Clinical Characteristics of KMT2A Gene-Related Wiedemann-Steiner Syndrome and Progress in Recombinant Human Growth Hormone Therapy for Short-Stature Children

Objective: Wiedemann-Steiner syndrome (WSS) due to KMT2A variant is a rare autosomal dominant genetic heterogeneity disorder associated with short stature, the exact genetic mechanism of which is still unknown. This study aims to define the clinical, therapeutic and molecular findings of three new WSS patients from unrelated families, and to summarize the clinical characteristics and response to recombinant human growth hormone (rhGH) therapy. Design, Patients and Measurements: Three male patients with short stature were included, and whole-exome sequencing (WES) was performed. All reported patients with WSS worldwide caused by KMT2A variants were reviewed. Results: The average age of the three patients was 8.3 +/- 8.9 years, with an average height Z-score of -3.9 +/- 1.8. Three KMT2A variants were detected with the aid of WES. A total of 333 cases of WSS have been reported, with 269 types of KMT2A gene variants described. WSS was characterized by intellectual disorder (92.9%, 250/269), developmental delay (87.9%, 175/199), generalized hypertrichosis (76.7%, 66/86) and short stature (70.9%, 61/86). The height Z-score of 14 patients received rhGH treatment significantly increased from -3.3 +/- 1.2 to -1.8 +/- 1.0 (p < 0.001) after an average treatment duration of 25.7 +/- 23.1 months, and was positively correlated with the duration of treatment (r = 0.899, p < 0.0001). There was no significant difference in the height Z-score change between seven growth hormone deficiency (GHD) patients and five non-GHD patients after rhGH treatment. Conclusions: This study provided a comprehensive analysis between phenotypes and genotypes of KMT2A variants and WSS. Our findings indicated that patients with WSS may experience favourable outcomes with rhGH therapy.