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Rhabdoid Tumor Predisposition Syndrome

Synonyms: Rhabdoid Predisposition Syndrome, RTPS

, MD, PhD, , MD, PhD, , MD, PhD, , MD, Prof, , PhD, , MD, , MD, , MD, PhD, Prof, , MD, Prof, and , MD, PhD, Prof.

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Summary

Clinical characteristics.

Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing rhabdoid tumors – rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. Rhabdoid tumors can occur in almost any anatomic location, commonly in the central nervous system (i.e., atypical teratoid/rhabdoid tumor [AT/RT]); more than 50% occur in the cerebellum.

Other common locations include extracranial extrarenal malignant rhabdoid tumors (e.g., rhabdoid tumors of the head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart) (eMRT), rhabdoid tumor of the kidney (RTK), and possibly small-cell carcinoma of the ovary (hypercalcemic type). Individuals with RTPS typically 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 SMARCA4- or SMARCB1-deficient tumors (synchronous or metachronous) and identification of a germline heterozygous pathogenic variant in SMARCA4 or SMARCB1 by molecular genetic testing.

Management.

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

Prevention of primary manifestations: Prophylactic bilateral oophorectomy may be discussed after childbearing.

Prevention of secondary manifestations: Consider risk-reducing treatment strategies (e.g., postpone or replace radiotherapy with high-dose chemotherapy or proton beam therapy; targeted therapy used concomitantly with, or before, standard chemotherapy).

Surveillance: From birth to age one year:

  • Monthly physical and neurologic examination, head ultrasound, and abdominal and pelvic ultrasound recommended.
  • If not feasible for patients with AT/RT, monthly head ultrasound plus abdominal and pelvic ultrasound every two to three months is a minimum requirement. If fontanelle closes prematurely consider head MRI every two to three months.
  • For patients with eMRT, RTK: monthly head, abdominal, and pelvic ultrasound examination.
  • If ultrasound is not sufficient consider MRI at least every two to three months for affected site and ultrasound for all other sites. Whole-body MRI is desirable but not universally available.

From age one year to age four to five years:

  • For patients with AT/RT: brain and total spine MRI every three months
  • If available, consider whole-body MRI. (Note: Whole-body MRI resolution may not be sufficent for brain MRI, which would then need to be performed separately).
  • For patients with eMRT, RTK: abdominal and pelvic ultrasound or MRI (or whole-body MRI) every three months.

After age four years:

  • Twice-yearly physical examination in a tumor predisposition clinic with targeted imaging for symptomatic areas.
  • For patients with SMARCA4-related SCCOHT: 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 in order to identify as early as possible those who would benefit from prompt initiation of screening, treatment, and preventive measures.

Genetic counseling.

RTPS is inherited in an autosomal dominant manner. The vast majority of individuals diagnosed with RTPS have the disorder as the result of a de novo germline SMARCB1 pathogenic variant. Most reported individuals diagnosed with SMARCA4-related RTPS inherited a pathogenic variant from an unaffected parent. Each child of an individual with a germline SMARCA4 or SMARCB1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. However, penetrance appears to be incomplete and the types of RTPS-related tumors can vary among different members of the same family. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Diagnosis

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:

  • Congenital presentation (i.e., prenatal diagnosis or symptoms within the first 28 days of life)
  • Early-onset rhabdoid tumor (age <12 months)
  • Advanced stage of rhabdoid tumor (RT) at diagnosis (e.g., >M1 by Chang classification; Stage ≥II in extracranial RT [Harisiadis & Chang 1977])
  • Synchronous rhabdoid tumors (>1 primary rhabdoid tumor)
  • Family history of rhabdoid tumor, small-cell carcinoma of the ovary hypercalcemic type, or other malignant entities such as cribriform neuroepithelial tumor, malignant peripheral nerve sheath tumor, and non-malignant schwannoma or meningioma
  • Family history of RTPS

Given the limited patient data available, germline molecular genetic testing for RTPS is recommended in any individual with:

  • A rhabdoid tumor (at any age), familial rhabdoid tumors, multifocal tumors, or congenital-onset tumors;
  • A SMARCB1-deficient tumor (as defined by histology, rhabdoid and non-rhabdoid) with a familial history of rhabdoid tumor OR non-specified cancer in early childhood (age <5 years);
  • A SMARCA4-deficient tumor (as defined by histology, rhabdoid and non-rhabdoid) with a familial history of rhabdoid tumor OR non-specified cancer in early childhood (age <5 years).

