Alopecia and Hypotrichosis as Characteristic Findings in Woodhouse‐Sakati Syndrome: Report of a Family with Mutation in the C2orf37 Gene

Abstract

Woodhouse-Sakati syndrome (WSS) is a rare autosomal recessive disorder characterized by alopecia, hypogonadism, diabetes mellitus, intellectual disability, sensorineural deafness, extrapyramidal signs, and low insulinlike growth factor 1 levels. Inter- and intrafamilial phenotypic variability have been reported. Mutations in the C2orf37 gene cause WSS. The present report describes the clinical signs and symptoms of three affected siblings from a consanguineous Bedouin family from Kuwait. Direct sequencing of the C2orf37 gene revealed that the c.436delC (p.Ala147Hisfs*9) mutation was present in a homozygous state in all affected siblings and in a heterozygous state in the parents and a healthy sister. Nine C2orf37 mutations causing WSS have been identified. This family shared the mutation reported earlier in Saudi families and families of Bedouin tribes from Qatar and Israel. No phenotypic or genotypic correlation has been observed. Despite the great phenotypic variability of WSS, hypotrichosis has been observed in all individuals with WSS reported. This condition has not been reported in the dermatologic literature. WSS should be included in the differential diagnosis of syndromic congenital hypotrichosis.

Woodhouse–Sakati syndrome in a family is associated with a homozygous start loss mutation in the DCAF 17 gene

“…However, the next closest in frame ATG is at codon 88, thus even if this ATG served as an initiation codon, start of translation at this site would cause the deletion of 87 residues from the N‐terminus of the mature DCAF17 polypeptide and probably such a protein would be functionless. Previously, 12 mutations in the DCAF17 were reported in various ethnic groups, including Arabic, Indian, Pakistani, Turkish, Italian and French . These include three nonsense (p.S114*, p.W129*, p.W302*), five deletion [(p.A17Gfs*43, p.K90Nfs*8, p.A147Hfs*9, p.N413Tfs*21, 59–7_499del (p.?)]…”

In silicoanalysis of coding SNPs and 3′-UTR associated miRNAs inDCAF17gene that may affect the regulation and pathogenesis of Woodhouse-Sakati Syndrome

“…(16)(17)(18) The disease was first described in 2008 by al Alazami et al, (4,11) Mutations in the DCAF17 gene are the cause of Woodhouse-Sakati syndrome. (3,19,20) It is located on chromosome 2q31.1. (4,21) it encodes a nucleolar protein with poorly understood function, adding to that the pathogenic mechanism underlying WSS is also un known.…”

The Use of High-Density SNP Array to Map Homozygosity in Consanguineous Families to Efficiently Identify Candidate Genes: Application to Woodhouse-Sakati Syndrome

“…The WSS phenotype is variable within and among families but is characterized overall by alopecia, hypogonadotropic hypogonadism (HH), sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. The alopecia is often present in early childhood in affected individuals, potentially involving scalp hair, eyebrows, eyelashes, and pubic and axillary hair [ 15 ]. HH becomes apparent when pubertal development is delayed or fails to occur, thus a later sign of WSS [ 16 ].…”

“…Exogenous hormone therapy can promote secondary sex characteristic development, as in our male patient presented here. Streak, hypoplastic, and absent gonads and uterine structures have also been described in WSS [ 5 , 7 , 10 , 11 , 15 , 16 ]. Hearing loss may be mild to profound though not present in all affected individuals.…”

“…WSS is caused by mutations in the gene encoding DCAF17 (DDB1 and CUL4 associated factor 17, C2ORF37), a transmembrane nuclear protein of uncertain function. Nine putative loss of function mutations in DCAF17 have been reported in association with WSS [ 6 , 9 – 13 , 15 ]: three nonsense mutations [c.341C>A (p.S114X), c.387G>A (p.W129X), and c.906G>A (p.W302X)], four intronic mutations that are predicted to result in DCAF17 missplicing (c.127+3delTAGinsAA, c.321+1G>A, c.1091+6T>G, and c.1422+5G>T), and two single nucleotide deletions (c.50delC and c.436delC). With the exception of c.436delC, a founder mutation identified in multiple families from the Arabian Peninsula [ 6 ], each of these is a private mutation found in a single consanguineous family.…”