Drash Syndrome: Wilms' Tumor, Male Pseudohermaphroditism and Renal Failure
M. R. Kouhsari MD, M. H. Akbar MD, S. M. Borhany MD
Department of Surgery, Razi Hospital, Rasht, Guilan University of Medical Sciences, Rasht, Iran.
Drash syndrome is an extremely rare condition and comprises the association of Wilms' tumor, male pseudohermaphroditism and degenerative glumerulopathy and presents in early childhood. It has been suggested that inactivation or a dominant negative mutation of the tumor suppressor gene WT1, residing on the short arm of chromosome 11 (11p13) is the primary event causing this syndrome. Herein, we report a case of Drash syndrome in a 32-month-old child whose parents were first cousins, suggesting an autosomal hereditary pattern of the condition.
Drash and colleagues reported the association of Wilms' tumor (WT), pseudohermaphroditism, and nephropathies for the first time in 1970,.1,2 Drash syndrome (DS) is a triad of WT, male pseudohermaphroditism and glomerulopathy.2-5 However, some authors believe that to establish the diagnosis of DS, the presence of two components of the triad should be adequate.6
Less than 5% of all patients with WT have associated genitourinary anomalies.7 The exact cause of DS is unknown, though, recent studies suggest that the inactivation or dominant negative mutation of the tumor suppressor gene WT1, residing on the short arm of chromosome 11 (11p13), might be the primary event causing this syndrome.7-13 Dominant negative mutations of DS have been observed in Denys DS. Most of the reported cases of DS have been sporadic.8 In 1994, two cases of this syndrome were reported with chromosomal defects of a paternal origin.11 As a consequence, many authors believe that paternal heredity may play a role in the genesis of the condition.7,11,12
In January 1994, a 32-month-old child presented with an abdominal mass which had been detected one month earlier. The patient gave also a history of apathy and somnolence, productive cough and one episode of vomiting. On admission, the patient had a hypertensive crisis with a blood pressure of 190/110 mm Hg which was managed with furosemide and captopril.
During the examination, the attending physician noticed the ambiguous genitalia which had been discovered at birth; the gender of the patient had been determined as female without performing karyotype. Her parents were first cousins.
Physical examination at the time of admission disclosed an oral temperature of 37° C, a heart rate of 110/min, blood pressure of 120/80 mm Hg, a body weight of 9 kg, a height of 98 cm, a head circumference of 45 cm, and an arm circumference of 13 cm. Mentally, she was oriented and appeared completely normal. Periorbital edema was present around both eyes. A vesicular breathing sound with coarse crepititions and rhonchi were heard over both lungs. Multiple engorged superficial veins were seen on the abdomen. A soft, smooth mass was palpable on the left side of the abdomen which extended from the left costal margin down to the pelvis and crossed the midline. The genitourinary system showed a peno-scrotal hypospadias with a scrotum which resembled a labia major a adhered together. Testicles were not present either in the scrotal sac or in the inguinal canal. Pitting edema was evident on both lower extremities. Routine laboratory tests were normal. Urinalysis showed moderate proteinuria and 1315 RBC/HPF. Sonography of the abdomen revealed a large right kidney with hydronephrosis and abnormally increased cortical echogenicity. The left kidney was not visible. A large mass with heterogenous echo pattern was recognized extending from the left subphrenic region down to the pelvis. A CT scan of the abdomen showed a large mass in front and underneath the left kidney which had displaced the retroperitoneal organs.
On exploratory laparotomy, a renal tumor on the left side and intra-abdominal testes were detected. A left nephrectomy along with bilateral orchiectomy were performed. Pathologic study revealed a WT and sections of ureter showed fibro-fatty tissues along with tumor invasion. Lymph nodes showed only sinus histiocytosis. Intra-abdominal testes were found to be histologically immature.
Forty-eight hours postoperatively, the patient developed oliguria, uremia, hyponatremia and hypokalemia. At this time the patient was on chemotherapy, and for ongoing renal failure underwent peritoneal and hemodialysis several times. Progressive renal failure and electrolyte imbalance ultimately resulted in cardiac arrhythmia and death.
A recent report from the National Wilms' Tumor Study (NWTS) Group discloses a median interval of 21 months4 from diagnosis to the onset of renal failure. This was simultaneous in our case. In 1996, the NWTS Group from the Houston Medical School4 reported that the most common etiology of renal failure in these patients was bilateral nephrectomy and that DS was found in 12 out of 55 children who developed chronic renal failure with the WT.4
Children with unilateral WT and a normal contralateral kidney have a low incidence of renal failure.4 However, if DS is present, progressive renal failure is the rule,14 as was the case in our patient.
Nephropathy is a common clinicopathologic finding in DS as reported by the study group at the Institute of Child Health in London.15
Understanding the molecular genetics of WT in human and animal studies has helped to explain the dominant negative mutation of the suppressor gene WT1.8,10,12
A Swedish study on clinical genetics reported that the mutant gene was shown to be of paternal origin in DS.5 The presence of the Muellerian system indicates a global defect in the genesis of fetal testicles,3,5,7 just as in our patient who was the product of a consanguineous marriage.
Research workers at the Department of Surgery of the Children's Hospital, Denver, Colorado, have shown a high incidence of intralobar nephrogenic arrest in complete and partial DS patients.15 This suggests the probability that events leading to WT in patients with DS might occur at an early stage of nephrogenesis. The association of pseudohermaphroditism, nephron disorder and WT raises the probability that an embryogenic event could have occurred prior to the differentiation of renal and genital structures and possibly affecting both,2,5 as described by Drash et al.
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13 Pelletier J, Bruening W, Kashtan CE, et al. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 1991;67(2):437-47.
14 Melocoton TL, Salusky IB, Hall TR, et al. A case report of Drash syndrome in a 46XX. Am J Kidney Dis 1991;18(4):503-8.
15 Jadresic L, Leake J, Gordon I, et al: Clinicopathologic review of twelve children with nephropathy; Wilms' tumor and genital abnormalities (Drash syndrome). J Pediatr 1990;117(5):717-25.
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