Note: (1) It remains to be determined whether adult-onset rhabdoid tumors are caused by germline pathogenic variants in SMARCA4 or SMARCB1. (2) As morphologic rhabdoid features may not be present in all rhabdoid tumor biopsies because of inter- and intratumoral heterogeneity, any small blue round cell tumors in infants and young children should be evaluated for absence of nuclear SMARCA4 or SMARCB1 staining.

Laboratory features on tumor tissue

  • Immunohistochemistry. Absence of SMARCA4 (formerly BRG-1) or SMARCB1 (formerly INI-1) staining in tumor tissue
  • Molecular genetic testing. Somatic SMARCA4 or SMARCB1 pathogenic variants identified in a rhabdoid tumor. Note: Fresh-frozen tumor is preferable; formalin-fixed, paraffin-embedded samples may also be suitable.

Establishing the Diagnosis

There is currently no consensus regarding formal diagnostic criteria for rhabdoid tumor predisposition syndrome (RTPS).

The diagnosis of RTPS is established in a proband with both of the following:

Molecular genetic testing approaches can include serial single-gene testing and use of a multigene panel.

Serial single-gene testing may be considered in individuals with absence of SMARCA4 or SMARCB1 identified on tumor immunohistochemistry:

A multigene panel that includes SMARCA4, SMARCB1, and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. 3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Rhabdoid Tumor Predisposition Syndrome

Gene 1Proportion of RTPS Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detectable by This Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
SMARCA4~5%-15% 54/9 individuals 6, 75/9 individuals 6, 7
SMARCB1~85%-95% 8~46% 6, 9~54% 6, 9
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include multiplex ligation-dependent probe amplification (MLPA) designed to detect single-exon deletions or duplications.

5.

In individuals with RTPS confirmed by germline molecular testing, a germline SMARCA4 pathogenic variant was identified in 3/50 individuals [EU-RHAB ‒ Author, personal communication], 6/35 individuals [Authors, personal communication], and 8/192 individuals [T Holsten, unpublished].

6.

EU-RHAB ‒ Author, personal communication

7.
8.

In individuals with RTPS confirmed by germline molecular testing, a germline SMARCB1 pathogenic variant was identified in 47/50 individuals [EU-RHAB ‒ Author, personal communication], 29/35 individuals [Author, personal communication], and 184/192 individuals [Holsten et al 2017].

9.

Clinical Characteristics

Clinical Description

Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing rhabdoid tumors.

Rhabdoid tumors are rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. The term rhabdoid is derived from the histologic resemblance of tumor cells to rhabdomyoblast. Rhabdoid tumors are characterized by heaps of cells with an eccentric nucleus and prominent nucleolus, abundant cytoplasm with eosinophilic inclusion bodies, and distinct cellular membranes. Immunohistochemically rhabdoid tumor cells are characterized by increased expression of vimentin (a nonspecific marker), epithelial membrane antigen (EMA), cytokeratins, and loss of SMARCB1 protein (a strong indicator for rhabdoid tumor).

As morphologic rhabdoid features may not be present in all rhabdoid tumor biopsies because of inter- and intratumoral heterogeneity, any small blue round cell tumor in infants and young children should be evaluated for absence of nuclear SMARCB1 staining.

Primary rhabdoid tumor locations include the following:

  • Central nervous system (atypical teratoid/rhabdoid tumor [AT/RT]; >50% are cerebellar)
  • Head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart (extracranial malignant rhabdoid tumor [eMRT])
  • Kidney (rhabdoid tumor of the kidney [RTK])
  • Ovary (small-cell carcinoma of the ovary [SCCOHT] ‒ hypercalcemic type)

Rhabdoid tumors have been reported in nearly all anatomic locations [Brennan et al 2013, Sredni & Tomita 2015, Frühwald et al 2016a].

