Constitutional mismatch repair deficiency (CMMRD; OMIM #276300) results from biallelic germline mutations of mismatch repair genes and is a rare, highly aggressive cancer predisposition syndrome that leads to malignant diseases already in childhood. It predisposes to leukemia or lymphomas, brain tumors, Lynch syndrome-associated tumors and other neoplasias. In addition, germ line deletions in the EPCAM gene (upstream of the MSH2 gene) can also lead to hypermethylation of the MSH2 promoter and consequently to the absence of MSH2 and thus trigger CMMRD.

Key Data

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Genes MSH2, MSH6, MLH1, PMS2 (mismatch repair genes, MMR genes),
Gene products MSH2, MSH6, MLH1, PMS2 (mismatch repair proteins),
Function Correction of incorrectly replicated base pairs and small insertions/deletions in DNA
Heredity Autosomal recessive
Prevalence Unknown, incidence increased in regions with high consanguinity rate
Genotype-phenotype correlation Not yet fully clarified. Biallelic germ strand mutations of the MMR genes often show the phenotypic picture of neurofibromatosis type 1, associated with various cancers already occurring in childhood.
Mutations in MSH6 and PMS2 are significantly more frequent and lead to a different clinical picture than mutations in MLH1 and MSH2. The latter lead more frequently to haematological cancers and the average age at first cancer diagnosis is lower than in carriers of biallelic mutations in MSH6 or PMS2. Patients with mutations in MSH6 or PMS2 are particularly prone to Lynch syndrome (LS)-associated cancers and brain tumors and usually develop another after surviving first cancer.
Due to the low monoallelic penetrance of PMS2 and MSH6, sick children often have unimpaired parents, even though they are carriers of the defective gene.
Penetrance Extremely high; most children do not reach adulthood.
For more precise information, long-term observations with significantly more patients are required.
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Diagnosis of CMMRD should be considered in cancer patients with one or more of the following characteristics simultaneously:

  • Café-au-lait spots and/or other NF1-typical skin changes and/or hypopigmented skin lesions

  • Consanguineous parents

  • Positive family history regarding LS-associated tumors

  • Second cancer disease

  • Sibling with cancer in childhood

”Care for CMMRD (C4CMMRD)” Diagnostic Protocol

The European consortium “Care for CMMRD (C4CMMRD)” also developed a diagnostic protocol according to which the presence of CMMRD is suspected at 3 or more points. If more than one of the following diseases or characteristics is present, appropriate points must be added.

Cancers/previous cancers: one is mandatory

LS-associated tumors at age <25 years 3 pts
Multiple adenomas of the bowel at age <25 years without APC/MUTYH mutation(s)
or single adenoma with high-grade dysplasia at age <25 years
3 pts
Glioma WHO grade III or IV at age <25 years 2 pts
NHL of the T-line or sPNET 2 pts
Any cancer disease at age <18 years 1 pt

Abbreviations in the table: LS, Lynch syndrome; NHL, non-Hodgkin lymphoma; sPNET, supratentorial primitive neuroectodermal tumor; NF1, neurofibromatosis type 1

Additional features: optional

Clinical signs of NF1 and/or ≥2 hyperpigmented and/or hypopigmented skin lesions Ø >1cm in the patient 2 pts
Presence of an LS in a first- or second-degree relative 2 pts
Cancer from the LS spectrum* at age <60 years in a first-, second- or third-degree relative 1 pt
Sibling with cancer from the LS spectrum*, high-grade glioma, sPNET or NHL 2 pts
Sibling with any kind of cancer in childhood 1 pt
Multiple pilomatrixomas on the patient 2 pts
A pilomatrixoma on the patient 1 pt
Corpus callosum agenesis or non-therapy-induced cavernoma in the patient 1 pt
Consanguineous parents of the patient 1 pt
Absence/reduced levels of Ig2/4 and/or IgA 1 pt

*colorectal carcinoma, endometrium, small intestine, ureter, renal pelvis, bile duct, gastric, bladder carcinomaAbbreviations in the table: LS, Lynch syndrome; NHL, non-Hodgkin’s lymphoma; sPNET, supratentorial primitive neuroectodermal tumor; NF1, Neurofibromatosis Type 1

Genetic Diagnostics

Immunohistochemistry of mismatch repair proteins in tumor material or in hematological cancers or healthy individuals suspected of CMMRD from a skin biopsy. The protein that is difficult to stain is the protein that may carry a mutation.

