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 1.0.2
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: SMARCA4, SMARCB1
• Condition: Rhabdoid tumor predisposition syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• SMARCA4 ⇔ 0016473 (familial rhabdoid tumor): Limited Actionability
• SMARCB1 ⇔ 0016473 (familial rhabdoid tumor): Limited Actionability

Actionability Rationale

The preliminary assertion was limited and there was consensus agreement with this assertion. Though this disorder can be quite severe, there were multiple factors that complicated scoring of this topic. There was limited evidence for multiple elements, including penetrance and effectiveness. Effectiveness data was based on AT/RT without stratification by germline vs. non-germline cases, and it is not clear whether effectiveness of multimodal therapy is the same in each. For both penetrance and effectiveness, there are differences in the availability of evidence for SMARCB1 and SMARCA4.

Final Consensus Scores

Gene Condition Pairs: SMARCA4 ⇔ 0016473 (OMIM:613325) SMARCB1 ⇔ 0016473 (OMIM:609322)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality from RTPS-related tumors / Imaging surveillance to guide detection and initiate multimodal treatment (including a combination of surgery, chemotherapy, and/or radiation therapy)	2	0D	2D 1	2	6DD

1. Extrapolated from studies of treatment of AT/RT in patients with unknown genetic status.

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

Prevalence of the Genetic Condition

The prevalence of rhabdoid tumor predisposition syndrome (RTPS), caused by germline pathogenic variants in SMARCB1 and rarely in SMARCA4, is unknown. Among newly diagnosed individuals with rhabdoid tumors (RTs), 25%-35% have a germline pathogenic variant in SMARCB1.
The incidence of RTs by tumor type (sporadic and germline cases combined) in children have been calculated and reported in the United States and the United Kingdom as follows:
•RT of the kidney (RTK): Annual incidence of 0.19 per million in children under 15 years.
•Atypical teratoid/rhabdoid tumor (AT/RT): Overall annual incidence of 0.7-0.89 per million and as high as 5.4 per million in infants (below 1 year of age). In infants, AT/RT may be the most malignant tumor of the posterior fossa.
•Extracranial and extra-CNS (central nervous system) malignant RTs (MRTs): Overall annual incidence of 0.32-0.6 per million, with the incidence decreasing with increasing age with 5 per million in the first year of life, down to 0.04 per million at age 10-14 years. [1, 2, 3, 4]

Clinical Features

RTPS is a cancer predisposition syndrome characterized by a markedly increased risk of developing RTs, which are rare and highly aggressive malignant tumors occurring predominantly in infants and young children. Patients who carry a germline pathogenic variant in SMARCB1 have RTPS type 1 (RTPS1); whereas those with SMARCA4 germline pathogenic variants have RTPS type 2 (RTPS2). In both types of RTPS, RTs can occur in almost any anatomic location, but most commonly in the kidney and the CNS (i.e., AT/RT, choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumor). Other common locations include extracranial extrarenal MRTs (e.g., head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart), and possibly small-cell carcinoma of the ovary (hypercalcemic type, SCCOHT). [1, 2, 5, 6, 7, 8]

Natural History

Individuals with RTPS typically present at a young age with synchronous multifocal tumors that exhibit aggressive clinical behavior. MRTs (including both intra- and extra-cranial) have a median age of onset of 20 months (range from birth through adulthood) with most cases presenting before 12 months of age. Patients with SCCOHTs have a median age of onset of 24 years (range from 14 months to 56 years). All tumor types observed in RTPS are highly aggressive and often fatal, with MRTs and SCCOHTs having 5-year survival rates of 10-30% and ~33%, respectively. Patients diagnosed under the age of 2 years have a poorer prognosis.
The clinical spectrum of RTPS is heterogeneous and manifestations can vary by genotype. SMARCB1 carriers may be at risk for developing other tumors including multiple schwannomas, malignant peripheral nerve sheath tumors, cribriform neuroepithelial tumors, meningiomas, and other rare tumors. Female carriers of SMARCA4 pathogenic variants have a high risk of developing SCCOHT. SCCOHT has not been reported in individuals with pathogenic variants in SMARCB1. [1, 2, 3, 5, 6]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs of an individual diagnosed with RTPS, the following are recommended:
•Refer asymptomatic individuals to a pediatric oncologist or tumor surveillance program.
•For individuals with AT/RT, examine cerebrospinal fluid.
•Refer for genetic counseling.
•Consider consulting a radiologist prior to therapy. (Tier 4) [2]