Individuals with RTPS typically present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior, often in one of the following clinical settings:

  • Prenatally detected synchronous rhabdoid tumors
  • Infantile-onset or congenital rhabdoid tumor, presentingat median age of four to seven months (range: prenatally – 60 months) (compared to individuals with sporadic rhabdoid tumor: median age 13-30 months; range: age 1 day - 228 months) [Bruggers et al 2011, Geller et al 2015, Frühwald et al 2016b]. Note: A bias toward increased molecular testing in younger individuals may confound the data.
  • Synchronous (multiple primary) rhabdoid tumors. Individuals with RTPS have a higher incidence of multiple rhabdoid tumors [Eaton et al 2011]. 28% of patients with RTPS in the EU-RHAB Registry had synchronous tumors; eight individuals had AT/RT and eMRT, four individuals had AT/RT and RTK, and two individuals with congenital synchronous tumors had AT/RT, multiple eMRT, and RTK [Frühwald et al 2016b].
  • Family history of rhabdoid tumor, cribriform neuroepithelial tumor (CRINET), and/or distinct combinations of rhabdoid tumor with one of the following: schwannoma, malignant peripheral nerve sheath tumor, meningioma, or CRINET [van den Munckhof et al 2012]
  • Family history of small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) for SMARCA4-related RTPS (germline SMARCB1 pathogenic variants have not been reported in individuals with SCCOHT) [Moes-Sosnowska et al 2015, Witkowski et al 2017]
  • Clinically aggressive rhabdoid tumor. Tumor progression at the time of follow up was identified in 91% of individuals with RTPS. Progression occurred while on chemotherapy in 58% of individuals with RTPS [Sredni & Tomita 2015, EU-RHAB ‒ Author, personal communication].
  • Rhabdoid tumor and syndromic features suggestive of 22q11.2 distal deletion syndrome (OMIM 611867)

Prognosis. Individuals with RTPS potentially have a worse prognosis than those with a sporadic rhabdoid tumor; although long-term survival has been reported in some [Ammerlaan et al 2008, Modena et al 2013, Kordes et al 2014, Seeringer et al 2014b].

Phenotype Correlations by Gene

SMARCA4. Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) has been reported in individuals with SMARCA4-related RTPS and has not been reported in individuals with germline SMARCB1 pathogenic variants.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

SMARCA4. Most individuals with SMARCA4-related RTPS have inherited the pathogenic variant from an unaffected, healthy parent. In SMARCA4-related RTPS the penetrance for rhabdoid tumor in the preceding generation of seven informative families was zero. However, in one family, two sibs with a SMARCA4 pathogenic variant were both affected [Schneppenheim et al 2010, Hasselblatt et al 2014].

SMARCB1. There are reports of reduced penetrance. Rarely a SMARCB1 pathogenic variant is inherited from an unaffected parent or a parent with late-onset or undiagnosed RTPS [Ammerlaan et al 2008]. Germline mosaicism accounts for at least half of the families with sibs affected by RTPS.

Nomenclature

Rhabdoid tumor predisposition syndrome may also be referred to as familial posterior fossa brain tumor syndrome.

Current data suggest the value of subgroup determination for diagnostic and therapeutic decision making [Torchia et al 2015, Johann et al 2016]:

  • ATRT-TYR is characterized by infratentorial location, younger age at diagnosis (<1year), and overexpression of the genes TYR and MITF.
  • In the subgroup ATRT-MYC tumors are mostly supratentorial, affected individuals are older (age 4-5 years) at diagnosis, and the genes MYC, HOTAIR, and HOX are overexpressed.
  • The subgroup ATRT-SHH tumor location may be infratentorial or supratentorial, diagnosis is between ages two and five years, and sonic hedgehog pathway genes are overexpressed.

Note: Torchia et al [2016] presented data on three subgroups that was similar to the subgroups described by Johann et al [2016]. A consensus on simplifying subgroup nomenclature is currently being sought.

Prevalence

Among newly diagnosed individuals with rhabdoid tumors, 25%-35% will have a germline pathogenic variant in SMARCB1 [Bourdeaut et al 2011, Eaton et al 2011, Hasselblatt et al 2014].

The incidence of rhabdoid tumors may be estimated according to the following data:

  • The age-standardized annual incidence rate is between five (extracranial rhabdoid tumors) and 8.1 per million (atypical teratoid/rhabdoid tumor) in children younger than age one year, and decreases to between 0.6 and 2.2 per million at ages one to four years [Brennan et al 2013, Frühwald et al 2016a].
  • In the US, annual incidence among children younger than age 15 is 0.89 per million for AT/RT, 0.32 per million for eMRT, and 0.19 per million for RTK [Heck et al 2013].

