Constitutional mismatch repair deficiency is a rare childhood cancer 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 ... Constitutional mismatch repair deficiency is a rare childhood cancer 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 1 (NF1; 162200), particularly multiple cafe-au-lait macules (summary by Baas et al., 2013). '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 1 (NF1; 162200). 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 FAP; 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. Wimmer and Etzler (2008) provided a review of the mismatch cancer repair syndrome and suggested that the prevalence may be underestimated.
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 ... 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, 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. Trimbath et al. (2001) reported a Guyanese girl with early-onset colorectal adenocarcinomas, ovarian neuroectodermal tumor, endometrial adenocarcinoma of the ovaries and uterus, and a brain tumor. She was from a highly consanguineous family. A half-brother died of acute lymphoblastic leukemia at age 4 years, and a half-sister had anaplastic astrocytoma and adenomatous polyps. She also had multiple cafe-au-lait spots. De Vos et al. (2004) reported a consanguineous family in which 3 sibs had early onset of brain tumors, 1 with a high-grade non-Hodgkin lymphoma and 2 with supratentorial primitive neuroectodermal tumors (SPNET), an aggressive embryonal tumor most likely derived from primitive neuroepithelial cells. All children also had cafe-au-lait spots, but no other features of NF1. No other family members had cancer, and examination of 2 of the children at young ages showed no bowel lesions. Menko et al. (2004) reported a boy, born of consanguineous parents, who developed a malignant oligodendroglioma at age 10 years and a colonic adenocarcinoma at age 12 years. Physical examination showed multiple cafe-au-lait spots without other features of NF1. Hegde et al. (2005) reported a family with 2 affected sibs. A son developed lymphoblastic lymphoma at age 5 years and invasive colonic adenocarcinoma at age 8. His sister developed glioblastoma multiforme at age 8 years. Both children had cafe-au-lait spots and mild axillary freckling. The children died at ages 9 and 10 years, respectively. The unaffected parents were of Pakistani origin and denied consanguinity. Auclair et al. (2007) reported a family in which 2 sisters had features suggestive of NF1, including cafe-au-lait spots and Lisch nodules, associated with fatal glioblastoma and adenomatous colonic polyps, respectively. There was no family history of NF1 and no mutations were identified in the NF1 gene. Family history revealed a maternal grand-aunt with endometrial cancer at age 59 and several paternal relatives with possible colon polyps. Neoplastic colonic tissue from the surviving sister with polyps showed absence of the MSH6 protein and microsatellite instability. Genetic analysis of the proband identified compound heterozygous mutations in the MSH6 gene (600678.0016; 600678.0017). Auclair et al. (2007) reported a second family in which a girl developed oligodendroglioma at age 19 years and colonic adenocarcinoma at age 24 years. She died 1 year later from rapid malignant evolution. A sister developed colon cancer at age 20 years and endometrial cancer at age 24; she had isolated cafe-au-lait spots. The parents were unaffected, but there was a remote family history of colorectal cancer. Genetic analysis identified 2 mutations in the PMS2 gene (600259.0011; 600259.0012). 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). A second patient was a boy of Moroccan descent with non-Hodgkin lymphoma, oligodendroglioma, and cafe-au-lait spots. The lymphoma and oligodendroglioma both showed low microsatellite instability and absence of staining for the MSH6 protein. Normal tissue was also MSH6-negative. Further genetic analysis could not be performed. A brother with cafe-au-lait spots had died of medulloblastoma at age 8 years. Kratz et al. (2009) reported a boy, born of consanguineous parents, who developed a rhabdomyosarcoma at age 3 years and a colonic adenocarcinoma at age 8. Genetic analysis identified a homozygous mutation in the PMS2 gene (C73X; 600259.0016). Two sibs in a second unrelated consanguineous family developed multiple colonic adenocarcinomas, and an anaplastic astrocytoma and an undifferentiated sarcoma, respectively, associated with lack of PMS2 protein expression. The findings were consistent with biallelic germline PMS2 mutations, although genetic testing was not possible. Family history in both patients revealed multiple cases of cancer. The findings expanded the types of tumors associated with the mismatch repair cancer syndrome. Baas et al. (2013) reported 3 