Downloaded from jmg.bmj.com on May 16, 2013 - Published by group.bmj.com 705 REVIEW Syndromes and constitutional chromosomal abnormalities associated This article is available free on JMG online via the JMG Unlocked open access trial, with Wilms tumour funded by the Joint Information Systems Committee. For further information, see R H Scott, C A Stiller, L Walker, N Rahman http://jmg.bmjjournals.com/cgi/content/ full/42/2/97 ............................................................................................................................... J Med Genet 2006;43:705–715. doi: 10.1136/jmg.2006.041723 Wilms tumour has been reported in association with over Multiple nephrogenic rests throughout the kid- ney are sometimes present and can be referred to 50 different clinical conditions and several abnormal as nephroblastomatosis. constitutional karyotypes. Conclusive evidence of an The dramatic advances in the treatment of increased risk of Wilms tumour exists for only a minority of Wilms tumour are such that long term survival is now the norm: exceeding 90% for disease these conditions, including WT1 associated syndromes, localised to the abdomen (stages 1–3), and over familial Wilms tumour, and certain overgrowth conditions 70% in metastatic disease (stage 4).7 The treat- such as Beckwith-Wiedemann syndrome. In many reported ment of Wilms tumour is determined both by stage and histological classification of the conditions the rare co-occurrence of Wilms tumour is tumour, with treatment protocols varying probably due to chance. However, for several conditions between countries. Surgical resection is comple- the available evidence cannot either confirm or exclude an mented in the majority of individuals by chemo- therapy. Currently in the United Kingdom increased risk, usually because of the rarity of the around 30% of individuals with Wilms tumour syndrome. In addition, emerging evidence suggests that an also receive radiotherapy. increased risk of Wilms tumour occurs only in a subset of A wide range of syndromes, congenital anomalies, and constitutional chromosomal individuals for some syndromes. The complex clinical and abnormalities have been reported in association molecular heterogeneity of disorders associated with with Wilms tumour. Data from the British Wilms tumour, together with the apparent absence of National Registry of Childhood Tumours showed that around 9% of individuals with Wilms functional links between most of the known predisposition tumour have a congenital anomaly, and a study genes, suggests that abrogation of a variety of pathways of long term childhood cancer survivors revealed can promote Wilms tumorigenesis. a syndrome diagnosis in 23 of 136 individuals (17%) with Wilms tumour.89This is the highest ........................................................................... proportion seen in any childhood malignancy. The aim of this article is to document the ilms tumour is the commonest child- syndromes, congenital abnormalities, and con- hood tumour of the kidney and has an stitutional chromosomal aberrations reported to Wincidence of 1 in 10 000.1 It is primarily occur in association with Wilms tumour, and to a sporadic disease and only 1–2% of individuals review the evidence for an increased risk of with Wilms tumour have a relative with this Wilms tumour in these conditions. Accurate tumour.2 The median age of diagnosis is between estimation of risk can be difficult in the absence 3 and 4 years; 80% of individuals are diagnosed of large prospective studies, which are rarely before the age of 5 years and diagnosis over the feasible in conditions reported in association age of 15 years is extremely rare.34 In 5% of with Wilms tumour, many of which are very See end of article for individuals with Wilms tumour both kidneys are rare. Where Wilms tumour is a diagnostic authors’ affiliations affected.5 criterion for the condition, risk estimation is ....................... The histology of Wilms tumour mimics the particularly difficult. It is probable that cases of a Correspondence to: differentiation of the developing kidney and is syndrome with Wilms tumour are more likely to Prof Nazneen Rahman, classically ‘‘triphasic’’, consisting of blastemal, be reported than cases without tumours, and Section of Cancer epithelial, and stromal components. Tumours are Genetics, Institute of that such reporter bias leads to an overestimate Cancer Research, 15 most often of mixed or blastemal histology, but of the tumour risk. Because of this difficulty of Cotswold Road, Sutton, various other histological patterns are seen. accurate risk estimation we have generally given Surrey SM2 5NG, UK; Persistent islands of embryonal cells, known as a qualitative risk estimate (for example, high, [email