Alternative titles; symbols
SNOMEDCT: 61665008; ORPHA: 252202; DO: 0112182;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p22.2 | Mismatch repair cancer syndrome 1 | 276300 | Autosomal recessive | 3 | MLH1 | 120436 |
A number sign (#) is used with this entry because of evidence that mismatch repair cancer syndrome-1 (MMRCS1) is caused by homozygous or compound heterozygous mutation in the mismatch repair (MMR) gene MLH1 (120436) on chromosome 3p22.
Mismatch repair cancer syndrome (MMRCS) is a rare autosomal recessive childhood cancer predisposition syndrome with 4 main tumor types: hematologic malignancies, brain/central nervous system tumors, colorectal tumors and multiple intestinal polyps, and other malignancies including embryonic tumors and rhabdomyosarcoma. Many patients show signs reminiscent of neurofibromatosis type I (NF1; 162200), particularly multiple cafe-au-lait macules (summary by Baas et al., 2013).
Wimmer and Etzler (2008) provided a review of the mismatch cancer repair syndrome and suggested that the prevalence may be underestimated.
Genetic Heterogeneity of Mismatch Repair Cancer Syndrome
MMRCS2 (619096) is caused by mutation in the MSH2 gene (609309) on chromosome 2p21-p16. MMRCS3 (619097) is caused by mutation in the MSH6 gene (600678) on chromosome 2p16. MMRCS4 (619101) is caused by mutation in the PMS2 gene (600259) on chromosome 7p22.
Patients with familial adenomatous polyposis (FAP; 175100), an autosomal dominant disorder that results from heterozygous mutations in the APC gene, may also develop brain tumors or extracolonic malignancies, resulting in a similar clinical phenotype.
Heterozygous mutations in the MMR genes result in hereditary nonpolyposis colorectal cancer (see, e.g., HNPCC1, 120435).
Turcot et al. (1959) reported a brother and sister with malignant tumors of the central nervous system associated with colonic polyps. The brother had a medulloblastoma of the spinal cord and colorectal adenocarcinomas; the sister had glioblastoma multiforme and a pituitary adenoma. The parents were third cousins, indicating autosomal recessive inheritance (Turcot, 1961). Turcot, a French Canadian, pronounced his name with a silent terminal 't'.
Yaffee (1964) described a patient with Gardner syndrome (see 175100), a variant of FAP with extracolonic manifestations, whose uncle 'died of Turcot syndrome.' The report suggested that the 2 phenotypes are similar and may be confused.
Baughman et al. (1969) reported a family in which a brother, 2 sisters, and possibly another brother had glioma and colonic polyposis inherited in an autosomal recessive manner. The authors referred to it as 'the glioma-polyposis syndrome.'
Everson and Fraumeni (1976) described 2 sibs who died from glioblastoma multiforme associated with focal nodular hyperplasia of the liver and cafe-au-lait spots. One sib had 4 adenomatous sigmoid polyps removed at age 22. No further colonic polyps were found on autopsy.
Itoh et al. (1979) described 2 sisters, born of first-cousin parents, with malignant cerebral neoplasms and colonic polyposis. One sister presented at age 19 with multiple colonic polyps for which colectomy was performed. At the age of 22, she presented with a grade 3 astrocytoma of the left frontal lobe, from which she eventually died. She had several cafe-au-lait spots. The younger sister was found at age 17 to have colonic adenomas, including adenocarcinoma in 2 large polyps, and 14 small primary gastric cancers, all of the signet ring cell type. She had total gastrectomy and total colectomy. She had several cafe-au-lait spots and 3 small lipomas. At the age of 21, she was found to have a grade 3 astrocytoma of the right temporal lobe, from which she eventually died. Panoramic radiographs of the jaws and radiologic survey of the skeleton showed no abnormality suggestive of Gardner syndrome.
From study of their own cases and those in the literature, Itoh et al. (1979) concluded that in the Turcot syndrome polyps are somewhat fewer in number than in FAP, but are generally larger in size. The ratio of polyps over 3 cm in diameter to all polyps was frequently more than 1% in Turcot syndrome, but usually less than 0.2% in FAP. The authors collected reports of 12 families plus several nonfamilial cases of Turcot syndrome. Bussey (1975) referred to a recessive form of FAP. Itoh et al. (1979) observed cases of this apparent type and found that the polyposis was of the Turcot type in terms of number and size.
