Genetic Predisposition to Wilms Tumour

Literature and regulatory information updated: 6 October 2026.

WT1-related disorder (Denys-Drash, Frasier and Meacham spectrum), non-syndromic predisposition genes (TRIM28, REST, CTR9, heterozygous DIS3L2, FBXW7, NYNRIN, KDM3B), rare syndromes with high risk (Perlman, osteopathia striata with cranial sclerosis due to AMER1, mosaic variegated aneuploidy, Fanconi anaemia D1/N and others) and familial Wilms tumour; WAGR spectrum disorder and the Beckwith-Wiedemann spectrum are covered in their Wilms tumour predisposition aspects

0. Initial Reference Table

1. Introduction

Wilms tumour, or nephroblastoma, is the most common renal neoplasm of childhood and a classical model of the relationship between embryonic development and cancer [1, 8]. In 1894, Birch-Hirschfeld brought together under a single designation more than twenty terms used for this tumour, and in 1899 Max Wilms published the monograph on mixed tumours of the kidney (Die Mischgeschwülste der Niere) that gave it its name [19, 20]. Therapeutic progress, from surgery with postoperative radiotherapy, which achieved 47% survival in the mid-twentieth century, to the introduction of actinomycin D by Sidney Farber, raised survival to approximately 90% by the end of the century, shifting the research focus towards reducing toxicity and towards children at increased risk [1, 20].

The history of predisposition began with clinical observations. In 1964, Miller, Fraumeni and Manning described the association of Wilms tumour with aniridia, hemihypertrophy and other congenital malformations; in the same year, Frasier and colleagues reported monozygotic twins with pure gonadal dysgenesis and gonadoblastoma; in 1967, Denys and colleagues associated male pseudohermaphroditism, Wilms tumour and parenchymal nephropathy; and in 1970 Drash and colleagues described the syndrome of pseudohermaphroditism, Wilms tumour, hypertension and degenerative renal disease [21–24]. In 1972, Knudson and Strong published a mutational model for Wilms tumour of the kidney [25]. In 1978, Riccardi and colleagues identified interstitial 11p deletions in patients with aniridia and Wilms tumour, with genitourinary anomalies and intellectual disability, the pattern subsequently termed WAGR syndrome [26]. In 1975, Perlman and colleagues described a new case of the syndrome of fetal gigantism, renal hamartomas and nephroblastomatosis with Wilms tumour [27].

The molecular era opened in 1990 with the cloning of WT1 at 11p13 by two independent groups [28, 29]. In 1991, Pelletier and colleagues found germline variants in the WT1 zinc fingers in ten cases of Denys-Drash syndrome, and in 1997 Barbaux and colleagues showed that Frasier syndrome results from intron 9 splice donor site variants, with a reduction in the +KTS isoform [30, 31]. These were followed by AMER1 (WTX), discovered in 2007 as a gene somatically inactivated in approximately one-third of tumours and associated in 2009 with osteopathia striata with cranial sclerosis; DIS3L2, identified in 2012 as the cause of Perlman syndrome; CTR9 (2014); REST (2015); TRIP13 (2017); and TRIM28, FBXW7, NYNRIN and KDM3B (2018–2019) [6, 32–39]. National cohort studies with systematic assessment subsequently showed that genetic or epigenetic predisposition, including kidney-confined mosaicism, is present in at least one-third of children with Wilms tumour in the Netherlands [7].

Clinical management rests on consensus documents from two groups and on expert reviews: the European recommendations of the SIOP-Europe Host Genome Working Group and SIOP-RTSG (2021), which cover all known genes and syndromes and use a 5% risk threshold; the North American AACR recommendations of 2017, updated in 2024 for the syndromes and in 2025 for the non-syndromic predisposition genes, with a 1% threshold; and the GeneReviews chapters on Wilms tumour predisposition (2022) and on WT1-related disorder (updated in 2025) [1, 3, 8, 10, 12, 15]. This article covers Wilms tumour predisposition as a spectrum, with emphasis on WT1-related disorder (including the constellations historically termed Denys-Drash and Frasier syndromes), the non-syndromic predisposition genes, the rare syndromes with high risk and familial Wilms tumour; WAGR spectrum disorder and the Beckwith-Wiedemann spectrum are covered in their Wilms tumour predisposition aspects.

2. Molecular Genetics and Pathophysiology

2.1. Nephrogenesis, nephrogenic rests and the two-hit model

Wilms tumour results from developmental arrest in the embryonic kidney, and nephrogenic rests are considered its precursors: pathogenic variants may predispose to rest formation, and additional events transform them into tumours [1, 7]. The topography of the rests has aetiological significance: intralobar rests predominate in WT1 syndromes and perilobar rests in overgrowth syndromes and trisomies 18 and 13 [4]. Knudson and Strong proposed a mutational model for Wilms tumour in 1972, and GeneReviews interprets the very high risk in children with a germline loss-of-function WT1 variant as consistent with the two-hit model [3, 25]. The same tumour suppressor mechanism was demonstrated in subsequently discovered predisposition genes: a somatic second hit in REST, CTR9, TRIM28 (frequently through mitotic recombination with loss of heterozygosity) and heterozygous DIS3L2 [7, 35, 36, 39, 40].

Phylogenetic analysis of 23 tumours and their corresponding kidneys showed premalignant clonal expansions in morphologically normal kidney tissue in 14 cases (61%), defined by somatic mutations shared with the tumour and absent from blood, with H19 locus hypermethylation in 58% of these expansions; in bilateral tumours, the expansions could have arisen before divergence of the left and right kidney primordia [9]. This observation explains how a bilateral tumour can result from an early postzygotic event confined to the kidneys, non-heritable if absent from germ cells, and supports the recommendation to study kidney tissue when germline testing is negative [1, 8]. In the German cohort of 129 children with familial or bilateral tumour, IC1 epigenetic alterations arose as early somatic events, with partial loss of imprinting or loss of heterozygosity at IGF2/H19 in normal kidney or blood, almost always without a clinical diagnosis of Beckwith-Wiedemann syndrome [41].

2.2. Architecture of predisposition

GeneReviews estimates that in 10–15% of patients the cause is a germline variant or an epigenetic alteration occurring early in embryogenesis [1]. In the exome study of 890 children with Wilms tumour (including 91 from 49 families), the 21 genes recognised at the time explained approximately 10% of unselected tumours: WT1, TRIM28, REST and 11p15 alterations with biallelic IGF2 expression each contributed approximately 2%, and the remaining 17 genes together no more than 2% [6]. Studies with systematic assessment found higher proportions: in the unselected Dutch national cohort (126 children, 2015–2020), 33.3% had a predisposing factor, including Beckwith-Wiedemann spectrum in 16%, WT1 alterations in 7.9% and heterozygous DIS3L2 variants in 4%, and 12 of the 42 diagnoses were made only in normal kidney DNA [7]; in the prospective Danish national cohort (24 children), 13% had a pathogenic germline variant (FBXW7, WT1 and REST, all in girls) and 33% had some indicator of predisposition, a proportion rising to 57% in girls [42]. The 2025 North American National Comprehensive Cancer Network (NCCN) guideline cites 10–15%, with reports of up to 30% [14]. These proportions measure different populations (unselected cohorts, cohorts with kidney tissue testing, series enriched for familial or bilateral cases) and are not interchangeable.

2.3. WT1

WT1 (11p13) encodes Wilms tumour protein, a transcription factor with a proline- and glutamine-rich interaction domain and four zinc fingers encoded by exons 7–10, expressed mainly in renal progenitors and podocytes, the urogenital ridge and gonadal progenitors [3]. More than 30 isoforms, generated by alternative splicing, alternative translation initiation sites and RNA editing, regulate urogenital differentiation according to their proportions; an alternative donor site in intron 9 adds three amino acids (lysine, threonine and serine, KTS) between the third and fourth zinc fingers [3, 31]. WT1 regulates glomerular slit diaphragm genes, such as those encoding nephrin and podocin, podocyte polarity and cytoskeleton, and has tumour suppressor and, in other contexts, oncogenic functions [3]. The gene was cloned in 1990 by two groups: Call and colleagues isolated, at the boundaries of the deletions defining the 11p13 locus, a gene of approximately 50 kb with messenger RNA of approximately 3 kb, expressed mainly in the kidney, encoding a protein with four zinc fingers; Gessler and colleagues identified a Krüppel-type zinc finger gene highly expressed in the fetal kidney and included in homozygous deletions in Wilms tumours [28, 29].

WT1-related disorder results from a dominant negative mechanism: missense, nonsense and frameshift variants in the zinc finger region cause loss, reduction or alteration of the isoforms' DNA-binding specificity [3]. In 1991, Pelletier and colleagues found point variants in the zinc fingers of one copy of WT1 in ten independent cases of Denys-Drash syndrome (nine in exon 9, zinc finger III; one in exon 8, zinc finger II), de novo in the two families studied and with reduction to homozygosity in the tumours [30]. Intron 9 donor site variants at +4 and +5 alter the ratio between isoforms with and without KTS: Barbaux and colleagues (1997) demonstrated that they cause Frasier syndrome, with predicted loss of the +KTS isoform and a reduction in the +KTS/−KTS ratio, and Klamt and colleagues showed that these variants, which preferentially affect a CpG dinucleotide, prevent synthesis of the +KTS isoform from the mutated allele without producing a mutant protein [31, 43]. More than 90% of pathogenic variants lie in exons 8 and 9 and intronic junctions; deletions of one or several exons have been described [3]. No founder WT1 variants or preferential geographical distribution have been described [3]. Germline WT1 alterations were estimated in 2–11% of patients with Wilms tumour in the European document, which acknowledges variation between geographical cohorts, in 1–5% in GeneReviews and in approximately 2% in the exome study; they usually occur de novo in isolated cases, and the tumour may be the first manifestation in a child with no other history [1, 6, 8].

Sources: GeneReviews, WT1 Disorder, based on Lipska 2014, Lehnhardt 2015, van Peer 2024 and Glénisson 2025; GeneReviews, Wilms Tumor Predisposition; SIOP-Europe/SIOP-RTSG 2021; PodoNet cohort [1, 3, 8, 44].

In the PodoNet cohort of 61 patients with WT1-related SRNS, diffuse mesangial sclerosis was present in 34%, urogenital anomalies or sex reversal in 52%, Wilms tumour in 38% and gonadoblastoma in 5%; truncating variants conferred the highest tumour risk (78%), and KTS intronic variants were associated with a median onset at age 4.5 years and median end-stage kidney disease at age 13.6 years [44]. In a combined database of 282 patients with Wilms tumour, median tumour age was 12.5 months with a germline WT1 alteration and 36 months without one, with earlier onset for truncating variants (12 months), followed by missense variants (18 months) and deletions (22 months); variants at codon 394 in the historical numbering (R394W/Q/L) had onset at 9, 12 and 18 months, and the greatest number of bilateral tumours occurred in the truncating group [45]. In the Dutch national cohort of 43 patients with a pathogenic WT1 variant, Wilms tumour was the only manifestation in 10 (nine girls) and occurred in 18 of 19 with truncating variants and 4 of 4 with deletions; all patients with missense variants and 6 of 7 with splicing variants developed chronic kidney disease, versus 5 of 19 with truncating variants, three of them in adulthood, with kidney failure at ages 24, 26 and 41 years [46]. In a retrospective French national series of 58 children with Denys-Drash syndrome (2000–2022), exon 8 variants were associated with earlier nephrotic syndrome, earlier kidney failure (median 0.3 versus 1.4 years) and higher mortality (35% versus 9%) than exon 9 variants, and more than 90% of truncating variants lay in exon 9 and were associated with Wilms tumour [47]. Somatic loss-of-function WT1 variants occur in approximately 15% of sporadic tumours, and somatic variants in other neoplasms, such as acute myeloid leukaemia, and the EWS-WT1 fusion in desmoplastic small round cell tumour are unrelated to germline disease [3].

2.4. The 11p13 and 11p15 regions

11p13 deletions including WT1 and PAX6 cause WAGR spectrum disorder [1, 26]. 11p15 alterations (IC1 gain of methylation, paternal uniparental disomy, IC2 loss of methylation) cause the Beckwith-Wiedemann spectrum and, when constitutional or mosaic, also apparently isolated Wilms tumours; the mechanism determines the correlation between molecular subtype and tumour risk, and surveillance differs between guidelines [1, 8, 12]. For this article, the key point is that 11p15 alterations are, together with WT1, the most frequent cause of predisposition in unselected cohorts and are often detected only in the kidney [7, 41].

2.5. TRIM28

TRIM28 (19q13.43) encodes a ubiquitously expressed transcriptional corepressor with a role in nephrogenesis that binds transcription factors in a context-dependent manner to control expression of genes and transposable elements during embryogenesis [38, 48]. Halliday and colleagues (2018) and Diets and colleagues (2019) identified germline loss-of-function variants, with inactivation of the second allele in the tumour through a variant, loss of heterozygosity by mitotic recombination or epigenetic silencing [38, 39]. The tumours have monomorphic epithelial histology, rare in other Wilms tumours, and do not stain for TRIM28 on immunohistochemistry, making this technique a means of identifying carriers [38, 48]. Germline variants occur in approximately 1% of isolated and 8% of familial cases [48]. In the exome study of 890 children, TRIM28 explained 21 of the 33 cases with a newly identified predisposition, the ten inherited variants were all maternal (p=0.00098) and 14 of 16 tumours were epithelial or predominantly epithelial [6]. The 2021 review confirmed maternal transmission in the 15 patients in whom origin was established and estimated penetrance at approximately 67% (18 affected among 27 carriers, probably biased) [48]; in 2024 a child with bilateral tumour who inherited the variant from the father was described, contradicting exclusively maternal transmission [49]. The European document therefore recommends surveillance regardless of the transmitting parent [8].

2.6. REST

REST (4q12) encodes a repressor zinc finger transcription factor that silences neuronal genes in non-neuronal cells [36, 50]. Mahamdallie and colleagues (2015) described 11 inactivating variants in four families with familial Wilms tumour and nine non-familial cases (13 of 558 cases versus 0 of 993 controls), with a second hit in two tumours; ten of the eleven clustered in the region encoding the DNA-binding domain and impaired transcriptional repression, and the gene was estimated to explain approximately 2% of tumours [36]. Families include unaffected obligate carriers, indicating reduced penetrance [10]. Truncating variants in the last exon (exon 5) cause hereditary gingival fibromatosis and, with sensorineural hearing loss, Jones syndrome; coexistence of Wilms tumour and gingival fibromatosis has been described in carriers, and AACR 2025 distinguishes loss-of-function variants in exons 2 and 3, associated with the tumour, from those in exon 5 and a deep intronic variant associated with deafness [10, 50]. A constitutional de novo deletion including REST was described in an infant with diffuse hyperplastic perilobar nephroblastomatosis [1].

2.7. CTR9 and familial Wilms tumour

CTR9 (11p15.4) encodes a component of the PAF1 complex, associated with RNA polymerase II and implicated in embryonic organogenesis and stem cell pluripotency; Hanks and colleagues (2014) found inactivating variants in 3 of 35 families with Wilms tumour, absent from 1,000 controls, with familial segregation and a second hit in available tumours [35]. In one family, two sisters developed tumours at 9 and 8 months, with a splicing variant inherited from their unaffected father that removes exon 9 [35]. The four families described up to 2024 inherited the variant, demonstrably or presumptively, from the father, and three led to exon 9 deletion [51]. CTR9 missense variants cause a neurodevelopmental disorder with no tumours described [8, 50].

Familial Wilms tumour accounts for approximately 1–2% of cases, with autosomal dominant transmission of reduced and variable penetrance [1, 4]. In the National Wilms Tumor Study, 93 of 6,209 patients (1.5%) from 63 families had a family history; 16.1% of familial and 7.1% of sporadic cases were bilateral, and paternal and maternal transmission were similar [52]. Linkage mapped the FWT1 (17q12-q21, in a Canadian family with seven cases) and FWT2 (19q13.3-q13.4, in five families) loci, whose genes have not been identified [4, 53, 54]. In 63 families studied by Rahman's group, causal variants explained 35%, mainly REST (8%), TRIM28 (8%) and WT1 (6%), followed by CTR9 (three families), H19 hypermethylation (two) and biallelic BRCA2, biallelic NYNRIN and CDC73 (one each); two-thirds of families remain without a known cause [6]. The Oxford Desk Reference reports that only 2 of 39 families in a British series had a WT1 variant, usually with genitourinary anomalies in boys [4].

