Clinical Guidance

No genotype-phenotype correlations have been identified.

Source: GeneReviews — "Rhabdoid Tumor Predisposition Syndrome"

Penetrance

SMARCB1. Penetrance of SMARCB1-related RTPS may be extremely high (90% by age 5 years) . However, these data may be based on selection bias, and larger series of systematically screened trios (parents and affected offspring) are needed to accurately define penetrance. Rarely a SMARCB1 disease-causing variant is inherited from an unaffected parent or a parent with late-onset or undiagnosed RTPS . Germline mosaicism may account for up to half of the families with sibs affected by RTPS. SMARCA4. Even less is known about the penetrance of SMARCA4-related RTPS. Penetrance is incomplete, as most individuals with SMARCA4-related RTPS have inherited the disease-causing variant from an unaffected, healthy parent [; ; ; ; EU-RHAB Author, personal communication].

Source: GeneReviews — "Rhabdoid Tumor Predisposition Syndrome"

Diagnostic Criteria

Suggestive Findings

Rhabdoid tumor predisposition syndrome (RTPS) should be suspected in an individual with any of the following clinical or laboratory features. Clinical features. Any rhabdoid tumor with the following features is particularly suspicious:

Source: GeneReviews — "Rhabdoid Tumor Predisposition Syndrome"

Differential Diagnosis

Demonstration of loss of the SMARCB1 or SMARCA4 protein (in tumor tissue) as a result of inactivation or loss of one allele of SMARCB1 or SMARCA4 (tumor tissue and constitutional samples) may suggest the diagnosis of rhabdoid tumor predisposition syndrome (RTPS). For example, an individual with a constitutional deletion of SMARCB1 and an epithelioid sarcoma was reported by . In such cases the absence of a clinical and family history of rhabdoid tumor(s) distinguishes these individuals from those with RTPS. Table 3. Hereditary Disorders in the Differential Diagnosis of Rhabdoid Tumor Predisposition Syndrome

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with rhabdoid tumor predisposition syndrome (RTPS), the following are recommended:

• For all individuals (regardless of age), a whole-body MRI should be offered at diagnosis.

• Individuals who have not yet developed a rhabdoid tumor should be referred to a pediatric oncologist or tumor surveillance program.

• In those with a tumor, prior to planning therapy consider consulting a radiologist to assist in the selection and review of subsequent imaging, to evaluate the size and location of the primary tumor, and to evaluate for the presence of synchronous tumors and/or metastases (whole-body MRI).

• For individuals with atypical teratoid/rhabdoid tumor (AT/RT), examine cerebrospinal fluid and determine classification according to Chang staging .

• Refer to genetic counseling to inform affected individuals and their families about the nature, mode of inheritance, and implications of RTPS to facilitate medical and personal decision making.

Treatment of Manifestations

Because of the rarity of RTPS, standards for management are evolving. Most individuals are treated using intensive multimodal therapeutic strategies combining surgery, radiotherapy, and chemotherapy according to institutional preference:

Source: GeneReviews — "Rhabdoid Tumor Predisposition Syndrome"

Clinical Guidance

Limit exposure to DNA-damaging agents including radiation (e.g., x-ray, CT, external beam radiotherapy), tobacco, UV light, and chemotherapy to minimize the lifetime risk of developing late-onset secondary cancers. Imaging tests utilizing radioactive compounds should be used only if absolutely necessary for essential health care. This recommendation is based on the increased risk of adverse effects in young developing children, not increased risk as a result of a SMARCA4 or SMARCB1 pathogenic variant.

Source: GeneReviews — "Rhabdoid Tumor Predisposition Syndrome"

Therapies Under Investigation

The following clinical trials are currently recruiting unless otherwise indicated. Table 4. Overview of Clinical Trials in Pediatric Malignant Rhabdoid Tumors Including Rhabdoid Tumor Predisposition Syndrome

Surveillance Guidelines

Surveillance guidelines for individuals with RTPS have been provided by , , and . Birth to age six months. Monthly (or at least every 2-3 months) thorough clinical examination including neurologic examination, ultrasound of the abdomen and neck, and head ultrasound or brain and spine MRI or whole-body MRI (imaging modality is based on resources and need for anesthesia). Clinically suspicious regions should initially be evaluated by ultrasound. Note: This intensive surveillance may only be possible in a research setting; recommendations are based on the high risk of tumors within this age group. Age seven months to 18 months. Every two to three months, thorough clinical examination including neurologic examination and ultrasound of the abdomen and neck; consider brain and spine MRI. Clinically suspicious regions should initially be evaluated by ultrasound. Note: Whole-body MRI resolution may not be sufficient for brain structures; MRI of the central nervous system will then need to be done separately. Age 19 months to five years. Every three months, thorough clinical examination including neurologic examination, ultrasound of the abdomen and neck, and brain and spine MRI. Clinically suspicious regions should initially be evaluated by ultrasound. After age five years the risk of developing a new rhabdoid tumor dramatically decreases . It remains worthwhile, however, to screen individuals with RTPS for other manifestations (e.g., schwannomas, SCCOHT).

Source: GeneReviews — "Rhabdoid Tumor Predisposition Syndrome"