unrelated children with MMRCS and structural brain anomalies. A boy, born of consanguineous parents, developed a B-cell non-Hodgkin lymphoma (NHL) at age 9 years. At age 11, he developed a mucoepidermoid carcinoma of the parotid gland, and 6 months later, he was diagnosed with a T-cell NHL. Brain MRI showed agenesis of the corpus callosum, an interhemispheric cyst, and several periventricular gray matter heterotopias. He also had multiple cafe-au-lait spots. Genetic analysis identified a homozygous truncating mutation in the PMS2 gene. A second boy, born of Polynesian parents, 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. The maternal family history was positive for colorectal cancer. Genetic analysis identified a homozygous missense mutation in the MLH1 gene in the patient (L73R; 120436.0034). The third patient was a boy who was noted to have dilation of the lateral ventricles on prenatal ultrasound and agenesis of the corpus callosum after birth. He developed an anaplastic astrocytoma of the spinal cord at age 2 years, 10 months. At age 5 years, he developed a T-lymphoblastic lymphoma, and died of sepsis during treatment 9 months later. Genetic analysis identified compound heterozygosity for 2 truncating mutations in the PMS2 gene. Two of the patients had normal psychomotor development, whereas the third was mildly delayed. Baas et al. (2013) identified 1 other published report of a patient with MMRCS and agenesis of the corpus callosum (Gururangan et al., 2008), and concluded that the prevalence of cerebral malformations associated with this syndrome may be as high as 6.6%, which is above the population birth prevalence of these malformations.
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 ... 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. In another family with colonic adenomas, 2 sibs with glioblastoma and cafe-au-lait spots, respectively, had a truncating mutation in the PMS2 gene (600259.0001); a second PMS2 mutation (600249.0005) was later identified in this family by De Vos et al. (2004), indicating autosomal recessive inheritance. In another family, 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. In affected members of a consanguineous Guyanese family with variable expression of colorectal adenocarcinoma, acute leukemia, brain tumors, and cafe-au-lait spots, Trimbath et al. (2001) identified a homozygous mutation in the PMS2 gene (600259.0013). In a 2-year-old infant with mismatch repair cancer syndrome manifest as T-cell acute lymphoblastic leukemia and multiple cafe-au-lait spots, Whiteside et al. (2002) identified a homozygous mutation in the MSH2 gene (609309.0014). Bougeard et al. (2003) described 2 sibs, a female who died of mediastinal T-cell lymphoma at the age of 15 months and her brother who died at age 4 years from a temporal glioblastoma. The phenotype was consistent with mismatch repair cancer syndrome. Study of glioblastoma DNA from the boy indicated compound heterozygosity for the 2 mutations in the MSH2 gene (609309.0015; 609309.0016). In this family, endometrial carcinoma was the cause of death at age 43 years in an aunt of the mother and at age 59 years in the grandmother of the father. Furthermore, an uncle of the father had died of astrocytoma at age 27 years. In affected members of a consanguineous family in which 3 sibs had early onset of brain tumors, but no colonic lesions, De Vos et al. (2004) identified a homozygous mutation in the PMS2 gene (600259.0004). In a boy with childhood onset of malignant oligodendroglioma, colonic adenocarcinoma, and cafe-au-lait spots, Menko et al. (2004) identified a homozygous mutation in the MSH6 gene (600678.0014). No germline mutations were identified in the NF1 gene. In a Pakistani girl with glioblastoma multiforme and early death, Hegde et al. (2005) identified a homozygous mutation in the MSH6 gene (600678.0015). Her brother had colonic adenocarcinoma and lymphoma, but DNA was not available for testing. In 2 sibs with brain tumor-polyposis syndrome, Ostergaard et al. (2005) identified compound heterozygosity for 2 mutations in the MSH6 gene (600678.0012; 600678.0013). A boy developed an anaplastic astrocytoma at age 9.4 years and later developed a T-cell lymphoma. His sister had a glioblastoma of the spinal cord at age 2 years. Both children had multiple cafe-au-lait spots without other features of NF1. Three additional heterozygous family members had colon and/or endometrial cancer. Ostergaard et al. (2005) concluded that the phenotype of cafe-au-lait spots, hematologic malignancies, and glioma results from a lack of activity of the MMR complex. The NF1-like features likely result from somatic mutations in the NF1 gene secondary to MMR deficiency. 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. - 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.