Novel clinical features associated with Clouston syndrome

Novel clinical features associated with Clouston syndrome Clouston syndrome (OMIM #129500), also known as hidrotic ectodermal dysplasia type 2, is a rare autosomal dominant ectodermal dysplasia. It is characterized by a triad of major features that include partial to complete hair loss, severe nail dystrophy, and palmoplantar hyperkeratosis with varying degrees of severity. In affected individuals, the hair is pale, fine, sparse, and grows very slowly, and total alopecia may occur. The eyebrows and eyelashes are absent or sparse and short. Nail abnormalities are characterized by thickened, ridged, hyperconvex nails, and paronychia is frequently reported. The teeth, sweat, and sebaceous glands are normal. Additional clinical features include sensorineural deafness, hyperpigmentation of the skin over large joints, and eccrine syringofibroadenoma (Table 1). Heterozygous mutations in the gap junction beta 6 gene, (GJB6, OMIM #604418), which encodes the gap junction protein connexin 30 (Cx30), result in Clouston syndrome. Four heterozygous missense mutations (G11R, V37E, D50N, and A88V) account for the majority of Clouston syndrome cases. Herein, we describe a Venezuelan child who presented with a mild phenotype resulting from an A88V mutation, in GJB6, who demonstrates novel clinical features associated with Clouston syndrome expanding the phenotypic spectrum. The patient was a 4-year-old Venezuelan boy, born from nonconsanguineous healthy parents (III:2), and the only affected individual in the family (Fig. 1a). Dermatologic examination at his first evaluation detected hair loss in the temporo-occipital area (Fig. 1b) with sparse, pale, brittle hair on the scalp, abnormalities of the eyebrows and eyelashes (Fig. 1c), and slight hypertrichosis on the posterior thorax (Fig. 1d). His fingernails and toenails were dystrophic, short, whitened, and thickened with distal wedge-shaped separation, associated with mild paronychia (Fig. 1e,f). He had palmar hyperhidrosis without palmoplantar keratoderma (Fig. 1g). There was hyperpigmentation in the periorbital region (Fig. 1c) and over the elbows and knees. Sweating and teeth were normal. Ophthalmic examination at 9 years of age detected myopia and astigmatism. Audiologic testing revealed mild sensorineural hearing loss. Targeted next generation sequencing detected a heterozygous mutation c.263C>T (rs28937872) in the GJB6 gene (NM_001110221.2) resulting in A88V (NP_001103691.1) nonsynonymous mutation (Fig. 2a). The mutation was confirmed by Sanger sequencing in the proband, and sequencing of both parents and the brother confirmed absence of this sequence variant, and hence this mutation arose de novo (Fig. 2b). A number of bioinformatics modeling tools were employed to determine the pathogeneicity of the A88V mutation and to predict the possible impact on the structure or function of Cx30 protein. Polyphen2 9 predicted the mutation as damaging (with a score of 0.984), and MutationTaster classified this variant as a disease-causing mutation. The conservation of the wild-type nucleotide was assessed using PhastCons and PhyloP, and