Rhabdoid tumor predisposition syndrome

Rhabdoid tumor predisposition syndrome (RTPS) is a rare hereditary cancer predisposition condition characterized by an increased risk of developing highly aggressive rhabdoid tumors, typically in early childhood. The syndrome is caused by germline pathogenic variants in the SMARCB1 gene (also known as INI1 or hSNF5, located on chromosome 22q11.23) in the majority of cases (RTPS type 1), or less commonly in the SMARCA4 gene on chromosome 19p13.2 (RTPS type 2). These genes encode components of the SWI/SNF chromatin-remodeling complex, which plays a critical role in tumor suppression. Loss of function of these proteins leads to uncontrolled cell growth and tumor formation. Rhabdoid tumors associated with this syndrome can arise in multiple body sites. The three main tumor types include malignant rhabdoid tumors of the kidney (RTK), atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system, and extra-renal rhabdoid tumors affecting soft tissues at various locations. These tumors are among the most aggressive pediatric cancers, typically presenting in infants and very young children, often before the age of two years. Symptoms depend on tumor location and may include a palpable abdominal mass, hematuria, signs of increased intracranial pressure (headache, vomiting, lethargy), focal neurological deficits, or soft tissue swelling. Some patients may develop multiple synchronous or metachronous rhabdoid tumors at different sites. Treatment of rhabdoid tumors is challenging and typically involves a multimodal approach including surgical resection, intensive chemotherapy, and in some cases radiation therapy. Despite aggressive treatment, prognosis remains poor, particularly for infants with disseminated disease. Current research is exploring targeted therapies, including EZH2 inhibitors and immune checkpoint inhibitors, as well as other novel agents aimed at exploiting the specific molecular vulnerabilities created by SMARCB1 or SMARCA4 loss. Genetic counseling is essential for affected families, as the syndrome follows an autosomal dominant inheritance pattern with incomplete penetrance, and de novo mutations account for a significant proportion of cases. Surveillance protocols for at-risk children carrying germline mutations are being developed at specialized centers.

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