Germline WT1 mutations in Wilms' tumor patients: Preliminary results

We conducted a comparative study of the prevalence of germline WT1 mutations in patients with Wilms' tumor. Patients in Group 1 have familial Wilms' tumor, bilateral disease, associated urogenital anomalies, and/or second cancers. Those in Group 2 are unilateral, sporadic Wilms' patients without other associated conditions. Patients with aniridia or Denys-Drash syndrome are known to have WT1 alterations, and are excluded from this study. Preliminary results on 96 subjects show that the overall germline WT1 mutation frequency is low (<5%). The work to date establishes the feasibility of identifying patients with germline WT1 mutations and, in the future, offering genetic predisposition testing to at-risk relatives. However, genetic predisposition testing of children for WT1 mutations raises many ethical, legal, and psychosocial issues; research is needed to evaluate risks and benefits. © 1996 Wiley-Liss, Inc.     

Cytogenetic abnormalities in mesoblastic nephroma: A link to Wilms' tumour?

Cytogenetic analysis of tumour material from a congenital mesoblastic nephroma is reported. Two cell lines were found, one with a normal 46,XY karyotype and the other with a hyperdiploid 51,XY karyotype, including a rearrangement of chromosome 11 at 11p15. This finding is of interest since loss of allelic heterozygosity at polymorphic 11p15 loci has been described in sporadic Wilms' tumour [1], and both cytogenetic [2] and molecular [3] changes of 11p15 are found in the Wiedemann-Beckwith syndrome, a condition with a predisposition to embryonal tumours, particularly Wilms' tumour. Our results lead us to speculate on the implications relating to the pathogenesis of this relatively benign tumour variant with respect to the current understanding of the genetics of Wilms' tumour. © 1993 Wiley-Liss, Inc.     

Analysis of paediatric tumour types associated with hemihyperplasia in childhood

In order to further explore the relationship between hemihyperplasia in children and the occurrence of embryonal tumours of childhood, the records at St Jude Children's Research Hospital were examined for patients who presented with a malignant tumour and hemihyperplasia. Of 27 evaluable patients, 19 had Wilms' tumour and one had massive bilateral nephroblastomatosis. The tumours were more likely to occur on the side affected by hemihyperplasia than to be found contralaterally. All but five of these patients developed the tumours before, the age of six. Twenty-two of the 27 patients developed tumours associated with allelic loss on chromosome band 11p15, suggesting that the locus associated with hemihyperplasia may be also located at chromosome band 11p15.     

Aniridia: Recent achievements in paediatric practice

Aniridia is a rare panocular disorder which primarily involves not only the iris, but also the retina, optic nerve, lens and cornea. Visual acuity deteriorates as a result of nystagmus, glaucoma, cataract, corneal opacities and retinal hypoplasia. Aniridia may appear as an isolated disorder, most often familial with autosomal dominance or sporadically in association with at least 12 syndromes. Both familial isolated and Wilms tumour, bilateral sporadic aniridia, genitourinary abnormalities and mental retardation syndrome-associated aniridia have been traced to a mutation of the PAX6 gene on band 11p13. Since genetic diagnosis of this disorder is already possible, counselling affected families should be preceded by karyotype studies and linkage analysis in familial cases of isolated aniridia. In sporadic cases of isolated aniridia or WAGR syndrome, we suggest that PAX6 mutation analysis be employed.     

Screening for wilms' tumour in patients with aniridia,Beckwith syndrome,or hemihypertrophy

The role of screening for early detection of Wilms' tumour (WT) in patients with aniridia (A), Beckwith-Weidemann syndrome (BWS) and hemihypertrophy (HH) has been explored. Of the 1,622 Wilms' tumour patients registered with the National Childhood Cancer Registry from 1971 to 1991, 41 were recorded as having A, BWS or HH. Twenty-eight of these had their anomaly diagnosed before the WT and 13 had screening procedures carried out, mainly abdominal ultrasound. In 8 patients the screening procedure detected the WT. There was no significant difference in stage distribution or outcome for any of the three subgroups who were not screened, screen-positive or screen-negative. We conclude that regular screening with abdominal ultrasound is not of proven value. Parents should be taught abdominal palpation and advised to seek appropriate advice for untoward symptoms. © 1995 Wi1ey-Liss Inc.     

