IMPE2023 Poster Presentations Sex Differentiation, Gonads and Gynaecology, and Sex Endocrinology (19 abstracts)
The first familial case of the WT1 Zinc Finger domain 4 pathogenic variant
Analia Gisela Yogi 1 , Shizuka Kirino 1 , Eriko Adachi 1 , Maki Gau 1 , Hisae Nakatani 1 , Ryosei Iemura 1 , Yamano Haruki 1 , Takayasu Mori 2 , Eisei Sohara 2 , Shinichi Uchida 2 , Kei Takasawa 1 , Tomohiro Morio 1 & Kenichi Kashimada 1
1Tokyo Medical and Dental University, Department of Pediatrics, Tokyo, Japan. 2Tokyo Medical and Dental University, Department of Nephrology, Tokyo, Japan
Background: Wilms Tumor 1 gene (WT1) is essential for gonadal development and testicular development. Pathogenic variants in its 1-3rd Zinc Finger (ZF) domains are one of the major causes of 46, XY disorders of sex development (DSD). Interestingly, the variants located on the 4th ZF were recently described to cause the reversed phenotype, 46, XX DSD. Due to its clinical phenotype, i.e., 46, XX testicular DSD, all reported nine patients were de novo, and no genetic inheritance have been reported.
Purpose: To report the first familial case of the WT1 ZF4 variant.
Case Report: A 16-year-old social female was born from healthy parents through natural conception and showed atypical external genitalia at birth. Plastic surgery was performed at age 2 years and, after the surgery, the patient dropped off from regular follow-up. At 16-year-old, she was referred to our hospital due to “primary amenorrhea”. Detailed analysis revealed the 46, XX karyotype with partially functioning testes (Tanner: Breast 1, pubic hair 2, hCG stimulation test: testosterone, 1.58 ng/mL to 2.57, MRI imaging study: a uterine remnant). Dysgenetic testes were confirmed histologically after surgical excision of gonads. Heterozygous missense variant was identified in the WT1 gene, c.1484G>A, p.Arg495Gln, located on the 4th Zn Finger domain. The familial analysis revealed the variant in the mother who had normal reproductive function with a minor phenotype, a bicornuate uterus. The brother had a history of bilateral cryptorchidism with chronic renal disease.
Discussion: To date, all reported 46, XX DSDs cases with WT1 ZF4 variants showed substantial masculinization of external genitalia with a testicular phenotype in the gonads, resulting in sterile. In contrast, the patient’s mother was fertile with a subtle phenotype in the uterus.
Conclusion: WT1 ZF4 pathogenic variants show a diverse phenotype from DSD to mild cases with normal fertility.
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