ESPE Abstracts (2019) 92 P1-270

Large Spectrum of DSD Phenotype Caused by Pathogenic Variants in Wilms Tumor Suppressor Gene 1

Maria Tereza Martins Ferrari1,2, Sorahia Domenice3,2, Berenice Bilharino Mendonça3,2, Daniela Rodrigues Moraes1, Rafael Loch Batista1,2, Nathalia Lisboa Gomes1, Mirian Yumie Nishi2, Maria Helena Sircili1, Tatiana Evelin Paula 2, Eduardo Costa 4, Elaine Maria Frade Costa1,2


1Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo de Medicina d, São Paulo, Brazil. 2Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, São Paulo, Brazil. 3Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 4Hospital de Clínicas de Porto Alegre, - Unidade de Desordens do Desenvolvimento Sexual Brazil, UFRGS, Porto Alegre, Brazil


Introduction: The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline mutations in WT1 have been classically associated with Denys–Drash (DDS) and Frasier syndrome (FS). Exonic missense mutations in the zinc-finger region are the cause of DDS and mutations affecting the canonic donor KTS splice site of intron 9 are the cause of FS. New phenotypes, as 46,XX testicular DSD, associated with WT1 variants have been disclosed with the development of massive parallel sequencing.

Objective: Retrospective analysis of phenotype and genotype correlation of 7 patients with pathogenic WT1 variants.

Subjects and Methods: Description of 7 patients with heterozygous pathogenic variants in WT1. The sequencing was performed by Sanger and by massively parallel sequencing targeted DSD-associated gene panel using Illumina platform.

Results: Six patients, five with 46,XY karyotype and one with 46,XX karyotype, were initially evaluated by atypical genitalia with range chronological age (CA) of 3 to 16 months; and one 46,XY patient with normal female genitalia and primary amenorrhea at age of 16 yrs. Three 46,XY patients underwent bilateral gonadectomy and germ cell tumors (in situ gonadoblastoma and unilateral dysgerminoma) were identified in two patients with partial gonadal dysgenesis (PGD) and complete gonadal dysgenesis (CGD) respectively. In both, intronic variants affecting splicing of WT1 exon 9 were identified, the IVS 9+4C>T and the IVS 9+5G> A variants, respectively. Two pathogenic missense WT1 variants: the c.1419 T>A (pHis473Gln) and the c.742 A>T (p.K248X) were identified in two patients with 46,XY PGD, in whom Willms tumors were diagnosed precociously, at four and six months of life. The novel c.1453_1456del variant in WT1 was identified in a 46,XX testicular DSD patient. Nephrotic proteinuria was diagnosed in five of six 46,XY patients, 3 of them underwent renal transplantation at 7, 8 and 24 years of age.

Conclusion: Pathogenic allelic variants in WT1 are associated with a broad spectrum of urogenital abnormalities. In patients with 46, XY gonadal dysgenesis and variants in WT1 it is mandatory to actively investigate the presence of glomerulopathy. In addition, variants in WT1 could be the cause of 46,XX testicular.