Differential Diagnosis

Sporadic tumors. Demonstration of loss of the SMARCA4 or SMARCB1 protein (in tumor tissue) due to inactivation or loss of one allele of SMARCB1 or SMARCA4 (tumor tissue and constitutional samples) may suggest the diagnosis of RTPS. For example, one individual with a constitutional deletion of SMARCB1 and an epithelioid sarcoma was reported by Le Loarer et al [2014]. The absence of a clinical and family history of rhabdoid tumor(s) distinguishes these individuals from those with RTPS.

Several other malignant tumors with somatic pathogenic variants of SMARCA4 or SMARCB1 have not yet been associated with germline pathogenic variants in SMARCA4 or SMARCB1 (see Molecular Genetics, SMARCA4 and SMARCB1, Cancer and benign tumors).

Management

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:

  • Refer individuals with RTPS who have not yet developed a rhabdoid tumor to a pediatric oncologist or tumor surveillance program.
  • Consider consulting a radiologist, prior to the planning of therapy, 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 (CSF) and determine classification according to Chang staging [Harisiadis & Chang 1977].

Treatment of Manifestations

Current data suggest the value of subgroup determination for diagnostic and therapeutic decision making [Torchia et al 2015, Johann et al 2016]:

  • ATRT-TYR is characterized by infratentorial location, younger age at diagnosis (<1year), and overexpression of the genes TYR and MITF.
  • In the subgroup ATRT-MYC tumors are mostly supratentorial, affected individuals are older (age 4-5 years) at diagnosis, and the genes MYC, HOTAIR, and HOX are overexpressed.
  • The subgroup ATRT-SHH tumor location may be infratentorial or supratentorial, diagnosis is between ages two and five years, and sonic hedgehog pathway genes are overexpressed.

Note: Torchia et al [2016] presented data on three subgroups that was similar to the subgroups described by Johann et al [2016]. A consensus on simplifying subgroup nomenclature is currently being sought.

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

  • The Children's Oncology Group has employed a combination of surgery, two cycles of induction chemotherapy (cisplatinum, cyclophosphamide, etoposide, vincristine, methotrexate), three cycles of high-dose chemotherapy with stem cell rescue (thiotepa, carboplatinum) as consolidation therapy, and radiotherapy according to age and stage [protocol ACNS0333 clinicaltrials.gov, Reddy et al 2016].
  • The Dana Faber Consortium has tested combination therapy with surgery, radiotherapy, and chemotherapy (vincristine, dactinomycin, cyclophosphamide, cisplatinum, doxorubicin, temozolomide and intrathecal methotrexate, cytarabine, and hydrocortisone) [clinicaltrials.gov, Chi et al 2009].
  • The EU-RHAB Registry recommends using combination therapy for rhabdoid tumors of any location (e.g., AT/RT, rhabdoid tumor of the kidney [RTK], extracranial malignant RT [eMRT]) including gross total resection, conventional chemotherapy (vincristine, dactinomycin, cyclophosphamide, doxorubicin, ifosfamide, carboplatinum, etoposide), intrathecal methotrexate, and permissive use of high-dose chemotherapy with stem cell rescue (carboplatinum, thiotepa) and radiotherapy (in individuals age >18 months). The feasibility of intensive multimodal regimen even in the youngest individuals including those affected by RTPS has been demonstrated [Seeringer et al 2014a, Bartelheim et al 2016].
  • The Canadian Brain Tumour Consortium retrospectively evaluated children diagnosed with rhabdoid tumors between 1995 and 2007. Among 40 individuals, 22 received conventional chemotherapy and 18 received high-dose chemotherapy (HDCT) regimens; 15 received adjuvant radiation. Notably, six of 12 long-term survivors never received any radiotherapy [Lafay-Cousin et al 2012].
  • Zaky et al evaluated the Head Start III experience for newly diagnosed patients with AT/RT. Between 2003 and 2009, 19 patients were treated with a combination of surgery and five courses of induction chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue and radiotherapy according to age and stage. In five patients toxicity-related deaths occurred; ten patients died due to disease progression. The three-year overall survivial (OS) and event-free survival rates were 26±10% and 21±9%, respectively [Zaky et al 2014].
  • Schrey et al summarized HDCT data by an individual pooled data analysis of 12 manuscripts and 389 publications including prospective and retrospective studies focused on the treatment of children diagnosed with AT/RT. Data of 332 patients demonstrated an improved outcome in those treated with HDCT-SCR and radiotherapy [Schrey et al 2016].
  • Fischer-Valuck evaluated data of 361 children diagnosed with AT/RT between 2004 and 2012. The five-year OS rate was 29.9%, and it was significantly higher for patients with localized disease treated with multimodal therapy (surgery, chemotherapy, and radiotherapy) with a five-year OS of 46.8%. Patients younger than age three years at diagnosis showed significantly worse OS (5-year OS 27.7%) compared to older patients (5-year OS 37.5%) and were also significantly less likely to receive multimodal therapy (specifically, the radiotherapy component). The authors suggest early radiotherapy as an important factor for long-term cure [Fischer-Valuck et al 2017].

