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Denys-Drash syndrome (DDS) manifests in small children
and consists of the triad of congenital nephropathy, Wilms tumor, and
ambiguous genitalia.
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Unknown. Approximately 150 cases have been reported. No
racial predilection.
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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.
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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.
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The majority of patients have an ambiguous genitalia 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.
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Although pure gonadal dysgenesis with male
pseudohermaphroditism is typical, 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 in their first year of life
with the typical symptoms of nephrotic syndrome (marked proteinuria with
hypoproteinemia [hypalbuminemia] resulting in recurrent 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 tumor is usually detected at approximately age 2 years and is
most often unilateral (80%). However, bilateral nephrectomy may be
prudent management for unilateral nephropathy to reduce the high likelihood
of developing a Wilms tumor in the contralateral kidney. Elective
gonadectomy can be performed because of the difficulty in screening for
gonadal malignancies. Most associated findings probably are incidental.
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Expect chronic renal anemia and
evaluate renal function with serum electrolytes, creatinine, and urea
preoperatively. Ask about the date of last hemodialysis, daily urine output,
and maximal allowable daily fluid intake. Depending on the laboratory
results and the clinical status (hypervolemia), hemodialysis may be
necessary. Consider end-organ involvement related to arterial hypertension,
hyperlipidemia, and/or hypercholesterolemia and whether chemotherapeutic
agents were used preoperatively for treatment of Wilms tumor. The patient
may have undergone renal transplantation requiring immunosuppressant drugs
(corticosteroids) and manifest related adverse effects.
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