2.8. DIS3L2: Perlman syndrome and heterozygous predisposition

DIS3L2 (2q37.1) encodes a cytoplasmic 3′-5′ exoribonuclease that degrades polyuridylated RNA, including precursors of the let-7 microRNA [34, 50]. Astuti and colleagues (2012) mapped the Perlman syndrome locus to 2q37.1 and identified biallelic germline variants; inactivation was associated with mitotic abnormalities and overexpression suppressed tumour cell line growth [34]. Murine models suggest that tumour risk may result from increased IGF2 expression [8]. 2q37 deletions extending to 2q37.1 and encompassing DIS3L2 are associated with Wilms tumour [8]. In the heterozygous state, DIS3L2 variants were identified in 4% of the Dutch cohort (three of five were exon 9 deletions; this exon is unstable, being flanked by LINE-1 repeats), inherited from unaffected parents and with a somatic second hit in 4 of 5 tumours; heterozygous exon 9 deletions occur in 0.05% of gnomAD alleles, implying reduced penetrance [7]. An international series of 34 children with a tumour and a heterozygous variant (28 exon 9 deletions) confirmed a second hit in 19 of 20 tumours, a median age of 41 months, 5 bilateral tumours, metastases in 32% and high-risk histology in 24%, without a recognisable phenotype and with probably low penetrance [40].

2.9. AMER1 (WTX)

AMER1 (Xq11.2) encodes a regulator of the canonical WNT pathway which, recruited to the plasma membrane, acts as a scaffold for the β-catenin destruction complex; its loss leads to accumulation of β-catenin in the nucleus and activation of the WNT pathway [50, 55, 56]. Rivera and colleagues (2007) discovered it as a gene inactivated in about one third of Wilms tumours (15 of 51), by a single event affecting the single X in boys or the active X in girls, in tumours without a WT1 variant [32]. Germline loss-of-function variants cause X-linked dominant osteopathia striata with cranial sclerosis; in 2009, Jenkins and colleagues concluded that these variants did not predispose to tumours, but Bach and colleagues (2021) described four girls with Wilms tumour, one with bilateral tumour, and a 2025 series added four more, bringing the total to ten cases with 20% bilaterality and ages between 5 months and 12 years [33, 57, 58]. GeneReviews estimates the risk at about 5% and the European document considers it apparently above 5%; somatic AMER1 variants occur in 15–30% of sporadic Wilms tumours and are not heritable [8, 55]. The statement that there is no clear predisposition is therefore outdated in the light of current sources.

2.10. Mitotic checkpoint and DNA repair genes

Mosaic variegated aneuploidy results from biallelic variants in BUB1B, TRIP13 or CEP57 [8]. Yost and colleagues (2017) identified biallelic loss-of-function TRIP13 variants in six children, all with Wilms tumour, with more variable aneuploidies, microcephaly, delay and seizures; cells from these patients and from individuals with biallelic BUB1B have severe spindle assembly checkpoint deficiency, unlike those with CEP57 or an unknown cause, without embryonal tumours [37]. Fanconi anaemia complementation groups D1 (biallelic BRCA2) and N (biallelic PALB2) are the only forms of the disease with an increased risk of Wilms tumour [4, 8, 59]. Bloom syndrome (BLM), constitutional mismatch repair deficiency and Li-Fraumeni syndrome (TP53) complete this group, with low risks [1, 8]. The presence of heterozygous variants in adult predisposition genes (BRCA2, PMS2, CHEK2, MUTYH) in 8.9% of children undergoing exome testing in the Dutch cohort, without a demonstrated second hit, does not prove a contribution to the tumour [7].

2.11. Other genes and regions

FBXW7 (truncating variants in four children, one de novo and one inherited from an unaffected father), NYNRIN (biallelic truncating variants in three children from two families) and KDM3B (one de novo variant in a child with bilateral tumour) were associated with Wilms tumour through exome studies [6]. Germline FBXW7 variants also cause a neurodevelopmental disorder, and KDM3B variants cause Diets-Jongmans syndrome, with intellectual disability and short stature [50]. DICER1 predisposition is rarely associated with Wilms tumour (one family with four cases and the variant c.2407G>A, p.Gly803Arg), and GLOW syndrome (global delay, lung cysts, overgrowth and Wilms tumour) results from mosaic variants in the RNase IIIb domain [1]. A 2025 series associated germline DROSHA variants with pineoblastoma and, in one child, Wilms tumour, with a second hit in all tumours analysed [60]. Among chromosomal regions, the 9q22.3 microdeletion including PTCH1 (7 tumours in 44 cases) and the 2p24.3 duplication including MYCN have been associated with the tumour [8]. ASXL1 (Bohring-Opitz syndrome), GPC3/GPC4 (Simpson-Golabi-Behmel syndrome), NSD1, PIK3CA, TRIM37 and CDC73 complete the set of syndromic genes, described in the differential diagnosis [1, 8].

3. Clinical Spectrum and Manifestations by System

3.1. Wilms tumour as a shared manifestation

Wilms tumour, or nephroblastoma, is an embryonal neoplasm of the kidney and the most common renal tumour of childhood; it usually presents as an abdominal mass in an apparently healthy child, and 25–30% of cases involve abdominal pain, fever, anaemia, haematuria or hypertension [1]. The Oxford Desk Reference estimates incidence at 1 per 10,000 children, with most diagnoses between 3 and 4 years, 90% by age 7 years and more than 90% of tumours unilateral [4]. Approximately 5–10% of patients have bilateral or multicentric tumours, a higher proportion in predisposed forms [1]. Histology is typically triphasic (blastema, stroma and epithelium), and definitive diagnosis is histological only; favourable-histology tumours are distinguished from anaplastic tumours, the latter associated with a somatic TP53 variant and poorer prognosis [1, 4]. Nephrogenic rests, foci of embryonic kidney tissue persisting abnormally after birth, are considered precursors: an autopsy study found them in approximately 1 in 100 newborns, versus a tumour incidence of 1 in 10,000 children, showing that most do not progress [1, 4]. Treatment combines surgery, chemotherapy and, in incomplete resection or metastatic disease, radiotherapy; estimated survival is approximately 90%, lower in anaplastic histology and bilateral, metastatic or relapsed disease [1]. The Oxford Desk Reference gives survival rates of 90% for localised and 70% for metastatic disease and therefore emphasises that the principal aim of early detection is to reduce treatment and the morbidity it entails [4].

In children with predisposition, the tumour occurs earlier, is more often bilateral or multifocal and is more often accompanied by nephrogenic rests, but survival following the tumour is, in WT1-related forms, similar to that of tumours without a known cause [1, 3]. Disease burden in syndromic forms frequently results from extrarenal manifestations and long-term renal function, which depend on the gene and mechanism, rather than solely from the tumour [1, 3].

3.2. WT1-related disorder (Denys-Drash and Frasier spectrum)

GeneReviews describes WT1-related disorder as a progressive glomerulopathy with congenital, infantile or childhood onset, unresponsive to corticosteroid therapy, frequently associated with disorders of testicular development (with or without alterations of the external genitalia and Müllerian structures) and Wilms tumour, and less frequently with congenital anomalies of the kidney and urinary tract (CAKUT), gonadoblastoma and 46,XX gonadal dysgenesis; in adulthood, most patients develop early gonadal insufficiency of variable severity [3]. The terms Denys-Drash syndrome, Frasier syndrome and Meacham syndrome, coined for clinical combinations described separately, are now understood as points on a phenotypic continuum and no longer have clinical utility, although the literature continues to use them for constellations: Frasier, steroid-resistant nephrotic syndrome (SRNS) with complete 46,XY gonadal dysgenesis and gonadoblastoma; Denys-Drash, SRNS with diffuse mesangial sclerosis on biopsy, Wilms tumour and 46,XY difference of sex development (DSD); Meacham, diaphragmatic hernia, pulmonary dysplasia, complex congenital heart disease and genitourinary anomalies, lethal early in life in most reports, before other manifestations such as SRNS or Wilms tumour can arise [3]. No reported patient with a confirmed WT1 variant and diaphragmatic defect had complex heart disease, prompting the proposal of a multigenic cause for the Meacham form [3]. The association of congenital diaphragmatic hernia with genital anomalies in a 46,XY individual places WT1 among the genes to be tested, alongside MYRF, ZFPM2 and GATA4. The Oxford Desk Reference retains the classical description: a triad of Wilms tumour, genitourinary anomalies that can be severe in 46,XY individuals, and nephropathy with hypertension and proteinuria progressing to renal failure, with mesangial sclerosis, a median age of 16 months at tumour diagnosis and non-penetrance described in carrier parents; and, for Frasier, nephropathy with focal segmental glomerulosclerosis, gonadoblastoma and less frequent Wilms tumour [4, 61].

Source: GeneReviews, WT1 Disorder, table 2, with data from Lipska 2014, Lehnhardt 2015, van Peer 2024 and Carré Lecoindre 2024 [3]. AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; LH, luteinising hormone.

Glomerulopathy usually begins with persistent proteinuria, which may fluctuate initially and subsequently worsens; SRNS may precede Wilms tumour by up to four years, coincide with diagnosis or occur afterwards, up to ten years after completion of oncological treatment, and progresses irreversibly to end-stage kidney disease [3]. Biopsy shows diffuse mesangial sclerosis mainly below two years of age and focal segmental glomerulosclerosis at older ages, and other lesions such as membranoproliferative glomerulonephritis have been described; because histology does not correlate with clinical findings and varies between carriers of the same variant, renal biopsy is no longer a first-line investigation at any age [3]. Wilms tumour risk in heterozygotes with an exonic variant was estimated at one tumour per nine years at risk, a calculation limited by the number of patients undergoing prophylactic nephrectomy at transplantation or peritoneal dialysis catheter placement; median age at diagnosis (1.3–1.6 years; range 0–4.5 years) is lower than for tumours without a known cause, bilateral tumours are more frequent with truncating variants (more than 50% versus less than 15%), and survival does not differ from that of tumours of unknown cause [3]. Gonadoblastoma occurs in 46,XY individuals with a disorder of testicular development, with an observed incidence of one gonadal tumour per 30 years at risk, and Sertoli cell tumours and other malignant germ cell tumours have been described [3]. Diaphragmatic hernia has been described in fewer than ten infants, and post-transplant lymphoproliferative disease occurred in 7–17% of transplant recipients, without it being possible to state that this exceeds the 25-year cumulative incidence of 3.6% (95% CI 2.7–4.8) observed across all transplanted children [3]. In 46,XX individuals, the ovaries and external genitalia are usually normal, with occasional bicornuate uterus; two cases of complete 46,XX gonadal dysgenesis and seven of 46,XX testicular or ovotesticular DSD have been described with variants in exon 10 (fourth zinc finger) or intron 9 splice sites [3].

The Oxford Desk Reference adds two incomplete presentations: children with only one or two cardinal signs, such as Wilms tumour and an undescended testis, in whom WT1 variants were found in approximately 2% of non-syndromic tumours; and isolated nephropathy with mesangial sclerosis or focal segmental glomerulosclerosis without the other signs [4]. The predisposition GeneReviews specifies that, in the absence of genitourinary anomalies, mesangial sclerosis, nephrogenic rests or bilateral tumours, the probability that a child with Wilms tumour has a germline WT1 variant is 0–5% [1].

3.3. Non-syndromic predisposition: TRIM28, REST, CTR9 and heterozygous DIS3L2

Carriers of these genes generally have no extrarenal signs enabling recognition before the tumour; suspicion arises from histology, age, bilaterality or family history [1, 10]. In TRIM28 carriers, age at diagnosis ranged from 5 months to 9 years (median 13 months), 83% of tumours occurred before age 7 years and 93% before age 8, tumours may be unilateral or bilateral, are predominantly epithelial, are frequently accompanied by nephrogenic rests and have a favourable prognosis, with low rates of metastasis or relapse; no other associated phenotype is known [1]. AACR 2025 reports that 86% of tumours occurred before age 7 years and 95% before age 8, with two diagnoses in the 11th year of life, and that 86% are predominantly epithelial and 45% of predominantly epithelial tumours have a TRIM28 variant [10]. In the study by Diets and colleagues, tumours were bilateral in six of 11 children, and 10 of 11 were accompanied by perilobar nephrogenic rests [39]. In REST carriers, age at diagnosis ranged from 6 months to 6 years (median 3.25 years), with predominantly unilateral tumours and triphasic, blastemal or epithelial histology; no other manifestations or neoplasms are consistently associated [1]. In families with CTR9, 9 of 14 known or obligate carriers had a tumour between 7 and 39 months, and no variants were found in 587 patients with non-familial tumour [10]. Heterozygous DIS3L2 carriers have no recognisable phenotype; tumours arise later (median 41 months, up to 101 months), and an international series found 32% metastatic disease, 24% high-risk histology, mainly post-chemotherapy blastemal histology, three relapses or second tumours and four deaths among 34 children [40].

3.4. Perlman syndrome

Perlman syndrome is an autosomal recessive overgrowth syndrome with polyhydramnios, macrosomia, facial dysmorphism (broad depressed nasal bridge, everted upper lip shaped as an inverted V, low-set ears, deep-set eyes, prominent forehead), renal dysplasia and nephroblastomatosis, multiple congenital anomalies and frequent developmental delay [8, 15]. More than half of children die in the first year from respiratory failure, sepsis or renal failure, and AACR 2017 cites 53% neonatal mortality; nephroblastomatosis is present in approximately 75% of cases [8, 15, 62]. In survivors of the neonatal period, Wilms tumour risk is 64% (SIOP), 65% (GeneReviews) or approximately 70% (AACR 2024), with early tumours (before age 2 years), bilateral in 55%; AACR 2017 gave 75%, and the Oxford Desk Reference 25–50% (and approximately 25% in another section) [1, 4, 8, 12, 15, 62]. It is distinguished from Beckwith-Wiedemann and Simpson-Golabi-Behmel syndromes by fetal ascites and facial dysmorphism in the absence of macroglossia, abdominal wall defects and polydactyly [15]. Hyperinsulinism has been described in Perlman syndrome [63].

3.5. Osteopathia striata with cranial sclerosis (AMER1)

In heterozygous girls, the disorder manifests as macrocephaly, characteristic facies (frontal bossing, hypertelorism, epicanthic folds, depressed nasal bridge, prominent mandible), orofacial clefting and hearing loss in approximately half, mild delay in a minority and radiological findings considered pathognomonic: cranial sclerosis, long-bone sclerosis and longitudinal metaphyseal striations [55, 56]. Boys may have a mild phenotype, similar to that of girls and more frequent with mosaicism, or a multiple malformation syndrome lethal in mid- or late gestation or the neonatal period, with polysyndactyly, hypoplastic or absent fibulae, congenital heart disease and cerebral, genitourinary and gastrointestinal anomalies; skull base sclerosis can compress cranial nerves and cause deafness, recurrent facial palsy or ophthalmoplegia [55, 56]. Nephrogenic rests have been described in male fetuses and Wilms tumours, so far only in girls, aged between 5 months and 12 years [55, 57, 58]. Approximately 90 molecularly confirmed patients had been described [55].

