8577 Gonadal function throughout life in XX and XY patients with a germline WT1 variant - lessons from a cohort of 80 patients
Authors: Carré Lecoindre M , Mallet D , Dossier C , Glenisson M , Grapin M , Brac de la Perriere A , Chakhtoura Z , Bouvattier C , Houang M , Pienkowski C , Zaegel N , Rayneau R , Blanc T , Martinerie L 
Published: October 2024

Disclosure: M. Carré Lecoindre: None. D. Mallet: None. C. Dossier: None. M. Glenisson: None. M. Grapin: None. A. Brac de la Perriere: None. Z. Chakhtoura: None. C. Bouvattier: None. M. Houang: None. C. Pienkowski: None. N. Zaegel: None. R. Rayneau,MD and PhD: None. T. Blanc: None. L. Martinerie: None.

The WT1 gene is involved in tissue homeostasis, tumorigenesis, as well as embryonic development of kidneys, bipotential gonads and ovarian determinism. Germline WT1 variants are known to generate kidney and gonadal developmental diseases associated with differences in genital development (DSD). However, the state of gonadal function, its evolution over time, and the impact of WT1 variants on pubertal development and fertility potential in patients have never been studied. A French national, retrospective, multi-center, observational study evaluated gonadal function over time in patients with a germline variant of the WT1 gene, according to XX or XY karyotype and genotype. Among the 80 patients included - the largest cohort to date - 30% had a XX karyotype, 95% of whom were assigned female at birth. Importantly, 40% of them had uterine malformation, which was not known to be associated with WT1 anomalies. Patients with a XY karyotype presented with DSD (59%), typical female genitalia (15%) or typical male genitalia with or without bilateral cryptorchidism (27%). Thirty percent of XX and 87% of XY patients had gonadal dysgenesis defined as gonads with a dysplastic and/or dysmorphic appearance on histology, surgery and/or imaging or biological hormonal markers compatible with gonadal insufficiency. However only 3 patients (4%) developed gonadal tumors to date. Spontaneous puberty was observed in 94% of XX and 60% of XY patients. However, 67% had impaired gonadal function - defined as AMH and/or inhibin B below the threshold for age and/or elevated FSH and/or LH above 10 UI/L - at the age of 12.6 years and 83% at the age of 16.2 years, considering all karyotypes and genotypes. Hormonal treatment had to be initiated in 57% of XY patients with a median age at 14.4 years old. No difference was seen between patients with or without renal failure (p-value = 0,37), nor regarding the timing of renal insufficiency. In addition, increased FSH, LH and decreased AMH or inhibin B plasma levels were observed independently from gonadotoxic treatment exposure in most patients. None of the patient has had children to date.In conclusion, most XX and XY patients with a germline variant of WT1 gene are affected by early gonadal insufficiency of variable severity with potential impact on puberty and fertility. Even though dialysis, immunosuppressors, gonadotoxic chemotherapies, local radiotherapy and gonadal surgery are known to impair gonadal function, the gonadal disease linked to WT1 variants is the principal factor of gonadal impairment. For these reasons, regular follow-up by an endocrinologist appears essential for both XY and XX patients, providing clear information about gonadal function and fertility.

Presentation: 6/1/2024