Constitutional Mismatch Repair Deficiency: Scoping Review of a Cancer-Predisposition Syndrome With Distinctive...

Area of Science:

• Genetics and Oncology
• Hereditary Cancer Syndromes

Background:

• Constitutional mismatch repair deficiency (CMMRD) is a rare, severe hereditary cancer predisposition syndrome.
• Caused by biallelic pathogenic variants in mismatch repair genes (MLH1, MSH2, MSH6, PMS2).
• Presents in childhood with hematological, brain, and GI cancers, plus neurofibromatosis type 1-like skin features.

Purpose of the Study:

• To explore the clinical characteristics of Constitutional mismatch repair deficiency (CMMRD).
• To provide a comprehensive overview of CMMRD manifestations and genetic associations.

Main Methods:

• Conducted a scoping review of medical literature.
• Performed a systematic search across medical databases.
• Included 127 relevant articles in the analysis.

Main Results:

• PMS2 is the most frequently affected gene, followed by MSH6, MLH1, and MSH2.
• Early childhood onset for blood and brain cancers across all variants; age of onset decreases with PMS2 to MSH2.
• Gastrointestinal tumors present in late adolescence for PMS2/MSH6 variants; rare in MLH1/MSH2.
• CMMRD patients exhibit larger, fewer café-au-lait macules than NF1 patients; PMS2/MSH6 variants show diverse skin findings (vascular tumors, nevi, pilomatricomas).

Conclusions:

• Advances in diagnostics, genetic testing, and surveillance improve survival and management for CMMRD.
• Understanding CMMRD's diverse clinical spectrum is crucial for early detection and effective patient care.