Top

Published in:

01-07-2009 | Brief Report

A novel WT1 mutation in a 46,XY boy with congenital bilateral cryptorchidism, nystagmus and Wilms tumor

Authors: Monica Terenziani, Michele Sardella, Beatrice Gamba, Maria Adele Testi, Filippo Spreafico, Gianluigi Ardissino, Fausto Fedeli, Franca Fossati-Bellani, Paolo Radice, Daniela Perotti

Published in: Pediatric Nephrology | Issue 7/2009

Abstract

The WT1 gene plays a crucial role in urogenital and gonadal development. Germline WT1 alterations have been described in a wide spectrum of pathological conditions, including kidney diseases, genital abnormalities and Wilms tumor (WT), frequently occurring in combination. We report on a novel WT1 nonsense mutation (c.1105C>T), introducing a premature stop codon in exon 8 (p.Q369X), in a young XY male patient who presented with bilateral cryptorchidism, nystagmus, mild proteinuria and WT, but no sign of severe nephropathy. Although the majority of congenital urogenital abnormalities are not due to constitutional defects of the WT1 gene, our findings provide a rational for considering WT1 mutational analysis as one of the screening options in newborns with congenital defects of the urogenital tract due to the associated high risk of WT.

Pritchard-Jones K, Fleming S, Davidson D, Bickmore W, Porteous D, Gosden C, Bard J, Buckler A, Pelletier J, Housman D, Van Heyningen V, Hastie N (1990) The candidate Wilms’ tumour gene is involved in genitourinary development. Nature 346:194–197PubMed

Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE (1991) Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci USA 88:9618–9622PubMed

Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE (1990) Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 60:509–520PubMed

Gessler M, Konig A, Bruns GA (1992) The genomic organization and expression of the WT1 gene. Genomics 12:807–813PubMed

Riccardi VM, Sujansky E, Smith AC, Francke U (1978) Chromosomal imbalance in the Aniridia-Wilms’ tumor association: 11p interstitial deletion. Pediatrics 61:604–610PubMed

Francke U, Holmes LB, Atkins L, Riccardi VM (1979) Aniridia-Wilms’ tumor association: evidence for specific deletion of 11p13. Cytogenet Cell Genet 24:185–192PubMed

Denys P, Malvaux P, Van Den Berghe H, Tanghe W, Proesmans W (1967) Association of an anatomopathological syndrome of male pseudohermaphroditism, Wilms’ tumor, parenchymatous nephropathy and XX/XY mosaicism. Arch Fr Pediatr 24:729–739PubMed

Drash A, Sherman F, Hartmann WH, Blizzard RM (1970) A syndrome of pseudohermaphroditism, Wilms’ tumor, hypertension, and degenerative renal disease. J Pediatr 76:585–593PubMed

Little M, Wells C (1997) A clinical overview of WT1 gene mutations. Hum Mutat 9:209–225PubMed

10.

Jeanpierre C, Denamur E, Henry I, Cabanis MO, Luce S, Cecille A, Elion J, Peuchmaur M, Loirat C, Niaudet P, Gubler MC, Junien C (1998) Identification of constitutional WT1 mutations in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database. Am J Hum Genet 62:824–833PubMedPubMedCentral

11.

Royer-Pokora B, Beier M, Henzler M, Alam R, Schumacher V, Weirich A, Huff V (2004) Twenty-four new cases of WT1 germline mutations and review of the literature: Genotype/phenotype correlations for Wilms tumor development. Am J Med Genet 127A:249–257PubMed

12.

Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K (1997) Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470PubMed

13.

Marlin S, Couet D, Lacombe D, Cessans C, Bonneau D (1994) Obesity: a new feature of WAGR (del 11p) syndrome. Clin Dysmorphol 3:255–257PubMed

14.

Bremond-Gignac D, Crolla JA, Copin H, Guichet A, Bonneau D, Taine L, Lacombe D, Baumann C, Benzacken B, Verloes A (2005) Combination of WAGR and Potocki-Shaffer contiguous deletion syndromes in a patient with an 11p11.2-p14 deletion. Eur J Hum Genet 13:409–413PubMed

15.

