FaCD Online Syndrome Fact Sheet

Last updated: 13 Jul 2012

Name: Constitutional Mismatch Repair Deficiency Syndrome

Synonym: CMMR-D, Mismatch Repair Cancer syndrome, MMRCS, Childhood Cancer Syndrome, CCS, Biallelic Mismatch Repair Gene Mutations Associated Early Onset Cancer, Lynch syndrome type III

Mode of Inheritance: AR

OMIM number: 276300  


MLH1, mapped to 3p21.3
MSH2, mapped to 2p21-p22
MSH6, mapped to 2p16
PMS2, mapped to 7p22

Tumor features

colorectal cancer
colorectal polyps
dudenal adenomas
endometrial cancer
glioblastoma (multiforme)
leukemia, acute
leukemia, acute lymphoblastic (ALL)
leukemia, acute myeloid (AML, incl. ANLL)
leukemia, chronic myeloid (CML)
neurofibroma, general
neurofibroma, plexiform
non-Hodgkin lymphoma
primitive neuroectodermal tumor (PNET)
small intestinal cancer

Tumor features (possible)

neuroblastoma, adrenal
ovarian sarcoma (incl. pPNET of ovary)
Wilms' tumor (nephroblastoma)

Non-tumor features

axillary freckling
café au lait spots
iris, Lisch nodules

Non-tumor features (possible)

corpus callosum agenesis
gray matter heterotopia of the brain


Multiple café-au-lait spots, axillary freckling, Lisch nodules of the iris and occasionally simple or plexiform neurofibromas and tibia dysplasia, all features also observed in NF1, and early-onset cancer are typical for this syndrome. Reported tumors include colorectal cancer, small intestinal cancer, oligopolyposis, leukemia (ALL, AML, AL not further specified, CML), non-Hodgkin lymphoma, brain tumors (glioblastoma, astrocytoma, oligodendroglioma medulloblastoma, supratentorial primitive neuroectodermal tumors (SPNET)), Wilms' tumor, ovarian neuroectodermal tumor, neuroblastoma, rhabdomyosarcoma and endometrial cancer. IgA-deficiency has been observed as well. In a few patients with CMMR-D, agenesis of the corpus callosum and gray matter heterotopia have been observed[16].
The syndrome is caused by biallelic mutations of the DNA Mismatch Repair (MMR) Genes MLH1, MSH2, MSH6 or PMS2.[1-12,17 reviewed in 13,14].

There is clinical overlap with Lynch syndrome, associated with single inherited MMR gene mutations. Lynch syndrome type III has therefore been coined as the name for the bi-allelic MMR gene mutation disorder[15]. Turcot syndrome features brain tumors & colorectal polyps; a subset of cases have in fact Constitutional Mismatch Repair Deficiency Syndrome.


[1] Ricciardone MD, Ozcelik T, Cevher B, Ozdag H, Tuncer M, Gurgey A, Uzunalimoglu O, Cetinkaya H, Tanyeli A, Erken E, Ozturk M. Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res 59[2], 290-293. 1999.
[2] Wang Q, Lasset C, Desseigne F, Frappaz D, Bergeron C, Navarro C, Ruano E, Puisieux A. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res 59[2], 294-297. 1999.
[3] De Rosa M, Fasano C, Panariello L, Scarano MI, 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 2000; 19(13):1719-1723.
[4] Whiteside D, McLeod R, Graham G, Steckley JL, Booth K, Somerville MJ, Andrew SE. A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res 2002; 62(2):359-362.
[5] Bougeard G, Charbonnier F, Moerman A, Martin C, Ruchoux MM, Drouot N, Frebourg T. Early onset brain tumor and lymphoma in MSH2-deficient children. Am J Hum Genet 2003; 72(1):213-216.
[6] Trimbath JD, Petersen GH, Erdman SH, Ferre M, Luce MC, Giardiello FM. Cafe-au-lait spots and early onset colorectal neoplasia. Familial Cancer 2001; 1(2):101-105.
[7] Menko FH, Kaspers GL, Meijer GA, Claes K, van Hagen JM, Gille JJ. A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancer. Familial cancer 2004; 3(2):123-7.
[8] Poley JW, Wagner A, Hoogmans MM, Menko FH, Tops C, Kros JM, Reddingius RE, Meijers-Heijboer H, Kuipers EJ, Dinjens WN, . Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies. Cancer 2007; 109(11):2349-56.
[9] Hegde MR, Chong B, Blazo ME, Chin LH, Ward PA, Chintagumpala MM, Kim JY, Plon SE, Richards CS. A homozygous mutation in MSH6 causes Turcot syndrome. Clinical cancer research : an official journal of the American Association for Cancer Research 2005; 11(13):4689-93.
[10] Plaschke J, Linnebacher M, Kloor M, Gebert J, Cremer FW, Tinschert S, Aust DE, von Knebel Doeberitz M, Schackert HK. Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor. European journal of human genetics : EJHG 2006; 14(5):561-6.
[11] Ostergaard JR, Sunde L, Okkels H. Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. American journal of medical genetics. Part A 2005; 139(2):96-105; discussion 96.
[12] Krüger S, Kinzel M, Walldorf C, Gottschling S, Bier A, Tinschert S, von Stackelberg A, Henn W, Görgens H, Boue S, Kölble K, Büttner R, Schackert HK. Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1. European journal of human genetics : EJHG 2008; 16(1):62-72.
[13] Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?. Human genetics 2008; 124(2):105-22.
[14] Herkert JC, Niessen RC, Olderode-Berends MJ, Veenstra-Knol HE, Vos YJ, van der Klift HM, Scheenstra R, Tops CM, Karrenbeld A, Peters FT, Hofstra RM, Kleibeuker JH, Sijmons RH. Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: Case series, review and follow-up guidelines. Eur J Cancer. 2011 May;47(7):965-82
[15] Felton KE, Gilchrist DM, Andrew SE. Constitutive deficiency in DNA mismatch repair: is it time for Lynch III? Clin Genet. 2007 Jun;71(6):499-500.
[16] Baas AF, Gabbett M, Rimac M, Kansikas M, Raphael M, Nievelstein RA, Nicholls W, Offerhaus J, Bodmer D, Wernstedt A, Krabichler B, Strasser U, Nyström M, Zschocke J, Robertson SP, van Haelst MM, Wimmer K. Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome.Eur J Hum Genet. 2012 Jun 13 [Epub ahead of print]
[17] Ilencikova D et al. High-grade brain tumors in siblings with biallelic MSH6 mutations. Pediatric blood & cancer 2011; 57:1067-70.