A novel WT1 mutation in familial wilms tumor

To the Editor: Wilms tumor (WT), the most frequent pediatric renal tumor, primarily occurs as a sporadic disease, but approximately 2% of cases have an affected relative [1]. While the underlying cause of most familial WTs is currently unknown, few reports described pedigrees associated with anomalies of the WT1 gene [2–5]. We report on a WT pedigree resulting from a novel WT1 mutation. The index patient, a 23-month-old (46, XY karyotype) presented with bilateral cryptorchidism and proximal severe penile hypospadia. Serial abdomino-pelvic ultrasounds did not reveal signs of renal pathology, and normal renal function was assessed by blood and urine tests. Apart from the presence of genitourinary (GU) anomalies, the child did not present any clinical evidence of known syndromes predisposing to WT development. At 23 months of age, following the onset of macroscopic hematuria, abdominal ultrasound revealed a left renal mass. The patient underwent radical nephrectomy, and histological examination revealed a unicentric, triphasic WT without anaplasia. Perilobar nephrogenic rests were present, as well as dysplastic medullary rays. The patient received treatment according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) TW-2003 protocol for stage IV disease, because of the presence of pulmonary metastases. At present, the child is in complete remission, 3 months after completing therapy. His mother had been successfully treated for stage II WT in 1978, when she was 22 months old. She showed a normal growth and development, without any GU abnormalities or syndromic signs. While she was considering the possibility of an assisted conception treatment due to her difficulty in conceiving, she got spontaneously pregnant at 32 years of age. No nephropathies or renal cancers were reported in other members of her family and no GU abnormalities were referred in her parents and her two brothers. Two novelWT1 germline variants, the silent variation c.981C>T and the frameshift mutation c.983delC (p.P328QfsX53) causing the loss of the C-terminal of the WT1 protein, were detected in the peripheral blood leukocytes (PBL) DNAs of both affected subjects (Fig. 1Aand B). TumorDNAwas available only fromthe child. WT1 sequencing revealed no further anomaly and loss of entire wild-type WT1 allele could be excluded based on the maintenance of heterozygosity for both the novel identified variants (Fig. 1C). Immunohistochemistry forWT1 on tumor cells disclosed a focal and weak immunoreactivity with WT clone WT49 (against amino acids 1–181 of theN-terminal ofWT1), but not withWT1 (C-19) antibody (against the last 19 amino acids of the C-terminal ofWT1) (Fig. 1E and F). This is consistent with the expression in the tumor of the mutated, but not of the constitutionally wild-type allele, and indicates a likely etiologic role of the mutated allele in tumorigenesis. The analysis of the CTNNB1 gene disclosed the c.133_135delTCT (p.S45del) in-frame deletion in tumor DNA (Fig. 1G), in agreement with the described co-occurrence of WT1 and b-cateninmutations in WTs [6].ThisWTpedigreeadds tothe fewalreadyreportedinwhicha role of WT1 mutation has been established.