Denys-Drash Syndrome

Denys-Drash syndrome (DDS) manifests in small children and consists of the triad of congenital nephropathy, Wilms tumor, and ambiguous genitalia.

Drash Syndrome.

Unknown. Approximately 150 cases have been reported. No racial predilection.

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.

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.

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.

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.

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.

Avoid hypovolemia and nephrotoxic agents in patients undergoing unilateral nephrectomy, and avoid renally excreted drugs in patients with renal failure or who are undergoing bilateral nephrectomy. Postoperative pain management may take the form of regional anesthesia or parenteral narcotics. Both must be viewed in the light of reduced or absent renal function.

Avoid drugs that depend on renal excretion or are nephrotoxic. Consider perioperative corticosteroid coverage for postrenal transplant patients.

Frasier Syndrome: Similarly to DDS, the mutation responsible for this disorder is on the WT1 gene, located on 11p13. However, this syndrome is caused by mutations of the alternative splice donor site of exon 9 and therefore is different from DDS. Patients present with complete gonadal dysgenesis (streak gonads) and pseudohermaphroditism. The nephrotic syndrome is caused by focal glomerular sclerosis, which progresses to end-stage renal disease between the ages of 10 and 20 years and requires either hemodialysis or kidney transplantation. Gonadoblastoma, but not Wilms tumor, is a frequent complication of Frasier syndrome and occurs later in life than does Wilms tumor in DDS. Nevertheless, clinical differentiation between the two syndromes may be difficult. Basically the same precautions before anesthesia, anesthetic considerations, and pharmacological implications apply as for DDS, except that the malignancy is gonadoblastoma instead of Wilms tumor.

Aniridia: It is estimated that approximately one third of patients with sporadic aniridia will develop a Wilms tumor, whereas approximately half of patients with aniridia, genitourinary anomalies (e.g., hypospadias), and mental retardation will develop a Wilms tumor. The association of Wilms tumor with aniridia, genitourinary anomalies, and mental retardation is known as the WAGR syndrome. Most patients have prominent lips and macrognathia. Other features may include congenital cataracts, nystagmus, ptosis, and blindness. The presence of ptosis and generalized hypotonia in a subgroup of patients suggests a susceptibility to malignant hyperthermia.

WAGR Syndrome: Characterized by congenital developmental abnormalities such as aniridia, genitourinary abnormalities, and mental retardation. With a probability of 30%, the risk of developing a Wilms tumor in patients with this syndrome is very high.

Beckwith-Wiedemann Syndrome: Most often sporadic occurring syndrome with exomphalos, macroglossia, gigantism, and hypoglycemia resulting from hyperinsulinism.