Michels and Stevens (1982) reported a 22-year-old female with multiple polyposis of the colon requiring colectomy at age 17, multiple basal cell carcinoma in the scalp first presenting at age 18, pontine glioma presenting at age 19, and a tumor of the left posterior parietal region, either a second primary tumor or metastatic adenocarcinoma of the colon; invasive adenocarcinoma had been found in the colon specimen. She also had multiple pigmented lesions on the back and arms. A sister died of cerebral glioma at age 8. The authors postulated autosomal recessive inheritance.
Li et al. (1983) reported a woman who developed colonic polyposis and carcinoma at the age of 31 years, and astrocytoma at age 37. Her brother and sister had died of astrocytoma at ages 18 and 33 years, respectively. Progressive neutropenia developed 3 months after radiotherapy for the brain tumor and acute myelomonocytic leukemia developed 19 months after treatment, suggesting radiosensitivity. Studies of cultured skin fibroblasts in 3 laboratories showed slight but significant radiosensitivity in an early passage subculture (after 6 to 10 doublings), but no abnormality in later subculture (after 21 to 29 doublings). Selective in vitro loss of radiosensitive cells may have accounted for the normality of later subcultures.
In a review of reported cases of Turcot syndrome, Van Meir (1998) found that non-FAP patients with glioblastoma had onset before age 26 years and average survival of 27 months, which is longer than that for sporadic glioblastoma.
Ricciardone et al. (1999) reported 3 Turkish sibs who developed hematologic malignancy at a very early age, 2 of whom displayed signs of NF1. All 3 children were diagnosed with a hematological malignancy by the age of 3 years (leukemia in 2 and non-Hodgkin lymphoma in 1). Two of the children had more than 10 cafe-au-lait spots, and 1 child had 2 fibromatous skin tumors.
Hamilton et al. (1995) analyzed 14 families with the clinical designation of 'Turcot syndrome' identified in 2 registries, and the family originally described by Turcot et al. (1959). Studies on autopsy slides of the glioblastoma and rectal adenoma from 1 of the cases reported by Turcot et al. (1959) showed DNA replication errors characteristic of hereditary nonpolyposis colorectal cancer (HNPCC; see 120435). Tissue samples from patients with mismatch repair (MMR) mutations showed DNA replication errors. Ten of 12 families classified as having polyposis were found to have heterozygous mutations in the APC gene (611731), indicating that they had familial adenomatous polyposis (FAP; see 175100) with the extracolonic manifestation of a brain tumor, mainly medulloblastoma (in 79%).
Baas et al. (2013) reported 3 unrelated children with MMRCS and structural brain anomalies. Patient 2, with MMRCS1, was a boy, born of Polynesian parents, who first presented with a glioblastoma multiforme and later developed a T-cell lymphoblastic lymphoma. He died of sepsis at the end of treatment. Brain imaging showed near complete agenesis of the corpus callosum, interhemispheric and intracerebral cysts, and right subcortical and periventricular heterotopia. He was also noted to have multiple cafe-au-lait spots. Early developmental milestones were delayed. The maternal family history was positive for colorectal cancer. See MMRCS4 (619101) for discussion of the other 2 patients.
Bakry et al. (2014) established an international childhood constitutional mismatch repair deficiency (CMMRD) consortium and collected comprehensive clinical and genetic data from 14 families. Overall, 22 (96%) of 23 children with MMRCS developed 40 different tumors. Brain tumors were the most common cancers reported (48%), followed by gastrointestinal tumors (32%) and hematologic malignancies (15%). Among the CNS neoplasms, the most prevalent type was high grade gliomas (74%), followed by medulloblastoma/PNET (10%) and low grade gliomas (16%). All children with MMRCS had cafe-au-lait spots. Other cutaneous manifestations included hypopigmentation and axillary freckling.
Wimmer et al. (2014) presented a 3-point scoring system for the suspected diagnosis of MMRCS in a pediatric or young adult cancer patient based on the type of tumor and additional features, such as abnormal skin pigmentation, brain malformations, secondary childhood tumors, and family history.