3.6. Mosaic variegated aneuploidy, Fanconi anaemia and other syndromes

Mosaic variegated aneuploidy is characterised by microcephaly, developmental delay, growth restriction and cataracts, with multiple mosaic monosomies and trisomies on karyotyping, sometimes with premature chromatid separation, and a high risk of cancer, particularly Wilms tumour, rhabdomyosarcoma and leukaemia [4, 64]. Wilms tumour risk is approximately 50% with BUB1B and 20% with TRIP13 according to the European document, whereas GeneReviews gives more than 85% and approximately 10%, respectively; all six children with biallelic TRIP13 in Yost's series developed Wilms tumour [1, 8, 37]. In Fanconi anaemia, only groups D1 (BRCA2) and N (PALB2) have an increased risk of Wilms tumour, approximately 20% and 40%, alongside early leukaemia and medulloblastoma [1, 4, 8]. In Mulibrey nanism (TRIM37), a recessive disorder with approximately 130 known cases, 89 of them Finnish, an update of the Finnish cohort found Wilms tumour in 8 of 101 patients, and a review of 14 cases showed a mean age of 1.6 years and remission in all [12, 15]. In Bohring-Opitz syndrome (ASXL1), Wilms tumour or nephroblastomatosis occurred in 3 of 43 patients (7%), including two bilateral tumours, and three hepatoblastomas have been described [8, 12]. In Simpson-Golabi-Behmel syndrome, a review of 189 cases found Wilms tumour and hepatoblastoma in 5.1% each, with a mean age of 28 months (0–84) for Wilms tumour [12]. In trisomies 18 and 13, the risk is around 1% and less than 1%; approximately 21 Wilms tumours have been described in trisomy 18, several in older children and predominantly in girls [8, 12].

3.7. Familial Wilms tumour

In families with Wilms tumour, most have no other clinical signs or other cancers, and transmission is consistent with autosomal dominant inheritance with incomplete penetrance [4, 35]. Age at onset, bilaterality, metastatic disease or a specific histology may cluster in some families, but intra- and interfamilial variability is substantial [4]. In the National Wilms Tumor Study, familial bilateral tumours were diagnosed at a mean age of 15.8 months, versus 35.2 months for familial unilateral tumours, and intralobar rests were twice as common in familial as in sporadic cases [52].

3.8. WAGR spectrum disorder and Beckwith-Wiedemann spectrum

WAGR (tumour risk of 45–60%, with frequent chronic kidney disease) and the Beckwith-Wiedemann spectrum (risk of 7–25% depending on subtype, with hepatoblastoma and other embryonal tumours) are the best-known predisposition syndromes [1]. When evaluating a child with Wilms tumour, both should be actively sought: aniridia by eye examination, and Beckwith-Wiedemann signs, sometimes subtle, by a clinician experienced in this spectrum, as recommended by AACR 2025 [1, 10].

The 2021 French National Diagnosis and Care Protocol (PNDS) of the Haute Autorité de Santé (HAS) for WAGR syndrome accepts the diagnosis in the presence of at least two of the four components (Wilms tumour risk, total or partial aniridia with the associated ocular anomalies, urogenital anomalies ranging from isolated cryptorchidism to more severe DSD, neurodevelopmental disorder) and/or an 11p13 deletion, and stresses that there is no recognised classification [13]. The deletion is interstitial and heterozygous, 1 to 26.5 Mb in size (mean 11 Mb), and the phenotype worsens with size; deletions extending to 11p14–p12 may include BDNF (obesity and intellectual disability, a phenotype termed WAGRO), LMO2, EXT2, ALX4, PRRG4 (hypothesised contribution to autistic traits) and TRIM44, and the PNDS reports, on the basis of a Russian study, that the tumour may depend on combined loss of WT1 and LMO2 rather than WT1 alone, a hypothesis that coexists with the second-hit model in the non-deleted WT1 allele [13]. The estimated tumour risk is 45–60% overall and 40–50% in sporadic aniridia with a deletion including WT1; some patients with PAX6 and WT1 deletions have no tumour, and gonadoblastoma is much rarer than nephroblastoma [13]. In girls, the external genitalia are usually normal and uterine or ovarian anomalies are found only on targeted investigation [13]. Tumours often arise in the first year of life, 90% before age 4 and 98% before age 7; bilateral disease exceeds 30%, compared with approximately 5% in non-syndromic tumours, nephroblastomatosis is frequent and histology is usually favourable [13]. In the SIOP-RTSG series of 1989–2019 (43 children with WAGR and tumour or nephroblastomatosis), the median age at diagnosis was 22 months (6–44), 37.5% had bilateral disease, none had metastases or anaplasia, 52.8% of tumours were of stromal type, nephrogenic rests were present in 78.9% and contralateral tumours appeared up to 7 years after the initial diagnosis [65]. The PNDS adds that, with a germline WT1 variant, fetal rhabdomyomatous nephroblastoma is more likely, a stromal variant with rare pulmonary metastases, poor response to chemotherapy and possible extension into the collecting system, but with a prognosis similar to that of classical nephroblastoma [13].

4. Clinical Recognition and Warning Signs

Genetic predisposition to Wilms tumour should be sought in two distinct clinical settings: the child who already has a tumour, where the question is whether a constitutional cause exists that changes treatment, surveillance of the remaining kidney and family counselling; and the child without a tumour in whom a syndrome, variant or family history warranting surveillance is recognised [1, 4]. GeneReviews lists bilateral tumour, multicentric unilateral tumour, early onset (before age 2 years), multiple unilateral or bilateral nephrogenic rests, signs of a predisposing syndrome and a family history of Wilms tumour, present in approximately 1–2% of patients, as suggestive features [1]. A unilateral unifocal tumour does not exclude predisposition: it is common in forms associated with TRIM28, FBXW7, NYNRIN and KDM3B, in Beckwith-Wiedemann syndrome and in isolated hemihyperplasia [1].

Histology guides the genetic hypothesis: stromal predominance, particularly with rhabdomyoblastic differentiation, and fetal rhabdomyomatous nephroblastoma are associated with WT1; epithelial histology with TRIM28 and FBXW7; and anaplastic tumour is usually associated with a somatic TP53 variant, although it may reflect a germline variant [1, 4]. Intralobar nephrogenic rests predominate in WT1 syndromes and perilobar rests in tumours associated with overgrowth conditions and trisomies 18 and 13 [4]. The Oxford Desk Reference organises history-taking around a three-generation pedigree with targeted questions about familial Wilms tumour, Li-Fraumeni syndrome and hyperparathyroidism–jaw tumour syndrome; review of the histopathology report; birth weight, increased in Beckwith-Wiedemann, Simpson-Golabi-Behmel and Perlman syndromes and decreased in mosaic variegated aneuploidy, Fanconi anaemia, Bloom syndrome and Mulibrey nanism; neonatal hypoglycaemia and feeding difficulties due to macroglossia; renal failure and glomerulosclerosis; genitourinary anomalies; developmental delay; and dysmorphic features [4].

For physical examination, the Oxford Desk Reference checklist includes weight, height and head circumference, assessment for aniridia and cataracts, hemihypertrophy, macroglossia, organomegaly and umbilical hernia, genitourinary anomalies, skeletal anomalies (Fanconi anaemia), documentation of dysmorphic features, blood pressure, urine testing for proteinuria and review of imaging and operative reports for genitourinary malformations [4]. In a child with hypospadias, the same book includes palpation for renal masses and blood pressure measurement, and cites the study by Albers and colleagues (1997), in which the cause was identified in 12 of 33 patients with severe hypospadias, three of whom had Drash syndrome [66].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and indications for genetic testing

There are no formal diagnostic criteria for WT1-related disorder: diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic WT1 variant, and a variant of uncertain significance neither establishes nor excludes the diagnosis [3]. For Wilms tumour predisposition in general, GeneReviews recommends considering molecular testing in children with physical, radiological or histological signs of predisposition, tumour before age 2 years and a family history of Wilms tumour or other tumours, and reports that some centres test all children with Wilms tumour [1]. AACR 2024 supports germline testing of all children with Wilms tumour or hepatoblastoma, in discussion with the family and according to institutional policies [12]. The 2015–2020 Dutch national cohort, in which all children with Wilms tumour were referred to genetics, found genetic or epigenetic predisposing factors in at least 42 of 126 patients (33.3%), and the authors recommend standardised genetic testing following counselling by a clinical geneticist; where this is not feasible, decision support tools such as MIPOGG may prioritise patients, although three of the 42 diagnoses (7%) would not have been selected by that tool [7]. The exome study by Mahamdallie and colleagues likewise recommends offering testing to all children with Wilms tumour and, in particular, TRIM28 testing in epithelial tumours [6].

5.2. Phenotype-guided testing strategy

GeneReviews proposes a phenotype-guided strategy [1]. With genitourinary anomalies or renal failure, WT1 sequencing is performed first, followed, if negative, by targeted gene deletion and duplication analysis; the iris should be examined to exclude aniridia and karyotyping considered in children with a female phenotype and a WT1 variant to identify complete sex reversal [1]. With signs of Beckwith-Wiedemann syndrome, testing begins with IC1 and IC2 methylation analysis, potentially in affected tissue to detect mosaicism, bearing in mind that CDKN1C variants are not associated with increased Wilms tumour risk [1]. With aniridia, the first investigation is chromosomal microarray (CMA), which detects 11p13 deletions including WT1 and PAX6, defines their size and, in its single-nucleotide polymorphism version, detects 11p15 uniparental disomy [1]. With pre- and postnatal overgrowth, a panel including DIS3L2, GPC3, GPC4 and NSD1 and 11p15 methylation testing is recommended; with asymmetric growth, PIK3CA testing in affected tissue [1]. In predominantly stromal tumours (more than 66% of the specimen), WT1 is sequenced, and in predominantly epithelial tumours, TRIM28; with a family history of specific cancers, DICER1, BRCA2, PALB2, CHEK2, TP53 or mismatch repair genes are tested [1]. In isolated bilateral or multifocal tumours, onset before age 2 years or familial cases, testing may begin with a panel including WT1, TRIM28 and REST, or extended to the other genes in the tables, with simultaneous or subsequent 11p15 methylation testing, because the tumour may be the first manifestation of Beckwith-Wiedemann spectrum [1]. In unilateral tumours without signs of predisposition, risk is low, but the family should be informed of the small probability of predisposition and the option of further assessment [1].

In WT1-related disorder, GeneReviews states that sequencing detects more than 90% of pathogenic variants and targeted deletion and duplication analysis less than 10%; some laboratories first sequence exons 8 and 9 and intronic junctions, where more than 90% of variants are located [3]. Assessment recommendations include karyotyping with SRY FISH or CMA to determine chromosomal sex in all children with ambiguous genitalia and all prepubertal children with a female phenotype [3]. In the Dutch cohort, 12 of the 42 diagnoses were made only in normal kidney DNA (mainly 11p15 alterations), and blood methylation testing by MS-MLPA had a detection threshold of approximately 10% [7].

For sporadic aniridia without a family history, the PNDS (French National Diagnosis and Care Protocol) recommends CMA as the first test, to confirm the 11p13 deletion and measure its size; as alternatives or complements, FISH with probes for PAX6 and/or WT1 and for the PAX6 regulatory region located in ELP4 (which may be deleted with the PAX6 locus intact) or MLPA, and high-resolution karyotyping (at least 550 bands), now little used but useful with FISH to characterise parental rearrangements [13]. While awaiting the result, all children with sporadic aniridia should undergo renal ultrasonography, every 1 to 3 months according to the PNDS [13]. The initial assessment for WAGR also includes blood and urine tests, pelvic ultrasonography for genital malformations, neurological examination with brain imaging if needed, and specialist endocrinological and paediatric nephrology assessment [13].

Algorithm based on GeneReviews, the 2021 European document and the Dutch cohort [1, 3, 7, 8].

5.3. Test limitations and report content

Each method has gaps that should be stated in the report. Sequencing WT1 exon 1 is difficult because of its high guanine and cytosine content; panels may not include 11p15 methylation studies; exome or genome sequencing may detect deletions and duplications with lower sensitivity than targeted techniques; and somatic mosaicism, frequent in Beckwith-Wiedemann spectrum and bilateral tumours, may escape detection in leukocyte DNA, justifying testing of normal kidney tissue or another tissue and, in undiagnosed cases, DNA storage, including culture of fibroblasts collected during nephrectomy [1, 3, 7, 8]. A germline variant found through tumour sequencing is confirmed as constitutional only in non-tumour DNA, and in AMER1, somatic variants, frequent in sporadic Wilms tumours, are not heritable [55]. The proportion of variants detectable by a method is not equivalent to the clinical sensitivity of the test, which depends on patient selection and the cohort's genetic architecture [3, 7].

WT1 nomenclature requires care: the existence of more than 30 isoforms through alternative splicing, alternative translation initiation sites and RNA editing means that the same variant has several HGVS names, and there is no consensus on the “canonical” protein sequence [3]. The MANE Select transcript is NM_024426.6, encoding NP_077744.4 [11]. The most frequent variant, originally described as p.Arg394Trp (R394W) by Pelletier and colleagues, corresponds to NM_024426.6:c.1399C>T, p.(Arg467Trp), NC_000011.10:g.32392020G>A; in transcript NM_000378.6 it is c.1348C>T, p.(Arg450Trp), and in NM_024424.5 it is c.1399C>T, p.(Arg467Trp) [3, 11, 68]. In ClinVar (VCV000003487), it is classified as pathogenic or likely pathogenic, with criteria provided by multiple submitters without conflicts [68]. The intron 9 variants typical of complete 46,XY gonadal dysgenesis are NM_024426.6:c.1447+4C>T (historical designations 1432+4C>T and IVS9+4C>T; NC_000011.10:g.32391968G>A) and NM_024426.6:c.1447+5G>A (1432+5G>A, IVS9+5G>A; NC_000011.10:g.32391967C>T); in transcript NM_024424.5 they correspond to c.1438+13C>T and c.1438+14G>A, illustrating how transcript choice changes the apparent intronic position [3, 11]. GeneReviews numbers amino acids according to NP_077742.3, which VariantValidator associates with NM_024424.5 rather than the MANE transcript; for p.(Arg467Trp), numbering coincides in the two transcripts [3, 11].

Source: VariantValidator, accessed 7 October 2026 [11].

The report should state the gene, versioned transcript, HGVS c. and p. and genomic nomenclature, zygosity (and, for recessive genes such as DIS3L2, NYNRIN, BUB1B, TRIP13, BRCA2 or PALB2, whether variants are in trans), tissue studied, five-class ACMG/AMP classification and method limitations, including absence of methylation or deletion testing where applicable [1, 3, 7]. Segregation within a family or the presence of a second hit in the tumour are research findings that strengthen interpretation but do not in themselves turn a variant of uncertain significance into a pathogenic one; the Dutch cohort, for example, considered several panel variants of uncertain significance non-causal because of absence of loss of heterozygosity or a second somatic variant [7].

5.4. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known [1, 3, 4]. In Perlman syndrome, prenatal ultrasound findings (polyhydramnios, macrosomia, visceromegaly, nephromegaly, hydronephrosis, ascites or hydrops) frequently raise suspicion before birth [50]. In osteopathia striata with cranial sclerosis, male fetuses with the severe form have multiple malformations lethal in mid- or late gestation, and GeneReviews advises including AMER1 in fetal multiple malformation panels even without the typical radiological pattern [50, 55].

In WAGR, the PNDS reserves prenatal diagnosis mainly for couples in which one parent carries a balanced chromosomal rearrangement involving 11p13: chorionic villus sampling at 12 weeks of gestation or amniocentesis from 15 weeks is offered, with CMA, karyotyping and/or FISH according to the context, and preimplantation genetic testing is possible if the couple is eligible for in vitro fertilisation with intracytoplasmic sperm injection [13]. Without a parental rearrangement, the recurrence risk is low, but germline mosaicism cannot be excluded, so the PNDS advises discussing invasive sampling in subsequent pregnancies [13]. Prenatal diagnosis is rare in the children of people with WAGR, who seldom have offspring [13].

6. Differential Diagnosis

Differential diagnosis comprises three questions: which syndrome or gene explains Wilms tumour in a particular child; which other causes explain the non-oncological phenotype prompting suspicion (steroid-resistant nephropathy, 46,XY DSD, overgrowth, aniridia); and whether a renal lesion detected during surveillance is a Wilms tumour, a nephrogenic rest or another lesion [1, 3, 8]. The Oxford Desk Reference emphasises that more than 50 syndromes have been described with Wilms tumour, but fewer than 5% of children with a tumour have a recognisable malformation syndrome and only a minority of these associations have a demonstrated increase in risk [4, 69].

