Constitutional mismatch repair deficiency presenting with six primary malignancies over nearly 8 years: a case report

Abstract

Constitutional mismatch repair deficiency (CMMRD) is a rare cancer predisposition syndrome typically manifesting in early childhood. We report an atypical, adult-onset case of CMMRD in a 26-year-old female harboring a homozygous PMS2 germline nonsense mutation (NM_000535.7:c.1738A>T, p.Lys580Ter). Over a nearly 8-year clinical course, the patient developed six primary malignancies alongside multiple gastrointestinal adenomas, undergoing eight separate resections within a multimodal treatment strategy. Pathological evaluation demonstrated consistent PMS2 loss across all primary malignancies, with duodenal adenocarcinoma uniquely exhibiting an additional secondary loss of MSH6. This longitudinal case illustrates the potential role of a multimodal therapeutic strategy centered on proactive, repeated surgical and endoscopic resections in achieving long-term disease control and survival in adult-onset CMMRD. Crucially, the persistent recurrence of metachronous intestinal adenomas despite prior immune checkpoint inhibitor therapy underscores the possibility that systemic immunotherapy may not eliminate the risk of emerging premalignant lesions, highlighting the need for lifelong periodic surveillance and timely local intervention.