Developed Wilms Tumor Research Articles

Genotype/Phenotype Correlation in Nephrotic Syndrome Caused by WT1 Mutations

The risk of developing Wilms tumor (WT) can be present or absent in patients with nephrotic syndrome (NS) caused by WT1 mutations. Here, the genotype/phenotype correlation regarding the outcome and risk for WT in 52 patients from 51 families with NS due to WT1 mutations is described. This study followed 19 patients with mutations in intron 9 splice donor site (KTS mutations), 27 patients with missense mutations, 4 patients with nonsense mutations, 1 patient with a splice site mutation in intron 8, and 1 patient with a deletion. Twenty-four different WT1 mutations were detected. Sixteen of the 19 patients with KTS mutations were females. These patients had isolated NS if karyotype was 46,XX and Frasier syndrome if karyotype was 46,XY. Patients with KTS mutations presented at a significantly older age and with a slower progression toward chronic kidney disease (CKD) stage 5, compared with missense mutations. Patients with nonsense mutations presented initially with WT. Six patients with missense mutations developed WT after the diagnosis of NS (interval-range from NS onset to WT of 0.1 to 1.4 years). (1) KTS mutations cause isolated NS with absence of WT in 46,XX females. (2) KTS mutations cause Frasier syndrome with gonadoblastoma risk in 46,XY phenotypic females. (3) KTS mutations cause NS with a slower progression when compared with missense mutations. (4) Missense mutations can occur with and without WT. (5) WT1 analysis is important in young patients with NS for early detection and tumor prophylaxis.

Wilms tumor arising in a child with X-linked nephrogenic diabetes insipidus

We report on a child with X-linked nephrogenic diabetes insipidus (NDI) who developed Wilms tumor (WT). Nephrogenic diabetes insipidus is caused by mutations of the arginine vasopressin receptor (AVPR2) or aquaporin-II (AQP2) genes. Wilms tumor is also genetically heterogeneous and is associated with mutations of WT1 (15-20%), WTX (20-30%) and other loci. The boy presented at 5 months with failure to thrive, polyuria, hypernatremia and abdominal mass. Analysis of leukocyte DNA showed a novel missense mutation (Q174H) of the AVPR2 gene, which was not present in his mother. In cells (WitS) isolated from the tumor, WTX mRNA expression and coding sequence were intact. However, we identified a 44-kb homozygous deletion of the WT1 gene spanning exons 4 to 10. The WT1 deletion was not present in leukocyte DNA from the patient or his mother. We also noted strong beta-catenin (CTNNB1) expression in the tumor cells and identified a heterozygote missense Ser45Cys mutation of exon 3 of CTNNB1. However, the mutation was absent both in the constitutional DNA of the patient and his mother. The concurrence of WT and NDI has not been previously reported and may be unrelated. Nevertheless, this case nicely illustrates the sequence of events leading to sporadic Wilms tumor.

Clinical and genetic findings of five patients with WT1-related disorders

To present phenotypic variability of WT1-related disorders. Description of clinical and genetic features of five 46,XY patients with WT1 anomalies. Patient 1: newborn with genital ambiguity; he developed Wilms tumor (WT) and chronic renal disease and died at the age of 10 months; the heterozygous 1186G>A mutation compatible with Denys-Drash syndrome was detected in this child. Patients 2 and 3: adolescents with chronic renal disease, primary amenorrhea and hypergonadotrophic hypogonadism; patient 2 had a gonadoblastoma. The heterozygous IVS9+4, C>T mutation, compatible with Frasier syndrome was detected. Patient 4: 9-year-old boy with aniridia, genital ambiguity, dysmorphisms and mental deficiency; a heterozygous 11p deletion, compatible with WAGR syndrome was detected. Patient 5: 2 months old, same diagnosis of patient 4; he developed WT at the age of 8 months. Constitutional abnormalities of WT1 cause gonadal and renal anomalies and predisposition to neoplasia and must be investigated in patients with ambiguous genitalia, chronic renal disease and(or) Wilms tumors; primary amenorrhea with chronic renal disease; and aniridia, genital ambiguity and dysmorphisms.