For aniridia, the French PNDS (French National Diagnosis and Care Protocol) for WAGR distinguishes isolated aniridia (intragenic PAX6 variant or deletion of the regulatory region in ELP4, with no attributable Wilms tumour risk), WAGR, WAGRO (more extensive deletion including BDNF, with obesity) and Gillespie syndrome (partial aniridia, cerebellar ataxia and intellectual disability due to ITPR1 variants, with autosomal recessive or dominant inheritance), which is diagnosed only after the 11p13 deletion has been excluded [13].

For nephropathy, the differential diagnosis of WT1-related disorder is that of monogenic SRNS and congenital nephrotic syndrome, for which GeneReviews refers to its genetic steroid-resistant nephrotic syndrome overview [3]. For 46,XY DSD and gonadal dysgenesis, it refers to the overview of non-syndromic disorders of testicular development; the Oxford Desk Reference places Drash and Frasier syndromes among causes of ambiguous genitalia and sex reversal, alongside campomelic dysplasia (SOX9) and WAGR [3, 61]. For diaphragmatic hernia, GeneReviews refers to a specific review [3].

Dysmorphology textbooks describe isolated Wilms tumours or scattered reports in numerous other syndromes, without a risk estimate warranting surveillance: mosaic trisomy 8, Silver-Russell syndrome, Marshall-Smith syndrome, Schinzel-Giedion syndrome, linear sebaceous naevus syndrome (with nodular nephroblastomatosis at one autopsy), hypomelanosis of Ito with hemihypertrophy, megalencephaly–capillary malformation–polydactyly syndrome, encephalocraniocutaneous lipomatosis and TP63-related ectodermal dysplasia [78]. In ischiospinal dysostosis due to biallelic BMPER variants, nephroblastomatosis and renal cysts may compromise renal function [79].

On surveillance imaging, a solid lesion is more likely to be malignant than a simple anechoic cyst, but nephrogenic rests, nephroblastomatosis and infected cysts may mimic a tumour; CT and MRI better discriminate tumours from nephrogenic rests, and MRI is preferred for surgical planning [8, 15]. Studies cited by the European document document radical nephroureterectomy for an infected cyst mistaken for a cystic tumour, supporting management of detected lesions in a specialist centre [8].

7. Treatments and Risk Management Strategies

There is no therapy directed at the predisposition itself: management rests on imaging surveillance for Wilms tumour in children at sufficient risk, treatment of the tumour with nephron preservation when possible and management of the manifestations specific to each entity, such as the nephropathy and gonadal dysgenesis of WT1-related disorder [1, 3, 8]. For WAGR spectrum disorder and the Beckwith-Wiedemann spectrum, the common elements of surveillance, the comparison between guidelines and, for WAGR, the points of the French PNDS concerning the tumour and the kidney are presented.

7.1. Purpose, benefits and costs of surveillance

The 2021 European document from the SIOP-Europe Host Genome Working Group and SIOP Renal Tumour Study Group (SIOP-RTSG) defines the purpose of surveillance as improving survival and reducing treatment toxicity by detecting smaller, lower-stage tumours; it acknowledges that no studies directly compare survival or morbidity between screened and unscreened children and that, given the good prognosis of Wilms tumour, the effect on overall survival may be small [8]. The expected benefit lies mainly in avoiding toxic treatments such as anthracyclines or radiotherapy and enabling nephron-sparing surgery: retrospective studies showed lower stages in screened children with Beckwith-Wiedemann syndrome or hemihypertrophy and smaller tumours in WAGR when detected through surveillance [8]. In WAGR with Wilms tumour, mortality was more often due to end-stage kidney disease than to the tumour, making nephron-sparing surgery particularly relevant in conditions at risk of renal failure, such as WT1-related conditions [8]. Among costs, the document mentions a 2001 cost–benefit analysis in a hypothetical Beckwith-Wiedemann syndrome cohort, considered reasonable at the time but requiring updating, false positives (two infected renal cysts resected for suspected cystic tumour, one with radical nephroureterectomy) and renal or hepatic findings in 25 of 63 children (40%) undergoing Beckwith-Wiedemann spectrum surveillance [8]. Consultation with the International WAGR Syndrome Association and the British Beckwith-Wiedemann syndrome support group showed that visits can cause anxiety for some parents and reassurance for others, that absence of surveillance also causes stress and that, overall, both groups consider the benefits to outweigh the burdens and would not oppose longer surveillance than proposed [8]. GeneReviews adds that economic cost, false positives, unnecessary interventions and psychosocial distress should be weighed in the decision [1].

7.2. How to conduct surveillance: modality, interval and organisation

Surveillance should be offered after parents receive risk counselling from a clinical geneticist or genetic counsellor; renal ultrasonography is the recommended modality because it avoids the radiation of computed tomography and the anaesthesia required for magnetic resonance imaging (MRI) in young children, and, although CT and MRI better distinguish tumours from nephrogenic rests, the consensus considers ultrasonography equally effective for initial detection [8]. Table 1 of the European document specifies high-frequency probes with paediatric presets (linear above 10 MHz in infants; curvilinear above 6 MHz and linear above 10 MHz in children), no fasting or bladder preparation, assessment of the entire renal parenchyma in longitudinal and transverse planes with the child supine and prone, recognition of normal variants (fetal lobulations, dromedary hump, column of Bertin, duplex or bifid collecting systems) and assessment of cystic or solid, single or multiple lesions, a solid lesion being more likely to be malignant than a simple anechoic cyst [8]. The target organ is the kidney alone, except in Beckwith-Wiedemann spectrum, lateralised overgrowth and Simpson-Golabi-Behmel syndrome, in which complete abdominal ultrasonography including the adrenal glands and liver is performed [8]. Surveillance may be undertaken locally by an operator experienced in paediatric ultrasonography, but detected lesions should be managed in a specialist centre [8, 69].

The 3-month interval is justified by rapid tumour growth, with the shortest estimated doubling time being 11 days; the European consensus preferred 3 months to 3–4 months because appointments are delayed in practice and intervals of 4 months or longer risk higher stages [8]. Surveillance should begin at birth or as soon as the syndrome is diagnosed and may begin on clinical suspicion while awaiting molecular results [8]. The 2017 and 2024 North American American Association for Cancer Research (AACR) recommendations likewise propose renal ultrasonography every 3 months from birth or diagnosis until the seventh birthday, with six-monthly physical examination by a specialist (geneticist or paediatric oncologist) including education about tumour manifestations, reinforcement of adherence and assessment of other syndrome manifestations; both include the adrenal glands in ultrasonography, and the 2024 version justifies this by the slightly increased risk of adrenal tumours in Beckwith-Wiedemann spectrum, especially with paternal uniparental disomy [12, 15]. AACR 2017 emphasises that examinations should be interpreted longitudinally, preferably by the same group of paediatric radiologists [15]. For suspicious lesions, AACR 2017 considers MRI the ideal modality for detecting multiple tumours and nephrogenic rests and planning partial nephrectomy [15]. The French WAGR PNDS requires ultrasonography to be performed by an experienced paediatric radiologist, integrated into paediatric nephrology follow-up, with MRI or CT to characterise any lesion detected; it justifies the 3–4-month interval by a tumour doubling time of approximately 6 weeks, a value taken from AACR 2017, whereas the European document uses the shortest estimated doubling time of 11 days [8, 13]. Without surveillance, the tumour usually presents as an abdominal mass, and haematuria, malaise associated with arterial hypertension (present in 25%) or pain due to fissuring or rupture occur in 20–30% of children [13].

7.3. When to stop surveillance

The European consensus recommends surveillance until the seventh birthday for all syndromes with an indication, because by age 7 years 90% of sporadic tumours, 94% of tumours in Beckwith-Wiedemann syndrome and more than 95% of tumours in WT1 syndromes have been diagnosed; in WT1 syndromes, more than 90–95% of tumours occur before age 5 years, but nephrogenic rests may progress to metachronous tumours after that age, nephroblastomatosis may escape ultrasonography, and patient representatives requested a longer duration, leading the group to abandon its previous proposal of 5 years [8]. AACR 2017 and 2024 likewise set the seventh birthday, covering the age by which 90–95% (2024: 95%) of tumours arise [12, 15]. GeneReviews proposes a residual risk calculation: in WAGR, with an overall risk of approximately 50%, 90% of tumours by age 4 years and 98% by age 7, residual risk is 5% at age 4 years (0.5 × 0.1) and 1% at age 7 years (0.5 × 0.02), leading to stopping between ages 5 and 8 years according to risk tolerance; for predispositions without an established age of risk, it recommends abdominal ultrasonography every 3 months until age 8 years [1]. The 2006 British recommendations provided for renal ultrasound surveillance every 3–4 months until age 5 years in all conditions except Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome and some families with familial Wilms tumour, in which it continued until age 7 years [4, 69]. Other sections of the same book present different schedules: every 3–4 months until age 7 years in high-risk overgrowth syndromes, including Perlman syndrome, and, for Simpson-Golabi-Behmel syndrome, ultrasonography of the kidneys, liver and adrenal glands every 4 months until age 8 years, as in Beckwith-Wiedemann syndrome [62, 80].

7.4. Who should undergo surveillance: risk thresholds and entity-specific recommendations

The European document primarily offers surveillance when childhood Wilms tumour risk exceeds 5%, taking other tumour risks into account between 1% and 5%, and estimated risks as the proportion of patients with tumour among those described with each syndrome, acknowledging selection bias in this estimate [8]. AACR adopts a 1% threshold and a uniform strategy by tumour type, not differentiated by genetic cause; in 2017 it stated that Europe typically used a 2% threshold, and in 2024 that most of Europe uses 5% [12, 15]. The 2006 British recommendations already used the 5% threshold [69]. European evidence grading, adapted from the ERN-PTEN surveillance guideline, distinguishes strong evidence (consistent, unlikely to change, with consensus), moderate evidence (consensus or a majority with inconsistent evidence or new evidence expected) and weak evidence [8].

LOM, loss of methylation; GOM, gain of methylation; IC, imprinting centre; CMMRD, constitutional mismatch repair deficiency. Risks in the “SIOP 2021” column are those of the European document and are not interchangeable with AACR or GeneReviews risks, calculated using different denominators.

Recommendations for genes without an associated syndrome were published by AACR in 2025: renal ultrasonography every 3 months from diagnosis until age 8 years and cascade testing of relatives for TRIM28, REST, CTR9 and heterozygous DIS3L2, the latter supported only by conference abstract data; no recommendation for FBXW7, NYNRIN and KDM3B; inclusion of REST and CTR9 in the panel for every child with Wilms tumour and TRIM28 testing in every predominantly epithelial tumour [10]. Extension until age 8 years is justified by this age covering 95% of tumours in TRIM28 carriers and by a DIS3L2-associated tumour occurring at age 8.3 years [10]. GeneReviews includes TRIM28 and REST among the most frequent genes, with risk described as unknown, and applies the general rule of every 3 months until age 8 years when age of risk is not established [1].

7.4.1. Overview of differences between guidelines

Sources: [1, 3, 8, 10, 12, 15, 69]. The ERKNet-ESPN consensus for congenital nephrotic syndrome recommends bilateral nephrectomy before transplantation in patients with a dominant WT1 variant [17].

Some divergences are internal to the documents themselves: AACR 2024 states in the text that surveillance is recommended in osteopathia striata, but the table indicates shared decision-making; the European document gives IC2 loss of methylation a risk of approximately 0.2% in the text and less than 1% in the table; and its DICER1 note refers to renal ultrasonography, whereas the guideline published by the same group and CanGene-CanVar recommends abdominal ultrasonography every 6 months from birth until age 6 years, targeting cystic nephroma, with a cumulative incidence of approximately 7% by age 6 years [8, 12, 81]. Choice between guidelines depends on the healthcare system: in a European service, the reference is the SIOP-Europe document, with subsequent updates for genes it did not cover (for example, heterozygous DIS3L2) considered case by case; in all cases, the decision should be shared with the family following counselling on the specific risk [8, 10, 12].

The French PNDS for WAGR syndrome (2021), prepared by the OPHTARA ophthalmology reference centre with paediatric nephrologists, oncologists and surgeons, is the only one of these documents dedicated to a single entity and diverges from the other guidelines on several points:

Sources: [1, 8, 12, 13, 15, 82].

Three of these differences have practical consequences. The 3–4-month interval of the PNDS is the one the European document expressly rejected, because scheduling delays lead to intervals of 4 months or more; in a European service, three-monthly ultrasonography is the reference, and the PNDS intensifies it only during the wait for the genetic result, with intervals as short as monthly [8, 13]. Stopping at 6–8 years in the appended algorithm does not match the 7 years in the text of the same document and approaches the residual-risk calculation of GeneReviews [1, 13]. The 50–60% kidney disease figure that the PNDS attributes to Hol and colleagues is, in that article, the estimate of chronic kidney disease from earlier studies, not of end-stage kidney disease, and the SIOP-RTSG series itself observed it in only 5 of 20 patients with data, with insufficient follow-up; the cumulative risk of renal failure measured in the National Wilms Tumor Study was 38% at 20 years [13, 65, 83].

7.5. After a tumour, bilateral tumour and familial Wilms tumour

In children with a diagnosed predisposition syndrome who have already had Wilms tumour or nephroblastomatosis, the European document recommends surveillance of the remaining kidney or kidneys with renal ultrasonography every 3 months until the seventh birthday, or longer if required by the treated tumour follow-up protocol [8]. AACR 2017 proposes that, once immediate post-tumour surveillance is complete, the child return to the previous surveillance schedule and that, beyond the age of risk, parents be engaged in discussion of whether other oncological surveillance is indicated, remembering that most of these syndromes are not associated with an increased risk of adult cancers [15].

In all patients with bilateral Wilms tumour or nephroblastomatosis, the European document recommends renal ultrasonography of the remaining kidney every 3 months until the seventh birthday and genetic testing to exclude germline genetic or epigenetic alterations; while awaiting results, siblings may be offered a single ultrasound [8]. Because recent evidence suggests that many bilateral tumours result from postzygotic events (mosaicism), testing of resected kidney tissue is recommended when germline testing is negative; if there is no germline diagnosis in the proband, three-monthly sibling surveillance is not recommended [8]. GeneReviews, which bases the same reasoning on work on embryonic tumour precursors, proposes screening for metachronous tumours by renal ultrasonography every 3 months until age 8 years after completion of treatment in bilateral or multifocal tumours without an identified molecular cause [1].

The European document defines familial Wilms tumour as the presence of at least two patients with Wilms tumour confirmed in clinical records, related up to the third degree [8]. If the responsible gene is not identified after germline testing, surveillance until the seventh birthday is recommended for first- and second-degree relatives of presumed carriers [8]. For bilateral tumours, AACR 2025 recommends universal genetic testing including 11p15.5 methylation and copy number, WT1 sequencing and copy number, and the genes REST, TRIM28, DIS3L2 and CTR9, abdominal ultrasonography every 3 months until at least age 8 years in any child treated for bilateral tumour, and no surveillance of relatives in the absence of a known variant; it reports that fewer than half of children with bilateral tumour have an identified syndrome and that girls with bilateral disease have a higher risk of new tumours [10]. For 11p15 mosaicism without clinical signs of Beckwith-Wiedemann, the same guideline does not recommend surveillance but asks that every child with Wilms tumour be examined by a clinician experienced in this spectrum [10]. When the causal alteration has not been identified, GeneReviews recommends abdominal ultrasonography every 3 months until age 8 years for the affected patient's offspring, considering the benefit of sibling surveillance uncertain: in a National Wilms Tumor Study analysis, 15 of 456 patients with bilateral tumour (3.3%) had a relative with Wilms tumour, and six of these patients clustered in three families, so the probability of detecting a tumour in a sibling of a patient with bilateral tumour without known familial disease is less than 1% [1].

Sources: [1, 8, 10, 12, 15].

The older Oxford Desk Reference did not recommend surveillance of siblings of an isolated unilateral case or relatives of non-syndromic bilateral cases without a family history, and estimated risk to survivors' offspring, especially after bilateral tumours, at less than 5%, without recommending surveillance of those offspring at the time [4]. This position predates evidence on postzygotic mosaicism and differs from GeneReviews, which recommends considering surveillance of offspring of patients with bilateral or multifocal tumour [1].

