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

Abstract

Purpose: Wiedemann-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.

Methods: We analyzed the clinical and genetic features of five patients with WDSTS, and comprehensively reviewed reported WDSTS diagnostic features.

Results: Four 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%).

Conclusion: Our 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.

Keywords: KMT2A; Recombinant human growth hormone; Wiedemann–Steiner syndrome.

Fig. 1

The typical features of patient 1 and 2

Fig. 2

Specific heights at follow-up for patients during rhGH treatment All patients were treated with rhGH at initial time in figure, patient 1 stop treatment because she can not visited hospital during COVID-19 and restart treatment after COVID-19, patient 3 stop rhGH when his bone age > 15 years. Numbers in parentheses indicate age(Y) and height(cm). P1 represents patient 1, P2 represents patient 2, P3 represents patient 3, P5 represents patient 5

Fig. 3

Clinical Phenotypes, Variant Distribution, and Spectrum in 260 patients The X-axis represents the number of participants and the Y-axis represents the clinical features. The colored boxes indicate affected individuals, the dark gray boxes indicateunaffected individuals, and the light gray boxes denote data not available in (A); The localization of the variants in common exons can be seen in (B), whereas (C) shows different variants detected in the gene