Keywords

6.1 Introduction

Wilms tumor (WT) is the most common renal malignancy in pediatrics and the fifth most common cancer in children under 15 years of age. Approximately 500 new cases are diagnosed annually in the United States representing about 6.3% of childhood cancers [1]. Approximately 5–10% of patients have bilateral disease; for patients with unilateral disease, the median age of diagnosis is 44 months, and for those with bilateral disease, it is 31 months [2].

Symptoms at presentation most commonly include a painless abdominal mass found by the parent or physician on routine examination. Elevations in blood pressure, hematuria, and abdominal pain can each occur in about 25% of the cases [3]. Multimodality therapy is most often needed and includes nephrectomy, chemotherapy, and radiation therapy, depending on the tumor stage at presentation. Long-term survival exceeds 90% for localized disease and is greater than 80% for metastatic disease [4]. Approximately 10% of tumors exhibit anaplastic histology, which confers a less favorable prognosis [5, 6].

WT has been a model for genetic studies of cancer development since the early 1970s. WT results from malignant transformation of renal stem cells that retain embryonic differentiation potential. It is now known that subsets of WT exhibit distinct gene expression profiles based on mutation patterns and the stage of embryonal cell differentiation at which the mutation occurred [7]. Although WT was one of the original tumors upon which Knudson based his “two-hit” model of tumorigenesis, the development of WT is complex and is likely to involve multiple genetic alterations. Numerous genes have been implicated in the pathogenesis of WT, some associated with constitutional mutations only, some associated with somatic mutations only, and others associated with both constitutional and somatic mutations [8, 9].

The most common somatic alterations that have been observed in WT converge on several pathways involved in renal development: transcriptional regulation (WT1, MYCN, SIX1, SIX2, and MLLT1, collectively found in ~20–25% of WT), microRNA (miRNA) processing (DGCR8, DROSHA, DICER1, and XPO5, collectively found in ~15–20% of WT), and WNT signaling (CTNNB1 and AMER1, collectively found in ~30–45% of WT) [8, 10, 11]. While uncommon in WT overall, somatic TP53 mutations are detected in 50–75% of anaplastic histology WT [8, 12, 13]. Additionally, approximately 70% of WT show evidence of increased IGF2 expression, which may arise via genetic or epigenetic changes [7, 10]. IGF2 is thought to contribute to but not be sufficient for Wilms tumorigenesis.

This chapter focuses on the constitutional genetic alterations that predispose to WT. Approximately 10% of WT are associated with constitutional mutations or epigenetic alterations involving more than 20 genes or loci (Table 6.1). WT1, TRIM28, REST, and 11p15 epimutations/uniparental disomy each account for approximately 2% of cases of WT with the remaining genes are very rare and collectively account for about 2% of cases of WT [9]. The constitutional mutations may occur with or without syndromic features.

Table 6.1 Constitutional mutations seen in patients with Wilms tumor
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6.2 Syndromic Wilms Tumor

6.2.1 WT1-Related Syndromes

A variety of germline WT1 mutations have been described, including missense mutations, deletions, insertions, and splice-site events. Together they have come to be described as a spectrum of disorders [14, 15]. These different types of mutations lead to distinct phenotypic features, including deletions, which cause WAGR syndrome; missense mutations, which cause Denys-Drash syndrome; and splice-site mutations, which result in Frasier syndrome. The risk of developing WT depends on the type of genetic alteration and varies with each syndrome, as described below. Somatic WT1 mutations that include stop and frameshift mutations occur in 10–20% of sporadic WT. Individuals with unilateral WT and no congenital anomalies are less likely to have a constitutional WT1 mutations (<5%), and patients with constitutional mutation are more likely to have bilateral or multifocal disease [16].

6.2.1.1 WAGR Syndrome

Cytogenetic studies in the 1960s and 1970s revealed that WAGR syndrome, a constellation of WT, aniridia, genitourinary abnormalities, and a range of developmental delays, is associated with constitutional deletions of chromosome 11p13. In 1990, the WT1 gene was identified as the gene responsible for the genitourinary anomalies and WT predisposition [17, 18]. Deletions of this locus also involve the PAX6 gene responsible for aniridia. The severity of this condition varies depending on the size of the deletion. In addition to Wilms tumor, aniridia, genitourinary malformations, and developmental disorders, affected individuals may experience focal segmental glomerular sclerosis, obesity, thought to be due to the deletion of the BDNF gene, and other possible medical issues [19,20,21,22]. WT1 encodes a zinc-finger transcription factor that plays a critical role in regulating other genes responsible for the development of the genitourinary system [16, 23]. Individuals with WAGR syndrome have a 30–60% risk of developing WT, yet WAGR syndrome is observed in only about 0.4–0.75% of children with WT. The incidence of bilateral disease among patients with WAGR syndrome is approximately 14–20% [20, 24, 25].