Familial Wilms' tumor: A descriptive study

Among 6,209 patients with Wilms' tumor entered on the National Wilms' Tumor Study (NWTS), 93 patients (1.5%) from 63 families had a positive family history. In 30 of these 63 families a (half) sibling or parent of the NWTS patient was confirmed to have had Wilms' tumor. Fifteen (16.1%) of the familial, but only 7.1% of sporadic cases, had bilateral disease. Mean ages at diagnosis were 15.8 vs. 35.2 months (P = 0.012) for bilateral vs. unilateral familial cases and 32.0 vs. 44.7 months for sporadic cases. Intralobar nephrogenic rests were found twice as frequently in association with the tumors of familial as with those of sporadic cases. Cases of bilateral and metastatic disease tended to cluster within specific families, suggesting heterogeneity in the genetic etiology. The number and age distribution of familial cases transmitted through the father were about the same as those of cases transmitted through the mother. This finding is inconsistent with models of genomic imprinting that involve familial transmission of a tumor-suppressor gene and it casts further doubt on the hypothesis that all bilateral cases are hereditary. © 1996 Wiley-Liss, Inc.     

WAGR syndrome with tetralogy of Fallot and hydrocephalus

Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome occurs sporadically due to deletion of chromosome 11p13. A variety of other abnormalities involving different systems have been reported in patients with WAGR syndrome. We report on a patient with WAGR syndrome with accompanying tetralogy of Fallot and hydrocephalus.     

Second primary neoplasms in a population-based series of patients diagnosed with renal tumours in childhood

Eight second malignant tumours developed in a population-based series of 218 patients diagnosed with renal tumours in childhood: renal cell carcinoma of the contralateral kidney, hepatocellular carcinoma, Hodgkin's disease, and 4 basal cell and 1 squamous cell carcinomas of skin. Excess risk of developing a second malignancy (excluding skin carcinomas but including a registrable spinal neurofibroma) was 14.7 (95% Cl 4.0-37.7, P = 0.0003) for Wilms' tumour patients. Cumulative incidence of second malignant neoplasms (excluding skin carcinoma) was zero at 10 years, 5.0% at 20 years, and 10.2% at 30 years. The most common second neoplasms seen were benign osseous/chondromatous tumours and 4 of the 7 Wilms' tumour patients with malignant tumours had previous or synchronous tumours of this kind. Development of bony exostoses may be a marker for those patients at particularly high risk of subsequent malignancy. © 1994 wiley-Liss, Inc.     

Thirty-year population-based review of childhood renal tumours with an assessment of prognostic features including tumour DNA characteristics

We have reviewed all paediatric kidney tumours seen in the West Midlands Health Authority Region over a 30-year period. There were 205 cases confirmed after a review of the pathology by three paediatric pathologists. Seven were cases of bone metastasising renal tumour (clear cell sarcoma), 5 were rhabdoid tumours, 2 were renal cell carcinomas, and 13 were mesoblastic nephromas. In 3 cases, it was not possible to define further the histological diagnosis. The remaining 175 cases were considered to be Wilms' tumour (86%), which is equivalent to an incidence of 5.7/10⁶/year. In the cases of Wilms' tumour, there were 91 boys and 84 girls (1.1:1). The majority of patients were Caucasian with only 7% of non-Caucasian origin. At presentation, 78% of the patients were less than 5 years old. All of these patients except 9 had surgery as part of their treatment, 154 children had total nephrectomy, 3 had partial nephrectomy, and 9 had other surgical procedures. The majority also received chemotherapy and radiotherapy. Sex, chemotherapy, and stage all had prognostic significance in univariate analysis. The actuarial survival at 10 years increased from 17% for patients treated in the first decade of the study to 78% for patients treated in the third. DNA characteristics were investigated using flow cytometry in paraffin-embedded material and adequate information was obtained in 73 cases of Wilms' tumour. Only 7 had aneuploid tumours. Univariate survival analysis of these 73 results showed that stage, sex, the percentage of cells in the synthetic phase and the proliferative index from the DNA investigations had predictive value. © 1993 Wiley-Liss, Inc.     

Management of Wilms' tumour

Wilms' tumour (WT) is the commonest renal tumour of childhood and its treatment is regarded as one of the success stories of paediatric oncology with over 90% cure rate. Most patients present with localized unilateral tumours. Histology and stage are important prognostic factors, and children with stage IV and diffuse anaplasia have poorer outcomes. Whilst there are differences in the treatment approaches around the world, outcomes are excellent for most subgroups of Wilms' tumour. The European Société Internationale d'Oncologie Pédiatrique (SIOP) recommends pre-operative chemotherapy to children over 6 months whilst the North American Children's Oncology Group offers primary nephrectomy and uses biomarkers for treatment stratification. Overall, 15% patients experience a relapse and their management depends on the initial treatment they had received. The focus of research is to decrease long term side effects, reduce treatment for selected subgroups, and improve our understanding of prognostic biomarkers to help tailor treatments. This article provides an overview for paediatricians giving an update on the important recent advances.     