Hyperplastic perilobar nephroblastomatosis: Long‐term survival of 52 patients

This study provides insight into the clinical behavior, diagnostic complexities, and long-term management of patients with hyperplastic perilobar nephroblastomatosis (HPLN). Fifty-two patients with HPLN with available long-term follow-up were retrospectively analyzed for pathologic, radiologic, and clinical features. The mean age at diagnosis was 16 months; the lesions were bilateral in 49 patients. Of 33 patients who initially underwent diagnostic biopsy and adjuvant chemotherapy, 18 (55%) developed Wilms tumor (WT) at a mean of 35 months from diagnosis. Of 16 patients whose initial therapy included nephrectomy and adjuvant therapy, three (19%) developed WT at a mean of 36 months from diagnosis. All three patients who underwent initial diagnostic biopsy and received no adjuvant therapy during their initial course developed WT 4, 4, and 10 months following diagnosis. 24/52 patients developed either a single (13 patients) or multiple (11 patients) WT throughout their course; 8/24 (33%) of WT were anaplastic. The time from initial diagnosis to the development of the last WT ranged from 13 to 116 months (mean 42 months). Three children with HPLN died of WT at 3, 5, and 6 years of age; 2/3 were anaplastic. HPLN is a self-limited, pre-neoplastic proliferative process associated with a high risk of developing WT. The accurate diagnosis and the choices of therapy during the often-complex course of HPLN depend on the availability and accurate interpretation of a combination of pathologic, radiologic, and clinical information. When such information is appropriately obtained, the long-term survival of patients with HPLN is excellent.

Wilms tumor screening is unnecessary in Klippel-Trenaunay syndrome.

Children with hemihypertrophy are screened for Wilms tumor, because this condition is a risk factor for developing the neoplasm. Patients with Klippel-Trenaunay syndrome (KTS) are often considered potential candidates for Wilms tumor, because they have unilateral overgrowth of the lower limb. In our experience, however, an association between KTS and Wilms tumor has not been observed. To determine whether KTS and Wilms tumor are associated, we reviewed our institutional experience for patients with both diagnoses and searched the Klippel-Trenaunay literature for patients with Wilms tumor. The National Wilms Tumor Study Group database also was studied to identify patients with KTS. Two-sided exact binomial tests were used to evaluate whether patients with 1 condition had an increased risk for the other. Ninety-five percent confidence intervals for these 2 risks were compared with the general population risks of Wilms tumor (1 in 10 000) and KTS (1 in 47 313). None of the 115 patients with KTS followed at our institution developed Wilms tumor. One case of Wilms tumor has been reported in 1363 patients with KTS in the literature, giving a confidence interval of (1/57 377) and (1/267). None of the 8614 patients in the National Wilms Tumor Study Group database had KTS, giving a confidence interval of (0, 1/2336). Because the risks of KTS and Wilms tumor in the population fall within these confidence intervals, one cannot conclude that the risks of KTS among Wilms tumor patients or Wilms tumor among KTS patients are any different from the corresponding risks in the general population. Patients with KTS are not at increased risk for developing Wilms tumor and thus should not undergo routine ultrasonographic screening.

Association of biallelicBRCA2/FANCD1mutations with spontaneous chromosomal instability and solid tumors of childhood

AbstractThe clinical, cytogenetic, and molecular findings of 2 Fanconi anemia (FA) subtype D1 kindreds, initially identified through a young child with a solid tumor (medullobastoma, Wilms tumor), are described. Each kindred subsequently had a second affected child; one developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies revealed an unusually high spontaneous chromosome aberration rate, contrasting with other FA subtypes. Molecular analysis revealed biallelicBRCA2/FANCD1mutations. The patients did not exhibit bone marrow failure. Our studies suggest that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role ofBRCA2in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood. Recognition of this constellation of findings has significant implications for medical management and genetic counseling of FA families.

Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients.