7.6. Wilms tumour treatment in the predisposed child

Children with predisposition are treated according to standard oncology protocols, with two particular considerations: nephron preservation and attention to metachronous tumour risk [3, 8]. The UMBRELLA SIOP-RTSG 2016 protocol recommends nephron-sparing surgery in children with genetic predisposition whenever size and location allow, and several studies have shown that it can be performed safely in unilateral or bilateral tumours in these syndromes [8]. AACR 2017 recommends it in syndromic tumours because of increased risk of recurrence in the ipsilateral or contralateral kidney, with MRI to detect multiple tumours and nephrogenic rests and plan partial nephrectomy; infiltration of adjacent structures, central location, tumour thrombus, rupture or collecting system involvement guide the choice between partial and total nephrectomy [15]. The 2025 NCCN guideline recommends neoadjuvant chemotherapy with the EE4A regimen (vincristine and dactinomycin) in children with localised unilateral renal tumour and a predisposing condition, advises against initial biopsy or resection and prioritises nephron-sparing surgery; in the Children's Oncology Group (COG) AREN0534 study, 63% (20 of 32) of predisposed children with unilateral tumour underwent partial nephrectomy, with 4-year event-free survival of 94% and overall survival of 100% [14, 84]. In the same study, among 189 evaluable children with bilateral tumour, induction with vincristine, dactinomycin and doxorubicin for 6 or 12 weeks enabled definitive surgical treatment of at least one kidney by 12 weeks in 84.0%, preservation of part of both kidneys in 39% and 4-year event-free and overall survival of 82.1% and 94.9%, versus 56% event-free survival in NWTS-5 [85]. In diffuse hyperplastic perilobar nephroblastomatosis (eight evaluable patients, all bilateral), treatment with vincristine and dactinomycin preserved 14 of 16 functioning kidneys, with no deaths at a median follow-up of 6.6 years, but relapses occurred after discontinuation [84].

In WT1-related disorder, the surgical decision weighs renal preservation against the inevitable progression of the glomerulopathy: GeneReviews recommends prophylactic bilateral nephrectomy when end-stage kidney disease is reached, the ERKNet-ESPN consensus recommends bilateral nephrectomy before transplantation in patients with a dominant WT1 variant, and AACR 2024 states that nephrectomy of the non-functioning kidney may be considered at transplantation [3, 12, 17]. In the SIOP-RTSG series of 43 children with WAGR and tumour or nephroblastomatosis, two died of hepatic sinusoidal obstruction syndrome during preoperative chemotherapy, and the authors advise intensive toxicity monitoring and surveillance of the remaining kidney [65]. In the same series, preoperative treatment lasted a median of 8 weeks in bilateral cases (4–26) and 4 weeks in unilateral cases, 11 of 13 children with bilateral disease who underwent surgery (85%) had nephron-sparing surgery, and among children with tumour the 5-year event-free survival was 84.3% and overall survival 91.2%, with no relapses, events being limited to contralateral tumours and non-tumour deaths [65].

The French WAGR PNDS describes treatment according to the European scheme (UMBRELLA protocol): 4 weeks of neoadjuvant chemotherapy with vincristine and dactinomycin in localised forms and with vincristine, dactinomycin and doxorubicin in metastatic forms (lung, more rarely liver), prolonged in bilateral forms to allow nephron-sparing surgery; surgery scheduled after chemotherapy, conservative whenever possible in syndromic tumours; postoperative radiotherapy reserved for tumour rupture, incomplete resection and lymph node or locoregional extension (the PNDS indicates 12.5 Gy retroperitoneal and whole abdomen in intraperitoneal rupture); and up to 27 weeks of postoperative chemotherapy from stage II, according to histology and stage [13]. The 12.5 Gy figure does not correspond to the doses of the SIOP-RTSG protocols, in which flank irradiation is prescribed in 1.8 Gy fractions, with 14.4 Gy in most patients who require it and a range of 10.8 to 25.2 Gy according to stage and histological risk; dose and volume follow the current oncology protocol [82]. The document gives no drug doses and refers them to the oncology protocol, which is the reference for the doses compared with the labels in section 7.8 [13]. It uses local staging I to III (I, tumour limited to the kidney and completely resected; II, extension beyond the capsule or into the renal sinus, completely resected; III, incomplete resection or involved locoregional lymph nodes), with stage IV for haematogenous metastases and V for synchronous bilateral involvement, and lists as prognostic factors the stage, the histological type after chemotherapy (favourable, regressive or high risk), tumour volume, which predicts lymph node involvement, metastases and the molecular characteristics of the tumour [13]. In synchronous bilateral tumours, which account for 4–7% of all Wilms tumours, arise before age 5 and have anaplastic histology in at least 10% (sometimes in one kidney only), the main challenge is to preserve functioning renal tissue; the prognosis, historically worse, now approaches that of unilateral forms with prolonged preoperative chemotherapy and surgery in specialist centres [13, 85]. In mosaic variegated aneuploidy, chemotherapy tolerance is a concern, and one case report described reduced-intensity chemotherapy for rhabdomyosarcoma, an observation that does not constitute a recommendation [50].

7.7. Management of non-oncological manifestations of WT1-related disorder

GeneReviews refers nephropathy management to the International Pediatric Nephrology Association (IPNA) recommendations for SRNS (2020) and the ERKNet-ESPN consensus on congenital nephrotic syndrome (2021), documents written for the phenotypes rather than specifically for WT1 [3, 50]. After diagnosis, it recommends urinary protein/creatinine ratio, 24-hour proteinuria, serum proteins, albumin, creatinine, cholesterol, IgG and C3, blood pressure measurement, karyotyping with SRY FISH or CMA in all people with ambiguous genitalia and all prepubertal children with a female phenotype, pelvic ultrasonography, hormone investigations guided by paediatric endocrinology, abdominal ultrasonography for synchronous or metachronous Wilms tumour and CAKUT, frontal and lateral chest radiographs to detect a small diaphragmatic hernia, particularly before starting peritoneal dialysis, and genetic counselling [3].

In persistent proteinuria, renin–angiotensin–aldosterone system inhibition with an angiotensin-converting enzyme inhibitor or AT1 receptor antagonist should be considered, and glomerulopathy should not be treated with immunosuppressants, which are ineffective and potentially toxic; this is the main management implication transferable from molecular diagnosis to treatment [3, 50]. Nephropathy does not recur after kidney transplantation, and most centres require a weight of 10 kg and/or at least one year after completion of Wilms tumour treatment for transplant listing [3]. Wilms tumour is treated according to standard oncology protocols, with nephron-sparing surgery whenever applicable, and GeneReviews indicates prophylactic bilateral nephrectomy when end-stage kidney disease is reached, at transplantation or peritoneal dialysis catheter placement [3]. Disorders of testicular development and 46,XX gonadal dysgenesis are managed by a multidisciplinary DSD team (clinical genetics, endocrinology, urology and psychology); to prevent gonadoblastoma, gonadectomy, decided by the DSD team, is recommended in people with disorders of testicular development, without consensus on age at surgery; diaphragmatic hernia should be repaired before peritoneal dialysis begins [3]. During pregnancy, because renal disease may progress, women with WT1-related disorder should be referred to a perinatal centre experienced in chronic kidney disease [3].

Surveillance recommended by GeneReviews includes screening for first proteinuria every 6 months until age 10 years and annually thereafter, surveillance for congenital nephrotic syndrome during the first three months, assessment of chronic kidney disease progression every 2 years, annual assessment of puberty or as directed by the DSD team, and abdominal ultrasonography every 3 months until age 7 years for Wilms tumour [3]. For WT1 syndromes without nephropathy, the Oxford Desk Reference recommends long-term annual blood pressure measurement and urinalysis, because renal failure may arise in adulthood [4]. ClinGen has a single actionability assertion for WT1, in the paediatric setting and restricted to Wilms tumour (document AC003, moderate actionability, complete status); there is no assertion for adults or for glomerulopathy, gonadal dysgenesis or gonadoblastoma [50].

7.8. Medicines used in Wilms tumour: regulatory status

No medicine is authorised in the United States or European Union for genetic predisposition to Wilms tumour itself, nor is there a therapeutic trial targeting it [86, 87]. The cytotoxic agents used to treat the tumour are older medicines with an indication in the US label, and in the European Union they are authorised through national procedures. The specific regimens (doses per cycle, number of cycles, adjustments for infants) are defined by the current oncology protocol (SIOP-RTSG/UMBRELLA or COG), which is the dose reference and was not consulted; for comparison, the labels indicate the following doses. Dactinomycin in the US label, for Wilms tumour, is 45 µg/kg intravenously once every 3–6 weeks for up to 26 weeks, as part of a multiphase regimen, with calculation by ideal body weight in obese or oedematous patients [88]. Vincristine, given exclusively intravenously and weekly, has in the US label the usual paediatric dose of 1.5–2 mg/m², with an initial dose of 0.05 mg/kg per week in children weighing 10 kg or less, and a 50% reduction if direct bilirubin is above 3 mg/100 mL [89]; the Portuguese SmPC indicates 2 mg/m² in children, 0.05 mg/kg per week in children weighing 10 kg or less and, in adults, 1.4 mg/m² up to a weekly maximum of 2 mg [90]. Doxorubicin in the US label is 60–75 mg/m² every 3 weeks as monotherapy and 40–75 mg/m² every 21–28 days in combination, with an increased risk of cardiomyopathy above 550 mg/m² cumulative and adjustment for bilirubin [91]; the Portuguese SmPC indicates 60–75 mg/m² every 3 weeks as monotherapy and 30–60 mg/m² every 3–4 weeks in combination with drugs of overlapping toxicity, and states that the dose in children may need to be reduced, referring to the protocols [92].

Sources: FDA labels and records (openFDA, Drugs@FDA) and EMA medicines list, accessed 7 October 2026 [86, 87]. On 26 October 2026, the SmPCs of vincristine and doxorubicin were consulted in Infomed (INFARMED); the search for dactinomycin in Infomed returned no results, and ANVISA was not consulted.

In WT1-related glomerulopathy, renin–angiotensin–aldosterone system inhibitors are recommended by GeneReviews and IPNA, which recommends discontinuing prednisolone and calcineurin inhibitors in monogenic SRNS and maintaining renin–angiotensin–aldosterone system inhibitors until advanced stages of chronic kidney disease; proteinuria in WT1 nephropathy is not a labelled indication for any angiotensin-converting enzyme inhibitor, and the reference doses are those for paediatric hypertension, by extrapolation [3, 16]. Enalapril in the US label (Epaned®, oral solution) has a paediatric initial dose of 0.08 mg/kg (up to 5 mg) once daily, with no studies above 0.58 mg/kg (or 40 mg), and is not recommended in neonates, in preterm infants before 44 weeks of corrected post-conceptional age or with a glomerular filtration rate below 30 mL/min/1.73 m² [93]; the Portuguese SmPC (Renitec®) indicates, in paediatric hypertension, 2.5 mg/day from 20 to less than 50 kg and 5 mg/day from 50 kg, with maximums of 20 mg/day and 40 mg/day, respectively, and the same exclusions of neonates and of glomerular filtration rate below 30 mL/min/1.73 m² [94]. Lisinopril (Zestril®) in the US label has an initial dose of 0.07 mg/kg (up to 5 mg) once daily from age 6, up to a maximum of 0.61 mg/kg (up to 40 mg), and is not recommended below age 6 or with a glomerular filtration rate below 30 mL/min/1.73 m² [95]. Use in younger children or with a glomerular filtration rate below 30 mL/min/1.73 m² is off-label.

7.9. Registered trials and studies

These studies address the tumour, biology or complications rather than predisposition. AREN0534 results derive from different populations (bilateral and predisposed unilateral) and a preoperative regimen differing from the European one, so they should not be directly compared with SIOP series; the 94% event-free survival in the predisposed unilateral subgroup rests on 34 evaluable patients and has a wide confidence interval (85.2–100%) [14]. In the European CTIS registry, Wilms tumour searches returned trials of metronomic chemotherapy in relapsed disease and of pulmonary metastatic disease, and trials of vaccines or cellular therapies targeting the WT1 antigen in adult neoplasms, which are unrelated to germline disease; the EU CTR registry was inaccessible [50, 97].

7.10. Developments in the last 12 months

Between October 2025 and October 2026, no new SIOP, AACR or COG surveillance guideline was identified, and official GeneReviews pages confirm that the predisposition (2022) and WT1-related disorder (May 2025) chapters have not been revised [1, 3]. Publications in this period are observational studies, case reports and preclinical work:

7.11. European Reference Networks and patient associations

ERN PaedCan (paediatric oncology) and ERN GENTURIS (genetic tumour risk syndromes) are the European networks relevant to predisposition and tumour treatment; ERKNet (rare kidney diseases, with a group dedicated to hereditary glomerulopathies) to WT1-related nephropathy; and ERN eUROGEN and Endo-ERN (sexual development and maturation group) to urogenital anomalies and DSD [18]. Whether Wilms tumour appears on the ERN GENTURIS thematic list was not confirmed. The European document recommends registering all children with a predisposition syndrome in national or international databases, such as DECIPHER or the Heidelberg and Hannover predisposition syndrome registry, and the International WAGR Syndrome Association maintains its own registry [8]. Patient resources include the International WAGR Syndrome Association, Childhood Cancer International and its European section, SIOP Europe, the Children's Cancer and Leukaemia Group in the United Kingdom and DSD Families; for WT1-related disorder, GeneReviews lists Kidney Care UK, ERKNet, NephCure Kidney International and the British RaDaR registry [3, 18].

In France, WAGR is managed by the OPHTARA reference centre for rare diseases in ophthalmology (coordinated at Necker-Enfants Malades University Hospital, AP-HP, with constituent centres in Paris and competence centres in Paris, the regions and the overseas territories of Guadeloupe and Réunion), part of the SENSGENE rare sensory diseases health network (filière); departments without an OPHTARA centre are directed to other centres in the network [13]. Follow-up is multidisciplinary, coordinated by the reference or competence centre, with ophthalmology, paediatric nephrology, paediatrics, paediatric neurology, paediatric oncology, paediatric oncological visceral surgery, and cytogenetics and clinical and molecular genetics, and the attending physician coordinates nephroblastoma and renal failure screening with the nephrologist [13]. The PNDS serves as the basis for the care protocol for exemption from patient co-payment as an off-list long-term condition (ALD hors liste), and support for visual and intellectual disability is provided through the Maison Départementale des Personnes Handicapées [13]. The French association GÊNIRIS (aniridia and rare diseases of the iris, with or without associated syndromes) should be presented to the family at the diagnosis disclosure consultation; the therapeutic education programme for aniridia was being developed in 2021, and at European level the PNDS lists ERN-EYE, EURORDIS, Aniridia Europe and the International WAGR Syndrome Association [13].

8. Reproductive Options and Family Counselling

8.1. General principles

Counselling depends on the cause: if the child has an identified syndrome, condition-specific counselling applies; if no cause is identified, empirical risk defined by the presentation (unilateral or bilateral, isolated or familial) is used [1]. The ideal time to determine genetic risk and discuss prenatal and preimplantation diagnosis is before pregnancy, and genetic counselling, including offspring risks and reproductive options, should be offered to affected or at-risk young adults [1]. In probands without a molecular diagnosis, DNA storage should be considered and, when somatic mosaicism is suspected, a skin biopsy at nephrectomy for fibroblast culture [1]. AACR 2024 notes that identifying a syndrome in a child with cancer enables cascade testing of parents and siblings, that carrier siblings should follow recommended surveillance and that cascade testing should be considered even in conditions with a high de novo occurrence rate [12]. The European consensus makes offering surveillance conditional on prior parental counselling by a clinical geneticist or genetic counsellor [8].