Note: RTPS most commonly affects infants; therapy presents a rather complex challenge due to the vulnerability of infants. The use of aggressive multimodal treatment on the developing nervous system and other organ systems of a young individual may profoundly affect developmental (e.g., neurodevelopmental) outcome, and entail significant short- and long-term side effects. Intensive induction chemotherapy may often achieve good responses and individuals may proceed with radiotherapy or (tandem) high-dose chemotherapy (HDCT) followed by autologous stem cell support.

It remains to be determined whether a subgroup of children may be cured by surgery and chemotherapy alone, thus avoiding the potential severe side effects of radiotherapy to the developing brain.

Prevention of Primary Manifestations

Prophylactic bilateral oophorectomy may be discussed with women with SMARCA4-related RTPS after childbearing because of the high risk of developing small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT).

Prevention of Secondary Complications

The intensive multimodal treatment strategies required for clinically aggressive tumors in children with RTPS lead to a higher rate of secondary complications. Therapies and interventions which may prevent secondary complications include the following:

  • Consideration of risk-reducing treatment strategies (e.g., postpone or replace radiotherapy with HDCT or proton beam therapy; targeted therapy used concomitant with – or before – standard chemotherapy)
  • Long-term or lifelong surveillance in RTPS survivors (see Surveillance)

Surveillance

Surveillance guidelines for patients with RTPS have been provided by Teplick et al [2011] and Foulkes et al [2017].

Birth to age one year. Monthly physical and neurologic examination, head ultrasound, and abdominal and pelvic ultrasound are desirable. If not feasible, alternate guidelines for patients with:

  • AT/RT are physical and neurologic examination, including head ultrasound monthly plus every two to three months abdominal and pelvic ultrasound as a minimum requirement. If fontanelle closes prematurely consider head MRI every two to three months.
  • eMRT or RTK are abdominal and pelvic plus head ultrasound examination monthly. If ultrasound is not sufficient consider MRI at least every two to three months for affected site and ultrasound for all other sites. Whole-body MRI is desirable but not universally available.

Age one year to age four to five years

  • AT/RT. Brain and total spine MRI examination every three months. If available whole-body MRI may be considered. Note: Whole-body MRI resolution may not be sufficent for brain MRI, which would then need to be performed separately.
  • eMRT or RTK. Abdominal and pelvic ultrasound examination or MRI every three months; alternatively, whole-body MRI

After age four years the risk of developing a new rhabdoid tumor dramatically decreases [Eaton et al 2011]. It remains worthwhile, however, to screen individuals with RTPS for other manifestations (e.g., schwannomas, SCCOHT). A practical approach would include annual physical examination with targeted imaging for symptomatic areas (e.g., neurologic deficit, change in physical features, menstrual disturbances) and referral to a tumor predisposition clinic.

Note: Individuals diagnosed with SMARCA4-related SCCOHT should be screened by abdominal and pelvic ultrasound examination every six months.

Table 3.

Surveillance Used in Individuals with Rhabdoid Tumor, Including Individuals with Rhabdoid Tumor Predisposition Syndrome

DisorderOrganScreening According to Type of Germline Alteration and Age
Predicted inactivating variantMissense
variant
SMARCB1-related RTPSBrainAge <1 yrAge 1 to 4-5 yrsNo screening /
very low risk
Head ultrasound monthly & abdominal, pelvic ultrasound every 1 (2-3) mosBrain, spine, & whole-body MRI every 3 mos
AbdomenAge <1 yrAge 1 to 4-5 yrsNo screening /
very low risk
Abdominal, pelvic, & head ultrasound monthly, alternatively MRI every 2-3 mos 1Abdominal & pelvic ultrasound or MRI every 3 mos
SMARCA4-related RTPSBrainInsufficient data 2
AbdomenInsufficient data
1.

