ESPEYB25 6. DSD and Gender Incongruence DSD Papers: Phenotypic Variation and Pubertal Outcomes In 46,XY Gonadal Dysgenesis (1 abstracts)
6.13. Phenotypic variation and pubertal outcomes in males and females with 46,XY partial gonadal dysgenesis
Tadokoro-Cuccaro R , Hughes IA , Cools M , van de Vijver K , Bilharinho de Mendonça B , Domenice S , Loch Batista R , Thomazini Dallago R , F Costa E , Lisboa Gomes N , T Maciel-Guerra A , Guerra-Junior G , Gabriel Ribeiro de Andrade J , Lucas-Herald A , Bryce J , Hannema S , Juul A , Globa E , McElreavey K , Baronio F , Rey R , Lopez Dacal J , Darendeliler F , Poyrazoglu S , Kolesińska Z , Niedziela M , Claahsen-van der Grinten HL , L T van den Akker E , Herrmann G , Atapattu N , Jain V , 1Sharma R , Bettendorf M , Konrad D , Lenherr-Taube N , Holterhus PM , Fica S , Skae M , Russo G , Stancampiano MR , Gazdagh G , Davies JH , Mohamed Z , Seneviratne SN , Güran T , Güven A , Wasniewska M , Mladenov V , Verkauskas G , Markosyan R , Korbonits M , Hiort O , Frielitz-Wagner IV , Ahmed SF & Thankamony A
J Clin Endocrinol Metab. 2025 Apr 10:dgaf223. doi: 10.1210/clinem/dgaf223
Brief summary: This international, multicenter study analyzed 310 individuals with 46,XY gonadal dysgenesis (GD), subdivided into complete (CGD) and partial forms (PGDf assigned female and PGDm assigned male). CGD patients typically presented with delayed puberty and elevated gonadotropins, while PGD cases were often diagnosed in infancy due to atypical genitalia. PGDm had more masculinized genitalia compared to PGDf. Müllerian structures were common in CGD and less frequent in PGD, reflecting differences in gonadal development. Comorbidities, particularly renal and neurodevelopmental, were prevalent, especially among those with WT1 mutations. Hormonal profiles confirmed impaired gonadal function, with CGD individuals showing the lowest testosterone, AMH, and inhibin B levels.
Genetic analysis identified causative mutations in 42.3% of participants, with SRY and WT1 variants predominant in CGD, while NR5A1 mutations were common in PGD, especially PGDm, and linked to spontaneous puberty. Pubertal outcomes varied: 80% of PGDm entered puberty naturally, with 59% reaching Tanner stage G5 without hormone therapy. In contrast, most with CGD required estrogen therapy. PGDf cases often showed both breast development and virilization.
Surgical interventions were frequent: PGDf typically underwent clitoral reduction and vaginoplasty; PGDm had orchidopexy and hypospadias repair. Gonadectomy was common, especially in CGD where tumor risk, highest with intra-abdominal gonads, was a major concern. Histology confirmed streak or dysgenetic gonads in many.
Sex reassignment occurred in 16.1% of PGDf and 5.3% of PGDm, mostly from female to male, with timing varying by region and cultural factors. The wide phenotypic spectrum of PGD, from female to near-male, complicates classification and management.
Despite advances in genetic testing, many cases remain unexplained. Individualized care, informed by phenotype, gonadal function, and local context, remains essential. This study highlights the need for multidisciplinary teams, careful tumor risk assessment, and long-term follow-up in managing 46,XY gonadal dysgenesis.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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