Rhabdoid Tumor Predisposition Syndromes (RTPS1/RTPS2)
Rhabdoid Tumour Predisposition Syndrome 1 (RTPS1, OMIM #609322, ORPHA 231108) and Rhabdoid Tumour Predisposition Syndrome 2 (RTPS2, OMIM #613325, ORPHA 231108) are extremely rare genetic conditions characterized by an increased risk for the development of rhabdoid tumours. Considering that the estimated annual incidence rate of rhabdoid tumours in childhood is less than 1 in 100,000 and that RTPS accounts for 25-35% of rhabdoid tumours, the prevalence is likely less than 1 in 100,000. However, this does not take into account reduced penetrance, phenotypic heterogeneity (specifically, small cell carcinoma of the ovary, hypercalcaemic type, has been considered separately for a long time) and possibly, underdiagnosis.
Rhabdoid tumours are aggressive malignant tumours most often occurring in infants and children < 3 years. Rhabdoid tumours have been reported in nearly all anatomic locations. Recurrent primary tumour locations include the central nervous system, head and neck region, abdomen, kidney and ovary (small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT).
RTPS is diagnosed in up to 80% of patients with congenital malignant rhabdoid tumours. Up to one third of patients with RTPS have multiple synchronous-multifocal tumours with bifocal manifestation most commonly in kidney and brain.
Consensus recommendations for clinical surveillance and genetic testing in RTPS have been described (Frühwald M.C. et al., 2021).
RTPS1 is caused by heterozygous germline pathogenic variants in the SMARCB1 gene, located on the long arm of chromosome 22 and coding for SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1 or INI-1). The inactivation or loss of one SMARCB1 allele results in loss of the SMARCB1 protein, which can be identified by tissue immunohistochemistry (IHC).
RTPS2 is caused by heterozygous germline pathogenic variants in the SMARCA4 gene, located on the short arm of chromosome 19 and coding for the transcription activator BRG1. Also, loss of BRG1 expression can be identified by IHC.
Germline pathogenic variants in SMARCB1 or SMARCA4 are identified by molecular genetic testing to establish the diagnosis of RTPS1 and RTPS2, respectively.
Both RTPS1 and RTPS2 are inherited in an autosomal dominant fashion, meaning that each child of an affected individual has a 50% chance to inherit the familial pathogenic variant and is at risk of developing disease. In RTPS1, the vast majority of individuals have de novo SMARCB1 germline variants. Germline mosaicism may account for up to half of the families with sibs affected by RTPS.
The penetrance of RTPS is not reliably estimated but may reach > 90% by age of 5 years for RTPS1, while penetrance of RTPS2 is incomplete.
Prenatal and preimplantation genetic diagnoses are possible if causative pathogenic variants have been identified in the parents (different legal/ethical perspectives could exist).
Early diagnosis, detection, genetic counselling of patients and relatives and surveillance in expert reference cancers are crucial factors in the optimal management of RTPS.
RTPS1
Proposed surveillance schedule by the SIOPE Host Genome Working Group (Frühwald M.C. et al., 2021, guideline not endorsed by ERN GENTURIS) consists of:
RTPS2
Given the lower incidence of rhabdoid tumours in individuals with germline pathogenic variants in SMARCA4 as compared to SMARCB1, there is more discussion towards surveillance, but the poor prognosis of rhabdoid tumours in RTPS2 suggests offering similar surveillance as for RTPS1.
For the risk of SCCOHT, affecting females from 5 to 46 years of age, abdominopelvic ultrasound should be considered in female carriers of germline pathogenic variants in SMARCA4 beyond the age of 5 years, with option for transvaginal ultrasound from adulthood onwards. The option of prophylactic risk-reducing bilateral salpingo-oophorectomy after family planning should be discussed.
* ERN GENTURIS uses AGREE II as a tool for the endorsement of guidelines. The quality of the guideline is evaluated through assessing the rigor and transparency of the guideline development process. The content of the guideline is not evaluated, although selection of the guideline for endorsement includes expert opinion on the usefulness of the content of the guideline.
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Thematic Group 4: Other rare – predominantly malignant – genturis
A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.