Expanding the clinical and mutational spectrum of biallelic <i>POC1A</i> variants: characterization of four patients and a comprehensive review of POC1A-related phenotypes

Abstract

SOFT syndrome (SOFTS) is an autosomal recessive disorder caused by biallelic POC1A variants, characterized by short stature, distinctive facial features, onychodysplasia, and hypotrichosis. To date, 21 pathogenic POC1A variants have been reported in 26 families. This study aims to broaden the phenotypic and genotypic spectrum of SOFTS with emphasis on the long-term effects of growth hormone (GH) therapy. We report four unrelated patients with three homozygous POC1A variants and demonstrate the transcriptional effects of two canonical splicing variants. All four patients had severe growth retardation, sparse hair/eyebrows, high/prominent forehead, long/triangular face, prominent nose, short middle/distal phalanges, puffy/tapering fingers, and prominent heels. Endocrine abnormalities included insulin resistance and impaired glucose tolerance, dyslipidemia, GH deficiency, central hypothyroidism, and precocious puberty. Two patients treated long-term with recombinant human GH showed insufficient responses. We also provide an extensive review of 43 cases including those we report, contributing to a better understanding of the full clinical and endocrinological spectrum of SOFTS.