Genetics and epidemiology of Wilms' tumor: The French Wilms' tumor study

A complete family history was obtained for 501 patients with Wilms' tumor, treated in departments of pediatric oncology in whole France. The information was collected by self-questionnaire and/or by interview of parents. The proportion of bilateral cases is 4.6% and there are 12 patients (2.4%) with a positive family history of Wilms' tumor. The affected relatives are most often distant and no first degree relative was affected. Apart from the well-known associations with aniridia, hemihypertrophy, genitourinary anomalies, Beckwith-Wiedeemann, and Drash syndromes, there is also a significant excess of congenital heart defects (P = .008) which remains to be explained. Several findings support the bimutational hypothesis such as earlier diagnosis and increased parental age in bilateral cases. No particular anomalies and no increased frequency of childhood cancer were found in patients' relatives. The frequency of Wilms' tumor in relatives was estimated to be less than 0.4% in sibs, 0.06% in unclesand aunts, and 0.04% in first cousins. These figures are very different from those found in retinoblastoma and suggest that the mechanism may be more complex in Wilms' tumor. This conclusion is in agreement with molecular biology studies in tumors and linkage analysis in multiple case families which suggest that more than one locus is involved. © 1992 Wiley-Liss, Inc.     

Billateral Polycystic Kidneys in a Girl with WAGR Syndrome

The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genito-urinary abnormalities, and mental retardation. An 8.5-year-old girl was initially investigated at the age of 18 months for congenital bilateral aniridia, cataracts, glaucoma and epicantus. The ultrasound (US) scan showed polycystic kidney disease. FISH study revealed deletion of the WT1 and PAX6 gene in the 11p13 WAGR region. Forty days after the first kidney US, the second US revealed a 3 cm tumor in the right kidney: a Wilms tumour, treated successfully with the Wilm’s tumor protocol. The authors conclude that the identification of the deletions in the WAGR region in patients with aniridia should definitely be done. In addition, Wilms tumor can have a very rapid growth, which, per se requires frequent and careful ultrasound kidney controls. Polycystic kidneys can be part of the WAGR presentation.     

Malignant tumours in the neonate.

One hundred and two cases of neonatal cancers, representing 2% of all paediatric malignancies, were seen during a 60 year period at The Hospital for Sick Children, Toronto, Canada. The neonatal cancers included neuroblastoma (47%), retinoblastoma (17%), soft tissue sarcoma (12%), central nervous system tumours (9%), leukaemia (8%), and a few cases of Wilms'' tumour, liver tumour, and miscellaneous tumours. The overall mortality from disease was 41%. Patients with retinoblastoma, Wilms'' tumour, and neuroblastoma had the best prognosis. Forty three patients (42%) survived their neonatal cancers; all were treated with surgery or radiochemotherapy, or both, but none suffered long term major handicaps as a result of treatment. There was one instance of second malignancy of the thyroid gland induced by radiation. We conclude that although neonatal cancers are difficult management problems, many patients can be cured. Physicians should discuss with parents the possible risks associated with treatment before treatment is begun.     

Risk of Wilms' tumour with multicystic kidney disease: a systematic review

Background: Children with multicystic kidney disease (MCKD) are increasingly managed conservatively and are followed up throughout childhood because they are perceived to be at increased risk of developing Wilms'' tumour. With this risk still poorly defined and somewhat controversial, the strategy and the duration of follow up do not seem to be based on evidence. Methods: Systematic review of the literature for all published cohort studies (prospective and retrospective) of children diagnosed to have unilateral MCKD and managed conservatively. Exclusion criteria: bilateral MCKD, nephrectomy (not for malignancy) during the follow up period. We estimated for children with MCKD the probability of developing Wilms'' tumour during the follow up period, with 95% CI using the Poisson distribution. Results: From 26 reviewed studies, no cases of Wilms'' tumour developed in 1041 eligible children. The mean probability of a child with unilateral MCKD to develop Wilms'' was therefore nil, with a 97.5% upper CI estimated at 0.0035 (or 3.5 per 1000 children). Conclusion: The development of a national or a European registry for children with MCKD would increase the precision of their risk estimate to develop Wilms'' tumour. In the meantime, there is no evidence to support any of the different modalities for following up these children by ultrasound, if indeed such a strategy is necessary.     