6.2.1.2 Denys-Drash Syndrome

Denys-Drash syndrome (DDS) is a rare autosomal dominantly inherited disorder with approximately 150 cases reported worldwide. It is characterized by the triad of incomplete male genital development, progressive glomerulopathy (diffuse mesangial sclerosis), and WT. While males can have normal genitalia, they typically have gonadal dysgenesis or ambiguous genitalia. The testes can be undescended, but they can also have complete sex reversal. Females typically exhibit normal genitalia and develop early onset/infantile nephropathy. Unlike the cytogenetic deletions found in WAGR, individuals with DDS typically harbor missense mutations in WT1 in exons 8 or 9, which affect the zinc-finger domains implicated in DNA binding [16, 23, 26, 27]. The risk of developing WT is estimated to be over 70% [28].

6.2.1.3 Frasier Syndrome

Frasier syndrome is an autosomal dominantly inherited disorder associated with nephropathy, gonadal dysgenesis, and gonadoblastoma. Genetic males typically have incomplete sexual development or complete sex reversal and appear as phenotypic females. They usually present with nephropathy and/or gonadoblastoma. Genetic females usually have normal genitalia and present with nephropathy. WT is infrequently seen in association with Frasier syndrome. WT1 mutations have been found in patients with Frasier syndrome and occur as germline point mutations in the intron 9 donor splice site [23, 29, 30]. The WT1 mutations that cause Frasier syndrome lead to an altered ratio of WT1 protein isoforms with impaired ability to control gene activity and regulate the development of the kidneys and reproductive organs [29, 30].

6.2.2 Overgrowth Syndromes

Evidence of increased susceptibility to WT has been demonstrated in several childhood overgrowth syndromes. The most completely characterized overgrowth syndrome is Beckwith-Wiedemann syndrome (BWS), but other overgrowth syndromes include the Simpson-Golabi-Behmel, Perlman, Sotos, and PIK3CA-related overgrowth syndrome (PROS) [23, 31,32,33,34,35]. Here we focus on the association of overgrowth syndromes with WT.

6.2.2.1 Beckwith-Wiedemann Syndrome

BWS is now described as a spectrum of disorders [31] and is the most common epigenetic overgrowth syndrome associated with Wilms tumor and other embryonic tumors. It affects ~1/10,340 individuals [32, 36] and is composed of characteristic clinical features including macroglossia, lateralized overgrowth (also called hemihypertrophy or hemihyperplasia), exomphalos/omphalocele, WT (multifocal, bilateral, or nephroblastomatosis), and hyperinsulinemia. Suggestive features of BWS include polyhydramnios, placentomegaly, macrosomia, large for gestational age (birth weight > 2 SD), neonatal hypoglycemia, facial nevus simplex, ear creases/pits, organomegaly (nephromegaly, hepatomegaly), umbilical hernia, diastasis recti, and various other embryonal cancers [31, 32, 37, 38]. The phenotypic subtypes, a proposed scoring system for diagnosing BWS, and recommendations for genetic testing were recently described [31].

Whereas cancer risk has historically been quoted at ~8%, more recent studies suggest a higher tumor risk of approximately 14.5%. This difference is attributed to mosaic BWS identified through tissue analysis, which has improved diagnostic yield from about 70% to over 80% [31, 32]. Among those developing an embryonal tumor, the most common type of tumor is WT, accounting for ~52% of tumors. Other tumors include hepatoblastoma (~14%), neuroblastoma (10%), rhabdomyosarcoma (5%), adrenocortical carcinoma (3%), and pheochromocytoma (<1%). The highest risk for development of these tumors is prior to 2 years of age, and this risk decreases around 8 years of age [31, 39]. There does not appear to be an increased risk for tumor development in adulthood associated with BWS.