Aniridia is an autosomal dominant eye anomaly caused by haploinsufficiency of the PAX6 gene, of which abnormalities include base alterations, position effects and deletions. When deletion involves its adjacent genes, i.e., those in the PAX6-WT1 critical region (WTCR), patients are predisposed to Wilms tumor. We studied 18 patients with aniridia, five of whom had chromosome deletion involving 11p13, two a translocation t(10;11)(p13;p13) or a der(14;21)(q10;q10)mat, and 11 had a normal karyotype. Fluorescence in situ hybridization (FISH) using four P1-derived artificial chromosome (PAC) clones located at WTCR was carried out in the 18 patients to identify a deletion extent. Of the 18 patients, eight had a deletion of WTCR: four had microscopic deletion and four a deletion of WTCR. Deleted region in one patient with a microscopic deletion was distal to the critical region. Four of the eight patients with a deletion encompassing WTCR developed Wilms tumor, and the other four did not (two were too young to be evaluated for the tumor development). The data in the present study, together with four similar previous works, indicate that of a total of 102 aniridia patients, 29 had a deletion spanning WTCR. Wilms tumor developed in 13 (45%) of the 29 patients, whereas patients without deletion in this region did not develop the tumor. In other words, aniridia patients with WT1 deletion run a high risk of developing Wilms tumor, and those without the deletion do not.

WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin

The WT1 tumor suppressor gene encodes a zinc finger transcription factor expressed in differentiating glomerular podocytes. Complete inactivation of WT1 in the mouse leads to failure of mesenchymal induction and renal agenesis, an early developmental phenotype that prevents analysis of subsequent stages in glomerular differentiation [1]. In humans with Denys-Drash Syndrome, a heterozygous germline mutation in WT1 is associated with specific defects in glomeruli and an increased risk for developing Wilms Tumor [2, 3]. WT1 target genes implicated in cell cycle regulation and cellular proliferation have been proposed [4], but the link between WT1 function and glomerular differentiation is unexplained. Here, we show that inducible expression of WT1 in rat embryonic kidney cell precursors leads to the induction of endogenous Podocalyxin, the major structural membrane protein of glomerular podocytes, which is implicated in the maintenance of filtration slits. Binding of WT1 to conserved elements within the Podocalyxin gene promoter results in potent transcriptional activation, and the specific expression pattern of Podocalyxin in the developing kidney mirrors that of WT1 itself. These observations support a role for WT1 in the specific activation of a glomerular differentiation program in renal precursors and provide a molecular basis for the glomerulonephropathy that is characteristic of Denys-Drash Syndrome.

Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia.

Aniridia is a severe eye disease characterized by iris hypoplasia; both sporadic cases and familial cases with an autosomal dominant inheritance exist. Mutations in the PAX6 gene have been shown to be the genetic cause of the disease. Some of the sporadic cases are caused by large chromosomal deletions, some of which also include the Wilms tumor gene (WAGR syndrome), resulting in an increased risk of developing Wilms tumor. Based on the unique registration of both cancer and aniridia cases in Denmark, we have made the most accurate risk estimate to date for Wilms tumor in sporadic aniridia. We have found that patients with sporadic aniridia have a relative risk of 67 (confidence interval: 8.1-241) of developing Wilms tumor. Among patients investigated for mutations, Wilms tumor developed in only two patients out of 5 with the Wilms tumor gene (WT1) deleted. None of the patients with smaller chromosomal deletions or intragenic mutations were found to develop Wilms tumor. Our observations suggest a smaller risk for Wilms tumor than previous estimates, and that tumor development requires deletion of WT1. We report a strategy for the mutational analysis of aniridia cases resulting in the detection of mutations in 68% of sporadic cases and 89% of familial cases. We also report four novel mutations in PAX6, and furthermore, we have discovered a new alternatively spliced form of PAX6.

