Endocrine Abstracts

Background: 48,XXYY is a sex chromosome tetrasomy with an array of associated findings including cardiac malformations, ventriculomegaly, asthma, tooth and nail differences, radioulnar synostosis, pes planus, endocrinopathies (i.e., hypergonadotropic hypogonadism), cryptorchidism, facial dysmorphisms (i.e., hypertelorism), developmental delays, behavioral concerns, and difficulties with reading and language processing. While sharing commonalities with 47,XXY, Klinefelter Syndrome (KS), 48,XXYY remains a unique condition deserving of dedicated study. As with KS, tall stature and hypergonadotropic hypogonadism are common features in adults with 48,XXYY, though are not generally present in childhood. Instead, childhood presentations of 48,XXYY consist of a heterogenous constellation of symptoms warranting a higher index of suspicion for an underlying genetic condition. Earlier identification through improved access to genetic testing has provided an opportunity to better characterize childhood presentations of 48,XXYY and to open a discussion about indications for genetic testing and development of evidence-based guidelines for patients.

Methods: In our case series of six pediatric patients with 48,XXYY presenting to a pediatric interdisciplinary Differences of Sex Development (DSD) clinic, we describe the unifying and differentiating aspects of their presentations. Information was gathered through retrospective chart review.

Results: There were 6 male patients between the ages of 9 months and 15 years seen in DSD clinic at the University of Utah from 2024-2026. This case series echoes trends observed in other studies, notably the heterogeneity in musculoskeletal and other organ system involvement and the near ubiquity of developmental and behavioral differences. While hypergonadotropic hypogonadism and tall stature are considered hallmark features in 47,XXY, our case series featured 2 patients with spontaneous pubertal development and progression and 1 patient with short stature.

Conclusion: Given the neurodevelopmental manifestations of 48,XXYY, genetic testing in children with relevant developmental concerns could lead to earlier identification, more supportive services, and subspecialty care/surveillance during childhood and adolescence. Furthermore, increased and earlier identification of patients with 48,XXYY will necessitate dedicated guidelines on preventative care and surveillance for this population, comparable to those developed for other sex chromosome aneuploidies such as 47,XXY.