8.2. WT1-related disorder

Transmission is autosomal dominant and most cases result from an apparently de novo variant; in rare families, a parent is heterozygous, symptomatic or asymptomatic, and penetrance appears higher when the variant is paternal in origin [3]. Fencl and colleagues described monozygotic twins with congenital nephrotic syndrome born to an asymptomatic 41-year-old father carrying the same variant, and Guaragna and colleagues described two families with vertical transmission of isolated SRNS [3]. Molecular testing of both parents of an apparently isolated case is therefore recommended; if the variant is not found in either parent's leukocyte DNA, sibling risk is slightly above population risk because of possible gonadal mosaicism, and the parent in whom the variant arose may have somatic mosaicism with a mild or absent phenotype [3]. If a parent is a carrier, risk to each sibling is 50%, without the phenotype being predictable because of intrafamilial variability and reduced penetrance; each child of a patient has a 50% probability of inheriting the variant, although most people with disorders of testicular development are infertile [3]. Overall penetrance is high and age-dependent, approximately 90% by the end of puberty [3]. Clarifying genetic status in older and younger at-risk relatives is recommended to begin early surveillance for glomerulopathy, Wilms tumour and gonadoblastoma; prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known [3]. In heterozygous women, pregnancy requires joint nephrology follow-up because of possible progression of renal disease [3].

8.3. Non-syndromic predisposition genes and recessive syndromes

TRIM28, REST and CTR9 are transmitted in an autosomal dominant manner with incomplete penetrance; each child of a carrier has a 50% probability of inheriting the variant [1, 10]. For TRIM28, initial evidence of a maternal parent-of-origin effect (all inherited variants transmitted by the mother in 15 patients) was challenged by a case of paternal transmission, and the European document and AACR 2025 recommend surveillance and testing of first-degree relatives regardless of the carrier parent's sex [8, 10, 48, 49]. For CTR9, all described families inherited the variant, demonstrably or presumptively, from the father, which should not be interpreted as a transmission rule without further data [51]. In REST, unaffected obligate carriers exist and the same family may include Wilms tumour and gingival fibromatosis [10, 50]. Heterozygous DIS3L2 variants are frequently inherited from a healthy parent, with probably low penetrance, requiring explanation that most carriers do not develop a tumour [7, 40].

In Perlman syndrome, Fanconi anaemia D1 and N, BUB1B- or TRIP13-related mosaic variegated aneuploidy, Mulibrey nanism and NYNRIN predisposition, inheritance is autosomal recessive and sibling recurrence risk is 25% [1, 8]. The 2006 British recommendations indicated that unaffected siblings and distant relatives of a child with Perlman syndrome do not need surveillance and that heterozygous BRCA2 carriers do not need Wilms tumour surveillance; adult cancer risks associated with BRCA2 heterozygosity lie outside this article's scope [69]. In X-linked dominant osteopathia striata with cranial sclerosis, a carrier woman transmits the variant to 50% of her children of either sex, with a male phenotype ranging from fetal or neonatal lethality to a mild form; a carrier father transmits it to all daughters and no sons (paternal transmission has only been described in mosaic fathers) [55].

8.4. Familial Wilms tumour, bilateral tumour and isolated unilateral tumour

In families with two or more cases without an identified gene, inheritance is typically autosomal dominant with reduced penetrance, and recommendations for surveillance of relatives are described in section 7.5 [1, 8, 10]. Bilateral tumours may result from postzygotic alterations confined to the kidneys and, in that case, are not heritable; because kidney-restricted mosaicism cannot be demonstrated with certainty, GeneReviews considers offspring risk potentially as high as 50% if germline mosaicism exists and advises considering surveillance of these children, whereas tumour probability for siblings of a child with bilateral tumour without known familial disease is less than 1% [1]. In a unilateral unifocal tumour without signs of predisposition after targeted assessment, risk to siblings and offspring is less than 1%: in a study of 96 long-term survivors of non-familial unilateral tumour, none of the 179 children had Wilms tumour [1]. The Oxford Desk Reference estimated risk to survivors' offspring, particularly after bilateral tumours, at less than 5%, at a time when few survivors had yet had children [4].

8.5. Reproductive options

When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible; perspectives on their use differ among professionals and families, and the decision is personal [1, 3]. The ERKNet-ESPN consensus recommends that communication of genetic results in congenital nephrotic syndrome include recurrence risk counselling by a clinical geneticist, with prenatal and preimplantation diagnosis options [17]. Most people with WT1-related disorder and disorders of testicular development are infertile, and early gonadal insufficiency also affects women, which should form part of fertility counselling [3]. ERN GENTURIS includes reproductive counselling of people with cancer predisposition syndromes among its areas of activity [18].

8.6. WAGR spectrum disorder

WAGR results from an unbalanced chromosomal rearrangement with high penetrance, almost always de novo; in rare cases, it derives from unbalanced transmission of a balanced parental rearrangement (mainly translocation, also insertion) or from a mosaic deletion in an asymptomatic parent [13]. The PNDS (French National Diagnosis and Care Protocol) considers a genetics clinic consultation as early as possible to be essential, together with cytogenetic study of the parents by karyotyping and FISH on metaphases and interphase nuclei; balanced parental rearrangements larger than 5–10 Mb are visible on conventional karyotyping, usually confirmed by FISH [13]. If parental testing is normal, the deletion is very probably de novo and the recurrence risk approaches that of the general population, but undetectable germline mosaicism cannot be excluded, and invasive sampling is discussed in subsequent pregnancies; if there is a parental rearrangement, the risk is much higher and prenatal diagnosis or preimplantation genetic testing is offered (section 5.4) [13]. A person with WAGR has, in theory, a 50% risk of transmitting the deletion; transmission by an affected person is exceptional owing to the severity of the syndrome and the genital anomalies, and the cases described concern small deletions with a moderate phenotype, including apparently isolated aniridia with PAX6 and WT1 deletion [13]. The PNDS recommends eye examination at birth or in early childhood of the children and siblings of people with aniridia, and family enquiry whenever a genetic or cytogenetic anomaly is identified [13]. The document itself states the recurrence risk for siblings differently in different sections (equal to that of the general population in the counselling section; very low, but with possible germline mosaicism, in the prenatal diagnosis section), and it is the latter formulation that supports the offer of prenatal diagnosis [13]. The disclosure consultation should be dedicated, with explanation of the diagnosis, planning of follow-up and genetic counselling, and is followed by a letter to the corresponding physicians [13].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Wilms tumour incidence

The international population-based IICC-3 study, with 163 registries and 2001–2010 data, calculated an age-standardised incidence rate of childhood renal tumours of 8.3 per million, higher in North America and Europe (9–10 per million) and lower in most Asian regions (4–5 per million); Wilms tumour accounted for more than 90% of renal tumours at each age between 1 and 7 years, and incidence remained stable between 1996 and 2010 [5]. The incidence rate of Wilms tumour at ages 0–14 years was 7.5 per million across all regions, 8.5 in North America, 9.2 in Western Europe, 8.8 in Eastern Europe, 8.4 in Northern and Southern Europe, 6.1 in South America, 6.3 in sub-Saharan Africa and 4.3 in East Asia; in the United States, it was 9.7 in Black children, 9.1 in non-Hispanic White children, 6.6 in Hispanic White children and 3.7 in Asian and Pacific Islander children [5]. The same study reports that in the 1970s incidence in Black populations was three times that in East Asian populations, that peak incidence is between ages 1 and 3 years in White populations and in the first year of life in East Asia, and that the tumour is approximately 10% more frequent in females [5]. A National Wilms Tumor Study review estimated approximately 1 case per 10,000 children before age 15 years, with a median age of 38 months, diagnosis on average 6 months later in girls and median ages of 17–27 months in bilateral tumours, aniridia, cryptorchidism or hypospadias, Beckwith-Wiedemann syndrome and intralobar rests [106]. Brazil (Aracaju, Curitiba, Goiânia and João Pessoa registries) and Portugal (Azores and Central, Northern and Southern region registries) contributed to IICC-3, but the article does not present separate national rates [5]. Orphanet presents country-specific European estimates from the RARECARE project, including Portugal, without explicitly indicating the denominator, so they are not used here as paediatric incidence [2].

9.2. Entity frequencies

Frequencies should be attributed to the entity to which they refer. WT1-related disorder has no known prevalence, with fewer than 500 patients described, and no founder variants or preferential geographical distribution described [3]. Orphanet records approximately 300 cases or families with Denys-Drash syndrome and approximately 150 with Frasier syndrome, 32 with Perlman syndrome, approximately 100 with osteopathia striata with cranial sclerosis and 2 with GLOW syndrome, all with prevalence below 1 per million where estimated, and a WAGR birth prevalence of 1–9 per million [2]. The PNDS (French National Diagnosis and Care Protocol) estimates WAGR prevalence at approximately 1 in 500,000 to 1 in 1,000,000, a value it acknowledges is poorly known and which lies below the Orphanet range; it also states that aniridia, with a population frequency of approximately 1 in 50,000, is found in approximately 1 in 70 children with Wilms tumour, that WT1 variants are identified in only 5–10% of isolated nephroblastomas and that approximately 22% of synchronous bilateral tumours are associated with syndromic anomalies [2, 13]. GeneReviews counts approximately 90 patients with molecularly confirmed osteopathia striata [55]. Mulibrey nanism is predominantly Finnish (approximately 89 of 130 known cases), with the founder TRIM37 variant c.493-2A>G [12, 15]. Predisposition proportions in cohorts (10% in the British exome study, 33.3% in the Dutch cohort, 13% germline variants in the Danish cohort, 24% in a Russian cohort enriched for bilateral tumours) depend on design and methods and are not population rates [6, 7, 42, 98].

9.3. Population diversity and sex differences

Available data suggest population differences in genetic architecture: in Japan, 25 of 31 children with bilateral tumour (81%) had WT1 alterations, versus 17–38% described in series of populations of European ancestry; in the same study, penetrance was 100% when small WT1 variants were inherited from the father and 67% when inherited from the mother or with 11p13 deletions [107]. The Dutch cohort acknowledges that it reflects a specific population and that predisposing factors differ between populations [7]. Regarding sex, in the Danish cohort all pathogenic germline variants occurred in girls, who had predisposition indicators in 57%; in the Dutch WT1 cohort, nine of the ten patients in whom tumour was the sole manifestation were girls, because WT1 variants affect 46,XX genitalia less, making suspicion harder in females [1, 42, 46]. AACR 2025 reports that girls with bilateral tumour have a higher risk of new tumours [10].

9.4. Special populations

In trisomy 18, high early mortality complicates risk estimation, and the surveillance decision should incorporate the family's goals of care [12]. The same guideline emphasises shared decision-making in syndromes with high very early mortality and those with low or non-specific tumour risks [12]. In children with WT1-related differences of sex development, recommendations should include professionals experienced in DSD [12].

10. Illustrative Clinical Case

10.1. Two children with de novo truncating WT1 variants and divergent courses (Al-Amoudi and colleagues, 2026)

Al-Amoudi and colleagues described, at a referral hospital in Saudi Arabia, two children with de novo truncating WT1 variants illustrating the two poles of the spectrum: one with nephropathy and DSD without tumour, the other with bilateral Wilms tumour as the first manifestation, without genital anomalies [108].

The first patient, a 46,XY boy followed for congenital hypothyroidism, was referred at 7 months because of ambiguous genitalia: prenatal ultrasonography had shown a retrovesical cyst, and at birth he had a small phallus, perineal hypospadias, fused labioscrotal folds and non-palpable gonads [108]. At 3 months he developed hypertension and acute kidney injury, and ileocolic intussusception (article figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC13108425/figure/fig-0001/) [108]. Renal ultrasonography showed enlarged hyperechoic kidneys, with poor corticomedullary differentiation, moderate left hydronephrosis and bilateral interpolar complex solid–cystic lesions with minimal vascularity, concordant on CT and MRI (figures 2 and 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC13108425/figure/fig-0002/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC13108425/figure/fig-0003/) [108]. WT1 sequencing identified the heterozygous variant NM_024426.6:c.1384C>T, p.(Gln462Ter), in exon 9, classified as likely pathogenic (PVS1, PM2, PP3) and absent in the parents [11, 108]. He progressed to end-stage kidney disease due to congenital nephrotic syndrome and began peritoneal dialysis; bilateral nephrectomy was planned, but he died at 16 months during the COVID-19 pandemic lockdown, which delayed treatment [108].

The second patient, an 8-month-old 46,XX girl born at term, presented with abdominal distension following an episode of diarrhoea and fever, with repeated hypotensive episodes and palpable masses in both flanks; external genitalia were normal [108]. Ultrasonography showed large masses at the lower poles of both kidneys, with a hypoechoic, probably necrotic centre and minimal vascularity (figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC13108425/figure/fig-0004/), and CT demonstrated a horseshoe kidney with heterogeneous masses in the fused lower poles (figure 5: https://pmc.ncbi.nlm.nih.gov/articles/PMC13108425/figure/fig-0005/) [108]. Biopsy showed spindle cells and primitive tubules, compatible with Wilms tumour described by the authors as stage IV [108]. Exome sequencing identified the heterozygous variant NM_024426.6:c.453G>A, p.(Trp151Ter), in exon 1, absent in the parents and classified as pathogenic [11, 108]. Chemotherapy, which included doxorubicin, did not prevent progression; the child underwent bilateral radical nephrectomy with peritoneal dialysis catheter placement, developed aspiration pneumonia with respiratory failure and sepsis, was readmitted for suspected septic shock in the setting of cardiomyopathy attributed to chemotherapy and died at 21 months after transition to comfort care [108].

Teaching points. The second child reproduces several cohort observations: in a 46,XX girl, a WT1 variant may cause no genital signs and the tumour may be the first manifestation, as in the Dutch cohort where nine of ten patients with isolated tumour were girls; truncating variants are associated with early bilateral tumours; and CAKUT (here, horseshoe kidney) occurs in approximately one in five carriers of truncating variants [3, 46]. The first case shows the other pole, with congenital nephrotic syndrome, 46,XY DSD and end-stage kidney disease in the first year, without tumour before death [108]. Genetic testing differed between the two (single gene versus exome), and only the first had clinical grounds for suspicion before any tumour [108]. The first case's variant, NM_024426.6:c.1384C>T, p.(Gln462Ter), differs from the historical Denys-Drash variant sometimes designated “c.1384C>T” in another numbering system (p.Arg394Trp, now c.1399C>T in the MANE transcript), showing the risk of confusing variants when the transcript is not specified [3, 11].

Critical appraisal. The authors argue that case 2 illustrates the importance of ongoing tumour surveillance even without genital anomalies, but the child was not under surveillance because there was no prior diagnosis; they also report that some experts favour prophylactic nephrectomy before tumour onset for high-risk variants, while others defer it [108]. The guidelines consulted do not recommend prophylactic nephrectomy before end-stage kidney disease: GeneReviews and the ERKNet-ESPN consensus place bilateral nephrectomy at end-stage kidney disease or before transplantation, and surveillance guidelines specifically aim to detect small tumours allowing nephron-sparing surgery [3, 8, 17]. Management described in a two-case report should not be generalised, and the authors do not report the cumulative anthracycline dose or the cardiac investigations supporting the cardiomyopathy diagnosis [108].

11. Prognosis and Long-Term Follow-Up

11.1. Oncological prognosis

Overall survival in Wilms tumour is around 90%, lower with anaplastic histology and bilateral, metastatic or relapsed disease [1, 8]. In WT1-related forms, survival does not differ significantly from that of tumours without a known cause [3]. TRIM28-associated tumours have a favourable prognosis, without metastatic disease in studies reviewed in 2021 [1, 48]. Heterozygous DIS3L2-associated tumours showed, in a series of 34 children, 32% metastases, 24% high-risk histology and four deaths, findings requiring confirmation in unselected cohorts [40]. Of the four children with truncating FBXW7 variants in the exome study, two died, one relapsed and one developed osteosarcoma at age 39 years [6]. In bilateral tumour treated according to AREN0534, 4-year event-free survival was 82.1% and overall survival 94.9% [85]. In Perlman syndrome, neonatal mortality dominates prognosis, but survivors have been described after multimodal treatment of surveillance-detected tumours and, in 2026, a child with a homozygous DIS3L2 exon 9 deletion with prolonged survival following sequential partial nephrectomies [12, 103]. In Mulibrey nanism, all 14 reviewed Wilms tumours entered remission [12]. Metachronous tumours may occur years after the first: in WAGR, up to 7 years after initial diagnosis [65].