A screening method in peripheral blood is the gMSI test. This test is offered in special laboratories (e.g. Prof. Wimmer in Innsbruck) and is suitable as fast screening for defects in MSH2, MLH1 and PMS2. MSH6 defects escape this method, but screening methods are also being developed here.

The diagnosis should be verified by mutation analysis of the four MMR genes. Thus both homozygous and heterozygous carriers of the mutation can be identified.

Differential Diagnoses

  • Lynch syndrome

  • Neurofibromatosis Type 1

Clinical Presentation

CMMRD is characterised by the early onset of cancer in children or young adults, with an average age of 7.5 years for the first cancer. The mean survival after diagnosis of the first cancer is 30 months.

Hematological Cancers (average age at first diagnosis 6.6 years)

  • NHL, especially T-lymphoblastic NHL, and other lymphomas

  • Acute lymphoblastic leukemia (ALL), especially T-cell ALL

  • Acute myeloid leukemia (AML)

  • Atypical chronic myeloid leukemia

Brain Tumors (average age at first diagnosis 10.3 years)

  • Glioblastoma and other astrocytic tumors

  • Supratentorial primitive neuroectodermal tumor

  • Medulloblastoma

Lynch Syndrome-Associated Cancers

  • Colorectal cancer

  • Small intestine cancers

  • Endometrial/ovarian cancer

  • Ureteral/kidney pelvic cancer


  • Sarcomas (osteosarcoma, rhabdomyosarcoma)

  • Neuroblastoma

  • Wilms’ tumor

  • Infantile myofibromatosis

  • Breast cancer

  • Primitive neuroectodermal tumor of the ovary

Therapeutic Considerations

There is no standardised procedure for the treatment of CMMRD patients. Unlike other syndromes with defective DNA repair, no increased cytotoxicity has been observed in CMMRD as a result of radio- or chemotherapy. On the other hand, it should be noted that cytostatic drugs such as mercaptopurine and temozolomide, which use an adequate mismatch repair system to exert their effect, are resistant to therapy. Alkylating substances or anthracyclines, on the other hand, have no limited efficacy and may be considered for the treatment of patients with CMMRD.

Furthermore, in individual cases significant effects could be achieved in the therapy of recurrent glioblastomas using immune checkpoint inhibitors.


Parents of affected children should be offered genetic counselling for a 25% risk of recurrence if both parents are tested heterozygous. In addition, genetic testing and the associated genetic counselling of all family members should be reconsidered.

Surveillance Recommendations

Surveillance Recommendations

The aim in the care of patients with CMMRD is to detect cancers or their precursors as early as possible so that early therapeutic intervention can take place. The clinical examination as well as various instrument and laboratory chemical examinations play an important role.

The European Consortium “Care for CMMRD (C4CMMRD)” and the International Biallelic Mismatch Repair Deficiency Consortium (BMMRD) have developed a protocol for the early detection of CMMRD patients based on currently available data on CMMRD cancers and their onset.

Children and Adolescents

Brain tumors

  • Cranial MRI from diagnosis CMMRD every 6 months (not to be replaced by whole-body MRI) and in case of clinical suspicion

  • Sonography through the open fontanel is not an adequate substitute for MRI

Various tumors

  • Whole-body MRI from 6 years of age (or as soon as possible without anesthesia) once a year (cannot replace cranial MRI)


  • Complete blood count from 1 year every 6 months


  • Abdominal ultrasound from 1 year on every 6 months (can be performed alternately with whole-body MRI)

Gastrointestinal tumors

  • Colonoscopy once a year from the age of 6; every 6 months from the appearance of polyps

  • Esophagogastroduodenoscopy and capsule endoscopy from 8 years of age once a year

  • Preventive colectomy depending on the number of polyps and their degree of dysplasia


Tumors of the genital tract and urinary tract

  • Gynecological examination, transvaginal sonography, endometrial biopsy (pipeline method), urine cytology, urine stix from 20 years once a year (see LS guidelines)

Additional Information

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