Early Pubertal Progression and Increased 11-Oxygenated Androgens in a Girl with Wiedemann-Steiner Syndrome and a KMT2A Variant: A Case Report

Introduction: The factors that determine the tempo of pubertal progression are not fully understood. Although a few patients with KMT2A variants were noted to have precocious puberty, in addition to various clinical features of Wiedemann-Steiner syndrome (WSS), the hormonal data of these individuals were unreported. Recently, high blood levels of 11-ketotestosterone, a potent 11-oxygenated androgen, were observed in a girl with WSS. Case Report/Case Presentation: We encountered a Japanese girl who experienced menarche at 9 years and 4 months of age. She showed pubertal levels of LH and estradiol and advanced bone age and was treated with a gonadotropin-releasing hormone analog. She exhibited hirsutism, craniofacial features, and mild intellectual disability but no other clinical features of WSS. Exome sequencing identified a hitherto unreported de novo variant at a splice acceptor site of KMT2A exon 5 (c.3335-1G>A). Her blood levels of 11-oxygenated androgens, androstenedione, and dehydroepiandrosterone were markedly elevated, while those of estrogen and testosterone were within normal ranges. Discussion: The present case implies possible roles of KMT2A in the hypothalamic-pituitary-gonadal axis or in adrenal steroidogenesis. The results of this study, together with previous findings, imply that overproduction of 11-oxygenated androgens contributes to advanced bone age and hypertrichosis in patients with WSS. Our data merit further validation.