This rare disorder is characterized by male pseudohermaphroditism, Wilms Tumours, and a characteristic glomerulonephropathy causing progressive renal failure. Not all patients have the complete triad, and nephropathy plus Wilms Tumours or urogenital abnormalities are sufficient to make the diagnosis. Wilms Tumours in Denys–Drash syndrome presents early (mean age 18 months) and is usually bilateral (Jadresic et al. 1991). Gonadoblastoma may also occur. The nephropathy is characterized by focal or diffuse glomerulosclerosis and typically presents with proteinuria, progressing to nephrotic syndrome and hypertension, and then reaching end-stage renal failure by 3 years of age (Coppes et al. 1993). Males (XY karyotype) with Denys–Drash syndrome usually have ambiguous genitalia or phenotypically normal female external genitalia (male pseudohermaphroditism). In addition, the internal genitalia is frequently dysplastic or inappropriate (Mueller 1994).
The risk of Wilms Tumours in children with truncating WT1 mutations or missense mutations in the zinc finger domains (as is typical for Denys–Drash syndrome) is estimated to be >50 %, and screening with 3–4 monthly renal ultrasonography is recommended (Scott et al. 2006). Indeed the risk of Wilms Tumours in Denys–Drash syndrome is high enough for bilateral prophylactic nephrectomy to be suggested for children with incomplete Denys–Drash syndrome (e.g., pseudohermaphroditism, hypogonadism, and renal failure) (Hu et al. 2004). Molecular genetic analysis of patients with this syndrome has demonstrated de novo germline WT1 mutations in most cases (Royer- Pokora et al. 2004). The majority of mutations affect the zinc finger domains and are thought to have a dominant negative effect on genital development (Little et al. 1993). Denys–Drash syndrome is allelic with Frasier syndrome.