Twenty‐four new cases of WT1 germline mutations and review of the literature: Genotype/phenotype correlations for Wilms tumor development

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Abstract
We report here 24 new Wilms tumor (WT) patients with germline WT1 alterations and a synopsis of our own previously described and literature cases in whom age of tumor‐onset, gender, and laterality were known. This combined database contains 282 patients, 117 patients with and 165 without WT1 germline alterations. Using this information we have determined the median age of tumor‐onset for patients with (12.5 months) and without WT1 gene alterations (36 months). The earliest onset was in patients with truncation (12 mo, 66 patients), followed by missense mutations (18 mo, 30 patients) and deletions (22 mo, 21 patients). Patients with the two most frequent nonsense mutations R362X and R390X and the Denys–Drash syndrome (DDS) hot spot mutation R394W/Q/L had a very early onset (9, 12, and 18 mo, respectively). The highest number of bilateral tumors was observed in the group of truncation mutations, with a higher percentage of bilateral tumors when truncations occurred in the 5′ half of the WT1 gene. In addition to genital tract anomalies (GU), early onset nephrotic syndrome with diffuse mesangial sclerosis and stromal‐predominant histology, tumor bilaterality, and early age of onset can now be added to the list of risk factors for carrying a germline WT1 mutation.