No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency

Abstract

Immunoglobulin class-switch recombination (CSR) and somatic hypermutations (SHMs) are prerequisites for antibody and immunoglobulin receptor maturation and adaptive immune diversity. The mismatch repair (MMR) machinery, consisting of homologs of MutSα, MutLα, and MutSβ (MSH2/MSH6, MLH1/PMS2, and MSH2/MSH3, respectively) and other proteins, is involved in CSR, primarily acting as a backup for nonhomologous end-joining repair of activation-induced cytidine deaminase-induced DNA mismatches and, furthermore, in addition to error-prone polymerases, in the repair of SHM-induced DNA breaks. A varying degree of antibody formation defect, from IgA or selective IgG subclass deficiency to common variable immunodeficiency and hyper-IgM syndrome, has been detected in a small number of patients with constitutional mismatch repair deficiency (CMMRD) due to biallelic loss-of-function mutations in one of the MMR genes (PMS2, MSH6, MLH1, or MSH2). To elucidate the clinical relevance of a presumed primary immunodeficiency (PID) in CMMRD, we systematically collected clinical history and laboratory data of a cohort of 15 consecutive, unrelated patients (10 not previously reported) with homozygous/compound heterozygous mutations in PMS2 (n = 8), MSH6 (n = 5), and MLH1 (n = 2), most of whom manifested with typical malignancies during childhood. Detailed descriptions of their genotypes, phenotypes, and family histories are provided. Importantly, none of the patients showed any clinical warning signs of PID (infections, immune dysregulation, inflammation, failure to thrive, etc.). Furthermore, we could not detect uniform or specific patterns of laboratory abnormalities. The concentration of IgM was increased in 3 out of 12, reduced in 3 out of 12, and normal in 6 out of 12 patients, while concentrations of IgG and IgG subclasses, except IgG4, and of IgA, and specific antibody formation were normal in most. Class-switched B memory cells were reduced in 5 out of 12 patients, and in 9 out of 12 also the CD38hiIgM− plasmablasts were reduced. Furthermore, results of next generation sequencing-based analyses of antigen-selected B-cell receptor rearrangements showed a significantly reduced frequency of SHM and an increased number of rearranged immunoglobulin heavy chain (IGH) transcripts that use IGHG3, IGHG1, and IGHA1 subclasses. T cell subsets and receptor repertoires were unaffected. Together, neither clinical nor routine immunological laboratory parameters were consistently suggestive of PID in these CMMRD patients, but previously shown abnormalities in SHM and rearranged heavy chain transcripts were confirmed.

Paediatric systemic lupus erythematosus as a manifestation of constitutional mismatch repair deficiency

“…The pathogenesis of pSLE in individuals with CMMRD is yet to be elucidated. Susceptibility to severe and persistent infections and autoimmunity have not been observed in the majority of patients with CMMRD 10. Although cancer remains a relatively rare outcome in pSLE, higher cancer risk has been documented in the past 17…”

“…The MMR system is involved in immunoglobulin class-switch recombination and in somatic hypermutation 9 10. However, increased susceptibility to severe and persistent infection, indicative of an immune defect, has not been observed.…”

“…In the literature, three female patients with CMMRD have been reported to have concomitant presentation of pSLE12–14 (table 1). Antinuclear antibodies (ANA) were reported in two other patients with CMMRD 10. However, data about features of pSLE in these patients were not provided.…”

Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy

“…As a recent study on a cohort of 15 consecutive, unrelated patients was unable to show uniform or specific patterns of laboratory immunological abnormalities,57 we did not include this rather unspecific feature in box 1.…”

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

“…An increasing number of CMMRD cases are being recorded. In 2014, the European Consortium of Care for CMMRD reported 147 patients with CMMRD described in the literature (4) and additional cases have been continued (5)(6)(7)(8). However, almost all cases were Caucasian, with only a few patients from Pakistani families (9).…”