Hypotrichosis‐lymphedema‐telangiectasia‐renal defect associated with a truncating mutation in the SOX18 gene

Abstract

SOX18 mutations in humans are associated with both recessive and dominant hypotrichosis-lymphedema-telangiectasia syndrome (HLTS). We report two families with affected children carrying a SOX18 mutation: a living patient and his stillborn brother from Canada and a Belgian patient. The two living patients were diagnosed with HLTS and DNA analysis for the SOX18 gene showed that both had the identical heterozygous C > A transversion, resulting in a pre-mature truncation of the protein, lacking the transactivation domain. Both living patients developed renal failure with severe hypertension in childhood for which both underwent renal transplantation. To our best knowledge this is the first report of renal failure associated with heterozygous mutations in the SOX18 gene. We conclude that this specific mutation results in a new, autosomal dominant condition and propose the acronym HLT-renal defect syndrome for HLTRS.

A novel autosomal dominant mutation in SOX18 resulting in a fatal case of hypotrichosis–lymphedema–telangiectasia syndrome

“…This variant is predicted to result in a protein truncated in size by 47%. Other pathogenic nonsense variants have been identified distal to the variant identified in this individual (Irrthum et al, ; Moalem et al, ; Valenzuela et al, ).…”

“…Although hypotrichosis is usually present at birth, Irrthum et al () reported an individual who did not develop hair loss until 6 months of age. Others with HLTS have developed alopecia universalis (Moalem et al, ). It is known that SOX18 is expressed in the hair follicles of humans and mice, and ragged mice had a notable privation of fur (Downes et al, ; Irrthum et al, ).…”

“…There is only one reported individual with HLTS who did not have lymphedema (Wünnemann et al, ), though several did not develop lymphedema until adolescence (Irrthum et al, ). Two showed signs of facial edema only (Moalem et al, ; Valenzuela et al, ). The chylothorax in this patient was more severe and recurrent than in previous reports.…”

“…Cardinal features include a generalized lack of body hair, lymphedema of the extremities, and scattered cutaneous telangiectasias. Less commonly observed vascular defects include enlargement of the ascending aorta (Wünnemann et al, ) and renal failure from chronic microangiopathy of the glomerular and extraglomerular vasculature (Moalem et al, ). In males, bilateral hydroceles are common.…”

“…A malfunctioning SOX18 transcription factor has been linked to various degrees of impaired maturation of these systems (Downes, Francois, Ferguson, Parton, & Koopman, ) and is responsible for the condition HLTS. Recessive (Irrthum et al, ) and dominant inheritance have been described, including two unrelated individuals with an identical de novo variant (Irrthum et al, ; Moalem et al, ).…”