EP1326 - ECE_2593 - Phenotypic and genetic heterogeneity of 46,XY gonadal dysgenesis: a pediatric case series

Abstract

The 46,XY differences of sex development (DSD) represent a rare group of conditions arising from discordance between chromosomal and phenotypic sex. In cases of complete 46,XY gonadal dysgenesis (GD), the absence of testicular differentiation results in hypergonadotropic hypogonadism and preserved Müllerian structures. These patients face a substantial risk of developing gonadal malignancies, necessitating early identification and management. We describe the clinical, biochemical, and molecular profiles of four pediatric patients with 46,XY DSD of distinct etiologies, aiming to highlight the diagnostic challenges and the necessity of multifaceted long-term management strategies. Four patients with complete 46,XY GD were included. Molecular analysis identified pathogenic variants in three cases: one WT1 splice-site variant (c.1432+4C>T) and two SRY variants (p.Arg30Ile and p.Glu89Argfs*15). The fourth patient was diagnosed based on clinical and biochemical criteria without an identified genetic variant. Gonadal malignancy was confirmed in 75% of cases (n = 3), including bilateral gonadoblastoma and mixed germ cell tumor. All patients underwent bilateral gonadectomy and subsequent pubertal induction (ages 12-16). At the latest follow-up (ages 16-21), full pubertal development and menarche were achieved in 100% of cases, with bone mineral density maintained within age-matched norms (Z-score: −0.3 to −1.7). Late diagnosis in the SRY group was associated with final heights significantly exceeding target height (up to +1.89 SD). This case series underscores the marked phenotypic and genetic heterogeneity of 46,XY gonadal dysgenesis and the high prevalence of early-onset malignancy (75%). Precise molecular diagnosis is important for timely tumor risk stratification, guiding the timing of prophylactic gonadectomy and optimizing pubertal induction to prevent excessive final height. A proactive, multidisciplinary approach is essential to safeguard bone health and ensure long-term psychosocial well-being in these complex DSD patients.Table 1Clinical, genetic, and endocrine characteristics of four patients with 46,XY differences of sex development (DSD).FeaturesCase 1Case 2Case 3Case 4Age at diagnosis/ presentation11 y (SRNS since 4 y)Neonatal period (Turner work-up)6 y (precocious pubertal signs)16 y (post-tumor resection)Genetic findingWT1 (NM_000378.6): c.1432+4C>T (splice-site)None identifiedSRY(NM_003140.3)c.89G>T, p.Arg30Ile (exon 1)SRY (NM_003140.3)c.264dup, p.Glu89Argfs*15Main diagnosisWT1 (heterozygous splice-site variant, not Frasier-associated)Frasier syndrome (46,XY DSD + CKD)Complete 46,XY gonadal dysgenesis (Swyer)Complete 46,XY gonadal dysgenesis (Swyer)Age at gonadectomy13 y (bilateral)1 y (bilateral)6 y (bilateral)16-17 y (right tumor, left streak gonad)