A standard treatment option for children with CNS AT/RT in patients (germline or sporadic genetic changes) has not yet been defined. Given the highly aggressive nature of RTs, most patients are treated with intensive multimodal therapy using a combination of surgery, chemotherapy, and radiation therapy. (Tier 2) [9]

A systematic review of multimodal therapies in 332 children and adolescents with AT/RT with unknown genetic status (median age at diagnosis: 37 months, range 1momth to 19 years), found that first-line high-dose chemotherapy (HDCT) followed by radiotherapy was associated with improved outcomes. Hazard ratios for recurrence-free survival (RFS) and overall survival (OS) for HDCT + radiotherapy were 0.551 (p = 0.01) and 0.393 (p = 0.002), respectively. HDCT + gross total resection or HDCT + intrathecal CT were not significantly associated with improved RFS or OS. (Tier 1) [10]

A U.S. National Cancer Database analysis including 361 AT/RT patients aged 0-18 years (genetic status unknown) diagnosed between 2004-2012 found that the 5-year OS rate was 29.9%, and it was significantly higher for patients with localized disease treated with multimodal therapy (surgery, chemotherapy, and radiotherapy) with a 5-year OS of 46.8%. Patients younger than age 3 years at diagnosis showed significantly worse OS (5-year OS 27.7%) compared to older patients (5-year OS 37.5%) and were also significantly less likely to receive multimodal therapy (specifically radiotherapy). (Tier 3) [2]

A standard treatment option for children with RTK (including those with germline genetic changes) has not yet been defined due to the rarity of this tumor. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimal treatment. (Tier 2) [11]

Treatment options for extrarenal (extracranial) soft tissue RTs in patients (including those with germline genetic changes) include surgical resection, when possible, chemotherapy as used for soft tissue sarcomas (but no single regimen is currently accepted as best), and radiation therapy. Three case series of 3, 14, and 26 primarily pediatric patients with unknown genetic status who underwent multimodal treatment combining chemotherapy and either/both surgery and radiation therapy, found that at 36 months, progression-free survival (PFS) ranged from 9-49%, with PFS at 6-7 years for 3 patients. No single treatment regimen demonstrated a superior response. (Tier 2) [12]

For female carriers of a germline pathogenic variants in SMARCA4, genetic counseling and prophylactic oophorectomy should be considered after completion of puberty. The risk of SCCOHT and the decision to undergo prophylactic surgery should be individualized and informed by family history, the patient’s age and reproductive plans, other clinical factors, and by emerging risk-estimation data. However, there is insufficient evidence to make any recommendations for risk-reducing salpingo-oophorectomy based solely on SMARCA4 status. (Tier 2) [1, 13]

Surveillance

Surveillance for known carriers of truncating germline SMARCB1 variants should include MRI of the brain and ultrasound of the abdomen/kidneys, every 3 months from birth (or diagnosis) until 5 years of age. Whole-body MRI maybe considered, but there is little data to guide clinicians in terms of best timing and schedule for this. There is little evidence regarding the effectiveness of surveillance for patients with RTPS. For known carriers of truncating germline SMARCA4 variants, abdominal ultrasound every 6 months may be justified. SMARCA4-deficient SCCOHT has not been seen in women over age 60, so screening recommendations can be altered in older women. There are no surveillance recommendations for known carriers of missense germline pathogenic variants in either gene since they are generally considered no/very low risk. (Tier 2) [1, 11]