If ultrasound is not sufficient consider MRI at least every two to three months.

2.

One in ten individuals with AT/RT had a SMARCA4 missense germline pathogenic variant detected

Agents/Circumstances to Avoid

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 only be used if absolutely necessary for essential health care.

Evaluation of Relatives at Risk

If a germline pathogenic variant in SMARCA4 or SMARCB1 has been identified in an affected individual, molecular genetic testing of apparently asymptomatic older and younger sibs and other at-risk relatives is appropriate. Early detection of individuals who are heterozygous for an SMARCA4 or SMARCB1 pathogenic variant allows prompt initiation of surveillance, treatment, and preventative measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

The following clinical trials are currently recruiting unless indicated otherwise:

  • NCT02114229: Phase I/II trial of Alisertib as a Single Agent in Recurrent or Progressive Central Nervous System (CNS) Atypical Teratoid Rhabdoid Tumors (AT/RT) and Extra-CNS Malignant Rhabdoid Tumors (MRT) and in Combination Therapy in Newly Diagnosed AT/RT
  • NCT02601937: Phase I trial of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
  • NCT02601950: Phase II trial Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
  • NCT03213665: Phase II trial Pediatric MATCH: Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (not recruiting)
  • NCT01747876: Phase I, Multi-center, Open-label Study of LEE011 in Patients with Malignant Rhabdoid Tumors and Neuroblastoma [Geoerger et al 2017] (not recruiting)
  • NCT02644460: Phase I trial, Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors (AflacST1501)

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Rhabdoid tumor predisposition syndrome (RTPS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk of the sibs of a proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with a germline SMARCA4 or SMARCB1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. However, penetrance appears to be incomplete and the types of RTPS-related tumors can vary among different members of the same family.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a germline SMARCA4 or SMARCB1 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells but also from tumor tissue) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

High-risk pregnancies (i.e., those with a family history of RTPS). Once the SMARCA4 or SMARCB1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Note: Rhabdoid tumors associated with RTPS may develop before birth; therefore, if the SMARCA4 or SMARCB1 pathogenic variant has been identified in the fetus, high-level ultrasound examination may be used to detect and identify prenatal manifestations of a primary tumor.

Low-risk pregnancies (i.e., those without a known family history of RTPS). If a primary tumor is detected on general prenatal ultrasound screening (and confirmed with high-level ultrasound), prenatal testing for a SMARCA4 or SMARCB1 pathogenic variant may be discussed. Note: Specific treatment for this patient group is currently not available; interventions may be discussed, but long-term survival has been also recorded in some affected individuals [Seeringer et al 2014b].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • American Childhood Cancer Organization (ACCO)
    PO Box 498
    Kensington MD 20895-0498
    Phone: 800-366-2223 (toll-free); 301-962-3520
    Fax: 301-962-3521
    Email: staff@acco.org
  • CancerCare
    275 Seventh Avenue
    Floor 22
    New York NY 10001
    Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
    Fax: 212-712-8495
    Email: info@cancercare.org
  • National Brain Tumor Society
    124 Watertown Street
    Suite 2D
    Watertown MA 02472
    Phone: 800-770-8287 (toll-free); 617-924-9997; 800-934-2873 (Toll-free Patient Services)
    Fax: 617-924-9998
    Email: info@braintumor.org
  • European Rhabdoid Registry (EU-RHAB)
    Stenglingstr. 2.
    Augsburg 86156
    Germany
    Phone: 00498214004342
    Fax: 0049821400174243
    Email: eurhab@klinikum-augsburg.de

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Rhabdoid Tumor Predisposition Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Rhabdoid Tumor Predisposition Syndrome (View All in OMIM)

601607SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY B, MEMBER 1; SMARCB1
603254SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 4; SMARCA4
609322RHABDOID TUMOR PREDISPOSITION SYNDROME 1; RTPS1
613325RHABDOID TUMOR PREDISPOSITION SYNDROME 2; RTPS2

Molecular Genetic Pathogenesis

Rhabdoid tumor predisposition syndrome is typically characterized by heterozygous germline pathogenic variants that predict inactivation of SMARCA4 (very rarely) or SMARCB1 (more commonly).

