ORPHA: 252202;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p22.1 | Mismatch repair cancer syndrome 4 | 619101 | Autosomal recessive | 3 | PMS2 | 600259 |
A number sign (#) is used with this entry because of evidence that mismatch repair cancer syndrome-4 (MMRCS4) is caused by homozygous or compound heterozygous mutation in the PMS2 gene (600259) on chromosome 7p22.
Mismatch repair cancer syndrome-4 (MMRCS4) is an autosomal recessive childhood cancer predisposition syndrome characterized by early-onset leukemia/lymphoma, brain tumors, colorectal/gastrointestinal cancers, and other rare malignancies, including rhabdomyosarcoma (summary by Li et al., 2015). Cafe-au-lait spots are usually present (De Vos et al., 2006).
For a discussion of genetic heterogeneity of mismatch repair cancer syndrome, see MMRCS1 (276300).
Hamilton et al. (1995) studied a family (family 12) with colonic adenomas in which 2 sibs had glioblastoma and cafe-au-lait spots, respectively. The 18-year-old male patient had had 2 colonic adenomas and 1 hyperplastic polyp by the time of total abdominal colectomy at age 13 years. He had non-Hodgkin lymphoma of the rectum at age 17 years. His sister had rectal carcinoma at age 11 years with only 3 adenomas of the sigmoid colon and rectum. Phenotypic adenomatous polyposis developed at age 14 years, for which she underwent total colectomy. In all, Hamilton et al. (1995) analyzed 14 families with the clinical designation of 'Turcot syndrome' identified in 2 registries. Tissue samples from patients with mismatch repair (MMR) mutations showed DNA replication errors.
De Rosa et al. (2000) reported 2 sisters with MMRCS4 and early-onset brain tumors. The proband presented with oligodendroglioma which was removed at age 14 years and recurred 3 years later. At age 18 years she was found to have developed colon carcinoma and died a few months after hemicolectomy. Her sister had a neuroblastoma at age 13 years and died at the age of 14 years.
Trimbath et al. (2001) described a 16-year-old Guyanese girl who presented with colorectal adenocarcinoma. She had 6 cafe-au-lait spots but no Lisch nodules or other signs of neurofibromatosis. At age 21 she developed a left ovarian neuroectodermal tumor and at age 23 she had endometrial carcinoma of the uterus and ovary. At age 24 she had a brain tumor. Her half sister developed anaplastic astrocytoma at age 7 years and 3 adenomatous polyps by the age of 20 years. The patient's half brother died of acute lymphoblastic leukemia at age 4 years. Both of these half sibs had multiple cafe-au-lait spots. The patient's paternal grandmother died of colorectal adenocarcinoma at age 53.
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.
De Vos et al. (2006) studied 13 patients with MMRCS4 from 6 consanguineous families of Pakistani origin. Ten of the 13 had cafe-au-lait spots; no information was available for the remaining 3 patients. De Vos et al. (2006) noted that the cafe-au-lait spots or patches had a ragged-edged, slightly diffuse appearance that was not typical of the more sharply delineated cafe-au-lait spots typical of neurofibromatosis type I (NF1; 162200).
Auclair et al. (2007) reported a family (C01204) 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.
Kratz et al. (2008) reported a Turkish girl with MMRCS4 who had been successfully treated for non-Hodgkin lymphoma at age 6 years and who presented at age 16 years with colorectal carcinomas. The patient's sister had cafe-au-lait spots and died from a supratentorial primitive neuroectodermal tumor at age 9 years. The parents and 4 sibs were healthy and without cancer history at time of report, although 1 sib also had cafe-au-lait spots.
Peron et al. (2008) reported a 12-year-old Turkish girl with MMRCS4 who exhibited Ig class switch recombination (CSR) deficiency. She presented with multiple cafe-au-lait spots and suffered from recurrent infections from the age of 1 year, leading to an immunodeficiency diagnosis at 9 years of age. A year later, she developed a colorectal adenocarcinoma. In vitro analysis showed that the CSR defect was characterized by the occurrence of double-strand DNA breaks in switch regions and abnormal formation of switch junctions.
Giunti et al. (2009) studied a family in which a male patient (patient 121), the second born of 3 sibs, was diagnosed with high-grade glioma at age 10 years 3 months. The presence of multiple cafe-au-lait spots raised the suspicion of NF1. His younger sister died at the age of 4 years due to a brainstem malignancy of undetermined type. His elder sister (121S) was diagnosed with mucinous carcinoma of the ascending colon at the age of 21 years. Parents were healthy and unrelated, and family history was otherwise unremarkable, except for a maternal second cousin, who had died of leukemia at the age of 11 years, and his mother, who had a diagnosis of colorectal cancer at 28 years.
Kratz et al. (2009) reported a boy (family 1), born of consanguineous parents, who developed a rhabdomyosarcoma at age 3 years and a colonic adenocarcinoma at age 8. Two sibs in a second unrelated consanguineous family (family 2) 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 2 unrelated children with MMRCS4 and structural brain anomalies. A boy (patient 1), 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. Another patient (patient 3) 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. Both of these patients had normal psychomotor development. Baas et al. (2013) also described a third patient with MMRCS1 (276300) and structural brain anomalies whose psychomotor development 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.
The transmission pattern of MMRCS4 in the family studied by Trimbath et al. (2001) was consistent with autosomal recessive inheritance.
In a family (family 12) with colonic adenomas, including 2 sibs with glioblastoma and cafe-au-lait spots, respectively, Hamilton et al. (1995) identified 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 a girl who developed oligodendroglioma at age 14 years and colon carcinoma at age 18 years, De Rosa et al. (2000) identified compound heterozygosity for mutations in the PMS2 gene (600259.0002, 600259.0003). The girl's sister had died at age 14 of neuroblastoma.