A phenotypically healthy parent with a pathogenic germline variant should be offered surveillance as for sibs – albeit at longer intervals as the risk of embryonal malignancies is very low. The type of late-occurring neoplasia’s for which heterozygous parents may be at risk is not clear from current data. (Tier 4) [2]

Circumstances to Avoid

Exposure to DNA-damaging agents (e.g., tobacco, UV light, chemotherapy) should be limited to minimize the lifetime risk of developing late-onset secondary cancers. (Tier 4) [2]

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

Mode of Inheritance

Autosomal Dominant [1, 2, 3, 5, 6, 7, 9, 11]

Prevalence of Genetic Variants

Among newly diagnosed individuals with rhabdoid tumors, 25%-35% will have a germline pathogenic variant in SMARCB1. (Tier 3) [1, 2]

The proportion of RTPS attributed to germline pathogenic variants in SMARCA4 is ~5-15%, and in SMARCB4 is ~85-95%. (Tier 3) [2]

Most RTs are characterized by loss-of-function (LoF) pathogenic variants in SMARCB1, and a small fraction of RTs are characterized by LoF pathogenic variants in SMARCA4. However, missense pathogenic variants have been identified. (Tier 4) [1]

Penetrance

The penetrance of germline SMARCB1 and SMARCA4 pathogenic variants is unknown. However, it appears that SMARCA4 variants are less penetrant for AT/RT than SMARCB1. (Tier 3) [1]

Although there are reports of reduced penetrance, most individuals diagnosed with RTPS have the disorder as the result of a de novo germline SMARCB1 variant. In rare cases, individuals diagnosed with RTPS inherited a SMARCB1 pathogenic variant from an unaffected parent with late-onset or undiagnosed RTPS. Parental germline mosaicism in SMARCB1-related RTPS has been reported, accounting for at least half of the families with sibs affected by RTPS, but the overall incidence is unknown and is presumed to be low. (Tier 3) [2]

Most reported individuals diagnosed with SMARCA4-related RTPS inherited a pathogenic variant from an unaffected, healthy parent. In SMARCA4-related RTPS the penetrance for RT in the preceding generation of 7 informative families was zero. However, in one family, two sibs with a SMARCA4 pathogenic variant were both affected. (Tier 3) [2]

The most recent report from the European registry for rhabdoid tumors (EU-RHAB) database, comprised of 197 pediatric patients (81 infants, 116 children) ascertained with RTs, found that most tumors are localized to the central nervous system. Germline pathogenic variants were detected in 36% of infants and in 5 % of children older than 1 year. Frequencies of different tumor types in all patients are reported here:
•AT/RT: 63% in infants, 78% in children (patients over the age of 1 year)
•RTK: 9% in infants, 8% in children
•MRT: 21% in infants, 13% in children
•Synchronous tumors: 7% of infants, 1% in children (Tier 5) [14]

The most recent study of the U.S.-based SEER 18 data (1986-2014) evaluating patients of all ages diagnosed with MRTs (genetic status not reported) reported the following primary tumor frequencies in 148 infants, 231 children, and 127 adults:
•AT/RT: 30% in infants, 66% in children (1-18 years), 4% (older than 18 years)
•RTK: 32% in infants, 31% in children, 37% in adults
•Bone and soft tissue: 33% in infants, 40% in children, 27% in adults
•Digestive system: 39% in infants, 4% in children, 57% in adults
•Other sites: 16% in infants, 16% in children, 69% in adults (Tier 5) [15]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) has been reported in individuals with SMARCA4-related RTPS but not in individuals with germline SMARCB1 pathogenic variants. (Tier 3) [2]

Most reported individuals diagnosed with SMARCA4-related RTPS inherited a pathogenic variant from an asymptomatic parent. Rarely a SMARCB1 pathogenic variant is inherited from an unaffected parent or a parent with late-onset or undiagnosed RTPS. (Tier 3) [2]

The types of RTPS-related tumors can vary among different members of the same family. (Tier 4) [2]

