Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released - Under Revision 1.2.3
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: WT1
• Condition: Wilms tumor
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• WT1 ⇔ 0008679 (wilms tumor 1; wt1): Moderate Actionability

Actionability Rationale

The assertion was changed from limited to moderate based on extrapolation from Beckwith-Wiedemann syndrome and idiopathic hemihypertropy case series. Even though there is limited evidence for effectiveness of the surveillance to improve downstream outcomes, the evidence may be limited due to the rarity of the condition and the likelihood that RCTs would be considered unethical related to the community practice standard which includes surveillance.

Final Consensus Scores

Gene Condition Pairs: WT1 ⇔ 0008679 (OMIM:194070)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality from WT / Surveillance via abdominal ultrasound	2	3N	0N	2	7NN

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Wilms tumor (WT) is the most common kidney cancer in childhood, with a prevalence of one in 10,000 children. In 10%-15% of individuals with WT, the cause is considered to be a germline pathogenic variant or an epigenetic alteration occurring early during embryogenesis. These may or may not be associated with a known congenital malformation syndrome or hereditary cancer syndrome. [1, 2, 3, 4]

Clinical Features

WT is a complex embryonal tumor with conventional triphasic histology (blastemic, epithelial, and stromal components). Nephrogenic rests, benign foci of embryonal kidney cells that persist abnormally into postnatal life, are considered to be WT precursors. Pathogenic variants may predispose to nephrogenic rests, while additional pathogenic variants transform nephrogenic rests into a WT. WT usually presents as an abdominal mass in an otherwise apparently healthy child. Abdominal pain, fever, anemia, hematuria, and hypertension are seen in 22% - 35% of affected children.
WT1 deletions are also associated with WAGR syndrome (WT, aniridia, genital anomalies, retardation), which is characterized by WT, aniridia, hemihypertrophy, genitourinary abnormalities, ambiguous genitalia, gonadoblastoma, and intellectual disability. However, this report will focus on WT1-related WT and not other outcomes associated with pathogenic variants of WT1 or larger deletions that include WT1. [2, 3, 4]

Natural History

Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%. [1, 2, 3, 4]

2. How effective are interventions for preventing harm?

Patient Management

There are no specific recommendations for management of WT associated with a WT1 pathogenic variant. (Tier 5) [5]

However, two small studies have assessed nephron-sparing surgery (NSS) in children with WT. A retrospective review of 8 children (aged 7 to 108 months) with syndromes predisposing to WT (Beckwith-Wiedemann syndrome, isolated hemihyperplasia, WAGR syndrome, and isolated 11p13 deletion) who underwent nephrectomy for unilateral tumors during a 10-year period was conducted with NSS performed in 6 and radical nephrectomies in 2. After a mean follow up of 36 months (range 6 to 72) no recurrences were documented and all children had normal creatinine levels. A second retrospective study of 18 children with bilateral WT at mean age 2.28±1.12 years successfully underwent unilateral or bilateral NSS during a 15-year period. The 4-year event-free survival and overall survival rates were 68.18 and 85.56%, respectively. In univariable analysis, tumor histology (p=0.0028) and disease stage (p=0.0303) appeared significantly associated with overall survival. (Tier 5) [5, 6, 7]

Surveillance

The goal of surveillance in individuals with a genetic predisposition to WT is to
detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome. (Tier 3) [4, 8, 9]

No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms. (Tier 5) [9, 10]

Circumstances to Avoid

No circumstances to avoid have been identified.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [4]

Prevalence of Genetic Variants

A recent meta-analysis revealed a pooled prevalence for WT1 variants in WT to be 0.141 (95% CI: 0.104-0.178). Information on the prevalence of WT1 variants in the general population was not available. (Tier 1) [11]

Penetrance

WT1 germline variants have reduced penetrance. (Tier 3) [4]

Information on the penetrance of variants was not available for the Pediatric context. [11]

Relative Risk

No information on relative risk is available.

Expressivity

WT1 germline variants have variable expressivity. (Tier 3) [4]

4. What is the Nature of the Intervention?

Nature of Intervention

Because surveillance is associated with economic and psychosocial costs including anxiety associated with exams, and false-positive results leading to unnecessary interventions, the decision to pursue surveillance requires careful consideration. [4]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Most cases of WT present prior to age 5 and have no apparent symptoms in the early stages. Signs and symptoms that do present are non-specific and could also be due to a variety of other disorders. Early detection is important to detect the tumor at an early stage. (Tier 3) [2, 4]

Date of Search: 05.17.2018

Reference List

1. Deng C, Dai R, Li X, Liu F. Genetic variation frequencies in Wilms' tumor: A meta-analysis and systematic review. Cancer Sci. (2016) 107(5):690-9.

2. Wilms' Tumor. National Organization for Rare Disorders. Publisher: National Organization of Rare Diseases. (2005) Accessed: 2018-06-25. Website: https://rarediseases.org/rare-diseases/wilms-tumor

3. Nephroblastoma. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=654

4. JS Dome, V Huff. Wilms Tumor Predisposition. 2003 Dec 19 [Updated 2016 Oct 20]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1294

5. Clericuzio C, Hingorani M, Crolla JA, van Heyningen V, Verloes A. Clinical utility gene card for: WAGR syndrome. Eur J Hum Genet. (2011) 19(4).

6. Romao RL, Pippi Salle JL, Shuman C, Weksberg R, Figueroa V, Weber B, Bagli DJ, Farhat WA, Grant R, Gerstle JT, Lorenzo AJ. Nephron sparing surgery for unilateral Wilms tumor in children with predisposing syndromes: single center experience over 10 years. J Urol. (2012) 188(4 Suppl):1493-8.

7. Tan XH, Zhang DY, Liu X, Lin T, He DW, Li XL, Wei GH. Retrospective analysis to determine outcomes of patients with bilateral Wilms tumor undergoing nephron sparing surgery: 15-year tertiary single-institution experience. Pediatr Surg Int. (2018) 34(4):427-433.

8. Scott RH, Walker L, Olsen OE, Levitt G, Kenney I, Maher E, Owens CM, Pritchard-Jones K, Craft A, Rahman N. Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch Dis Child. (2006) 91(12):995-9.

9. Scott, Richard H., Rahman, Nazneen. Genetic Predisposition to Wilms Tumor. Renal Tumors of Childhood: Biology and Therapy. (2014) Accessed: 2018-06-27. Website: https://www.springer.com/us/book/9783662440025

10. Choyke PL, Siegel MJ, Craft AW, Green DM, DeBaun MR. Screening for Wilms tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy. Med Pediatr Oncol. (1999) 32(3):196-200.

11. Kaneko Y, Okita H, Haruta M, Arai Y, Oue T, Tanaka Y, Horie H, Hinotsu S, Koshinaga T, Yoneda A, Ohtsuka Y, Taguchi T, Fukuzawa M. 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.