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Gonadal function in patients with germline variants of WT1: results from the French GONADVENIR’s retrospective study.
Morgane Carré Lecoindre 1 , Delphine Mallet 2 , Mathilde Glenisson 3 , Claire Dossier 4 , Aude Brac de la Perrière 5 , Zeina Chakhtoura 6 , Claire Bouvattier 7 , Catherine Pienkowski 8 , Nadia Zaegel 9 , Muriel Houang 10 , Rachel Rayneau 11,12 , Thomas Blanc 13,14 & Laëtitia Martinerie 15,14,16
1Endocrinologie Pédiatrique, Centre de Référence Maladies Endocriniennes Rares de la Croissance et du Développement, Hôpital Universitaire Robert-Debré, GHU APHP Nord Université, Paris, France. 2Service Biochimie et Biologie Moléculaire - UM Pathologies endocriniennes, rénales et musculaires CHU de Lyon, HCL GH Est, Bron, France. 3Chirurgie Pédiatrique, Hôpital Universitaire Robert-Debré, GHU APHP Nord Université Paris Cité, Paris, France. 4Néphrologie Pédiatrique, Centre de référence du Syndrome néphrotique idiopathique, Hôpital Universitaire Robert-Debré, GHU APHP Nord Université Paris Cité, Paris, France. 5Endocrinologie, Diabétologie et maladies métaboliques, Hôpital Universitaire cardiologique, CHU de Lyon, HCL GH Est, Bron, France. 6Endocrinologie et médecine de la Reproduction, Hôpitaux Universitaires Pitié Salpêtrière, GHU APHP Sorbonne Université, Paris, France. 7Endocrinologie Pédiatrique, Centre de Référence Maladies Endocriniennes Rares du Développement. Génital, Hôpital Universitaire Kremlin Bicêtre, GHU APHP Université Paris Saclay, Le Kremlin Bicêtre, France. 8Endocrinologie Pédiatrique, Hôpital Universitaire Purpan, Toulouse, France. 9Endocrinologie, CHRU Nancy, Nancy, France. 10Endocrinologie Pédiatrique, Hôpital Trousseau, GHU APHP Sorbonne Université, Paris, France. 11Endocrinologie Pédiatrique, Centre de Référence Maladies Hypophysaires Rares (HYPO), Hôpital Universitaire de la Timone, APHM, Marseille, France. 12Faculté de Médecine Aix Marseille Université, Marseille, France. 13Chirurgie Pédiatrique, Hôpital Universitaire Necker Enfants Malades, GHU APHP Centre Université de Paris, Paris, France. 14Université Paris Cité, Faculté de Santé, UFR de Médecine, Paris, France. 15Endocrinologie Pédiatrique, Centre de Référence Maladies Endocriniennes Rares de la Croissance et du Développement, Hôpital Universitaire Robert-Debré, GHU APHP Nord Université Paris Cité, Paris, France. 16Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin Bicêtre, France
Introduction: Germline variants of WT1 are known to generate kidney and gonadal diseases, including differences in sex development (DSD), chronic kidney disease and early kidney and gonadal tumors. However, the state of gonadal function, its evolution over time, and the impact of WT1 disease on puberty and fertility in this population have never been studied.
Methods: GONADVENIR is a French national, retrospective, observational study designed to investigate gonadal function over time, according to karyotype and genotype, in a wide cohort of patients with a germline variant of WT1.
Results: Eighty patients were included, at a median age of 14.2 +/- 5 years. 30% had a XX karyotype, 95% of whom were assigned female at birth and 40% presented with uterine malformations. 70% had a XY karyotype, 95% of whom had DSD, including 14% who were assigned female at birth. 30% of XX and 87% of XY patients had gonadal dysgenesis (attested by dystrophic aspect observed during surgery or imaging, a dysplastic aspect on pathology, and/or biological gonadal failure) and 3 developed gonadal tumors. 94% of XX and 60% of XY patients had spontaneous onset of puberty, however 57% of all XY patients were treated with hormonal replacement therapy (HRT) at the end of study. In summary, 90% of the patients from our cohort had features of gonadal disease by the age of 15 years old. Increased FSH, LH and decreased AMH and Inhibin B were observed, before or at the onset of pubertal time in the majority of patients and was not different between patients transplanted and/or exposed to gonadotoxic treatment. Impaired gonadal function was detected earlier in XY than in XX patients (P = 0,015), and more frequently in XY patients with severe DSD (External Genitalia Score (EGS) < 7) and in XY (P = 0,001) patients with a missense variant of exons 8 or 9 (MS E8-9) compared with patients with a truncating variant (TP) (P = 0,037). These latter patients develop a more moderate gonadal disease that is inversely correlated with the development of nephroblastoma.
Conclusion: In conclusion, patients with a germline variant of WT1 are mostly affected by early gonadal insufficiency of variable severity depending on karyotype and genotype. Regular follow-up by an endocrinologist, from the average physiological age of puberty onset is essential for both XY and XX patients, as well as providing clear information about gonadal function and fertility, and evocating fertility preservation and risk of transmission.
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