4. What is the Nature of the Intervention?

Nature of Intervention

Since RTPS most commonly affects infants; therapy presents a complex challenge due to the vulnerability of these young patients. The use of aggressive multimodal treatment on the developing nervous system and other organ systems of a young individual may profoundly affect developmental (e.g., neurodevelopmental) outcome, and entail significant short- and long-term side effects. With multimodal therapy, toxicity-related deaths have been reported, but are lower than deaths due to disease progression. Additionally, intensive multimodal treatment strategies required for clinically aggressive tumors in children with RTPS lead to a higher rate of secondary complications, which may be prevented by opting for long-term or lifelong surveillance and considering risk-reducing treatment strategies (e.g., postpone or replace radiotherapy with chemotherapy or proton beam therapy; targeted therapy used concomitant with or before standard chemotherapy). [2]

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

Chance to Escape Clinical Detection

Evidence that RTPS may go undiagnosed includes reports of reduced penetrance, inheritance from unaffected parents, and late-onset cases. (Tier 3) [2]

Historically, AT/RT lesions were often confused with medulloblastoma. (Tier 3) [5]

Date of Search: 03.09.2021

Reference List

1. Foulkes WD, Kamihara J, Evans DGR, Brugières L, Bourdeaut F, Molenaar JJ, Walsh MF, Brodeur GM, Diller L. Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. Clin Cancer Res. (2017) 23(1557-3265):e62-e67.

2. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A. Rhabdoid Tumor Predisposition Syndrome. GeneReviews®. (1993)

3. Rhabdoid tumor. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=69077

4. Atypical teratoid rhabdoid tumor. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=99966

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. RHABDOID TUMOR PREDISPOSITION SYNDROME 1; RTPS1. MIM: 609322: 2020 Mar 24. World Wide Web URL: http://omim.org.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. RHABDOID TUMOR PREDISPOSITION SYNDROME 2; RTPS2. MIM: 613325: 2018 Feb 15. World Wide Web URL: http://omim.org.

7. Mitchell SG, Pencheva B, Porter CC. Germline Genetics and Childhood Cancer: Emerging Cancer Predisposition Syndromes and Psychosocial Impacts. Curr Oncol Rep. (2019) 21(1534-6269):85.

8. Teplick A, Kowalski M, Biegel JA, Nichols KE. Educational paper: screening in cancer predisposition syndromes: guidelines for the general pediatrician. Eur J Pediatr. (2011) 170(1432-1076):285-94.

9. PDQ Pediatric Treatment Editorial Board. Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment (PDQ®): Health Professional Version. PDQ Cancer Information Summaries. (2002)

10. Schrey D, Carceller Lechón F, Malietzis G, Moreno L, Dufour C, Chi S, Lafay-Cousin L, von Hoff K, Athanasiou T, Marshall LV, Zacharoulis S. Multimodal therapy in children and adolescents with newly diagnosed atypical teratoid rhabdoid tumor: individual pooled data analysis and review of the literature. J Neurooncol. (2016) 126(1573-7373):81-90.

11. PDQ Pediatric Treatment Editorial Board. Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®): Health Professional Version. PDQ Cancer Information Summaries. (2002)

12. PDQ Pediatric Treatment Editorial Board. Childhood Soft Tissue Sarcoma Treatment (PDQ®): Health Professional Version. PDQ Cancer Information Summaries. (2002)

13. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. (2021) Accessed: 2021-03-10. Website: https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

14. Seeringer A, Bartelheim K, Kerl K, Hasselblatt M, Leuschner I, Rutkowski S, Timmermann B, Kortmann RD, Koscielniak E, Schneppenheim R, Warmuth-Metz M, Gerß J, Siebert R, Graf N, Boos J, Frühwald MC. Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry. Klin Padiatr. (2014) 226(1439-3824):143-8.

15. Cai W, Liu X, Ge W, Wu D, Xu J, Bai R, Hu H. Factors Affecting the Outcomes of Patients with Malignant Rhabdoid Tumors: A Population-Based Study. Int J Med Sci. (2021) 18(1449-1907):911-920.