Rhabdoid Tumor Predisposition Syndrome

Clinical characteristics: Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk for the development of rhabdoid tumors – rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. Malignant rhabdoid tumors can occur in almost any anatomic location. They often occur in the central nervous system (i.e., atypical teratoid/rhabdoid tumor]); more than 50% occur in the cerebellum. Other common locations include extracranial malignant rhabdoid tumors (e.g., rhabdoid tumors of the head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart), rhabdoid tumor of the kidney, and possibly small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT). More than 70% of individuals with RTPS present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior.

Diagnosis/testing: The diagnosis of RTPS is established in a proband with a rhabdoid tumor and/or a family history of rhabdoid tumor and/or multiple SMARCB1- or SMARCA4-deficient tumors (synchronous or metachronous), and a heterozygous disease-causing germline variant in SMARCB1 (RTPS1) or SMARCA4 (RTPS2) identified by molecular genetic testing.

Management: Treatment of manifestations: Because of the rarity of RTPS, standards for management are evolving. Most individuals are treated using intensive multimodal therapeutic strategies – according to institutional preference – combining surgery, radiotherapy, and chemotherapy. The intensive multimodal treatment strategies required for clinically aggressive tumors in children with RTPS lead to a high rate of secondary complications. Consider risk-reducing treatment strategies (e.g., postpone or replace radiotherapy with high-dose chemotherapy or proton beam therapy; use targeted therapy concomitantly with, or before, standard chemotherapy).

Prevention of primary manifestations: Prophylactic risk-reducing bilateral salpingo-oophorectomy may be discussed following the end of family planning in women with SMARCA4-related RTPS because of the high risk of developing SCCOHT. The medical and ethical ramifications involved require an interdisciplinary approach including counseling and further research.

Surveillance: For all individuals with a disease-causing germline variant in SMARCB1 or SMARCA4 (regardless of age), whole-body MRI should be offered at diagnosis:

1. 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

2. Age seven 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 as whole-body MRI resolution may not be sufficient for brain structures.

3. 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.

4. After age five years. Every six months, thorough clinical examination including neurologic examination and annual whole-body MRI. Individuals with SMARCA4-related SCCOHT should have an abdominal and pelvic ultrasound every six months.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual to identify as early as possible those who would benefit from prompt initiation of tumor surveillance.

Genetic counseling: RTPS is inherited in an autosomal dominant fashion. The vast majority of individuals with SMARCB1-related RTPS have a de novo disease-causing SMARCB1 germline variant. Most reported individuals diagnosed with SMARCA4-related RTPS inherited a disease-causing variant from a parent without a history of a rhabdoid tumor or SCCOHT. Each child of an individual with a germline SMARCB1- or SMARCA4 disease-causing variant has a 50% chance of inheriting this variant. The penetrance of SMARCB1-related RTPS may be extremely high in individuals who inherit a SMARCB1 disease-causing variant. The penetrance of SMARCA4-related RTPS appears to be incomplete. The types of RTPS-related tumors vary among family members with the same disease-causing variant. Once the SMARCB1 or SMARCA4 disease-causing variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.