11.2. Renal function

Long-term morbidity in WT1 syndromes is predominantly renal. In the National Wilms Tumor Study (1969–1995), cumulative risk of renal failure at 20 years after tumour diagnosis was 62% in Denys-Drash syndrome (13 of 22) and 38% in WAGR (10 of 46), versus less than 1% in 5,358 patients with unilateral tumour without genitourinary anomalies [83]. SRNS inevitably progresses to end-stage kidney disease, within weeks to months in congenital nephrotic syndrome, around age 2.5 years in half of children with missense variants at DNA-binding residues, around age 10 years with missense variants outside this region and in adolescence with intron 9 variants [3]. With truncating variants, proteinuria generally arises in the second decade after nephrectomy, and in the Dutch cohort three of five patients with chronic kidney disease reached kidney failure in adulthood (24, 26 and 41 years), leading the authors to recommend lifelong renal function surveillance [3, 46]. Nephropathy does not recur after transplantation, and in a Chinese series of 13 transplanted children all grafts were functioning after 32 months, with Epstein-Barr viraemia in five and post-transplant lymphoproliferative disease in two [3, 102].

In WAGR, kidney disease results from nephron reduction and the toxicity of tumour treatment or, independently of it, from focal segmental glomerulosclerosis, and may lead to end-stage kidney disease in adolescence or early adulthood [13]. The older National Wilms Tumor Study series, summarised in the PNDS (French National Diagnosis and Care Protocol), recorded end-stage kidney disease in 34–40% of survivors with WAGR and tumour and an estimated survival of 48% (±17%) at 27 years; Hol and colleagues cite a 20-year overall survival of 47.8% in WAGR compared with 85.5% in patients without WAGR, with mostly non-tumour mortality, and could not confirm it owing to lack of follow-up [13, 65]. In end-stage kidney disease due to focal segmental glomerulosclerosis without nephron reduction, survival is that of the non-syndromic form and depends on access to transplantation [13]. Hence the PNDS recommendation of lifelong clinical and laboratory surveillance (blood pressure, proteinuria, creatinine and glomerular filtration rate), particularly after bilateral tumour, and of nephrological follow-up of all children treated for a renal tumour, especially those with a single kidney [13].

11.3. Gonadal function and other late effects

Early gonadal insufficiency affects 67% of patients with WT1-related disorder at age 12.6 years and 83% at 16.2 years, across all karyotypes and genotypes and independently of renal function, with spontaneous puberty in 94% of 46,XX and 60% of 46,XY individuals [3]. Gonadoblastoma risk persists while dysgenetic gonads remain, and gonadectomy is decided by the DSD team [3]. Late effects of tumour treatment include doxorubicin cardiotoxicity, with a risk of late cardiovascular dysfunction especially in children treated before age 5 years and a recommendation for periodic long-term cardiovascular monitoring, and dactinomycin-associated hepatic veno-occlusive disease in younger children [86].

11.4. Follow-up schedule

Sources: [1, 3, 4, 8, 10, 12, 13, 46, 55].

Transition to adult care should maintain syndrome-specific renal, gonadal and, where applicable, oncological surveillance; once Wilms tumour surveillance ends, AACR recommends discussing with the family the need for other oncological surveillance, remembering that most of these syndromes are not associated with adult cancers [15]. Affected or at-risk young adults should receive genetic counselling on offspring risks and reproductive options, ideally before pregnancy [1]. In WAGR, the French PNDS asks for the transition to adult services to be organised at the end of adolescence, to avoid interruption of renal follow-up [13].

12. Summary and Final Considerations

Wilms tumour predisposition is a heterogeneous set of constitutional, germline or mosaic causes explaining approximately 10–15% of tumours in classical estimates and at least one-third when blood and normal kidney are studied systematically [1, 6, 7]. WT1 is the paradigm: its variants produce a continuum from steroid-resistant glomerulopathy and 46,XY gonadal dysgenesis to Wilms tumour, with clear correlations between variant type and risk (truncating variants with the highest tumour and bilaterality risk; zinc finger missense variants with the earliest nephropathy; intron 9 variants with complete gonadal dysgenesis, gonadoblastoma and low tumour risk) [3, 8]. The terms Denys-Drash syndrome and Frasier syndrome describe constellations within this continuum and no longer define distinct entities [3].

Non-syndromic predisposition genes (TRIM28, REST, CTR9, heterozygous DIS3L2) are recognised only through genetic testing, guided by histology (epithelial in TRIM28), age, bilaterality or family history, and have incomplete penetrance; reported parent-of-origin effects (maternal in TRIM28, paternal in CTR9) are not absolute rules [1, 48, 49, 51]. Rare high-risk syndromes, such as Perlman syndrome, BUB1B- or TRIP13-related mosaic variegated aneuploidy and Fanconi anaemia D1/N, are recognised through the extrarenal phenotype, and osteopathia striata with cranial sclerosis (AMER1) has come to be considered a predisposition syndrome [8, 12, 57].

Ultrasound surveillance every 3 months is the main risk management tool; European and North American guidelines agree on the interval but differ on the risk threshold (5% versus 1%), duration (7 versus 8 years for non-syndromic genes), modality (renal versus abdominal) and specific entities such as WT1 intron 9 variants, trisomy 18 or heterozygous DIS3L2 [8, 10, 12, 15]. No strategy has been evaluated in randomised trials, and expected benefit lies mainly in detecting smaller tumours requiring less treatment and allowing nephron preservation, essential in conditions at risk of renal failure [4, 8]. Every child with Wilms tumour should be assessed for syndrome signs and have access to counselling and genetic testing, and bilateral tumours require germline testing and, if negative, kidney tissue testing [7, 8, 10, 12]. Long-term follow-up of WT1 syndromes is predominantly renal and gonadal and should continue into adulthood [3, 46].