Racial variation in incidence of Wilms' tumor: Relationship to congenital anomalies

This is a study of the occurrence of Wilms' tumor and associated anomalies in all incident cases in the Greater Delaware Valley by race. The average annual incidence of Wilms' tumor in this population of 2 million children is significantly higher among nonwhites than whites. A significantly larger proportion of black cases has a Wilms' tumor-associated condition including aniridia, genito-urinary anomalies, the Beckwith-Wiedemann Syndrome, and hemihypertrophy. For very young patients, there was a greater tendency for blacks to have bilateral tumors or a tumor-associated anomaly, features characteristic of the hereditary form of Wilms' tumor. The excess risk of Wilms' tumor among blacks may be a result of a higher proportion having a hereditary predisposition or more common exposure to agents capable of inducing germinal mutations.     

Analysis of gene dosage on chromosome 11 in children suffering from Beckwith-Wiedemann syndrome

The Beckwith-Wiedemann syndrome (BWS) is composed of multiple congenital malformations coupled with a high concurrent risk for the development of specific rare childhood tumours. The syndrome is characterised by a complex mode of inheritance, but recent evidence indicates that it is an autosomal dominant trait with variable penetrance. It has been previously suggested that major rearrangements of the short arm of chromosome 11 are involved in the aetiology of the disease. We undertook to search for rearrangements in 11p in four patients with BWS and their parents and siblings. By using cloned DNA fragments homologous to four genes located on 11p, namely catalase, parathyroid hormone, insulinlike growth factor II and the proto-oncogene c-Ha-Ras, we subjected DNA from the patients to a restriction fragment length polymorphism (RFLP) analysis after digestion with restriction enzymes. We found no evidence for any large scale deletions or amplifications in this chromosomal region. We therefore conclude that altered gene dosage is not, as has been suggested, a requirement for the development of BWS. This raises the question of whether some other molecular mechanism is responsible for the malformations observed.Abbreviations BWS Beckwith-Wiedemann syndrome - IGFII insulin like growth factor II - RFLP restriction fragment length polymorphism - SSC 0.15 M sodium chloride, 0.015 M sodium citrate - WAGR Wilms/aniridia/genitourinary abnormality syndrome     

Sporadic bilateral retinoblastoma and 13q-chromosomal deletion

Unilateral retinoblastoma (Rb) is usually a sporadic occurrence while bilateral (multi-focal) cases are often familial. Sporadic bilateral Rb associated with a long-arm deletion of a D-group chromosome has been reported in 8 children. We have studied a 6-year-old female with bilateral sporadic retinoblastoma, treated during infancy by enucleation and radiotherapy. Chromosome banding studies on peripheral lymphocytes revealed an interstitial deletion from the long arm of a chromosome 13: del(13) (q12q14). Three additional patients reported in the literature had interstitial 13q- deletions, involving slightly different though overlapping regions. The only chromosomal region consistently missing in all of these 4 cases appears to be part of the lightly staining band 13q14. We, therefore, propose this site as the precise location of a gene (or genes) involved in retinal development. Our patient lacked features of the classic 13q- or 13-ring syndrome, which involves deletion of a more distal portion of the 13 long arm. When compared to reported patients with Rb and 13q-, it became apparent that there may be a separate recognizable syndrome consisting of moderate growth and developmental delay, characteristic facies and external ears, and bilateral sporadic Rb, which is associated with an interstitial 13q- deletion.     

How curable is relapsed Wilms' tumour? The United Kingdom Children's Cancer Study Group.

Three hundred and eighty one children with Wilms'' tumour were treated on the United Kingdom Children''s Cancer Study Group WT1 Study (1980/6). Seventy one patients relapsed during or after treatment, which included surgery and chemotherapy, with irradiation depending on stage and histology. Despite treatment with various combinations of chemotherapy, surgery, and radiotherapy there were only 17 survivors. For unfavourable histology, any stage, only two of 20 survive. We conclude that, after relapse, even for patients who have had localised disease and favourable histology, the ''salvage'' rate is little more than 50% and for all others the likelihood of cure is very small. Three of 41 children who relapsed less than 12 months from diagnosis survive, compared with 14 of 30 who relapsed later. It is essential that even with this ''good prognosis'' tumour initial treatment is optimal and given by centres experienced in management of children''s cancer. Furthermore, there is a clear need for additional effective chemotherapeutic agents for relapsed patients.     

B-cell non-Hodgkin's lymphoma presenting as a primary renal tumour in a child

A 6-year-old boy presented with a unilateral renal tumour thought to be a Wilms' tumour. He had started a treatment but review of the histology and immunohistochemical studies proved the tumour to be a primary renal B-cell lymphoma. This case illustrates the importance of an open-minded approach in the histological examination of small round cell tumours in the kidney and immunohistochemical studies in such cases are strongly advocated. © 1995 Wiley-Liss, Inc.