Bremond-Gignac D, Gerard-Blanluet M, Copin H, Bitoun P, Baumann C, Crolla JA, Benzacken B, Verloes A (2005) Three patients with hallucal polydactyly and WAGR syndrome, including discordant expression of Wilms tumor in MZ twins. Am J Med Genet A 134:422–425PubMed

16.

Manoukian S, Crolla JA, Mammoliti P, Testi MA, Zanini R, Carpanelli M, Piozzi E, Sozzi G, De Vecchi G, Terenziani M, Spreafico C, Collini P, Radice P, Perotti D (2005) Bilateral prexial polydactyly in a WAGR syndrome patient. Am J Med Genet A 134:426–429PubMed

17.

Lennon PA, Scott DA, Lonsdorf D, Wargowski DS, Kirkpatrick S, Patel A, Cheung SW (2006) WAGR(O?) syndrome and congenital ptosis caused by an unbalanced t(11;15)(p13;p11.2)dn demonstrating a 7 megabase deletion by FISH. Am J Med Genet A 140:1214–1218PubMed

18.

Hu M, Craig J, Howard N, Kan A, Chaitow J, Little D, Alexander SI (2004) A novel mutation of WT1 exon 9 in a patient with Denys–Drash syndrome and pyloric stenosis. Pediatr Nephrol 19:1160–1163PubMed

19.

Schumacher V, Thumfart J, Drechsler M, Essayie M, Royer-Pokora B, Querfeld U, Muller D (2006) A novel WT1 missense mutation presenting with Denys-Drash syndrome and cortical atrophy. Nephrol Dial Transplant 21:518–521PubMed

20.

Devriendt K, Deloof E, Moerman P, Legius E, Vanhole C, de Zegher F, Proesmans W, Devlieger H (1995) Diaphragmatic hernia in Denys-Drash syndrome. Am J Med Genet 57:97–101PubMed

21.

Scott DA, Cooper ML, Stankiewicz P, Patel A, Potocki L, Cheung SW (2005) Congenital diaphragmatic hernia in WAGR syndrome. Am J Med Genet A 134:430–433PubMed

22.

Cho HY, Lee BS, Kang CH, Kim WH, Ha IS, Cheong HI, Choi Y (2006) Hydrothorax in a patient with Denys-Drash syndrome associated with a diaphragmatic defect. Pediatr Nephrol 21:1909–1912PubMed

23.

Antonius T, van Bon B, Eggink A, van der Burgt I, Noordam K, van Heijst A (2008) Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G > A(Arg366His) mutation. Am J Med Genet A 146A:496–499PubMed

24.

Kohsaka T, Tagawa M, Takekoshi Y, Yanagisawa H, Tadokoro K, Yamada M (1999) Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome. Hum Mutat 14:466–470PubMed

25.

Kaltenis P, Schumacher V, Jankauskiene A, Laurinavicius A, Royer-Pokora B (2004) Slow progressive FSGS associated with an F392L WT1 mutation. Pediatr Nephrol 19:353–356PubMed

26.

Kanemoto K, Ishikura K, Ariyasu D, Hamasaki Y, Hataya H, Hasegawa Y, Ikeda M (2007) WT1 intron 9 splice acceptor site mutation in a 46,XY male with focal segmental glomerulosclerosis. Pediatr Nephrol 22:454–458PubMed

27.

Niaudet P, Gubler MC (2006) WT1 and glomerular diseases. Pediatr Nephrol 21:1653–1660PubMed

28.

Suri M, Kelehan P, O’neill D, Vadeyar S, Grant J, Ahmed SF, Tolmie J, McCann E, Lam W, Smith S, Fitzpatrick D, Hastie ND, Reardon W (2007) WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations. Am J Med Genet A 143A:2312–2320PubMed

29.

Bardeesy N, Zabel B, Schmitt K, Pelletier J (1994) WT1 mutations associated with incomplete Denys-Drash syndrome define a domain predicted to behave in a dominant-negative fashion. Genomics 21:663–664PubMed

30.