BWS is caused by changes occurring in both growth-promoting and growth-suppressing genes. Family linkage studies conducted in the 1980s identified chromosome 11p15 as the locus responsible for BWS [40,41,42]. This locus contains several imprinted genes in which only one parental allele is normally expressed (Fig. 6.1). The genes are clustered into two domains or imprinting centers, commonly referred to as imprinting center 1 (IC1), previously described as differentially methylated region 1 (DMR1), and imprinting center 2 (IC2), also known as differentially methylated region 2 (DMR2) [40, 41, 43,44,45,46,47]. IC1 contains the insulin-like growth factor 2 (IGF2) and H19 genes. IGF2 encodes a growth factor and H19 encodes an untranslated RNA of unclear significance. The paternal allele of IC1 is normally methylated, resulting in expression of IGF2 and silencing of H19. IC2 contains several genes including KCNQ1, KCNQ1OT1, and the tumor suppressor gene CDKN1C (p57/K1P2). IC2 is normally methylated on the maternal allele, resulting in expression of KCNQ1 and CDKN1C and repression of KCNQ1OT1. BWS may arise from various genetic and epigenetic changes at the 11p15 locus, each of which is associated with distinct phenotypes and cancer risk, as follows:

  1. 1.

    Loss of methylation (hypomethylation) of IC2 on the maternally derived chromosome (~35–50% of BWS cases) is associated with typical BWS facial features such as macroglossia, ear creases/pits, and facial nevus. Epigenetic defects of IC2 are also more frequently seen with prematurity, abdominal wall defects (omphalocele, umbilical hernia, and diastasis recti), and undescended testes. Individuals with this epigenetic finding have a low risk of WT (<1%) and other cancers (2.6%–4.4%) [32, 39]. Subfertility with or without the use of assisted reproductive technologies is associated with this subset of BWS.

  2. 2.

    Paternal uniparental disomy (pUPD11) (~18.5%–23% of BWS cases), in which the paternal allele recombines and replaces the maternal allele, affects both IC1 and IC2. This subtype has a high association with babies who are large for gestational age and who have lateralized overgrowth, hyperinsulinism, hypoglycemia, and a risk of developmental delay. The risk for WT in this group is approximately 8% [31].

  3. 3.

    Hypermethylation of IC1 (~5–9% of BWS cases) is frequently associated with babies who are large for gestational age and who have diastasis recti, as well as organomegaly (hepatomegaly, splenomegaly, and nephromegaly). Undescended testes are also common to this subgroup. Tumor incidence is greatest for those with IC1-associated BWS, with approximately 52% developing a tumor. This subgroup is associated with the highest chance for bilateral/multifocal WT or nephroblastomatosis (32%) and other tumors (19.4%) [31, 32].

  4. 4.

    Mutations of the maternal CDKN1C gene (2–5% of BWS cases, but 40% of familial BWS cases) tend to be affected by omphalocele and preterm birth. Changes in the CDKN1C gene confer a low risk of WT, but neuroblastoma tends to be more common among those with a change in this gene [31, 32, 41, 43, 48].

  5. 5.

    Various other genetic and epigenetic changes including genome-wide paternal UPD (GWUPD11), duplications, deletions, inversions, and translocations of 11p15 account for a small percentage of BWS cases (~3–6%) [31, 32].

  6. 6.

    Recommended molecular testing for BWS includes methylation testing, copy number variant testing, CDKN1C mutation analysis, SNP array to distinguish between pUPD and GWpUPD, and tissue analysis. While the International Consensus Group recommends different screening for BWS-associated tumors based on the underlying epigenetic/molecular cause for BWS [31], other groups do not yet recommend epigenetic/molecular subtype-defined screening [32] (Table 6.2).

Fig. 6.1
figure 1

The Beckwith-Wiedemann syndrome locus. The chromosome 11p15.5 locus contains several imprinted genes clustered in two imprinting centers, IC1 (telomeric (tel) and IC2 (centromeric (cen)). Each domain has a differentially methylated region that controls expression of surrounding genes. In normal individuals, the differentially methylated region of IC1 is methylated in the paternal allele, resulting in expression of IGF2 and silencing of H19. In normal individuals, the differentially methylated region of IC2 is methylated in the maternal allele, resulting in expression of CDKN1C and KCNQ1 and silencing of KCNQ1OT

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Table 6.2 Syndromes and conditions with Wilms tumor (WT) surveillance recommendations
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6.2.2.2 Simpson-Golabi-Behmel Syndrome

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked recessive condition. It can be caused by mutations in glypican-3 (GPC3) at Xp26, intragenic or whole-gene deletion of GPC3, which can include a portion or all of GPC4, or duplication of GPC4. Most cases arise from mutations in GPC3 [49,50,51]. As GPC3 is located on the X chromosome, female carriers are usually asymptomatic or have mild features due to skewed X inactivation.

