Rhabdoid Tumor Predisposition Syndrome Type 1 (PDQ®)–Health Professional Version

Molecular Genetics

The SMARCB1 gene encodes the SMARCB1 protein (also called INI1 or BAF47), a member of the SWI/SNF chromatin remodeling complex, which helps control gene transcription.[1,2] Rhabdoid tumors develop when both copies of the SMARCB1 gene are inactivated, or in some cases, when both copies of the SMARCA4 gene are inactivated. Individuals with germline SMARCA4 variants have a diagnosis of rhabdoid tumor predisposition syndrome type 2. Loss of SMARCB1/INI1 expression (detected by immunohistochemistry) is included in the diagnostic criteria for rhabdoid tumors.[3]

In individuals with rhabdoid tumor predisposition syndrome type 1 (RTPS1), tumor development follows the Knudsen two-hit hypothesis. The first hit is caused by the inactivation of one copy of SMARCB1, typically by a truncating variant, copy-number change, or structural variant. The second hit is typically due to chromosomal deletion or loss of heterozygosity.[4] It is estimated that approximately 25% to 35% of rhabdoid tumor cases are associated with a germline variant in SMARCB1.[5-7] Higher rates have been reported in certain subgroups, including patients diagnosed at younger than 6 months (55%) and patients with multifocal tumors (78%).[8,9] It is recommended that all patients diagnosed with rhabdoid tumors consider genetic evaluation.[10] Whole- and partial-gene deletions, nonsense, and frameshift variants are seen most commonly, frequently affecting exons 2 through 7 of the SMARCB1 gene.[5,6,11] Single nucleotide variants, duplications, and splice-site variants occur more rarely.[5,11,12] A case of ring chromosome 22 has also been reported in an individual with RTPS1.[13]

Inheritance

RTPS1 is inherited in an autosomal dominant manner. Penetrance is reported as greater than 90% for most types of truncating variants in SMARCB1.[7] However, these estimates are based on a modest number of observations and ascertainment of affected individuals and families. Most cases appear to be de novo, and individuals with rhabdoid tumors are often the first person in the family to be affected.[6,14,15] This may be due to the aggressive nature of rhabdoid tumors. However, incomplete penetrance and late-onset tumors, including schwannoma and meningioma, have been reported in a small subset of families who are unaffected by rhabdoid tumors and carry a germline SMARCB1 variant.[5,11] Gonadal mosaicism in a parent has been well documented in RTPS1. Therefore, negative genetic testing of parental blood cannot rule out the risk that more than one child may inherit the pathogenic variant and have a diagnosis of RTPS1.[5,6,11,16,17] Genetic counseling has been suggested to discuss topics like prenatal testing and potential reproductive recurrence risk relevant to gonadal mosaicism.[5,6]

Related Disorders

Germline alterations in the SMARCB1 gene are primarily associated with two additional hereditary conditions, schwannomatosis and Coffin-Siris syndrome (CSS). Cases of schwannoma have been reported in RTPS1 kindreds. However, rhabdoid tumors have not been reported in individuals with CSS. Generally, SMARCB1 variants associated with CSS are missense variants that cluster in the first and last exons of the gene.[11] In patients with schwannomatosis, variants are often nontruncating and occur in the 3’ untranslated (UTR) region of SMARCB1.[18] However, nonsense SMARCB1 variants or deletions/duplications of the whole gene/multiple exons are more often associated with rhabdoid tumors.[11,18] While these patterns represent the common genotype-phenotype correlations, they are not final, and overlap can be seen. However, exon-spanning deletions appear to occur exclusively in patients with RTPS1.[11] While genotype-phenotype correlations exist across these three disorders, there is limited information regarding genotype-phenotype correlations specific to RTPS1.

Genetic Counseling

Experts in the field of cancer genetics recommend a referral for genetic counseling or genetic evaluation for children who have been diagnosed with atypical teratoid/rhabdoid tumors (AT/RTs), malignant rhaboid tumors (MRTs), or any other SMARCB1-deficient tumors. These recommendations are based on the American Association for Cancer Research's (AACR) Childhood Cancer Predisposition Workshop and the European Society for Paediatric Oncology's (SIOPE) Host Genome Working Group guidelines.[1,2] In the event that a child with an AT/RT or MRT died before completing the evaluation, counseling may be provided to parents and siblings.

Rhabdoid Tumor Predisposition and Fertility Preservation

Treatments for AT/RTs and MRTs may reduce fertility in boys and girls.[3,4] Therefore, the medical team may offer fertility preservation to these patients. Parents of children with AT/RTs and MRTs who undergo fertility preservation should be advised that if a germline SMARCB1 truncating variant is found, 50% of children derived from preserved gonadal tissue will inherit a SMARCB1 pathogenic variant and have a risk of developing rhabdoid tumors. Prenatal genetic counseling is advised for individuals with RTPS1.

Outcomes and Treatment Modification

In patients with AT/RTs or extracranial rhabdoid tumors, germline SMARCB1 variants are associated with poor outcomes. The risk of metastasis may also be associated with a germline variant.[5,6] Despite intensive therapy, fewer than half of children with rhabdoid tumor predisposition syndrome type 1 (RTPS1) become long-term survivors. There are no data suggesting that treatment of patients with AT/RTs or MRTs should be modified because of a germline RTPS1 diagnosis.

For information about the treatment of AT/RTs, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment. For information about the treatment of MRTs, see the Rhabdoid Tumors of the Kidney section in Wilms Tumor and Other Childhood Kidney Tumors Treatment and the Rhabdoid Tumor NOS (Extrarenal) section in Childhood Soft Tissue Sarcoma Treatment.

Surveillance

In 2017, a group of experts in childhood cancer genetics created the first recommendations for cancer surveillance for patients with RTPS1.[7] Since children with germline SMARCB1 truncating variants have an increased risk of developing AT/RTs in early childhood, screening recommendations include brain magnetic resonance imaging (MRI) every 3 months until age 5 years, after which surveillance ceases. Because of the risk of MRTs of the kidney, abdominal ultrasonography is recommended every 3 months from birth, with no upper age limit to stop surveillance. Whole-body MRI may also be considered until age 5 years. Screening is not recommended for children with a germline missense pathogenic variant in the SMARCB1 gene because the risk of tumor development is very low.

In 2021, the SIOPE Host Genome Working Group published guidelines for clinical surveillance and genetic testing in patients with RTPS1.[2] These guidelines recommend an age-based approach to surveillance. Central nervous system (CNS) and abdominal imaging occur every 1 to 3 months for patients younger than 6 months, every 2 to 3 months for patients aged 7 to 18 months, and every 3 months for patients aged 19 months to 5 years. Yearly whole-body MRI is recommended for patients aged 5 years and older.

Surveillance in Survivorship

For children with tumors and SMARCB1 truncating variants, surveillance should be ongoing to detect primary disease recurrence. Survivors of AT/RTs will continue to require abdominal ultrasonography to screen for MRTs. Conversely, children with MRTs of the kidney will continue to undergo CNS surveillance for AT/RTs until age 5 years if they have a germline truncating variant in SMARCB1.[2]

Level of evidence: 5

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics, cancer risks, and management of rhabdoid tumor predisposition syndrome type 1. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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PDQ® Cancer Genetics Editorial Board and PDQ® Pediatric Treatment Editorial Board. PDQ Rhabdoid Tumor Predisposition Syndrome Type 1. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/publications/pdq/information-summaries/genetics/rtps1-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 38630976]

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