Chromosomal Instability Syndrome of Total Premature Chromatid Separation with Mosaic Variegated Aneuploidy Is Defective in Mitotic-Spindle Checkpoint

Skin fibroblast cells from two unrelated male infants with a chromosome-instability disorder were analyzed for their response to colcemid-induced mitotic-spindle checkpoint. The infants both had severe growth and developmental retardation, microcephaly, and Dandy-Walker anomaly; developed Wilms tumor; and one died at age 5 mo, the other at age 3 years. Their metaphases had total premature chromatid separation (total PCS) and mosaic variegated aneuploidy. Mitotic-index analysis of their cells showed the absence of mitotic block after the treatment with colcemid, a mitotic-spindle inhibitor. Bromodeoxyuridine-incorporation measurement and microscopic analysis indicated that cells treated with colcemid entered G1 and S phases without sister-chromatid segregation and cytokinesis. Preparations of short-term colcemid-treated cells contained those cells with chromosomes in total PCS and all or clusters of them encapsulated by nuclear membranes. Cell-cycle studies demonstrated the accumulation of cells with a DNA content of 8C. These findings indicate that the infants' cells were insensitive to the colcemid-induced mitotic-spindle checkpoint.

Screening for Wilms tumor in children with Beckwith‐Wiedemann syndrome or idiopathic hemihypertrophy

Background Children with Beckwith-Wiedemann syndrome and idiopathic hemihypertrophy (BWS/HH) are at increased risk for developing Wilms tumor and screening with abdominal sonography is frequently recommended. However, there is a paucity of published data supporting this strategy. The purpose of this study was to determine whether sonographic screening at intervals of 4 months or less reduced the proportion of late-stage Wilms Tumor (WT) in children with BWS/HH. Procedure A case series analysis was employed to compare the proportion of late-stage (stage III or IV) Wilms tumor in patients with BWS/HH who were screened with sonography (n = 15) to the proportion of late-stage Wilms tumor in unscreened patients with BWS/HH (n = 59). Patients were identified from the BWS Registry and from previously published studies. Screened patients had sonograms at intervals of 4 months or less. Results None of the 12 screened children with Wilms tumor had late-stage disease, whereas 25 of 59 (42%) of unscreened children had late-stage Wilms tumor, a difference that was statistically significant (P < 0.003). Three children had false positive screening studies. They were operated on for suspected Wilms tumor but the lesions proved to be complicated renal cysts (n = 2) or nephroblastomatosis (n = 1). Conclusions This study suggests that children with BWS/HH may benefit from screening sonograms at intervals of 4 months or less. However, false positive screening exams may result in unnecessary surgery. Given the rarity of BWS/HH, a larger, prospective international screening study is necessary to determine if the benefits of screening outweigh the risks. Med. Pediatr. Oncol. 32:196–200, 1999. © 1999 Wiley-Liss, Inc.

Screening for Wilms tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy.

Children with Beckwith-Wiedemann syndrome and idiopathic hemihypertrophy (BWS/HH) are at increased risk for developing Wilms tumor and screening with abdominal sonography is frequently recommended. However, there is a paucity of published data supporting this strategy. The purpose of this study was to determine whether sonographic screening at intervals of 4 months or less reduced the proportion of late-stage Wilms Tumor (WT) in children with BWS/HH. A case series analysis was employed to compare the proportion of late-stage (stage III or IV) Wilms tumor in patients with BWS/HH who were screened with sonography (n = 15) to the proportion of late-stage Wilms tumor in unscreened patients with BWS/HH (n = 59). Patients were identified from the BWS Registry and from previously published studies. Screened patients had sonograms at intervals of 4 months or less. None of the 12 screened children with Wilms tumor had late-stage disease, whereas 25 of 59 (42%) of unscreened children had late-stage Wilms tumor, a difference that was statistically significant (P < 0.003). Three children had false positive screening studies. They were operated on for suspected Wilms tumor but the lesions proved to be complicated renal cysts (n = 2) or nephroblastomatosis (n = 1). This study suggests that children with BWS/HH may benefit from screening sonograms at intervals of 4 months or less. However, false positive screening exams may result in unnecessary surgery. Given the rarity of BWS/HH, a larger, prospective international screening study is necessary to determine if the benefits of screening outweigh the risks.