GPC3 and GPC4 encode cell surface heparan sulfate proteoglycans that interacts with the WNT signaling pathway and affects several growth factors [52]. GPC3 is composed of eight exons. GPC4 is positioned 3′ to GPC3 and consists of nine exons [53].

SGBS is characterized by pre- and postnatal macrosomia, macrocephaly, macroglossia, macrostomia, coarse facial features, ear abnormalities (preauricular tags, creases, helical dimple, and hearing loss), skeletal defects (vertebral fusions, scoliosis, rib abnormalities, congenital hip dislocation, large hands with or without post axial polydactyly), cardiac abnormalities (septal defects, pulmonic stenosis, aortic coarctation, transposition of the great vessels, patent ductus arteriosus, and patent foramen ovale), mild to moderate intellectual disability, and genitourinary defects (nephromegaly, multicystic kidneys, hydronephrosis, hydroureter/duplicated ureters, bifid scrotum, cryptorchidism, hydrocele, and inguinal hernia). Additional features that can be seen included cleft lip and palate, supernumerary nipples, diastasis recti/umbilical hernia, heart defects, diaphragmatic hernia, and gastrointestinal anomalies (pyloric ring, Meckel’s diverticulum, intestinal malrotation, hepatosplenomegaly, pancreatic hyperplasia, choledochal cysts, pancreatic duct duplication, and polysplenia). Affected individuals are at increased risk (5–10%) for embryonal tumors, including WT, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma [54, 55]. Approximately 9% of patients with SGBS due to GPC3 mutations have developed WT [49, 50, 55].

6.2.2.3 Perlman Syndrome

Perlman syndrome (PS) is a rare autosomal recessively inherited disorder. The locus for PS has been mapped to chromosome 2q37.1, and germline-inactivating mutations have been identified in the DIS3L2 gene, which encodes a protein involved in microRNA processing [56]. PS is characterized by congenital overgrowth nephromegaly with renal dysplasia, polyhydramnios, inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad, flat nasal bridge, low-set ears, and developmental delay [57, 58]. PS has a high rate of neonatal mortality, but among individuals who survive beyond the neonatal period, there is a 64% incidence of WT [58]. The tumor is diagnosed at an earlier age in these individuals compared with sporadic cases (usually less than 2 years of age), and there is a high frequency of bilateral tumors (55%) [57, 58]. Histological examination of the kidneys in children with PS frequently demonstrates nephroblastomatosis, which is a precursor lesion for WT [57].

6.2.2.4 Sotos Syndrome

Sotos syndrome is an autosomal dominant disorder. About 80–90% of individuals with Sotos syndrome type 1 have a demonstrable mutation or deletion of the nuclear receptor SET domain-containing protein 1 (NSD1) gene on chromosome 5q35. NSD1 encodes a protein that belongs to a family of nuclear receptors that bind to DNA response elements for ligands such as steroid and thyroid hormones and retinoids [59]. Sotos syndrome type 2 is caused by a mutation in the NFIX gene on chromosome 19p13, and type 3 is caused by a mutation in the APC2 gene also located on chromosome 19p13. To date, types 2 and 3 are not known to be associated with tumor predisposition. The diagnosis of Sotos syndrome is established by a combination of clinical findings and molecular genetic testing.

Sotos syndrome is an overgrowth condition with cardinal facial features including prominent forehead with receding hairline; down-slanting palpebral fissures; long narrow face with a long, pointed chin; and a large head circumference (>2 SD). It is also associated with mild to severe intellectual dysfunction and behavioral problems. Brain anomalies, seizures, cardiac anomalies, joint laxity, renal abnormalities, and scoliosis can be present as well [60, 61]. There is a 2–3% risk of developing a tumor including one of the following: WT, sacrococcygeal teratoma, neuroblastoma, ganglioma, acute lymphoblastic leukemia, small cell lung cancer, and astrocytoma [60, 62, 63].

