Congenital hypotrichosis 14 is a nonsyndromic form of alopecia associated with pathogenic variants in the lanosterol synthase (LSS) gene. Recent studies have expanded the spectrum of LSS-related phenotypes, including congenital cataracts, alopecia-intellectual disability syndrome, and palmoplantar keratoderma. Currently, investigations into this disease are still limited, and its treatment remains elusive. In this study, we aimed to report six Chinese patients who were diagnosed with hypotrichosis 14, whose conditions were attributed to five novel and recurrent variants in the LSS gene identified via whole exome sequencing. Moreover, the reported LSS gene has also been summarized. We described six patients in five Chinese families with hair loss, and one of whom had a rare accompanying phenotype of hypergonadotropic hypogonadism, which has rarely been reported. Five novel variants were discovered in the LSS gene, including c.919_921del (p.His307del), c.1987 C > T (p.Arg663Trp), c.982 C > T (p.Arg328*), c.1405_1407del (p.Glu469del) and c.193_200dup (p.Pro68Argfs*14). Our comprehensive summary of phenotypes caused by LSS gene variants not only enriches the existing knowledge on congenital hypotrichosis 14 but also provides crucial guidance for more accurate genetic counseling and potentially new directions for future research in understanding the disease mechanism and developing targeted therapies.

Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1 Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified.