Clouston syndrome or hidrotic ectodermal dysplasia is a rare genetic condition first described by Nicolle and Hallipre in 1895. It has been recognized in many western countries but rare in Asia with limited mutation-proved publications available. Rajagopalan and Tay have reported phenotypical characteristics of a Malaysian-Chinese family with Clouston syndrome in the year 1977. We are reporting the new generation of Clouston syndrome from the same ancestry reported four decades ago confirmed by gene analysis after six generations.
A 10-year-old boy presented with a history of alopecia since early infancy. He was born with sparse hair, eyebrows, and lashes. The hair subsequently dropped and the regrowth was minimal with fine hair shafts. There were no apparent hair pigmentary abnormalities [Figures 1 and 2]. He has had nail changes since early infancy that gradually became yellowish discolored. His fingernails demonstrate distal onycholysis while his toenails were thickened and wedge shaped [Figure 3]. He had focal keratoderma on bilateral palmoplantar surfaces since the age of 2-year-old, and the surface area of involvement progresses with time [Figure 4]. Cutaneous sensation and sweating were intact, and there were no dental or skeletal defects. Substantial abnormal findings were limited mainly to the skin, hair, nails, palms, and soles.
Proband’s female siblings aged 13 and 6 years old, mother, and maternal grandfather were examined. They had a similar presentation of childhood-onset alopecia, palmoplantar keratoderma, and variable degree of onychodystrophy. Their physical growth, sexual development, and intelligence were age appropriate. There was an absence of abnormal sweating and thermoregulation. They have normal dentition with no decay. Other systemic examinations were unremarkable, including the visual and hearing assessments.
Detailed family history revealed that some family members on the maternal side were affected and it was observed that affected showed autosomal dominant pattern. They presented with varying degrees of dystrophic nails since birth, early infancy onset of alopecia with or without hypotrichosis, and progressive palmoplantar keratoderma [Figure 5]. The three siblings were referred for genetic testing, and mutation screening for gap junction beta 6 (GJB6) gene (Gene ID: 10804/MIM: 604418) was carried out. A heterozygous nonsynonymous mutation c.263C>T that replaced amino acid alanine at position 88 with valine (p. 88A>V) was detected in all the three siblings [Figure 6]. The p.88A>V gene mutation (Chr13: g20223218C>T) has previously been reported as a pathogenic variant in hidrotic ectodermal dysplasia. DNA sequencing of the same gene for DNA samples from three healthy controls showed native nucleotide C at the position c. 263 or Chr13: g20223218.
The main cause of Clouston syndrome is the mutations in the GJB6 gene encoding connexin30 protein. To date, five mutations of GJB6 have been found in patients with Clouston syndrome, namely the G11R, V37E, D50N, A88V, and N14S genes, besides mutations in GJA1 (V41L) and GJB2 (R127H).
In conclusion, we illustrate the first case report of mutation-proved Clouston syndrome affecting three siblings from a large Chinese-Malaysian family which was found to carry the c.263C>T (A88V) mutations in their GJB6 gene mutations across six generations. No treatment is currently available, but genetic counseling plays a key role in help preventing furture generations being affected.
Declaration of consent
The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s)/guardian(s) of the patient. In the form, the parent(s)/guardian(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child/children will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This study was financially supported by Women and Children Hospital, Kuala Lumpur, Malaysia.
Conflicts of interest
There are no conflicts of interest.
The authors would like to thank the Pediatric Dermatology Unit, Pediatric Department, Women and Children Hospital, Kuala Lumpur, Malaysia, Department of Research, National Skin Center, Singapore, and Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore.
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