Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30‐year SIOP‐RTSG experience

Abstract

Background WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. Methods Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) registries and the SIOP‐RTSG network (1989‐2019). Events were defined as relapse, metachronous tumors, or death. Results Forty‐three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6‐44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5‐year event‐free survival rate was 84.3% (95% confidence interval, 72.4%‐98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%‐100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). Conclusions Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. Lay Summary WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor. In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP‐RTSG) and the SIOP‐RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur. Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised.

Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature

“…The most common predisposition syndromes and their underlying genetic defect include WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) (WT1 deletion), Denys-Drash syndrome (WT1 mutation) and Beckwith-Wiedemann Syndrome (LOH or loss of imprinting (LOI) of 11p15). Excluding metachronous tumors, both COG and SIOP studies did not observe a higher relapse rate in WAGR patients than in non-syndromic WT patients [99,100]. Similarly, excluding contralateral metachronous recurrences, RFS rates adjusted for tumor stage and histology in patients with Beckwith-Wiedemann Syndrome were similar to non-syndromic patients [101].…”

Wilms tumour surveillance in at-risk children: Literature review and recommendations from the SIOP-Europe Host Genome Working Group and SIOP Renal Tumour Study Group

“…Diagnosing lower stage tumours can, however, avoid the need for toxic treatment such as anthracyclines or radiotherapy, reducing direct and late side-effects. It has been retrospectively demonstrated that children with BWS or hemihypertrophy undergoing WT surveillance had significantly lower stage WT compared with children not participating in a surveillance program [2,3] and that WTs in patients with Wilms tumour, aniridia, genitourinary anomalies and range of developmental delays (WAGR) syndrome are significantly smaller if they are surveillance-detected than symptomatic tumours [14]. Analysis of a registry-based cohort could provide stronger unbiased evidence in the future.…”

“…If WT surveillance is indicated, we recommend continuing surveillance until a child's 7th birthday regardless of the underlying CPS diagnosis. By the age of 7 years, 90% of sporadic WTs [3], 94% of WTs in children with BWS [3] and >95% of WTs in children with WT1-related syndromes [14,19,24] have been diagnosed, and this age has been previously recommended by other groups [5,10]. For other CPS, the number of reported patients with WT was too small to determine this percentage.…”

“…Among patients with WT1-related syndromes, >90e95% of WTs are diagnosed before the age of 5 years, although patients with nephrogenic rests progressing to (metachronous) tumours after the age of 5 years have been reported [14,25]. Although we have previously suggested screening patients with WT1-related syndromes until the age of 5 years [4] and to prolong surveillance only for patients with a prior diagnosis of WT/nephroblastomatosis [14], the consensus group agreed to recommend surveillance until the 7th birthday for all CPS including WT1-related syndromes. Factors that influenced this decision were that nephroblastomatosis may not be identified on ultrasound, to maintain consistency with other WT predisposition genes/syndromes and in response to patient/parent representatives' views.…”

“…Based on data extracted from four published cohorts of patients with WAGR syndrome (Supplemental Table 3), WTs were reported in~55% of all patients [44e47]. Reported ages at WT diagnosis varied from 0.3 to 25 years (median ages: 15e23 months) [14,19,32,45,46,48]. Similar to patients with WT1 variants, patients with WAGR syndrome are at risk of developing metachronous tumours [14] and renal failure [19].…”