Rhabdoid Tumor Predisposition Syndrome 1

A number sign (#) is used with this entry because rhabdoid tumor predisposition syndrome-1 (RTPS1) is caused by heterozygous germline mutation in the SMARCB1 gene (601607) on chromosome 22q11.

Somatic mutations in the SMARCB1 gene are also found in atypical teratoid and rhabdoid (AT/RT) tumors.

Description

The rhabdoid tumor predisposition syndrome is an autosomal dominant cancer syndrome predisposing to renal or extrarenal malignant rhabdoid tumors and to a variety of tumors of the central nervous system, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumors (Sevenet et al., 1999).

Rhabdoid tumors are a highly malignant group of neoplasms that usually occur in children less than 2 years of age. Malignant rhabdoid tumors (MRTs) of the kidney were first described as a sarcomatous variant of Wilms tumors (Beckwith and Palmer, 1978). Later, extrarenal rhabdoid tumor was reported in numerous locations, including the central nervous system (CNS) (Parham et al., 1994). Classification has been difficult because of considerable variation in the histologic and immunologic characteristics within and between rhabdoid tumors of the liver, soft tissues, and CNS. In the CNS, rhabdoid tumors may be pure rhabdoid tumors or a variant that has been designated atypical teratoid tumor (AT/RT).

Genetic Heterogeneity of Rhaboid Tumor Predisposition Syndrome

See also RTPS2 (613325), caused by germline mutation in the SMARCA4 gene (603254) on chromosome 19p13.

Clinical Features

Bonnin et al. (1984) described 7 patients with rhabdoid tumors of the kidney who had CNS tumors that differed in their histology. Weeks et al. (1989) reported on a series of 111 cases of which 13.5% with renal rhabdoid tumors had a CNS malignancy.

Burger et al. (1998) reported on a pediatric oncology group study of 55 patients with atypical teratoid/rhabdoid tumors of the central nervous system. The aim of the study was to define the clinical and pathologic features. The lesion occurred primarily in children younger than 2 years. The neoplasms were located in the posterior fossa (36 patients) and the supratentorial compartment (17 patients) or were multifocal in both compartments (2 patients) at presentation. Histologically, the tumors were composed of small cells and large, pale cells in a jumbled architectural arrangement. The small cell component resembled medulloblastoma and occasionally had cords of cells in a mucinous background, simulating chordoma. The cytoplasm of the larger cells was conspicuous with a somewhat 'rhabdoid' appearance, although rhabdoid features were not always prominent. The neoplasms showed striking polyphenotypic immunoreactivity. In contrast to patients with medulloblastoma, the neoplasm with which these lesions are often confused, the outcome of patients was uniformly poor.

Sevenet et al. (1999) reported 3 unrelated families in which sibs had multiple cases of aggressive malignant tumors of the central nervous system, including malignant rhabdoid tumors, atypical teratoid and rhabdoid tumors, choroid plexus carcinomas, and medulloblastoma. All had onset at less than 3 years of age.

Taylor et al. (2000) reported a multigenerational family with RTPS. The proband presented at age 18 months with a cerebellar malignant rhabdoid tumor. The mother of the proband was completely healthy, but a maternal uncle had died at age 2 years from a posterior fossa choroid plexus carcinoma. A sib of the maternal grandfather had died in infancy from a disease process consistent with a pediatric brain tumor.

Swensen et al. (2009) reported a family with hereditary schwannomatosis (162091) spanning 4 generations associated with a germline duplication in the SMARCB1 gene (601607.0009). Affected individuals developed painful skin lumps in their teenage years. Two family members with mutations had malignant rhabdoid tumors, and a third was believed to have a rhabdoid tumor. These 3 patients all died before 2 years of age. Two rhabdoid tumors and several schwannomas showed somatic loss of the SMARCB1 gene. Swensen et al. (2009) noted that this was the first reported case of familial occurrence of both conditions.

Mapping

Biegel et al. (1996) sublocalized a rhabdoid tumor locus to the region between the constant region genes of the immunoglobulin lambda locus (see 147220) and BCR (151410) in a 500-kb span of 22q11.

Cytogenetics

Biegel et al. (1990) described monosomy 22 in 3 rhabdoid tumors of the CNS, and Biegel et al. (1992) reported a rhabdoid tumor with an unbalanced 9;22 translocation leading to loss of 22q11.2-qter. Douglass et al. (1990) reported a CNS tumor with monosomy 22; Muller et al. (1995) reported on a rhabdoid tumor of the pineal region with monosomy 22.

Using a probe for chromosome 22, Burger et al. (1998) found that 7 of 8 scorable cases of atypical teratoid/rhabdoid tumors of the CNS showed a solitary signal by FISH, consistent with monosomy 22. The eighth scorable case showed 3 signals by FISH and had a translocation involving chromosome 22 reported by conventional cytogenetics.

Misawa et al. (2004) observed a translocation t(1;22) with concurrent deletion of 22q11.2 resulting in homozygous deletion of the SNF5 (SMARCB1) gene in a newly established cell line derived from an extrarenal rhabdoid tumor. The patient was a 5-month-old boy who was found to have a thoracic mass without metastases at the time of diagnosis. Cytogenetic analysis of peripheral lymphocytes demonstrated a normal male karyotype. Combined total resection, chemotherapy, and radiation therapy led to apparent cure by the age of 4 years.

Molecular Genetics

Germline Mutations in the SMARCB1 Gene

In affected members of 3 different families with the rhabdoid predisposition syndrome, Sevenet et al. (1999) identified heterozygous germline loss-of-function mutations in the SMARCB1 gene (see, e.g., 601607.0003). Tumor tissue, when available, showed somatic loss of heterozygosity (LOH) at the SMARCB1 locus. In all tested cases, DNA from parents demonstrated normal SNF5/INI1 sequences, thereby indicating the de novo occurrence of the mutations, which were shown to involve the maternal allele in 1 case and the paternal allele in 2 other cases. The data indicated that constitutional mutation of this gene predisposes to renal or extrarenal MRT and also to a variety of tumors of the CNS, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroectodermal tumor.

In a multigenerational family with RTPS, Taylor et al. (2000) identified a heterozygous splice site mutation of the SMARCB1 gene (601607.0004), predicted to cause a truncation of the protein. The unaffected mother of the proband also carried the mutation.

Somatic Mutations in the SMARCB1 Gene

Versteege et al. (1998) mapped the most frequently deleted part of chromosome 22q11.2 from a panel of 13 cell lines from malignant rhabdoid tumors and observed 6 homozygous deletions that delineated the smallest region of overlap, which fell in the region of the SNF5/INI1 gene. Analysis of 12 of these lines showed somatic frameshift or nonsense mutations in the SMARCB1 gene (see, e.g., 601607.0001; 601607.0002). All were associated with loss of heterozygosity (LOH) at the other allele, consistent with the 2-hit recessive model of oncogenesis and consistent with the hypothesis that SNF5/INI1 is the MRT tumor suppressor gene. Versteege et al. (1998) noted that the SWI/SNF complexes, which have been identified in organisms from yeast to humans, are thought to be important in the remodeling of chromatin structure, and the authors concluded that altered chromatin organization at specific DNA sites may be crucial in the process of oncogenesis.