protected]. nephrogenic rests, are believed to be precursor uk moderate, or low) rather than a precise figure. lesions with the potential to develop into Wilms For a comprehensive assessment of conditions Received13February2006 tumour. Nephrogenic rests are classified accord- reported in association with Wilms tumour, Revised version received ing to their position within the renal lobe as we undertook extensive searches for relevant 7 April 2006 perilobar nephrogenic rests or intralobar nephro- articles using the PubMed, Online Mendelian Accepted for publication genic rests. They are reported to occur in 1% of 10 April 2006 Published Online First perinatal necropsies and in up to 40% of kidneys Abbreviations: BWS, Beckwith-Wiedemann syndrome; 11 May 2006 removed in the treatment of Wilms tumour IHH, isolated hemihypertrophy; WAGR, Wilms-aniridia- ....................... (,25% intralobar and ,15% perilobar).6 genitourinary-mental retardation www.jmedgenet.com Downloaded from jmg.bmj.com on May 16, 2013 - Published by group.bmj.com 706 Scott, Stiller, Walker, et al Inheritance in Man (OMIM), and the Winter-Baraitser tions of three cardinal features: Wilms tumour, genitourinary dysmorphology databases (see electronic database section at abnormalities, and renal dysfunction. the end of the paper). To facilitate searches we created a database of more than 8000 references with ‘‘Wilms tumour’’ WAGR syndrome or ‘‘nephroblastoma’’ in the title or abstract, which we WAGR (Wilms-aniridia-genitourinary-mental retardation) downloaded from PubMed. We then searched this database syndrome (OMIM 194072) was the first WT1 associated for generic terms such as ‘‘syndrome’’ and ‘‘malformation’’. condition to be characterised and is found in around 7–8/ We also reviewed the references of identified papers for 1000 individuals with Wilms tumour.12 It manifests with additional relevant literature. complete or partial aniridia, ambiguous external genitalia and cryptorchidism in males, and intellectual impairment. CONDITIONS WITH AN INCREASED RISK OF WILMS The risk of renal failure is high, affecting around 40% of TUMOUR individuals by the age of 20 years (median age of diagnosis 15 The conditions in which there is conclusive evidence of an years).13 Heterozygous constitutional microdeletions at 11p13 increased risk of Wilms tumour are shown in table 1. They encompassing both WT1 and PAX6 are responsible for WAGR, can be broadly classified into five groups: WT1 associated with the WT1 deletion causing the genitourinary features and phenotypes caused by mutations or deletions of the WT1 Wilms tumour predisposition and deletion of PAX6 resulting gene; familial Wilms tumour; overgrowth conditions; tumour in aniridia. Approximately 30% of individuals with aniridia predisposition syndromes in which Wilms tumour is one of a carry microdeletions that encompass WT1, with the remain- number of benign or malignant tumours that can occur; and der usually harbouring smaller deletions or intragenic PAX6 constitutional chromosomal disorders. mutations.14 These latter individuals are not at increased risk of Wilms tumour. Rare individuals with 11p13 microdele- WT1 associated syndromes tions involving WT1 but excluding PAX6 have been reported The Wilms tumour 1 (WT1) gene is located at 11p13 and and present with Wilms tumour or genitourinary abnormal- encodes a zinc finger transcription factor with a crucial role in ities, or both, but without aniridia.15 16 renal and gonadal development. It consists of a C-terminal zinc finger DNA binding domain and an N-terminal Denys-Drash syndrome transactivational domain, and occurs in multiple alternatively Denys-Drash syndrome (OMIM 194080) classically describes spliced isoforms.10 WT1 acts as a classic tumour suppressor the triad of Wilms tumour, nephropathy, and genitourinary gene and the wild type allele is somatically inactivated in abnormalities in males, which may be severe enough to result tumours occurring in individuals with constitutional WT1 in pseudohermaphroditism.17 18 The nephropathy results from mutations or deletions. The median age of Wilms tumour a characteristic mesangial sclerosis and typically presents diagnosis in such individuals is younger than in unselected with hypertension and proteinuria, usually progressing to series of Wilms tumour cases (,1 year in WT1 associated renal failure and requiring renal replacement therapy before syndromes, 3 to 4 years in unselected Wilms tumour series) the age of 10 years.19 Genitourinary abnormalities in males and tumours are more likely to be bilateral (38% in WT1 are very common but are highly variable in severity, ranging associated syndromes; 5% in unselected Wilms tumour from mild hypospadias to female external genitalia and series). The tumours