PMS2 – Constitutional Mismatch Repair Deficiency Syndrome

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare autosomal recessive childhood cancer predisposition disorder caused by biallelic germline mutations in DNA mismatch repair genes, most frequently PMS2. Affected individuals present with high-grade brain tumors, early-onset colorectal cancers, hematological malignancies, and café-au-lait macules, often mimicking neurofibromatosis type 1 (PMID:28381238).

Genetic evidence includes over 150 probands from more than 50 unrelated families harboring biallelic truncating and missense PMS2 variants, with consistent autosomal recessive segregation and absence of cancer in heterozygous carriers (PMID:28381238; PMID:15077197). One recurrent pathogenic allele is c.400C>T (p.Arg134Ter), which abolishes PMS2 protein function and leads to microsatellite instability in tumors.

Segregation analyses across multiple pedigrees demonstrate co-segregation of homozygous PMS2 mutations with early-onset cancers, including three confirmed homozygotes among six affected relatives in a five-generation consanguineous family (PMID:30478739).

Functional studies in PMS2-deficient mouse and human cells confirm a key role for PMS2 in mismatch repair and somatic hypermutation. PMS2-null models exhibit increased tandem base substitutions and defective endonuclease activity, while mutations in the conserved DQHA(X)2E(X)4E motif (e.g., p.Glu705Lys) impair repair and homeologous recombination (PMID:9618520; PMID:17567544).

No significant conflicting evidence has been reported to refute the PMS2–CMMRD association. Diagnostic criteria and surveillance guidelines emphasize early recognition of cutaneous features, tumor spectrum, and family history to prompt targeted PMS2 testing.

In summary, biallelic PMS2 loss-of-function variants produce a definitive autosomal recessive CMMRD syndrome underpinned by robust genetic segregation and mechanistic functional data. Early genetic diagnosis enables tailored surveillance and improved clinical management.

References

• Familial cancer • 2017 • Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD) PMID:28381238
• American journal of human genetics • 2004 • Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome PMID:15077197
• Familial cancer • 2019 • Hereditary brain tumor with a homozygous germline mutation in PMS2: pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome PMID:30478739
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2 PMID:9618520
• DNA repair • 2007 • Mutations affecting a putative MutLalpha endonuclease motif impact multiple mismatch repair functions PMID:17567544

Evidence Based Scoring (AI generated)