SMARCA4 with its ATPase activity is the catalytic subunit and SMARCB1 is a core protein of the SWI/SNF chromatin remodeling complex. SWI/SNF interacts with various pathways (p16-Rb pathway, Wnt-β-catenin pathway, sonic hedgehog signal pathway, polycomb pathway, MYCC, Aurora A) and affects many essential biological functions in developing organs, including cell cycle and cell differentiation, gene expression, DNA repair [Biegel et al 2014, Kim & Roberts 2014, Kohashi & Oda 2017].

Although unrelated to RTPS, somatic variants are known to occur in other genes encoding multiple members of the SWI/SNF chromatin remodeling complex (reviewed in Biegel et al [2014]).

SMARCA4

Gene structure. Multiple transcript variants encoding different isoforms have been identified; for a detailed summary of gene and transcript information, see Table A, Gene.

By convention, pathogenic variants are numbered based on the sequence of the transcript encoding the longest isoform, which is transcript NM_001128849.1, comprising 36 exons.

Pathogenic variants. Reported pathogenic variants include nonsense and intragenic deletions that predict inactivation (see Table A, Locus-Specific Databases and HGMD). To date, only a single missense SMARCA4 variant has been reported in an affected individual and his unaffected father [Hasselblatt et al 2014].

Normal gene product. The transcript NM_001128849.1 encodes the 1679-amino acid isoform A (NP_001122321.1). SMARCA4, known as transcription activator BRG1, is a catalytic component of the ATP-dependent SWI/SNF chromatin remodeling complex (hSWI/SNF/BAF) and is essential for the transcriptional activation of genes. For a detailed summary of transcript and protein isoform information, see Table A, Gene.

Abnormal gene product. See Molecular Genetic Pathogenesis.

Cancer and benign tumors. Sporadic rhabdoid tumors may occur as single tumors in the absence of any other findings of RTPS and harbor somatic (acquired) SMARCA4 variants that are not present in the germline [Schneppenheim et al 2010, Biegel et al 2014]. In these circumstances predisposition to these tumors is not heritable.

The routine application of immunohistochemistry to all neural tumors has identified other tumors with loss of SMARCA4 expression (reviewed in Biegel et al [2014] and Margol & Judkins [2014]). Whether SMARCA4 plays a role in development of these tumors is not known.

SMARCB1

Gene structure. SMARCB1 comprises nine exons, produces a 1.749-bp transcript variant 1 (NM_003073.3), and encodes the isoform A.

Pathogenic variants. Reported pathogenic variants predict inactivation (nonsense, frameshift, whole- and partial-gene deletion); Biegel et al [2014] summarized the types and percentages of germline pathogenic variants identified in a large cohort of individuals with rhabdoid tumor.

Common germline pathogenic variants of SMARCB1 reported in rhabdoid tumors may be found in locus-specific databases and HGMD (see Table A, Locus-Specific Databases and HGMD).

Normal gene product. The SMARCB1 protein contains 385 amino acids (NP_003064.2) and is a core component of the ATP-dependent SWI/SNF chromatin remodeling complex (hSWI/SNF/BAF). It plays important roles in cell proliferation, differentiation, cellular antiviral activities, and inhibition of tumor formation.

Abnormal gene product. See Molecular Genetic Pathogenesis.

Cancer and benign tumors. Sporadic rhabdoid tumors may occur as single tumors in the absence of any other findings of RTPS and harbor somatic (acquired) SMARCB1 variants that are not present in the germline [Biegel et al 2014]. In these circumstances predisposition to these tumors is not heritable.

The routine application of immunohistochemistry to all neural tumors has identified other tumors with loss of SMARCB1 expression (reviewed in Biegel et al [2014] and Margol & Judkins [2014]). Whether SMARCB1 plays a role in development of these tumors is not known.

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Chapter Notes

Author Notes

Website: www.rhabdoid.de

The European Rhabdoid Registry (EU-RHAB) was established in 2010 to define a standard of care for affected patients with malignant rhabdoid tumors, to further the understanding of basic molecular mechanisms by coordinating the collection and analysis of biologic materials in order to identify potential targets for pharmaceutical treatment, and eventually to shape the basis for Phase I/II trials.

Acknowledgments

We thank P Neumayer and I Lechner for expert assistance in data acquisition, management, and analysis.

Revision History

  • 7 December 2017 (sw) Review posted live
  • 8 March 2017 (mcf) Original submission
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