Germline mismatch repair gene mutations in children with tumors: a case series from two centers

Mismatch repair (MMR) deficiency can lead to constitutional mismatch repair deficiency (CMMRD) syndrome and Lynch syndrome (LS). These two genetic disorders are associated with a broad spectrum of tumor types, including a variety of brain tumors. Usually, tumors associated with LS are more common in adults and rarely occur in children. The characterizations of café-au-lait macules (CALMs) are relatively similar in CMMRD syndrome and neurofibromatosis type 1 (NF1), which often causes difficulties in the diagnosis of CMMRD syndrome.

We identified five patients with MMR gene germline mutations and tumors from the University of Hong Kong - Shenzhen Hospital (four cases) and Hong Kong Children's Hospital (one case) within a 2-year period (June 2021 to June 2023). The clinical features of these patients were reviewed and compared with those detailed in the literature. Of the four patients with CMMRD syndrome, two had medulloblastomas, one had low-grade glioma, and one had desmoid fibromatosis. The only LS patient was diagnosed with medulloblastoma at the age of 10. In terms of the gene mutations of the CMMRD syndrome patients, two had the MSH6 mutation (one of whom had the de novo mutation), one patient had the MLH1 mutation, and no known genetic mutation was detected in the other patient. The LS patient had the MSH2 mutation. Three of the four CMMRD syndrome (75%) patients and the one LS patient had a positive family history of malignancy. Currently, the origin and mechanism of de novo mutations in the MMR gene that cause CMMRD syndrome and LS remain elusive. In this study, all the four CMMRD syndrome patients had CALMs since birth, but no further follow up or clinical surveillance was performed until their tumors developed. We summarized several CALM-related genetic syndromes and highlighted their differences in terms of the clinical features. This could facilitate the differentiation of the different types of CALM-associated hereditary syndromes and help to reduce delays in diagnosis.

More than half of CMMRD syndrome and LS patients have no family history of cancer; thus, the absence of a positive family history does not rule out CMMRD syndrome and LS. A better diagnostic approach is to perform genetic testing to rule out the risk as early as possible when a newborn presents with cafe-au-lait spots, which are a typical feature of hereditary syndromes. Therefore, it is important to use germline genetic testing, combined with clinical phenotypic observation, to establish a diagnosis of a cancer susceptibility syndrome caused by an MMR gene mutation.