Long-term kidney function in children with Wilms tumour and constitutional WT1 pathogenic variant

Abstract

Background Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children. Methods Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome. Results We identified 25 patients (60% male, median age at diagnosis 14 months, range 4–74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3–16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years. Conclusions Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.

Spectrum of Clinical Manifestations in Children With WT1 Mutation: Case Series and Literature Review

“…In marked contrast, there is a strong consensus for prophylactic gonadectomy in all phenotypic females with 46 XY sex reversal. Moreover, our results show the increased risk of malignancy in phenotypic males with DSD and emphasize the need for close surveillance and a low threshold for prophylactic gonadectomy (47)(48)(49)(50).…”

“…Hence, this mutation should be considered in toddlers, as well as in cases of bilateral Wilm's tumor (5). A recent single center retrospective analysis of 25 long-term Wilm's tumor survivors with WT1 pathogenic variants confirmed male predominance (60%), early age occurrence (median 14 months), multiple genetic variants, high incidence of bilateral disease (52%), and genitourinary malformations (44%) (47). This recent report emphasized the importance of early genetic diagnosis to better inform surgical management toward the preservation of renal mass when oncologic management is not compromised.…”

“…Currently, there is no consensus for prophylactic nephrectomies. In the literature review, there were no specific recommendations in favor of prophylactic bilateral nephrectomy, and most recently, the recommendation has been for renal sparing surgery in the case of unilateral Wilm's tumor (14,(47)(48)(49). In marked contrast, there is a strong consensus for prophylactic gonadectomy in all phenotypic females with 46 XY sex reversal.…”

Prechemotherapy Transperitoneal Robotic-Assisted Partial Nephrectomy (RAPN) for a Wilms Tumor: Surgical and Oncological Outcomes in a Four-Year-Old Patient

“…According to the UMBRELLA SIOP Protocol, NSS is recommended only in specific cases following neoadjuvant chemotherapy: bilateral, syndromic (for genetic predisposition—less than a year old), nephroblastomatosis [ 17 ], high risk of metachronous tumors for or bilateral WT [ 18 ], solitary and horseshoe kidney [ 19 ], and the constitutional WT1 pathogenic variant that increases the risk of kidney failure [ 20 ]. In non-syndromic cases of unilateral WTs, NSS is considered for small tumors (volume <300 mL) without lymph node involvement, where a significant preservation of kidney function is anticipated [ 21 ], provided the surgeon can achieve complete tumor excision and prevent tumor spillage [ 22 ], as was the case in the scenario described.…”

Wilms tumor (nephroblastoma) – clinical and genetic aspects

“…Therefore, prior knowledge of the presence of a constitutional WT1 pathogenic variant and its subtype may have important implications in predicting the risk and rate of deteriorating function of the remaining nephrons [25,26]. On the other hand, Falcone et al [27] described long-term kidney function in 25 children with WT and WT1 pathogenic variants and noted kidney survival in 72% of them at median follow-up of 9 years. Only 28% of patients required hemodialysis at 5.6 years (median; range: 0-16) after WT diagnosis.…”