6.2.2.5 PIK3CA-Related Overgrowth Spectrum (PROS)

PIK3CA-related overgrowth (PROS) is a disorder that results from a mutation in the PIK3CA gene, located on chromosome 3q26.32, which is present in the mosaic state. PROS encompasses a number of rare originally clinically defined conditions including acrocephaly-cutis marmorata telangiectasia congenita (MCAP), fibroadipose hyperplasia, CLOVE syndrome, Klippel-Trenaunay syndrome, hemimegalencephaly, and isolated lymphatic malformation [33,34,35, 64,65,66,67,68,69]. These conditions are characterized by segmental asymmetric overgrowth, vascular malformations, lymphatic malformations, lipomatous overgrowth, and skin manifestations such as epidermal nevi and have also been found to be associated infrequently with nephroblastomatosis and Wilms tumor [65, 70, 71].

6.2.3 Additional Wilms Tumor-Related Cancer Predisposition Syndromes

WT can occur as part of a cancer predisposition syndrome involving other well-defined genetic conditions such as seen with Fanconi anemia, Bloom syndrome, DICER1 syndrome, Li-Fraumeni syndrome, and mosaic variegated aneuploidy. However, WT is usually not the main neoplasm associated with each of these syndromes.

6.2.3.1 Fanconi Anemia

Fanconi anemia is classified as a chromosomal breakage syndrome. It is typically characterized by short stature, radial ray defects, aplastic anemia/bone marrow failure, oral/head and neck cancers, acute myelogenous leukemia, and solid tumors of the head and neck, skin, gastrointestinal tract, and genitourinary tract [72]. There are approximately 21 different subtypes of Fanconi anemia, but there are two subgroups that are primarily characterized by risk for WT, medulloblastoma, and AML. Fanconi anemia subtype D1 (FANCD1) occurs from biallelic inheritance of mutations in the BRCA2 gene located on chromosome 13q13.1, and Fanconi anemia subtype N (FANCN) arises from biallelic inheritance of mutations in the PALB2 gene located on chromosome 16p12.2, which encodes a binding partner of BRCA2 [73,74,75]. Both are tumor suppressor genes. FANCD1 is associated with a 20% risk of WT [23, 74], whereas FANCN is associated with a 40% risk of WT [75]. Other subtypes of Fanconi anemia are not currently known to be associated with increased WT risk.

6.2.3.2 Bloom Syndrome

Bloom syndrome is a chromosomal breakage syndrome that is caused by biallelic inheritance of mutations in the BLM gene located on chromosome 15q26.1, which plays a role in chromosome stability [76]. This syndrome is characterized by growth deficiency including microcephaly, immune deficiency, photosensitivity, hyper- and hypopigmented skin findings, infertility in men, early menopause in women, insulin resistance, and the risk for a number of malignancies including leukemia; lymphoma; oropharyngeal, gastrointestinal, genitourinary, breast, skin, and lung cancers; and WT [77, 78]. Among the ~145 people in the Bloom syndrome registry as of 2018, 8% were reported as having WT with a mean age of 3 years [79].

6.2.3.3 Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by heterozygous germline mutations in the tumor suppressor gene TP53, which is located on chromosome 17p13.1 [80]. Cancer risk varies by gender across the age spectrum. The cumulative cancer risk for female TP53 mutation carriers is reported in one cohort to be 18%, 49%, 77%, and 93% by ages 20, 30, 40, and 50 years, respectively, whereas the cumulative risks for males is 10%, 21%, 33%, and 68% by the same ages [81, 82]. LFS is characterized by multiple cancers in one’s lifetime. Some of the more common cancers include but are not limited to early-onset breast cancer among females (frequently triple receptor positive), osteosarcoma less than 10 years of age, anaplastic rhabdomyosarcoma less than 3 years of age, adrenal cortical carcinoma, and brain tumors including choroid plexus carcinoma, high-grade glioma, diffuse nodular medulloblastoma (commonly the sonic hedgehog subtype), and hypodiploid ALL [82]. WT is not one of the classic cancers found in this syndrome but has been reported in families harboring TP53 mutations and in several mutation-negative families that meet clinical criteria for LFS [83].

