatia, Brazil, the UK, India, and Canada. Fourteen are females and eighteen are males. Below is select data from the registry.
| Plantar Keratoderma | 56% |
|---|---|
| Always (never goes away) | 47% |
| Sometimes (clears up at times) | 9% |
| Seldom (feet usually clear) | 0% |
| Plantar Keratoderma – Onset | |
|---|---|
| Birth or less than 1 year | 11% |
| 1 to 4 years old | 28% |
| 5 to 14 years old | 44% |
| 15 years and over | 17% |
| Plantar Pain | 50% |
|---|---|
| Often require medications for pain | 9% |
| Very painful, but do not use medications | 13% |
| Somewhat painful | 13% |
| Palmar Keratoderma | 50% |
|---|---|
| Always (never goes away) | 31% |
| Sometimes (clears up at times) | 9% |
| Seldom (hands usually clear) | 9% |
| Toenail Dystrophy | 63% |
|---|---|
| all 10 toenails thickened | 47% |
| 7-9 toenails thickened | 9% |
| 4-6 toenails thickened | 3% |
| 1-3 toenails thickened | 3% |
| Toenails – Onset | |
|---|---|
| Birth or less than 1 year | 70% |
| 1 to 4 years old | 25% |
| 5 to 14 years old | 5% |
| 15 years and over | 0% |
| Fingernail Dystrophy | 63% |
|---|---|
| all 10 fingernails thickened | 56% |
| 7-9 fingernails thickened | 0% |
| 4-6 fingernails thickened | 3% |
| 1-3 fingernails thickened | 3% |
| Fingernails – Onset | |
|---|---|
| Birth or less than 1 year | 70% |
| 1 to 4 years old | 25% |
| 5 to 14 years old | 5% |
| 15 years and over | 0% |
| Oral Leukokeratosis | 13% |
|---|---|
| Cysts | 0% |
| Follicular Hyperkeratosis | 0% |
| Natal or Prenatal Teeth | 0% |
Data from 2022 Sample Size N=32
References
- Cammarata-Scalisi F, Rinelli M, Pisaneschi E, et al. Novel clinical features associated with Clouston syndrome. Int J Dermatol. 2019;58(8):e143-e146. doi:10.1111/ijd.14507
- Hu YH, Lin YC, Hwu WL, Lee YM. Pincer nail deformity as the main manifestation of Clouston syndrome. Br J Dermatol. 2015;173(2):581-583. doi:10.1111/bjd.13703
- Lamartine, J., Munhoz Essenfelder, G., Kibar, Z. et al. Mutations in GJB6 cause hidrotic ectodermal dysplasia. Nat Genet 26, 142–144 (2000). https://doi.org/10.1038/79851
- Leung, A. K., Leong, K. F., & Lam, J. M. (2021). Clouston syndrome. Consultant, 61(1), 29-31.
Above photos are from individuals in the IPCRR with confirmed GJB6 mutations.
