ECEESPE2025 Rapid Communications Rapid Communications 16: Reproductive and Developmental Endocrinology Part 2 (6 abstracts)
Genotype-phenotype correlation in patients having a WT1 germline variant : lessons from a large French cohort
Morgane Carré Lecoindre 1,2 , Delphine Mallet 3 , Morel Bouvattier Claire 2 , Zeina Chakhtoura 4 , Mathilde Glenisson 5 , Catherine Pienkowski 6 , Muriel Houang 7 , Rachel Reynaud 8 , Nadia Zaegel 9 , Aude Brac De La Perrier 10 , Claire Dossier 11 , Thomas Blanc 12,13 & Martinerie Laetitia 1,12,14
1Hôpital Universitaire Robert-Debré, GHU APHP Nord Université Paris Cité, Endocrinologie Pédiatrique, Centre de Référence Maladies Endocriniennes Rares de la Croissance et du Développement, Paris, France; 2Hôpital Universitaire Kremlin Bicêtre, GHU APHP Université Paris Saclay, Endocrinologie Pédiatrique, Centre de Référence Maladies Endocriniennes Rares du Développement Génital, Le Kremlin Bicêtre, France; 3CHU de Lyon, HCL GH Est, Service Biochimie et Biologie Moléculaire - UM Pathologies endocriniennes, rénales et musculaires, Bron, France; 4Hôpitaux Universitaires Pitié Salpêtrière, GHU APHP Sorbonne Université, Endocrinologie et médecine de la reproduction, Paris, France; 5Hôpital Universitaire Robert-Debré, GHU APHP Nord Université Paris Cité, Chirurgie Pédiatrique, Paris, France; 6Hôpital Universitaire Purpan, Endocrinologie Pédiatrique, Toulouse, France; 7Hôpital Universitaire Trousseau, GHU APHP Sorbonne Université, Endocrinologie Pédiatrique, Paris, France; 8Hôpital Universitaire de la Timone, APHM, Endocrinologie Pédiatrique, Centre de Référence Maladies Hypophysaires Rares (HYPO), Marseille, France; 9CHRU Nancy, Endocrinologie, Nancy, France; 10Hôpital Universitaire cardiologique, CHU de Lyon, HCL GH Est, Endocrinologie, Diabétologie et maladies métaboliques, Bron, France; 11Hôpital Universitaire Robert-Debré, GHU APHP Nord Université Paris Cité, 4Néphrologie Pédiatrique, Centre de référence du Syndrome néphrotique idiopathique, Paris, France; 12Université Paris Cité, Faculté de Santé, UFR de Médecine, Paris, France; 13Hôpital Universitaire Necker Enfants Malades, GHU APHP Centre Université de Paris, Chirurgie Pédiatrique, Paris, France; 14Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin Bicêtre, France
JOINT27
WT1 germline variants are known to generate renal and gonadal conditions, including Differences in sex development (DSD), chronic kidney disease and early kidney and gonadal tumors. GONADVENIR is a French national, retrospective study partly designed to investigate the genotype phenotype correlation in renal and gonado-genital conditions according to genetic groups recently defined by a genetic consortium. Eighty patients were included, at a median age of 14.2±5 years. Among those, 33 (41.3%) had a missense variant of exons 8 or 9 (MS E8-9), 24 (30%) had a variant generating WT1 truncated protein (TP), 14 (17.5%) had a donor splice site variant in intron 9 (DSS I9), and 9 patients had rarer variants. Patients from MS E8-9 group developed mostly (94%) congenital or early steroid-resistant nephrotic syndrome (SRNS), at a median age of 0.7 years (0.3-1.7), significantly earlier than patients from DSS I9 group (P <0.0001) who developed SRNS (64%) around 3.7 years (2.5-10.8). Histologically, biopsies revealed diffuse mesangial sclerosis in 77% of patients from MS E8-9 group, a pathognomonic renal signature. In addition, we found that 88% of TP group developed nephroblastoma at a median age of 1.3 years (0.8-1.6) compared to only 30% in MS E8-9 and 14% in DSS I9 groups. Regarding gonado-genital conditions, 95% of XY patients had DSD, significantly more severe in the MS E8-9 group with External Genitalia Score (EGS) around 4 or 5 and the DSS I9 group with 90% of severe DSD (EGS <7) including 50% of female phenotype, compared to the TP group (P=0.01) where 70% had moderate DSD (EGS >7). Interestingly, we found uterus malformations in 9 patients with XX karyotype (39%), of whom 8 (89%) were from MS E8-9 group. In addition, patients with XX caryotype developed more frequently premature ovarian insufficiency in the MS E8-9 group than in the DSS I9 group (P=0.026). Finally, we found that patients from the MS E8-9 group had more risk over time than in the TP group to develop gonadal function impairment and premature testicular insufficiency with respective Hazard Ratio at 3.3 (P <0.001) and 3.5 (P <0.01). In conclusion, WT1 germline variants generate, rather than syndromes, a spectrum of renal and gonadal damages. Our study is the largest cohort reported to date and contributes to a better knowledge of the genotype-phenotype correlation, which may help practitioners to better understand their patients’ diseases and provide a more individualized follow-up.
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Endocrine Abstracts
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