6.2.3.4 DICER1 Syndrome

Wilms tumor is infrequently associated with DICER1 syndrome, also known as DICER1-related pleuropulmonary blastoma cancer predisposition syndrome [84,85,86]. This condition is autosomal dominantly inherited and caused by a mutation in the DICER1 gene, which is located on chromosome 14q32.13 and is an RNase III-family endonuclease that cleaves precursor microRNAs (pre-miRNA) into active miRNA [84]. Approximately 80% of affected individuals inherit a mutation from a parent, while 20% of cases arise de novo. The DICER1 mutation shows incomplete penetrance. The condition is characterized by pleuropulmonary blastoma usually prior to 6 years of age, cystic nephroma prior to 4 years of age, thyroid nodules and thyroid cancer over the life spectrum, ovarian Sertoli-Leydig cell tumors from childhood to the end of the female reproductive life cycle, nasal chondromesenchymal hamartoma, Wilms tumor prior to 5 years, botryoid rhabdomyosarcoma, pineoblastoma, pituitary blastoma, and a ciliary body medulloepithelioma [85]. There is a low risk of WT associated with most DICER1 variants but a higher risk (18%) associated with the Gly803Arg variant [87, 88].

6.2.3.5 Mosaic Variegated Aneuploidy

There are three different types of mosaic variegated aneuploidy (MVA) including type 1 (associated with mutations in BUB1B), type II (associated with mutations in CEP57), and type 3 (associated with mutations in TRIP13). MVA1 is believed to be an autosomal recessive condition characterized by aneuploidy of multiple different chromosomes. The BUB1B gene is located on chromosome 15q15.1 and encodes one of the key proteins involved in the mitotic spindle checkpoint [53]. Patients with MVA1 can have a variable phenotype. Those who have been identified as having biallelic BUB1B mutations are more likely to present with growth retardation, mental retardation, and microcephaly and have shown an increased risk of rhabdomyosarcoma, whereas those with monoallelic BUB1B mutations with an unidentifiable second mutation have been characterized as having growth deficiency, mental retardation microcephaly, intrauterine growth retardation, cataracts, Dandy-Walker malformation, WT, and less commonly rhabdomyosarcoma. It is estimated that the risk of WT in individuals with MVA1 ranges from 25% to over 85% [89, 90], but BUB1B mutations are uncommon in sporadic WT [23]. MVA type 2 has not been reported in association with WT, though WT has been reported among those with MVA type 3, which results from biallelic loss of function mutations in TRIP13, located on 5p15.33 [91]. Affected individuals are known to have microcephaly, developmental delay, seizures, café au lait spots and abnormal skin pigmentation, and WT. Biallelic TRIP13 mutations are associated with a substantial impairment of spindle assembly checkpoint, which leads to chromosomal missegregation [91].

6.2.3.6 Mulibrey Nanism

Mulibrey nanism is an autosomal recessively inherited condition caused by mutations in the TRIM37 gene located on chromosome 5p15.33 [92, 93]. This gene acts as a checkpoint regulator during cell division and ensures proper chromosome separation when cells divide [94, 95]. The condition is characterized by intrauterine growth retardation and postnatal failure to thrive, craniofacial features (scaphocephaly, facial triangularity, high and broad forehead, and low nasal bridge), perimyocardial heart disease/progressive cardiomyopathy, insulin resistance with type 2 diabetes, and additional features including a high-pitched voice, ocular findings including yellowish dots on ocular fundi, cutaneous naevi flammei, hepatomegaly, and fibrous dysplasia of long bones. Mild muscular hypotonicity has also been noted as has an increased frequency of respiratory infection [96]. Individuals with mulibrey nanism are at elevated risk for a variety of neoplasms. Females experience an increased risk for gynecological tumors including sex cord stromal tumors, ovarian adenofibroma, ovarian adenocarcinoma, and endometrial adenocarcinoma [97]. They also experience an increased frequency for premature ovarian failure and infertility. Additional tumors seen in association with this syndrome include thyroid cancer, gastrointestinal carcinoid tumor, neuro-pituitary Langerhans cell histiocytosis, acute lymphoblastic leukemia, liver tumors, and WT [96,97,98]. The risk to develop WT is about 4–6% [97, 98].