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 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 nonsense mutation in the PMS2 gene (R802X; 600259.0004). In affected members of 5 of 6 consanguineous Pakistani families with MMRCS4, De Vos et al. (2006) identified homozygosity for the R802X mutation. There was evidence of a founder effect. Affected members of the remaining family studied by De Vos et al. (2006) carried a homozygous tyr181-to-ter mutation (Y181X) resulting from a 1-bp deletion.
In 2 sibs from a family (C01204) with MMRCS4, Auclair et al. (2007) identified compound heterozygosity for 2 mutations in the PMS2 gene (600259.0011, 600259.0012).
In a 12-year-old Turkish girl with colorectal adenocarcinoma and Ig class switch recombination (CSR) deficiency, Peron et al. (2008) identified homozygosity for a 4-exon deletion/18-bp insertion in the PMS2 gene (600259.0018).
In a boy (family 1) with MMRCS4, Kratz et al. (2009) identified a homozygous mutation in the PMS2 gene (C73X; 600259.0016).
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 (121S) 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.
In 13 patients from 7 unrelated Inuit families with an attenuated form of MMRCS, Li et al. (2015) identified a homozygous c.2002A-G transition in the PMS2 gene (600259.0019). Analysis of patient cells showed that the mutation resulted in a splicing defect and nonsense-mediated mRNA decay, although there were minor amounts of full-length transcripts and some residual normal full-length functional protein. Haplotype analysis indicated a founder effect estimated to have appeared late in the 11th century. The authors estimated an allele frequency of 1 in 16 individuals in the Inuit population of Nunavik in northern Quebec. The age at cancer onset in individuals homozygous for the c.2002A-G mutation was significantly later (median age 22 years) compared to individuals homozygous for truncating PMS2 mutations (8 years). There was also a difference in the tumor spectrum, with brain tumors being significantly less prevalent in c.2002A-G homozygotes (15%) compared to truncating homozygotes (67%). However, 1 patient homozygous for the c.2002A-G mutation developed a primitive neuroectodermal tumor at age 3 years. Li et al. (2015) concluded that even a low level of PMS2 expression likely delays cancer onset.
Auclair, J., Leroux, D., Desseigne, F., Lasset, C., Saurin, J. C., Joly, M. O., Pinson, S., Xu, X. L., Montmain, G., Ruano, E., Navarro, C., Puisieux, A., Wang, Q. Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum. Mutat. 28: 1084-1090, 2007. [PubMed: 17557300] [Full Text: https://doi.org/10.1002/humu.20569]
Baas, A. F., Gabbett, M., Rimac, M., Kansikas, M., Raphael, M., Nievelstein, R. A. J., Nicholls, W., Offerhaus, J., Bodmer, D., Wernstedt, A., Krabichler, B., Strasser, U., Nystrom, M., Zschocke, J., Robertson, S. P., van Haelst, M. M., Wimmer, K. Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome. Europ. J. Hum. Genet. 21: 55-61, 2013. [PubMed: 22692065] [Full Text: https://doi.org/10.1038/ejhg.2012.117]
De Rosa, M., Fasano, C., Panariello, L., Scarano, M. I., Belli, G., Iannelli, A., Ciciliano, F., Izzo, P. Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene. Oncogene 19: 1719-1723, 2000. [PubMed: 10763829] [Full Text: https://doi.org/10.1038/sj.onc.1203447]
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Giunti, L., Cetica, V., Ricci, U., Giglio, S., Sardi, I., Paglierani, M., Andreucci, E., Sanzo, M., Forni, M., Buccoliero, A. M., Genitori, L., Genuardi, M. Type A microsatellite instability in pediatric gliomas as an indicator of Turcot syndrome. Europ. J. Hum. Genet. 17: 919-927, 2009. [PubMed: 19156169] [Full Text: https://doi.org/10.1038/ejhg.2008.271]
Gururangan, S., Frankel, W., Broaddus, R., Clendenning, M., Senter, L., McDonald, M., Eastwood, J., Reardon, D., Vredenburgh, J., Quinn, J., Friedman, H. S. Multifocal anaplastic astrocytoma in a patient with hereditary colorectal cancer, transcobalamin II deficiency, agenesis of the corpus callosum, mental retardation, and inherited PMS2 mutation. Neuro Oncol. 10: 93-97, 2008. [PubMed: 17993636] [Full Text: https://doi.org/10.1215/15228517-2007-037]
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Kratz, C. P., Holter, S., Etzler, J., Lauten, M., Pollett, A., Niemeyer, C. M., Gallinger, S., Wimmer, K. Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome. J. Med. Genet. 46: 418-420, 2009. [PubMed: 19293170] [Full Text: https://doi.org/10.1136/jmg.2008.064212]
Kratz, C. P., Niemeyer, C. M., Juttner, E., Kartal, M., Weninger, A., Schmitt-Graeff, A., Kontny, U., Lauten, M., Utzolino, S., Radecke, J., Fonatsch, C., Wimmer, K. Childhood T-cell non-Hodgkin's lymphoma, colorectal carcinoma and brain tumor in association with cafe-au-lait spots caused by a novel homozygous PMS2 mutation. (Letter) Leukemia 22: 1078-1080, 2008. [PubMed: 18007577] [Full Text: https://doi.org/10.1038/sj.leu.2405008]
Li, L., Hamel, N., Baker, K., McGuffin, M. J., Couillard, M., Gologan, A., Marcus, V. A., Chodirker, B., Chudley, A., Stefanovici, C., Durandy, A., Hegele, R. A., and 10 others. A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype. J. Med. Genet. 52: 348-352, 2015. [PubMed: 25691505] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102934]
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