Diagnosis of a case of homozygous constitutional MMR‑deficiency by the use of a gene‑panel in a non-consanguineous family: A case report

Abstract

Constitutional MMR-deficiency syndrome (CMMRD) is a rare but severe hereditary syndrome of pediatric cancer caused by bi-allelic pathogenic variants in one of the mismatch DNA repair genes (MMR): MLH1, MSH2, MSH6, and PMS2. This syndrome occurs when patients inherit altered alleles from both of their heterozygote parents affected by Lynch syndrome. In total, ~150 patients have been identified at present, the majority of which were Caucasian. The present case report described the diagnosis of CMMRD in a Chinese boy with atypical clinical features caused by a homozygous pathogenic variant in MSH6 gene, identified by the use of a gene-panel. This is the first case diagnosed in a Chinese (Asian) population. These data indicated that CMMRD affects patients of any ethnic origin, implying a potentially high prevalence. Notably, the homozygous bi-allelic inactivation was caused by a random event in an apparently closed population, as opposed to a consanguineous marriage, additionally suggesting a high risk of CMMRD for individuals living in relatively closed populations.

Rare single‐nucleotide variants of MLH1 and MSH2 genes in patients with Lynch syndrome

“…As The occurrence of the homozygous variants does not necessarily follow a particular pattern, so almost any sequence of the MMR genes can be a probable region for their presence. [44][45][46] The 2) and classified as pathogenic based on ACMG guidelines (Table 4). In our study, this variant has been detected in a 52 years old man with tumor stage II, and positive family history.…”

“…This phenomenon was discovered in European and Asian populations and in recent years, there has been an increase in the number of studies and case reports on this occurrence. As The occurrence of the homozygous variants does not necessarily follow a particular pattern, so almost any sequence of the MMR genes can be a probable region for their presence 44–46 …”

Non-Hodgkin’s Lymphoma and Colorectal Carcinoma: Metachronous Occurrence in a Patient With Underlying DNA Mismatch Repair Syndrome

“…In contrast, patients with CMMRD develop cancers from infancy. So surveillance programs for such patients should be initiated early in life [1][2][3].…”

“…Constitutional mismatch repair deficiency (CMMRD) is a rare cancer predisposition syndrome that results from biallelic mutations in mismatch repair genes [ 1 - 2 ]. This disorder is similar to Lynch syndrome (LS) that manifests usually in young adults.…”

“…Awareness of CMMRD is needed especially in pediatric oncologists as well as general pediatricians because these children often present with clinical stigmata of neurofibromatosis 1 (NF 1) [ 1 - 2 ]. Patients with NF 1 are also at high risk of developing cancers but they do so usually in teenage or young adulthood.…”