Management of Denys-Drash syndrome: A case series based on an international survey

Abstract

Denys-Drash syndrome (DDS), a condition caused by mutations in the tumor-suppressor gene WT-1, is associated with a triad of disorders: ambiguous genitalia, nephrotic syndrome leading to end-stage renal disease (ESRD), and Wilms’ tumor. Given the variable disease course, management is challenging. We aimed to describe the evolution of DDS and the range of management strategies by summarizing the clinical courses of cases collected from a questionnaire sent to the international pediatric nephrology community. 15 respondents provided information on 23 patients; 21 DDS cases were confirmed and analyzed. At DDS diagnosis, 6 patients had a Wilms’ tumor (group A) and 15 had no Wilms’ tumor (group B). Three group A patients had unilateral nephrectomy. Two of these still had renal function, with no second tumor, at 36 months and 16 years of age, and 1 progressed to ESRD. Three had bilateral nephrectomy before ESRD. Eight group B patients progressed to ESRD, all of whom later had all renal tissue removed. Two group B patients subsequently developed a unilateral Wilms’ tumor and had bilateral nephrectomy pre-ESRD. Three had bilateral nephrectomy prior to reaching ESRD without ever having a Wilms’ tumor. Two group B patients remained tumor-free with renal function at last follow-up. Two main management approaches were taken: pre-emptive nephrectomy prior to ESRD and conservative surveillance. Based on the known risks associated with ESRD in infants and young children, the variable course of DDS, and the relatively good prognosis associated with Wilms’ tumor, a guiding principle of preservation of renal function is most logical. Most would advocate bilateral prophylactic nephrectomy after ESRD is reached due to the high tumor risk, which is likely heightened after transplant.

Syndromic Wilms tumor: a review of predisposing conditions, surveillance and treatment

“…Of children with DDS and WT, 20% will have bilateral masses (6). They are also at risk of developing gonadoblastoma (16).…”

“…There are several case reports of tragic presentations of acute renal failure in patients with a previous diagnosis of gonadal dysgenesis. Based on these case reports, authors conclude that all patients with gonadal dysgenesis should undergo genetic screen for WT1 mutation in order to make the diagnosis early (16,43,44). General screening recommendations of serial ultrasound every 3 months until the age of 7 apply (24), although it should be noted that DDS patients, on average, are diagnosed just over a year of age (21).…”

“…Following nephrectomies, they could be transplanted within 6-8 weeks, avoiding the inherent decrease in quality of life and higher morbidity/mortality from prolonged dialysis. One potential con is the higher mortality rate infants on dialysis face than if they were older, aged 5-20 years (16). Prior to prophylactic nephrectomy in a child who does not require renal replacement therapy, eligibility for transplant should be considered, such as the patient's size.…”

Approach to the Virilizing Girl at Puberty

“…Some of these genetic anomalies will cause isolated DSD, whereas others are associated with additional developmental defects in other organ systems and may form a characteristic syndrome. For example, heterozygous dominant-negative mutations of the Wilms tumor suppressor gene ( WT1 ) on chromosome 11 can lead to the Denys-Drash syndrome, which is associated with kidney and gonad malformations and a high risk for developing a Wilms tumor ( 21 ). The 46,XY babies with Denys-Drash syndrome have varying degrees of gonadal dysgenesis, leading to ambiguous external genitalia or even a female phenotype with variable virilization during later pubertal development depending on presence of functional testicular tissue ( 21 ).…”

“…For example, heterozygous dominant-negative mutations of the Wilms tumor suppressor gene ( WT1 ) on chromosome 11 can lead to the Denys-Drash syndrome, which is associated with kidney and gonad malformations and a high risk for developing a Wilms tumor ( 21 ). The 46,XY babies with Denys-Drash syndrome have varying degrees of gonadal dysgenesis, leading to ambiguous external genitalia or even a female phenotype with variable virilization during later pubertal development depending on presence of functional testicular tissue ( 21 ). Moreover, spontaneous virilization at puberty has been reported in several cases with nonsyndromic 46,XY DSD resulting from NR5A1/SF1 variants ( 22 , 23 ).…”