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A novel WT1 heterozygous nonsense mutation (p.K248X) causing a mild and slightly progressive nephropathy in a 46, XY patient with Denys–Drash syndrome Thatiana Evilen da Silva & Mirian Yumie Nishi & Elaine Maria Frade Costa & Regina Matsunaga Martin & Filomena Marino Carvalho & Berenice Bilharinho Mendonca & Sorahia Domenice

Received: 2 December 2010 / Revised: 25 February 2011 / Accepted: 28 February 2011 / Published online: 11 May 2011 # IPNA 2011

Abstract WT1 mutations have been described in a variety of syndromes, including Denys-Drash syndrome (DDS), which is characterized by predisposition to Wilms’ tumor, genital abnormalities and development of early nephropathy. The most frequent WT1 defects in DDS are missense mutations located in exons 8-9. Our aim is to report a novel WT1 mutation in a 46,XY patient with a DDS variant, who presented a mild nephropathy with a late onset diagnosed during adolescence. He had ambiguous genitalia at birth. At 4 months of age he underwent nephrectomy (Wilms’ tumor) followed by chemotherapy. Ambiguous genitalia were corrected and bilateral gonadectomy was performed. Sequencing of WT1 identified a novel heterozygous mutation (c.742A>T) in exon 4 that generates a premature stop codon (p.K248X). Interestingly, this patient has an unusual DDS nephropathy progression, which reinforces that patients carrying WT1 mutations should have the renal function carefully monitored due to the possibility of late-onset nephropathy. Keywords Denys-Drash syndrome . WT1 gene . Wilms’ tumor . proteinuria T. E. da Silva : M. Y. Nishi : E. M. F. Costa : R. M. Martin : B. B. Mendonca : S. Domenice (*) Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM42, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, 155, PAMB, 2º andar, Bloco 6, 05403–900 Sao Paulo, SP, Brazil e-mail: [email protected] F. M. Carvalho Departamento de Patologia, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil

Introduction The Wilms’ tumor (WT) suppressor gene 1 (WT1) is essential to the normal development and function of the urogenital tract. The spectrum of WT1-associated disorders is particularly complex. WAGR syndrome (WT, aniridia, genitourinary abnormalities, and mental retardation; MIM 194072) is caused by heterozygous deletion of the 11p13 region, which contains both WT1 and PAX6 (Paired box gene 6) [1]. Both Frasier syndrome (FS; MIM 136680) and Denys–Drash syndrome (DDS; MIM 194080) are characterized by gonadal and renal abnormalities, a predisposition to tumor development, and an association with de novo constitutional WT1 point mutations [1, 2]. The FS phenotype, caused by heterozygous mutations in intron 9 of WT1, consists of female external genitalia and gonadal dysgenesis in 46,XY patients, high risk of gonadoblastoma and renal failure in the second decade of life. The renal failure is usually caused by focal segmental glomerulosclerosis [2]. The DDS phenotype is characteri

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