Bakry et al. (2014) performed tumor immunohistochemistry (IHC) for the 4 mismatch repair proteins (MLH1, 120436; PMS2, 600259; MSH6, 600678; MSH2, 609309) on 26 available tumors and found loss of the corresponding MMR protein in all 17 tumors from germline MMRCS patients. Additionally, screening of intratumoral normal tissue by IHC stained negative, which correlated with genetic confirmation of MMRCS. Bakry et al. (2014) concluded that IHC was 100% sensitive and specific in diagnosing mismatch repair deficiency of the corresponding gene. In contrast, MSI on 28 tumors and paired normal tissues and was neither sensitive nor specific as a diagnostic tool compared to IHC (p less than 0.0001).
Bakry et al. (2014) suggested the following approach for the diagnosis of individuals and families with suspected MMRCS. In a child less than 18 years, with either (1) cafe-au-lait spots and a history of family consanguinity, or (2) cafe-au-lait spots and a family member with MMRCS related tumors, they recommended IHC staining of tumor or normal tissue for the 4 MMR proteins. Negative staining should prompt genetic testing to initiate surveillance protocol and provide counseling to family members.
MMRCS is transmitted in an autosomal recessive pattern of inheritance (summary by Wimmer et al., 2014).
In an international childhood MMRCS consortium study of 14 families, Bakry et al. (2014) found that the penetrance of cancers was exceptionally high. Upon referral to the consortium, 4 of 23 MMRCS patients were unaffected; however, during the study period, 3 of them were diagnosed with tumors. The family history of MMRCS children was not typical of Lynch syndrome (120435) as few cancers were reported in adult family members. Lynch-related tumors in adults were only observed in 2 of 14 families, whereas MMRCS-related tumors were seen in all families (p = 0.0007). Of the 28 parents in the study, only 1, a mother, had a history of cancer. The mother had died of an unspecified brain tumor at age 25 but based on the family history of multiple consanguineous generations, she likely had MMRCS as well.
In an childhood MMRCS consortium study, Bakry et al. (2014) used a surveillance protocol for MMCRS previously reported by Durno et al. (2012). The protocol includes a semiannual brain MRI, annual GI endoscopy, and blood work including complete blood count, ESR, and LDH every 4 months. In total, 39 asymptomatic lesions were detected including 2 malignant gliomas, 2 gastrointestinal carcinomas, and 6 cases of gastrointestinal polyposis. All tumors were amenable to complete resection. At a mean follow-up of 61 months, all patients enrolled in the surveillance protocol were alive.
Tops et al. (1992) presented evidence that the gene responsible for Turcot syndrome was not allelic to APC: a brother and sister with Turcot syndrome had completely different haplotypes for RFLPs from the 5q21-q22 region; furthermore, an unaffected sister had the same 5q haplotypes as an affected brother.
'Turcot syndrome' classically refers to the combination of colorectal polyposis and primary tumors of the central nervous system (Hamilton et al., 1995). Trimbath et al. (2001) and Ostergaard et al. (2005) noted that the original definition of Turcot syndrome may be too restrictive, and suggested that the full manifestation of biallelic mutations in MMR genes includes the additional findings of early-onset hematologic malignancies and cafe-au-lait spots suggestive of neurofibromatosis type I.
Several authors have observed 2 main groups of so-called 'Turcot syndrome.' Itoh and Ohsato (1985) noted that the colonic lesions seen in Turcot's original cases were characterized by autosomal recessive inheritance and multiple colonic polyps (up to 100), some of which exceeded 3 cm in diameter; the polyps frequently showed malignant transformation in the second and third decades of life. A distinct group of patients showed autosomal dominant inheritance of multiple small colonic polyps similar to classic familial adenomatous polyposis (FAP; see 175100); the CNS tumor in these patients appeared to be an additional chance occurrence. Due to the similar phenotypes, FAP patients with brain tumors have sometimes been referred to in the past as having 'Turcot syndrome' (see, e.g., Lewis et al., 1983 and Lasser et al., 1994).
Mastronardi et al. (1991) and Dupuis and Verellen-Dumoulin (1995) also identified 2 distinct syndromes comprising polyposis and CNS tumors. One shows autosomal recessive inheritance of polyps and gliomas, with CNS tumors as a primary feature; this group includes the original kindred of Turcot et al. (1959). The other group shows autosomal dominant FAP with CNS tumors, usually medulloblastomas, as an extracolonic manifestation. The colonic polyps in Turcot syndrome occur earlier, are less numerous and larger, and undergo malignant transformation earlier compared to those in FAP.