6.2.3.7 CDC73-Related Disorders

Mutations in the CDC73 (HRPT2) gene, located on chromosome 1q31.2, show variable expressivity, and the phenotype may include (1) hyperparathyroidism-jaw tumor syndrome, (2) isolated parathyroid carcinoma, and (3) familial isolated hyperparathyroidism [99,100,101,102]. Hyperparathyroidism-jaw tumor syndrome is characterized by an increased risk for primary hyperparathyroidism due to parathyroid adenomas (95%) or parathyroid carcinoma (10–15%), ossifying fibromas of the mandible or maxilla (30–40%), malignant and benign uterine tumors, and renal lesions (20%) including cysts, hamartomas, and infrequently WT [9, 99, 103, 104]. More recently, isolated WT has been reported in association with mutations in CDC73, though the full spectrum of the disorder may not yet have manifested among this small number of affected individuals [9]. WT can result at a later age including at least one individual who developed bilateral WT at 53 years of age [103, 104].

6.2.3.8 Bohring-Opitz Syndrome

Bohring-Opitz syndrome (BOS), which has previously been reported as Oberklaid-Danks syndrome, is a rare genetic syndrome caused by a mutation in the ASLX1 gene located on chromosome 20q11.21. Cases to date have arisen de novo, and ~ 17 individuals reported in the medical literature have an identifiable mutation [105]. BOS is characterized by specific facial features (microcephaly and trigonocephaly, prominent metopic ridge, low tone, nevus flammeus, large/wide-set eyes, cleft palate, micrognathia), distinct posture (flexion at the elbows, wrists, and metacarpophalangeal joints), failure to thrive and feeding difficulties, seizures, severe cognitive impairment, limited mobility, mostly non-verbal, recurrent infections, congenital anomalies (including brain malformations, cardiac anomalies with possible bradycardia, and apnea), and severe myopia. Individuals with BOS have an increased but infrequent risk for WT (bilateral and nephroblastomatosis reported), and cases to date have been diagnosed from infancy to 6 years of age. The estimated risk of WT is ~7%, but this is based on a limited number of reported cases and larger studies are needed [105].

6.2.3.9 FBXW7-Related Wilms Tumor

FBXW7 is an autosomal dominant tumor suppresser gene located on chromosome 4q31.3 that has been found to predispose to WT [9, 106]. FBXW7 mutations may contribute to a predisposition of a variety of tumors beyond WT. An individual with a FBXW7 non-synonymous mutation and an extra-renal rhabdoid tumor and another individual with a WT and adult-onset osteosarcoma have been reported [9]. FBXW7 deletion has been associated with a variety of tumors including adult WT, Hodgkin lymphoma, and breast cancer [9, 107]. Another individual with a translocation disrupting FBXW7 (t(3:4)(q21;q31) has been described in an adult male with a history of a renal cell carcinoma [9, 108].

6.2.3.10 KDM3B-Related Wilms Tumor

The KDM3B gene is located on 5q31.2, and cancer-predisposing mutations are inherited in an autosomal dominant manner. Mutations have been described in association with WT, hepatoblastoma, acute myeloid leukemia, and Hodgkin lymphoma [9, 109]. Affected individuals have also been reported to have non-cancerous medical features including hyper- and hypopigmented macules, hip dysplasia, autism, and intellectual disabilities. The spectrum of medical issues associated with mutations in KDM3B needs further delineation. Pathogenic mutations have been described as both non-synonymous and truncating mutations.

6.3 Non-syndromic Wilms Tumor

6.3.1 Non-syndromic WT1-Related Wilms Tumor

Some individuals with a WT1 mutation only develop WT without the syndrome-related manifestations of Denys-Drash, Frasier, or WAGR syndromes. Hence, affected individuals can display an “incomplete” phenotype. The chance of isolated Wilms tumors arises from a WT1 mutation in about 5% [16, 110, 111].

6.3.2 TRIM28-Related Wilms Tumor

TRIM28 is a tumor suppressor gene that plays a role in DNA repair and maintenance of genomic integrity. It is located on chromosome 19q13.4 and has been implicated in pathogenicity of WT [9, 112, 113]. Both familial and de novo pathogenic truncating and less frequently missense TRIM28 mutations have been identified in individuals with WT. Other childhood and adult cancers have not been found in association with this gene, suggesting that mutations in TRIM28 predominantly predispose to both unilateral and bilateral WTs. One individual with a TRIM28 mutation and WT has also been reported to have esophageal atresia and a heart defect, though it is not clear if TRIM28 played a role in the development of these malformations [113], and 2 of 21 individuals (both males) with TRIM28 mutations and WT were reported to have autism and delays [9]. TRIM28 mutations show incomplete penetrance. Those resulting in WT have been significantly associated with maternal inheritance of the pathogenic allele. Hence, there appears to be a parent of origin effect [9, 113]. Histology among TRIM28-related WT is predominantly epithelial, and nephroblastomatosis has been reported [9, 112,113,114].