Nephrogenic Rests and Renal Abnormalities in Brachmann-De Lange Syndrome

We report renal abnormalities found in four cases of Brachmann-de Lange syndrome (BDLS). In two there were nephrogenic tests and renal cortical cysts, a further case showed cortical cysts, and the fourth had dilated collecting ducts. The literature describing renal abnormalities in BDLS has been reviewed, and this includes a report of one individual with BDLS who developed Wilms tumor. The genetic basis of BDLS has not been elucidated, although a submicroscopic abnormality of chromosome 3 seems likely. Nephrogenic rests may be Wilms' tumor precursor lesions and are seen in syndromes associated with Wilms' tumors. Mutations of genes on chromosome 11 are the most common genetic abnormalities associated with Wilms' tumor, but other chromosomes have also been implicated. The frequency of renal abnormalities in the BDLS suggests that the involved gene may be important in renal development and also possibly in Wilms' tumors.

Screening of children with hemihypertrophy, aniridia, and Beckwith-Wiedemann syndrome in patients with Wilms tumor: a report from the National Wilms Tumor Study.

To evaluate the usefulness of regular radiographic screening to detect an asymptomatic intraabdominal tumor in patients with an increased risk of developing Wilms tumor, we reviewed the files of patients with hemihypertrophy, aniridia, or Beckwith-Wiedemann syndrome who were registered on the National Wilms Tumor Studies. Screening was employed infrequently in the management of children with hemihypertrophy, with only 25% (6/24) of those whose hemihypertrophy was identified more than 30 days prior to the diagnosis of Wilms tumor undergoing such examinations. Most patients with aniridia were evaluated regularly for the occurrence of Wilms tumor. There were more stage 1 tumors identified in patients whose tumor was detected only through radiographic evaluation. The role of routine radiographic screening needs to be carefully evaluated in a homogeneous group of patients such as those with aniridia using a prospective study design to determine if such screening improves the survival rate of children with this rapidly growing, but readily treatable form of childhood cancer.

A Case Report of Drash Syndrome in a 46,XX Female

Progressive renal insufficiency, male pseudohermaphrotidism, and Wilms tumor are known as the triad of Drash syndrome. The renal involvement has been reported in association with Wilms tumor with or without pseudohermaphroditism. The nephropathy progresses rapidly, is unresponsive to steroids, and eventually requires dialysis. The case we report is a 46,XX phenotypic female child who had diffuse mesangial sclerosis (DMS) and developed Wilms tumor 3 years after initiating dialysis for end-stage renal disease (ESRD). Any child presenting with DMS should be considered at risk for development of Wilms tumor and should be investigated for the presence of XY gonadal dysgenesis. Once ESRD develops in such a child, prophylactic nephrectomy and possibly gonadectomy should be undertaken.

High-resolution studies in patients with aniridia-Wilms tumor association, Wilms tumor or related congenital abnormalities.

We attempted to determine whether all cases of AWTA (anirida-Wilms tumor association) or any of the following groups of patients show 11p deletion: cases of Wilms tumor with congenital abnormalities other than aniridia, those without any congenital abnormalities, tumor itself in cases of Wilms tumor without constitutional 11p deletion and cases of aniridia or hemihypertrophy without Wilms tumor. We studied a total of 29 index patients including five cases of AWTA, four cases of Wilms tumor with various congenital abnormalities, 16 cases of Wilms tumor without other abnormalities, three cases of aniridia in one of which Wilms tumor developed later and a case of hemihypertrophy. In all five cases of AWTA and in a case of aniridia who later developed Wilms tumor, 11p deletion involving the p13 band was detected. The mother of the latter also showed an identical 11p deletion. The common segment of deletion was the middle part of the p13. Two possible hypotheses on the mechanism through which Wilms tumor might develop were evaluated, based on the distribution of break points. All other cases, including five with tumor culture, showed a normal karyotype.