Diagnosis and recombinant human growth hormone treatment of Wiedemann-Steiner syndrome: discovery of novel KMT2A variants and review of existing literature

PurposeWiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder with broad and variable phenotypes including short stature. This study aims to determine the long-term effect of recombinant human growth hormone (rhGH) treatment on WDSTS and summarize the phenotypes and genotypes of WDSTS.MethodsWe analyzed the clinical and genetic features of five patients with WDSTS, and comprehensively reviewed reported WDSTS diagnostic features.ResultsFour patients had short stature, one exhibited early puberty, and all exhibited distinctive facial features, intellectual disabilities, and hypertrichosis. Two patients had subnormal GH peaks. Three patients treated with rhGH for 1.5-4.9 years showed height gains (1.8, 1.1, and 1.9 standard deviations score [SDS]); patient 5 received rhGH and leuprolide for 1 year, with 0.2 SDS in height gain and controlled bone age. Five KMT2A gene variants were identified, four of which were novel. Our review (54 articles including 260 WDSTS cases) revealed that growth retardation, intellectual delay, distinctive facial features, and hirsutism are frequent findings of the condition. Among the 229 KMT2A gene variants described, frameshift variants were the most common (37.7%).ConclusionOur findings broaden the KMT2A gene variant, clinical, and molecular spectra used to diagnose and treat WDSTS, and highlight the crucial role of genetic testing in WDSTS diagnosis and the effectiveness of rhGH therapy.