Paraf et al. (1997) also proposed that Turcot syndrome, which they referred to as the 'brain tumor-polyposis (BTP) syndrome,' could be classified into 2 distinct entities. Patients with BTP syndrome type 1 have early onset of malignant gliomas and colorectal adenomas without polyposis; these are non-FAP cases. Neoplasms from these patients show DNA replication errors consistent with mutations in DNA mismatch repair genes. In contrast, BTP syndrome type 2 includes patients in FAP kindreds who develop CNS tumors. These patients have germline APC mutations which predispose to brain tumors. Risk analysis showed an increased incidence of medulloblastoma in FAP patients. By contrast, APC mutations were not found in sporadic glioma or medulloblastoma.
Hamilton et al. (1995) studied 14 families with the clinical designation of 'Turcot syndrome' identified in 2 registries, and the family originally described by Turcot et al. (1959). Studies on autopsy slides of the glioblastoma and rectal adenoma from 1 of the cases reported by Turcot et al. (1959) showed DNA replication errors characteristic of HNPCC. DNA from Turcot's original subjects was unavailable and, since no affected family members were known to be living, mutation status could not be determined. In family 14, an individual with glioblastoma and colorectal cancer had a mutation in the MLH1 gene (120436.0003). Tissue samples from patients with MMR mutations showed DNA replication errors. Ten of 12 families classified as having polyposis were found to have heterozygous mutations in the APC gene, indicating that they had FAP with the extracolonic manifestation of a brain tumor, mainly medulloblastoma (in 79%).
Ricciardone et al. (1999) reported 3 Turkish sibs who developed hematologic malignancy at a very early age, 2 of whom displayed signs of NF1. All were homozygous for a mutation in the MLH1 gene (120436.0010). Hematologic malignancy was diagnosed in all 3 by the age of 3 years. Both parents had colon cancer at an early age. The phenotype in the offspring was consistent with the mismatch repair cancer syndrome.
Defects in the MMR genes are associated with microsatellite instability (MSI) in tumor DNA. One system classifies MSI into type A, defined by smaller allelic shifts, and type B, defined by comparatively larger allelic shifts. Using a 5-mononucleotide marker panel to analyze MSI, Giunti et al. (2009) found that only 2 of 34 pediatric glioma tumor samples had unstable markers consistent with MSI. Both of these tumors were glioblastoma multiforme, and both patients had a family history of the mismatch repair cancer syndrome. Genetic analysis identified compound heterozygous mutations in the PMS2 gene in 1 patient and a heterozygous mutation in the MLH1 gene in the other; a second MLH1 mutation was not identified in the second patient. Both tumors showed small size shifts in the alleles compared to the constitutional DNA, with differences in the range of 1 to 2 bp. A colorectal tumor from 1 patient's affected sister showed the larger type B MSI. Giunti et al. (2009) noted that colorectal cancers often have higher degrees of instability compared to gliomas, perhaps because of the higher cell turnover of intestinal cells compared to neurons. The findings suggested that the finding of type A MSI in pediatric gliomas may be an indicator of Turcot syndrome.
Poley et al. (2007) identified biallelic germline mismatch repair gene defects in 2 of 15 children with more than 1 cancer. In a 4-year-old boy with glioblastoma, nephroblastoma, and cafe-au-lait spots, they identified compound heterozygosity for 2 mutations in the MLH1 gene (120436.0027; 120436.0028). Both his parents, who were each heterozygous for a respective mutation, came from families with HNPCC2 (609310). Poley et al. (2007) also studied a patient in whom various cancer and normal tissues lacked staining for MSH6 (600678); see MMRCS3 (619097).
In a boy (patient 2) with MMRCS1, agenesis of the corpus callosum, and gray matter heterotopia, Baas et al. (2013) identified a homozygous missense mutation in the MLH1 gene in the patient (L73R; 120436.0034).
Modifier Genes
Kikuchi et al. (1993) found no constitutional abnormality of the conserved regions of the TP53 (191170) gene (exons 5-9) in 2 patients with the glioma-polyposis syndrome, but did find independent alterations in the TP53 gene in the tumors, suggesting that TP53 may play a role in progression but not in initiation of the disease.
Wang et al. (2003) demonstrated that somatic mutations of the NF1 gene occur more commonly in MMR-deficient cells. They observed NF1 alterations in 5 of 10 tumor cell lines with microsatellite instability compared to none of 5 MMR-proficient tumor cell lines. Somatic NF1 mutations were also detected in 2 primary tumors exhibiting microsatellite instability.
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