13. Bibliographic References

1. Turner JT, Brzezinski J, Dome JS. Wilms Tumor Predisposition. 2003 Dec 19 [updated 2022 Mar 24]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 20301471. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1294/
2. Orphanet. Nephroblastoma (ORPHA:654), WAGR syndrome (ORPHA:893), Denys-Drash syndrome (ORPHA:220), Frasier syndrome (ORPHA:347), Perlman syndrome (ORPHA:2849), Osteopathia striata-cranial sclerosis syndrome (ORPHA:2780) and GLOW syndrome (ORPHA:404476): nomenclature (2026-07-02) and epidemiological data (2026-06-23) [Internet]. Paris: INSERM; accessed 2026 Oct 7. Available at: https://api.orphacode.org and https://www.orphadata.com
3. Lipska-Ziętkiewicz BS. WT1 Disorder. 2020 Apr 30 [updated 2025 May 15]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 32352694. Available at: https://www.ncbi.nlm.nih.gov/books/NBK556455/
4. Firth HV, Hurst JA. Wilms tumour. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 620–2.
5. Nakata K, Colombet M, Stiller CA, Pritchard-Jones K, Steliarova-Foucher E; IICC-3 Contributors. Incidence of childhood renal tumours: an international population-based study. Int J Cancer. 2020;147(12):3313-27. doi:10.1002/ijc.33147. PMID: 32902866.
6. Mahamdallie S, Yost S, Poyastro-Pearson E, Holt E, Zachariou A, Seal S, et al. Identification of new Wilms tumour predisposition genes: an exome sequencing study. Lancet Child Adolesc Health. 2019;3(5):322-31. doi:10.1016/S2352-4642(19)30018-5. PMID: 30885698.
7. Hol JA, Kuiper RP, van Dijk F, Waanders E, van Peer SE, Koudijs MJ, et al. Prevalence of (epi)genetic predisposing factors in a 5-year unselected national Wilms tumor cohort: a comprehensive clinical and genomic characterization. J Clin Oncol. 2022;40(17):1892-902. doi:10.1200/JCO.21.02510. PMID: 35230882.
8. Hol JA, Jewell R, Chowdhury T, Duncan C, Nakata K, Oue T, et al. Wilms tumour surveillance in at-risk children: literature review and recommendations from the SIOP-Europe Host Genome Working Group and SIOP Renal Tumour Study Group. Eur J Cancer. 2021;153:51-63. doi:10.1016/j.ejca.2021.05.014. PMID: 34134020.
9. Coorens THH, Treger TD, Al-Saadi R, Moore L, Tran MGB, Mitchell TJ, et al. Embryonal precursors of Wilms tumor. Science. 2019;366(6470):1247-51. doi:10.1126/science.aax1323. PMID: 31806814.
10. Brzezinski JJ, Becktell KD, Bougeard G, Brodeur GM, Diller LR, Doria AS, et al. Update on surveillance guidelines in emerging Wilms tumor predisposition syndromes. Clin Cancer Res. 2025;31(1):18-24. doi:10.1158/1078-0432.CCR-24-2488. PMID: 39466169.
11. VariantValidator [online tool; version 4.0.1, database vvdb_2025_3, vvta_2025_02]. Queries NM_024426.6:c.1399C>T, c.1447+4C>T, c.1447+5G>A, c.1384C>T and c.453G>A, genomic projection NC_000011.10 and MANE Select transcripts of WT1, TRIM28, REST, CTR9, DIS3L2 and AMER1, on 2026 Oct 7. Available at: https://rest.variantvalidator.org
12. Kalish JM, Becktell KD, Bougeard G, Brodeur GM, Diller LR, Doria AS, et al. Update on surveillance for Wilms tumor and hepatoblastoma in Beckwith-Wiedemann syndrome and other predisposition syndromes. Clin Cancer Res. 2024;30(23):5260-9. doi:10.1158/1078-0432.CCR-24-2100. PMID: 39320341.
13. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Syndrome WAGR. Saint-Denis La Plaine: HAS; 2021 Oct 14 [text dated 2021 Jul 5; Centre de Référence des Maladies Rares en Ophtalmologie OPHTARA]. Available at: https://www.has-sante.fr/jcms/p_3283422
14. Balis F, Green DM, Armstrong A, Aye J, Benedetti D, Brown B, et al. Wilms tumor, version 2.2025, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2025;23(8):319-42. doi:10.6004/jnccn.2025.0037. PMID: 40763792.
15. Kalish JM, Doros L, Helman LJ, Hennekam RC, Kuiper RP, Maas SM, et al. Surveillance recommendations for children with overgrowth syndromes and predisposition to Wilms tumors and hepatoblastoma. Clin Cancer Res. 2017;23(13):e115-22. doi:10.1158/1078-0432.CCR-17-0710. PMID: 28674120.
16. Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2020;35(8):1529-61. doi:10.1007/s00467-020-04519-1. PMID: 32382828.
17. Boyer O, Schaefer F, Haffner D, Bockenhauer D, Hölttä T, Bérody S, et al. Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group. Nat Rev Nephrol. 2021;17(4):277-89. doi:10.1038/s41581-020-00384-1. PMID: 33514942.
18. European Reference Networks and patient associations: ERN PaedCan (https://paedcan.ern-net.eu/), ERN GENTURIS (https://www.genturis.eu/), ERKNet (https://www.erknet.org/), ERN eUROGEN (https://eurogen-ern.eu/), Endo-ERN (https://endo-ern.eu/), International WAGR Syndrome Association (https://wagr.org/), Childhood Cancer International Europe (https://ccieurope.eu/), Childhood Cancer International (https://www.childhoodcancerinternational.org/), SIOP Europe (https://siope.eu/), Children's Cancer and Leukaemia Group (https://www.cclg.org.uk/) and DSD Families (https://www.dsdfamilies.org/) [Internet]; accessed 2026 Oct 7.
19. Srinidhi R, Raveenthiran V. Robert Abbe and Wilms' tumor. J Indian Assoc Pediatr Surg. 2026;31(4):525-30. doi:10.4103/jiaps.jiaps_10_26. PMID: 42565126.
20. Raffensperger J. Max Wilms and his tumor. J Pediatr Surg. 2015;50(2):356-9. doi:10.1016/j.jpedsurg.2014.10.054. PMID: 25638637.
21. Miller RW, Fraumeni JF, Manning MD. Association of Wilms's tumor with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med. 1964;270:922-7. doi:10.1056/NEJM196404302701802. PMID: 14114111.
22. Frasier SD, Bashore RA, Mosier HD. Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. J Pediatr. 1964;64:740-5. doi:10.1016/s0022-3476(64)80622-3. PMID: 14149008.
23. Denys P, Malvaux P, Van Den Berghe H, Tanghe W, Proesmans W. [Association of an anatomo-pathological syndrome of male pseudohermaphroditism, Wilms' tumor, parenchymatous nephropathy and XX/XY mosaicism]. French. Arch Fr Pediatr. 1967;24(7):729-39. PMID: 4292870.
24. Drash A, Sherman F, Hartmann WH, Blizzard RM. A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease. J Pediatr. 1970;76(4):585-93. doi:10.1016/s0022-3476(70)80409-7. PMID: 4316066.
25. Knudson AG, Strong LC. Mutation and cancer: a model for Wilms' tumor of the kidney. J Natl Cancer Inst. 1972;48(2):313-24. doi:10.1093/jnci/48.2.313. PMID: 4347033.
26. Jones KL, Jones MC, del Campo M. Aniridia–Wilms tumor association (WAGR syndrome). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 48–9.
27. Perlman M, Levin M, Wittels B. Syndrome of fetal gigantism, renal hamartomas, and nephroblastomatosis with Wilms' tumor. Cancer. 1975;35(4):1212-7. doi:10.1002/1097-0142(197504)35:4<1212::aid-cncr2820350427>3.0.co;2-2. PMID: 163679.
28. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990;60(3):509-20. doi:10.1016/0092-8674(90)90601-a. PMID: 2154335.
29. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990;343(6260):774-8. doi:10.1038/343774a0. PMID: 2154702.
30. Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, et al. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991;67(2):437-47. doi:10.1016/0092-8674(91)90194-4. PMID: 1655284.
31. Barbaux S, Niaudet P, Gubler MC, Grünfeld JP, Jaubert F, Kuttenn F, et al. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet. 1997;17(4):467-70. doi:10.1038/ng1297-467. PMID: 9398852.
32. Rivera MN, Kim WJ, Wells J, Driscoll DR, Brannigan BW, Han M, et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science. 2007;315(5812):642-5. doi:10.1126/science.1137509. PMID: 17204608.
33. Jenkins ZA, van Kogelenberg M, Morgan T, Jeffs A, Fukuzawa R, Pearl E, et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet. 2009;41(1):95-100. doi:10.1038/ng.270. PMID: 19079258.
34. Astuti D, Morris MR, Cooper WN, Staals RH, Wake NC, Fews GA, et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat Genet. 2012;44(3):277-84. doi:10.1038/ng.1071. PMID: 22306653.
35. Hanks S, Perdeaux ER, Seal S, Ruark E, Mahamdallie SS, Murray A, et al. Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour. Nat Commun. 2014;5:4398. doi:10.1038/ncomms5398. PMID: 25099282.
36. Mahamdallie SS, Hanks S, Karlin KL, Zachariou A, Perdeaux ER, Ruark E, et al. Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nat Genet. 2015;47(12):1471-4. doi:10.1038/ng.3440. PMID: 26551668.
37. Yost S, de Wolf B, Hanks S, Zachariou A, Marcozzi C, Clarke M, et al. Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation. Nat Genet. 2017;49(7):1148-51. doi:10.1038/ng.3883. PMID: 28553959.
38. Halliday BJ, Fukuzawa R, Markie DM, Grundy RG, Ludgate JL, Black MA, et al. Germline mutations and somatic inactivation of TRIM28 in Wilms tumour. PLoS Genet. 2018;14(6):e1007399. doi:10.1371/journal.pgen.1007399. PMID: 29912901.
39. Diets IJ, Hoyer J, Ekici AB, Popp B, Hoogerbrugge N, van Reijmersdal SV, et al. TRIM28 haploinsufficiency predisposes to Wilms tumor. Int J Cancer. 2019;145(4):941-51. doi:10.1002/ijc.32167. PMID: 30694527.
40. van Peer SE, Treger TD, Wegert J, Hol JA, Le Gall J, Jakkula EE, et al. Wilms tumor characteristics in children with heterozygous germline DIS3L2 variants. Genet Med. 2025;27(9):101478. doi:10.1016/j.gim.2025.101478. PMID: 40481679.
41. Wegert J, Appenzeller S, Treger TD, Streitenberger H, Ziegler B, Bausenwein S, et al. Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor. Genome Med. 2025;17(1):49. doi:10.1186/s13073-025-01482-0. PMID: 40340749.
42. Stoltze UK, Hildonen M, Hansen TVO, Foss-Skiftesvik J, Byrjalsen A, Lundsgaard M, et al. Germline (epi)genetics reveals high predisposition in females: a 5-year, nationwide, prospective Wilms tumour cohort. J Med Genet. 2023;60(9):842-9. doi:10.1136/jmg-2022-108982. PMID: 37019617.
43. Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P, et al. Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum Mol Genet. 1998;7(4):709-14. doi:10.1093/hmg/7.4.709. PMID: 9499425.
44. Lipska BS, Ranchin B, Iatropoulos P, Gellermann J, Melk A, Ozaltin F, et al. Genotype-phenotype associations in WT1 glomerulopathy. Kidney Int. 2014;85(5):1169-78. doi:10.1038/ki.2013.519. PMID: 24402088.
45. Royer-Pokora B, Beier M, Henzler M, Alam R, Schumacher V, Weirich A, et al. Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. Am J Med Genet A. 2004;127A(3):249-57. doi:10.1002/ajmg.a.30015. PMID: 15150775.
46. van Peer SE, Kuiper RP, Hol JA, Egging S, van der Zwaag B, Lilien MR, et al. Clinical characterization of a national cohort of patients with germline WT1 variants including late-onset phenotypes. Kidney Int Rep. 2024;9(12):3570-9. doi:10.1016/j.ekir.2024.09.007. PMID: 39698353.
47. Glénisson M, Grapin M, Blanc T, Preka E, Hogan J, Aurelle M, et al. Genotype-phenotype correlations in Denys-Drash syndrome in children. Kidney Int Rep. 2025;10(4):1205-12. doi:10.1016/j.ekir.2025.01.014. PMID: 40303223.
48. Hol JA, Diets IJ, de Krijger RR, van den Heuvel-Eibrink MM, Jongmans MC, Kuiper RP. TRIM28 variants and Wilms' tumour predisposition. J Pathol. 2021;254(4):494-504. doi:10.1002/path.5639. PMID: 33565090.
49. Whitworth J, Armstrong R, Maher ER. Wilms tumour resulting from paternal transmission of a TRIM28 pathogenic variant — a first report. Eur J Hum Genet. 2024;32(3):361-4. doi:10.1038/s41431-024-01545-7. PMID: 38282073.
50. GeneGuidance. Gene and condition curation: WT1, AMER1, REST, DIS3L2, CTR9, FBXW7, KDM3B, BUB1B, TRIP13 [database]. Version dated 26 September 2026; accessed 2026 Oct 7.
51. Iman A, Majaliwa E, Kambainei LG, Mremi A, Mensenkamp AR, Hamel BC. Novel CTR9 germline pathogenic splice site variant in siblings with Wilms tumor from Tanzania. Eur J Med Genet. 2024;72:104973. doi:10.1016/j.ejmg.2024.104973. PMID: 39293508.
52. Breslow NE, Olson J, Moksness J, Beckwith JB, Grundy P. Familial Wilms' tumor: a descriptive study. Med Pediatr Oncol. 1996;27(5):398-403. doi:10.1002/(SICI)1096-911X(199611)27:5<398::AID-MPO2>3.0.CO;2-H. PMID: 8827065.
53. Rahman N, Arbour L, Tonin P, Renshaw J, Pelletier J, Baruchel S, et al. Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12-q21. Nat Genet. 1996;13(4):461-3. doi:10.1038/ng0896-461. PMID: 8696342.
54. McDonald JM, Douglass EC, Fisher R, Geiser CF, Krill CE, Strong LC, et al. Linkage of familial Wilms' tumor predisposition to chromosome 19 and a two-locus model for the etiology of familial tumors. Cancer Res. 1998;58(7):1387-90. PMID: 9537236.
55. Gear R, Savarirayan R. Osteopathia Striata with Cranial Sclerosis. 2021 Apr 15 [revised 2023 Mar 30]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 33856753. Available at: https://www.ncbi.nlm.nih.gov/books/NBK569515/
56. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Osteopathia striata with cranial sclerosis (MIM 300373). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 616–20.
57. Bach A, Mi J, Hunter M, Halliday BJ, García-Miñaúr S, Sperotto F, et al. Wilms tumor in patients with osteopathia striata with cranial sclerosis. Eur J Hum Genet. 2021;29(3):396-401. doi:10.1038/s41431-020-00718-4. PMID: 32879452.
58. Campwala I, Schienda J, Murphy AJ, Hashimi B, Perry T, Cost N, et al. Wilms tumor in children with AMER1/WTX germline pathogenic variants: a multicenter case series. Pediatr Blood Cancer. 2025;72(8):e31798. doi:10.1002/pbc.31798. PMID: 40399763.
59. Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39(2):162-4. doi:10.1038/ng1947. PMID: 17200671.
60. Fiorica PN, Golmard L, Kim J, Bao R, Lin FY, Roy A, et al. Germline pathogenic DROSHA variants are linked to pineoblastoma and Wilms tumor predisposition. Clin Cancer Res. 2025;31(8):1491-503. doi:10.1158/1078-0432.CCR-24-2785. PMID: 39992227.
61. Firth HV, Hurst JA. Ambiguous genitalia, including sex reversal. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 56–7.
62. Firth HV, Hurst JA. Overgrowth. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 272–5.
63. Arnoux JB, de Lonlay P. Congenital hyperinsulinism and genetic disorders of insulin resistance and signalling. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 6, section 6.1 Clinical Presentation. doi:10.1007/978-3-662-63123-2_6.
64. Firth HV, Hurst JA. Chromosomal mosaicism (postnatal). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 653.
65. Hol JA, Jongmans MCJ, Sudour-Bonnange H, Ramírez-Villar GL, Chowdhury T, Rechnitzer C, et al. Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: the 30-year SIOP-RTSG experience. Cancer. 2021;127(4):628-38. doi:10.1002/cncr.33304. PMID: 33146894.
66. Firth HV, Hurst JA. Hypospadias. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 186–7.
67. Firth HV, Hurst JA. Multiple endocrine neoplasia (MEN). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 593.
68. National Center for Biotechnology Information. ClinVar: VCV000003487 (NM_024426.6(WT1):c.1399C>T (p.Arg467Trp)) [Internet]. Bethesda (MD): NCBI; accessed 2026 Oct 7. Available at: https://www.ncbi.nlm.nih.gov/clinvar/variation/3487/
69. Scott RH, Walker L, Olsen ØE, Levitt G, Kenney I, Maher E, et al. Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch Dis Child. 2006;91(12):995-9. doi:10.1136/adc.2006.101295. PMID: 16857697.
70. Jones KL, Jones MC, del Campo M. Simpson-Golabi-Behmel syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 224.
71. Jones KL, Jones MC, del Campo M. Sotos syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 202.
72. Jones KL, Jones MC, del Campo M. Fanconi pancytopenia syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 452.
73. Jones KL, Jones MC, del Campo M. Mulibrey nanism syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 120.
74. Jones KL, Jones MC, del Campo M. Bohring-Opitz syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 238.
75. Firth HV, Hurst JA. Li–Fraumeni syndrome (LFS). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 584.
76. Jones KL, Jones MC, del Campo M. 2q37 deletion syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 84.
77. Firth HV, Hurst JA. Edwards syndrome (trisomy 18). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 670.
78. Jones KL, Jones MC, del Campo M. Trisomy 8 syndrome (p. 18), Silver-Russell syndrome (p. 112), Marshall-Smith syndrome (p. 214), Schinzel-Giedion syndrome (p. 306), Linear sebaceous nevus syndrome (p. 702–5), Hypomelanosis of Ito (p. 710), Megalencephaly-capillary malformation-polydactyly syndrome (p. 732), Encephalocraniocutaneous lipomatosis (p. 740), TP63-related ectodermal dysplasia (p. 764). In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022.
79. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Ischiospinal dysostosis (MIM 608020). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 785–6.
80. Firth HV, Hurst JA. Coarse facial features. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 106–9.
81. Bakhuizen JJ, Hanson H, van der Tuin K, Lalloo F, Tischkowitz M, Wadt K, et al. Surveillance recommendations for DICER1 pathogenic variant carriers: a report from the SIOPE Host Genome Working Group and CanGene-CanVar Clinical Guideline Working Group. Fam Cancer. 2021;20(4):337-48. doi:10.1007/s10689-021-00264-y. PMID: 34170462.
82. Mul J, Seravalli E, Bosman ME, van de Ven CP, Littooij AS, van Grotel M, et al. Estimated clinical benefit of combining highly conformal target volumes with Volumetric-Modulated Arc Therapy (VMAT) versus conventional flank irradiation in pediatric renal tumors. Clin Transl Radiat Oncol. 2021;29:20–26. doi:10.1016/j.ctro.2021.04.007. PMID: 34027140
83. Breslow NE, Takashima JR, Ritchey ML, Strong LC, Green DM. Renal failure in the Denys-Drash and Wilms' tumor-aniridia syndromes. Cancer Res. 2000;60(15):4030-2. PMID: 10945603.
84. Ehrlich PF, Tornwall B, Chintagumpala MM, Chi YY, Hoffer FA, Perlman EJ, et al. Kidney preservation and Wilms tumor development in children with diffuse hyperplastic perilobar nephroblastomatosis: a report from the Children's Oncology Group study AREN0534. Ann Surg Oncol. 2022;29(5):3252-61. doi:10.1245/s10434-021-11266-6. PMID: 35072864.
85. Ehrlich P, Chi YY, Chintagumpala MM, Hoffer FA, Perlman EJ, Kalapurakal JA, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017;266(3):470-8. doi:10.1097/SLA.0000000000002356. PMID: 28795993.
86. U.S. Food and Drug Administration. Labels for dactinomycin for injection (ANDA203385, 2024), vincristine sulfate injection (ANDA071484, 2026) and doxorubicin hydrochloride (NDA050629, 2026); Drugs@FDA records for Cosmegen (NDA050682) and Oncovin (NDA014103) [Internet]. Silver Spring (MD): FDA; accessed 2026 Oct 7. Available at: https://api.fda.gov/drug/label.json and https://api.fda.gov/drug/drugsfda.json
87. European Medicines Agency. Medicines output: list of authorised medicines [Internet]. Amsterdam: EMA; accessed 2026 Oct 7. Available at: https://www.ema.europa.eu/en/documents/report/medicines-output-medicines_json-report_en.json
88. Meitheal Pharmaceuticals Inc. Dactinomycin for injection: US prescribing information. ANDA 213463; version effective 13 Nov 2020. DailyMed. Accessed 7 Oct 2026 and 26 Oct 2026.
89. Hospira, Inc. Vincristine sulfate injection, USP: US prescribing information. ANDA 071484; version effective 30 Dec 2025. DailyMed. Accessed 26 Oct 2026.
90. INFARMED, I.P. Vincristina Teva 1 mg/ml solução injetável, Teva Pharma: summary of product characteristics (Infomed); first authorisation 4 Jun 1984. Infomed. Accessed 26 Oct 2026.
91. Pfizer Laboratories. Doxorubicin hydrochloride injection: US prescribing information. NDA 050629; version effective 30 Apr 2026. DailyMed. Accessed 26 Oct 2026.
92. INFARMED, I.P. Doxorrubicina Accord concentrado para solução para perfusão: summary of product characteristics (Infomed, med_id 47925); text approved 17 Jan 2024. Infomed. Accessed 26 Oct 2026.
93. Azurity Pharmaceuticals. Epaned (enalapril maleate) oral solution: US prescribing information. NDA 208686; version effective 16 Dec 2025. DailyMed. Accessed 26 Oct 2026.
94. INFARMED, I.P. Renitec 20 mg comprimidos (enalapril), Organon Portugal: summary of product characteristics (Infomed). Infomed. Accessed 26 Oct 2026.
95. Upsher-Smith Laboratories, LLC. Zestril (lisinopril) tablets: US prescribing information. NDA 019777; version effective 2 Jan 2025. DailyMed. Accessed 26 Oct 2026.
96. ClinicalTrials.gov. NCT00945009, NCT00898365, NCT06401330, NCT04005820, NCT01252901, NCT03050268 and NCT07605884 [Internet]. Bethesda (MD): U.S. National Library of Medicine; accessed 2026 Oct 7. Available at: https://clinicaltrials.gov/
97. European Medicines Agency. Clinical Trials Information System (CTIS), public search for “Wilms”, “nephroblastoma” and “renal tumour” [Internet]; accessed 2026 Oct 7. Available at: https://euclinicaltrials.eu/
98. Semenova V, Sagoyan G, Zhukovskaya E, Kozlova V, Gegelia N, Mitrofanova A, et al. Genetic and epigenetic drivers of Wilms tumor predisposition in Russian pediatric patients: a multicenter study. Int J Mol Sci. 2026;27(9):4066. doi:10.3390/ijms27094066. PMID: 42123644.
99. Vujanić GM, Furtwängler R, Chowdhury T, Vokuhl C, Wegert J, Graf N. Nephrogenic rests/nephroblastomatosis in patients with unilateral Wilms tumor are not associated with an increased risk of relapse: an analysis of patients treated on the SIOP-WT-2001 protocol in the SIOP-UK-CCLG and SIOP-GPOH studies (2001-2022). Pediatr Blood Cancer. 2026;73(10):e70598. doi:10.1002/1545-5017.70598. PMID: 42535789.
100. Welter N, Schenk JP, Wegert J, Gessler M, Kager L, Wagenpfeil S, et al. The fate (outcome) of clinically apparent single lesion and oligofocal nephroblastomatosis treated according to SIOP/GPOH protocols for Wilms tumor. Pediatr Blood Cancer. 2026;73(7):e70354. doi:10.1002/1545-5017.70354. PMID: 42053023.
101. Laustsen MM, Stoltze UK, Larsen KB, Olsen TE, Wadt KAW, Sørensen PL, et al. Novel truncating WT1 germline variant in a case of familial Wilms tumor. Cancer Genet. 2026;304-305:160-4. doi:10.1016/j.cancergen.2026.04.007. PMID: 42105606.
102. Abasi R, Zhilang L, Mengjie J, Longshan L, Xiaoyun J, Yuxin P. Kidney transplantation outcomes in children with WT1-associated kidney disease: a single-center cohort study. Front Pediatr. 2026;14:1884378. doi:10.3389/fped.2026.1884378. PMID: 42568457.
103. Levy E, Elliott L, Miller MA, Kramer M. Prolonged survival with homozygous deletion of exon 9 in Perlman syndrome: a case report. Case Rep Genet. 2026;2026:9916711. doi:10.1155/crig/9916711. PMID: 42040973.
104. Vempuluru VS, Sanjeev Patne G, Chattannavar G, Mishra DK, Kaliki S. Sequential presentation of Wilms' tumor and orbital rhabdomyosarcoma in a child with mosaic variegated aneuploidy syndrome 3. Orbit. 2026:1-7. doi:10.1080/01676830.2026.2715719. PMID: 42595739.
105. Palhazi B, Paikari A, Clarén G, Appenzeller S, Imdahl F, Daniel C, et al. The absence of Trim28 in nephron progenitors results in impaired kidney development and function. Development. 2026;153(15):dev205188. doi:10.1242/dev.205188. PMID: 42522414.
106. Breslow N, Olshan A, Beckwith JB, Green DM. Epidemiology of Wilms tumor. Med Pediatr Oncol. 1993;21(3):172-81. doi:10.1002/mpo.2950210305. PMID: 7680412.
107. Kaneko Y, Okita H, Haruta M, Arai Y, Oue T, Tanaka Y, et al. A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation. Br J Cancer. 2015;112(6):1121-33. doi:10.1038/bjc.2015.13. PMID: 25688735.
108. Al-Amoudi W, Alhuthil R, Alnwiji A, Alqarni MS, Murad S, Alsagheir A. Denys-Drash syndrome by WT1 gene: clinical variability and management challenges in two Saudi infants. Case Rep Endocrinol. 2026;2026:8875066. doi:10.1155/crie/8875066. PMID: 42040317. PMCID: PMC13108425.