ORPHA: 252202;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p21-p16.3 | Mismatch repair cancer syndrome 2 | 619096 | Autosomal recessive | 3 | MSH2 | 609309 |
A number sign (#) is used with this entry because of evidence that mismatch repair cancer syndrome-2 (MMRCS2) is caused by homozygous or compound heterozygous mutation in the MSH2 gene (609309) on chromosome 2p21-p16.
Mismatch repair cancer syndrome-2 (MMRCS2) is an autosomal recessive childhood cancer predisposition syndrome characterized by hematologic malignancy, brain tumors, and gastrointestinal tumors. Multiple cafe-au-lait spots reminiscent of neurofibromatosis type I (NF1; 162200) may be present. Microsatellite instability may be detected in tumor samples (Muller et al., 2006).
For a discussion of genetic heterogeneity of mismatch repair cancer syndrome (MMRCS), see MMRCS1 (276300).
Whiteside et al. (2002) studied a 2-year-old boy who presented with failure to thrive and gastrointestinal infection, which led to the diagnosis of T-cell acute lymphoblastic leukemia (ALL). He had multiple cafe-au-lait spots, present from birth, of a size and number that fulfilled that criterion for a diagnosis of NF1. However, he had no neurofibromas, axillary or inguinal freckling, Lisch nodules, optic glioma, sphenoid wing dysplasia, pseudarthrosis, or previous history of malignancy. His parents were nonconsanguineous but were from the same ethnic, religious, and geographic background. There was no family history of either NF1 or cancers indicative of hereditary nonpolyposis colon cancer (HNPCC; see 120435). Whiteside et al. (2002) noted that the young age of the parents may explain the lack of observed cancer at that time.
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. 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.
Muller et al. (2006) studied 2 brothers, born of consanguineous Pakistani parents, with early-onset HNPCC. Both boys were found to have numerous gastrointestinal polyps and carcinomas at age 11 and 12 years, respectively, as well as multiple cafe-au-lait spots. Neither had additional hematologic malignancies or brain tumors. Muller et al. (2006) commented on the very early onset in these patients; patients with heterozygous mutations have disease onset at an average age of 45 years.
The transmission pattern of MMRCS2 in the family reported by Whiteside et al. (2002) was consistent with autosomal recessive inheritance.
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). Each parent was heterozygous for the mutation.
In a 4-year-old boy with MMRCS2 who had died from a temporal glioblastoma, Bougeard et al. (2003) detected compound heterozygosity for 2 mutations in the MSH2 gene (609309.0015, 609309.0016). Each parent carried one of the mutations in heterozygosity;
In 2 brothers with early-onset HNPCC born of consanguineous Pakistani parents, Muller et al. (2006) detected a homozygous splice site mutation in the MSH2 gene (609309.0020). Each unaffected parent was heterozygous for the mutation.
Bougeard, G., Charbonnier, F., Moerman, A., Martin, C., Ruchoux, M. M., Drouot, N., Frebourg, T. Early-onset brain tumor and lymphoma in MSH2-deficient children. (Letter) Am. J. Hum. Genet. 72: 213-216, 2003. [PubMed: 12549480] [Full Text: https://doi.org/10.1086/345297]
Muller, A., Schackert, H. K., Lange, B., Ruschoff, J., Fuzesi, L., Willert, J., Burfeind, P., Shah, P., Becker, H., Epplen, J. T., Stemmler, S. A novel MSH2 germline mutation in homozygous state in two brothers with colorectal cancers diagnosed at the age of 11 and 12 years. Am. J. Med. Genet. 140A: 195-199, 2006. [PubMed: 16372347] [Full Text: https://doi.org/10.1002/ajmg.a.31070]
Whiteside, D., McLeod, R., Graham, G., Steckley, J. L., Booth, K., Somerville, M. J., Andrew, S. E. A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res. 62: 359-362, 2002. [PubMed: 11809679]