ESPE Abstracts

The WT1 gene has a crucial role in the genesis of the bipotential genital ridge and subsequently in the specification of the Sertoli cells of testis. Mutations involving the WT1 gene are associated with a wide range of phenotypes impacting testis-determination and development including Denys-Drash syndrome, Frasier syndrome and Meacham syndrome. Here, we describe two sibs with DSD carrying a de novo mutation in the WT1 gene. A girl was born with Prader IV intersex genitals. Cytogenetic examination revealed the a 46,XX, SRY-negative karyotype. Hormonal androgen levels were elevated and congenital adrenal hyperplasia was excluded. At three months of age explorative laparotomy identified a uterus and two macroscopically undifferentiated gonads. Histology identified testicular tissue in both gonads. At six months of age she had a feminization genioplasty. At age of 12 she underwent a bilateral gonadectomy and histological examination revealed ovotestis in both gonads. A diagnosis of 46,XX ovotesticular DSD was indicated. A male sib was born 14 years later. At birth he presented with male external genitalia, but testes were not palpable in the scrotum nor in the inguinal canal. After birth he underwent surgery for a diaphragmatic hernia. His karyotype was 46,XY. At 2 years of age laparoscopy identified a rudimentary testis on the right side. Orchidectomy was performed on the left side and histological examination did not find any testicular tissue only pieces of funiculus spermaticus and epididymis tissue. At age 9 his FSH: 0.6 IU/l, LH <0.11 IU/l, Te< 0.43 nmol/l, E2 <92 pmol/l hormone levels were in prepubertal range. The combination of diaphragmatic hernia with 46,XY DSD suggested the diagnosis of Meacham syndrome. Exome sequencing revealed a de novo missense mutation of the highly conserved fourth zinc-finger of WT1 (p.Arg495Gly) in both sibs. Normal ploidy was established by qPCR. This is the first time that mutation has been identified in the WT1, in a girl with ovotesticular DSD and her brother with 46,XY gonadal dysgenesis and hernia diaphragmatic. These cases confirm that mutations involving WT1 can impact on the development of both the testis and the ovary and that WT1 mutations can result in Meacham syndrome.