ESPE Abstracts (2018) 89 P-P2-349

A 46,XX Female with WT1 Mutation, Congenital Nephrotic Syndrome and a Complex Disorder of Sex Development

Sara Cicconea,b, Carla Bizzarria, Stefano Piccac, Cinzia Orazid, Chiara Lucchettie & Marco Cappaf


aUnit of Endocrinology and Diabetes, ‘Bambino Gesù’ Children’s Hospital, Rome, Italy; bDepartment of Pediatrics, Endocrine Unit, ‘Bufalini’ Hospital, Cesena, Italy; cUnit of Nephrology-Urology, ‘Bambino Gesù’ Children’s Hospital, Rome, Italy; dUnit of Radiology, ‘Bambino Gesù’ Children’s Hospital, Rome, Italy; eUnit of Gynecology, ‘Bambino Gesù’ Children’s Hospital, Rome, Italy; fUnit of Endocrinology and Diiabetes, ‘Bambino Gesù’ Children’s Hospital, Rome, Italy


Background: The Wilms tumor suppressor gene 1 (WT1) is essential for kidney and gonadal development. WT1 gene mutations are associated with two syndromes called Denys-Drash (DDS) and Frasier (FS) that clinically overlap and differ in the type of mutation and in the age at nephropathy onset. In 46,XY subjects WT1 mutations are associated with steroid-resistant nephrotic syndrome (NS), Wilms tumor, disorder of sex development (DSD) with dysgenetic gonads and gonadoblastoma risk. On the contrary, the impact of WT1 gene on the genital development of 46,XX subjects is not clear.

Case report: We report the case of a girl with chronic kidney failure due to steroid-resistant congenital NS. Biopsy at onset evidenced mesangial proliferative glomerulonephritis with focal-segmental glomerular sclerosis. Due to end-stage renal disease, peritoneal dialysis was started in the first months of life. The child received kidney transplantation when she was 3, with acute rejection at the age of 5. Regular hemodialysis was started when she was 12. Chromosomal analysis revealed a normal 46,XX female karyotype. Mutational analysis of WT1 gene identified the heterozygous mutation c.1097>A, producing the amino acid change Arg366His. This mutation had been described in 46,XY patients with Denys-Drash syndrome. At the age of 14, the girl was referred to endocrinological observation for primary amenorrhea despite a complete pubertal development (Tanner stage 5). Weight was 44 kg (25th centile), height 161.4 cm (50–75th centile), BMI 16.9 kg/mq (10–25th centile). Bone age corresponded to chronological age. She showed androgenetic alopecia and voice deepening. Endocrine tests showed pubertal gonadotrophins (FSH 8.8 mU/ml, LH 3.6 mUI/ml), with estradiol 92.8 pg/ml, testosterone 190.2 ng/dl and anti-mullerian hormone 1.3 ng/ml. Basal and post-ACTH adrenal androgens were normal. Pelvic ultrasound showed bilateral dysgenetic gonads in the inguinal canals, uterotubaric agenesis, vaginal atresia and urogenital sinus. Gonadectomy was then performed and histological examination showed hypotrophic ovaries with cystic follicles and interstitial fibrosis.

Discussion: WT1 knockout mice lack gonads in both sexes, suggesting a role of the gene in the formation of the genital ridge, an early stage of development in which the gonad is still undifferentiated. Nowadays, little is known about the role of WT1 in the development of the female reproductive system. Sporadic cases of 46,XX females are reported with a WT1 mutation and minor abnormalities such as streak ovaries or bicornuate uterus. To our knowledge, this is the first report on a 46,XX female presenting heterozygous WT1 mutation, congenital nephrotic syndrome, and a complex DSD associated with gonadal dysgenesis.

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