6.3.3 NYNRIN-Related Wilms Tumor

NYNRIN -truncating mutations inherited in an autosomal recessive manner have been reported in association with WT [9]. Little is known about the NYNRIN gene, which is located on chromosome 14q12, but it is believed to be play a role in microRNA processing (Peng et al., 2018). Mutations in this gene are not known to be associated with other childhood or adult-onset tumors, though the number of affected individuals reported in the medical literature is limited [9].

6.3.4 REST-Related Wilms Tumor

REST is located on chromosome 4q12 and is a dominantly inherited tumor suppressor gene in which mutations in the DNA-binding domain affect transcription. This gene accounts for approximately 2% of WT development, and both familial and non-familial cases have been reported. While REST plays a role in cellular differentiation and embryonic development, no medical problems of statistical significance have been associated with mutations in REST beyond WT [115].

6.3.5 CTR9-Related Wilms Tumor

CTR9 is a part of the polymerase-associated factor 1 complex, which resides on chromosome 11p15.4 and plays a role in RNA polymerase II regulation. It is important in embryonic organogenesis and maintenance of embryonic stem cell pluripotency [116]. CTR9 has been implicated as a tumor suppressor gene that contributes to the pathogenesis of Wilms tumor [116, 117]. It has not been found in association with other tumors or syndromic features. While there have been several genes identified in recent years that have been found in association with familial WT, some families that exhibit a familial pattern of WT inheritance have no identifiable gene mutation suggesting that there remain undiscovered familial WT genes [9, 75].

6.4 Surveillance

Surveillance imaging is recommended for individuals with a genetic predisposition to WT [31, 118, 119]. The principle of surveillance is to enable detection of WT at a small size, resulting in lower tumor stage, though there is limited evidence-based data that surveillance results in improved WT-related outcomes. Practical surveillance recommendations have been developed based on the premise that surveillance is worthwhile in individuals who have greater than a 1% [119] or 5% risk of developing WT [31, 118]. Most expert recommendations are for surveillance to continue until the age when about 90–95% of the WT will have occurred; therefore, the duration of surveillance varies according to the genetic disorder and how conservative the provider and family wish to be (Table 6.2). For WT1-related disorders, 94% of WT occur by the age of 5 years and 98% occur by 6 years [120]. For the BWS spectrum, 93% of WT occur by 7 years, 95% occur by 8 years, and 96% occur by 9 years. For most of the other conditions, the risk period is not well-defined, and various surveillance periods have been recommended (Table 6.2). For individuals who are selected to undergo surveillance, the recommended procedure is renal ultrasonography every 3 months. As WT can have a doubling time of 7–21 days, this frequency of screening optimizes the chance of detecting a tumor when it is a small size [121]. Genetic counseling should be performed when concern is raised for a cancer predisposition syndrome both prior to and following genetic testing [122].

6.5 Summary and Future Directions

Our understanding of WT genetics has evolved considerably since WT1 was described in 1990. In contrast to the situation with retinoblastoma, where RB gene mutations are the primary event in the vast majority of tumors, WT may arise through several distinct genetic pathways. Somatic mutations in WT1, AMER1, and CTNNB1 together provide the genetic basis for about one-third of all WT. Other common somatic mutations involve miRNA processing genes, accounting for approximately 15% of WT. Genetic and epigenetic alterations of the 11p15/IGF2 locus are seen in more than 70% of WT, though these alterations are not thought to be sufficient for Wilms tumorigenesis. Somatic TP53 mutations are observed in most anaplastic histology WT but are rare in tumors without anaplasia. The most commonly observed genes with constitutional mutations in patients with WT are WT1, TRIM28, IGF2, REST, and CTR9, though constitutional mutations have been described in more than 16 other genes. Despite the recent tremendous expansion of knowledge, the genetic basis of many WTs remains unaccounted for. Ongoing comprehensive genomic analyses, including whole-genome sequencing and gene expression, methylation, microRNA expression, and single-nucleotide polymorphism arrays will likely elucidate additional genetic lesions that drive Wilms tumorigenesis or modify its clinical behavior.