Baird PN, Santos A, Groves N, Jadresic L, Cowell JK (1992) Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. Hum Mol Genet 1:301–305PubMed

31.

Clarkson PA, Davies HR, Williams DM, Chaudhary R, Hughes IA, Patterson MN (1993) Mutational screening of the Wilms’s tumour gene, WT1, in males with genital abnormalities. J Med Genet 30:767–772PubMedPubMedCentral

32.

Ogawa O, Eccles MR, Yun K, Mueller RF, Holdaway MD, Reeve AE (1993) A novel insertional mutation at the third zinc finger coding region of the WT1 gene in Denys-Drash syndrome. Hum Mol Genet 2:203–204PubMed

33.

Barbosa AS, Hadjiathanasiou CG, Theodoridis C, Papathanasiou A, Tar A, Merksz M, Gyorvari B, Sultan C, Dumas R, Jaubert F, Niaudet P, Moreira-Filho CA, Cotinot C, Fellous M (1999) The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms’ tumor. Hum Mutat 13:146–153PubMed

34.

Little S, Hanks S, King-Underwood L, Picton S, Cullinane C, Repley E, Rahman N, Pritchard-Jones K (2005) A WT1 exon 1 mutation in a child diagnosed with Denys–Drash syndrome. Pediatr Nephrol 20:81–85PubMed

35.

Chiang PW, Aliaga S, Travers S, Spector E, Tsai AC (2008) Case report: WT1 exon 6 truncation mutation and ambiguous genitalia in a patient with Denys–Drash syndrome. Curr Opin Pediatr 20:103–106PubMed

36.

Little SE, Hanks SP, King-Underwood L, Jones C, Rapley EA, Rahman N, Pritchard-Jones K (2004) Frequency and heritability of WT1 mutations in nonsyndromic Wilms’ tumor patients: a UK Children’s Cancer Study Group Study. J Clin Oncol 22:4140–4146PubMed

37.

Kaplinsky C, Ghahremani M, Frishberg Y, Rechavi G, Pelletier J (1996) Familial Wilms’ tumor associated with a WT1 zinc finger mutation. Genomics 38:451–453PubMed

38.

Heathcott RW, Morison IM, Gubler MC, Corbett R, Reeve AE (2002) A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X. Hum Mutat 19:462PubMed

39.

Perotti D, Mondini P, Terenziani M, Spreafico F, Collini P, Fossati-Bellani F, Radice P (2005) WT1 gene analysis in a sporadic early-onset and bilateral wilms tumor patients without associated abnormalities. J Pediatr Hematol Oncol 27:197–201PubMed

40.

Wagner N, Wagner KD, Theres H, Englert C, Schedl A, Scholz H (2005) Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms’ tumor transcription factor Wt1. Genes Dev 19:2631–2642PubMedPubMedCentral

41.

Nordenskjold A, Fricke G, Anvret M (1995) Absence of mutations in the WT1 gene in patients with XY gonadal dysgenesis. Hum Genet 96:102–104PubMed

Title: A novel WT1 mutation in a 46,XY boy with congenital bilateral cryptorchidism, nystagmus and Wilms tumor
Authors: Monica Terenziani
Michele Sardella
Beatrice Gamba
Maria Adele Testi
Filippo Spreafico
Gianluigi Ardissino
Fausto Fedeli
Franca Fossati-Bellani
Paolo Radice
Daniela Perotti
Publication date: 01-07-2009
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 7/2009
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-008-1056-y

At a glance: The STEP trials

Springer Medicine

A novel WT1 mutation in a 46,XY boy with congenital bilateral cryptorchidism, nystagmus and Wilms tumor

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2009

A child with sickle cell trait and macroscopic hematuria: answer

A child with sickle cell trait and macroscopic hematuria: question

Fatal infection in children with lupus nephritis treated with intravenous cyclophosphamide

Polycystic kidney and hepatic disease with mental retardation and hand anomalies in three siblings

Growth after renal transplantation

Membranoproliferative glomerulonephritis associated with a mutation in Wilms’ tumour suppressor gene 1