Constitutional Mismatch Repair Deficiency Syndrom C18.-

Constitutional mismatch repair deficiency syndrome-4 (MMRCS4) is a very rare autosomal recessive childhood cancer predisposition syndrome characterized by early-onset leukemia/lymphoma, brain tumors, colorectal/gastrointestinal carcinomas, and other rare malignancies, including rhabdomyosarcomas. Cafe-au-lait spots are usually present (De Vos et al. 2006).

To date, approximately 200 affected individuals have been described in the literature, presenting with a total of over 320 different neoplasms, including hematologic neoplasms (24%), brain/CNS tumors (35%), and colorectal or other Lynch syndrome-associated tumors (38%).

CMMRDS is caused by biallelic inactivating variants in the mismatch repair genes (MMR genes) MLH1, MSH2, MSH6 or PMS2.

Heterozygous variants in the MMR genes are responsible for Lynch syndrome (LS, HNPCC), which can lead to the development of colorectal, endometrial, and other gastrointestinal and gynecologic tumors.

In CMMRDS, on the other hand, pathogenic variants in one of the MMR genes are homozygous or mixed heterozygous, resulting in complete loss of function of the corresponding gene product. CMMRDS is inherited in an autosomal recessive manner. In contrast to Lynch syndrome, in which the MLH1 or MSH2 genes are most frequently affected and the MSH6 and PMS2 genes are less frequently affected, 60% of cases in CMMRDS are due to biallelic variants in the PMS2 gene. The penetrance of Lynch syndrome-associated tumors in heterozygous PMS2 carriers is relatively low compared with MLH1/MSH2/MSH6 carriers, so family history may be unremarkable.

Lynch syndrome-associated tumors are usually observed in the 2nd or 3rd decade of life, whereas hematologic and CNS tumors are diagnosed during childhood.

Affected individuals develop numerous adenomatous polyps in the GI tract, so that the patient's appearance resembles (attenuated) familial adenomatous polyposis (FAP) or Turcot syndrome. In addition, non-neoplastic changes are also observed: café-au-lait spots, axillary freckling or even plexiform neurofibromas - as also seen in neurofibromatosis type 1 - have been diagnosed in some of the CMMRDS patients.

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