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At a glance

Denys-Drash Syndrome (DDS) has an onset during childhood and consists of the triad of congenital nephropathy (mesangial renal sclerosis), Wilms’ tumor (90% of affected individuals), and ambiguous genitalia (pseudohermaphroditism). Clinically, this medical condition is manifested with early Nephrotic Syndrome (edema, abdominal distention, and recurrent infections) that is usually present at birth but more between 1 and 2 years of age. It progresses to mesangial renal sclerosis, and ultimately end-stage renal failure—usually within the first 3 years of life.

Synonym

Drash Syndrome; Wilms Tumor with Pseudo- or True Hermaphroditism Syndrome.

History

This medical condition was first described in 1967 by P. Denys and later detailed by Allan L. Drash in 1970.

Incidence

The exact incidence remains unknown. However, approximately 200 cases have been reported in the medical literature. There is no racial predilection.

Genetic inheritance

Probably arises as a spontaneous mutation. The mutation is usually not present in parents; however, affected sibling pairs have been reported. DDS is the result of a so-called heterozygous dominant-negative mutation in the Wilms tumor suppressor gene 1 (WT1), with the gene locus mapping to 11p13. The same mutation has been reported in patients with isolated Wilms tumor. Most patients are pseudohermaphrodites with a 46,XY karyotype.

Pathophysiology

The dominant-negative mutation results in cellular WT1 levels less than 50% of normal in these patients. Diffuse mesangial fibrosis of the kidney results in progressive nephropathy and subsequent renal failure and associated hypertension. Wilms tumor is present in 74% and gonadal malignancies (gonadoblastoma) in 4% of patients.

Diagnosis

The majority of affected patients have an ambiguous genitalia (pseudohermaphroditism) or appear phenotypically female. The combination of ambiguous genitalia with typical renal involvement and arterial hypertension is suggestive of the disease. Kidney biopsy shows diffuse mesangial sclerosis with expansion of the mesangial matrix and subcapsular atrophy. Intracytoplasmic deposits of fibrillary material results in mesangial cell expansion.

Clinical aspects

Although pure gonadal dysgenesis with male pseudohermaphroditism is typical in these patients, the clinical variability of the external genitalia ranges from bifid scrotum with micropenis and palpable gonads to penoscrotal hypospadias with cryptorchidism or clitoral hypertrophy with labial fusion. Gonadal dysgenesis presents as streak ovaries and dysgenetic testes, respectively. Usually, patients present during the first year of life with typical symptoms of Nephrotic Syndrome (marked proteinuria with hypoproteinemia and hypoalbuminemia) resulting in recurrent systemic infections, marked edema, abdominal distension secondary to ascites, hyperlipidemia, and hypercholesterolemia. Patients may have varying degrees of renal dysfunction/failure, but glomerular filtration rate usually declines quickly and results in end-stage renal disease requiring either dialysis or renal transplantation at approximately age 3 years. Hypertension, failure to thrive, and delayed psychomotor milestones may develop as a result of renal failure. Wilms ...

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