Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6

Abstract

We report on a nonconsanguineous family in which two siblings with cutaneous manifestations leading to a diagnosis of neurofibromatosis type 1 (NF1) developed CNS tumors at an early age. In addition, one of them developed a T-cell lymphoma. Neither parent had NF1. The mother was known to be heterozygous for a MSH6 mutation, and the father was found to be heterozygous for a different MSH6 mutation. Screening of MSH2, MLH1, MSH6, PMS1, PMS2, and MLH3 in the affected children disclosed that they both were compound heterozygote for the MSH6 mutations of their parents. Most recently, about a dozen other cases of inherited bi-allelic deficiency of mismatch repair (MMR) genes associated with early onset CNS tumors, hematologic malignancy, gastrointestinal neoplasia, café-au-lait spots, and other NF1 features have been reported. In the present study, we summarize the clinical findings of 27 individuals homozygous or compound heterozygous for an MMR gene mutation reported in the medical literature. We suggest that biparentally inherited mutations of one of the MMR genes should be considered in children with multiple café-au-lait spots who have early-onset CNS tumors, hematologic malignancies, or early onset gastrointestinal neoplasia.

Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors

“…Because the MMR genes mlh1, msh2, and msh6 are known to play a role in class switch recombination (49)(50)(51)(52), it is tempting to speculate that their deficiency can directly lead to immune malignancies, without the need for creating a genomic instable situation that mutates other tumor suppressors. The fact that some patients with biallelic MMR inactivation were reported to be IgA-deficient supports this idea (11). Also, MMR-deficient mice show a reduction in isotype switching (49,50,52).…”

“…In the years following the discovery of HNPCC, continuous monitoring of HNPCC families has revealed several cases of humans with innate inactivating mutations in both alleles of a MMR gene, resulting from inbreeding or coincidence (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). These patients lack the MMR protein from the beginning and therefore develop cancer at extremely early ages, generally before the age of 10 years.…”

Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

“…[32][33][34] Children with CMMRD syndrome are known to manifest CALMs and axillary freckling. 35 Few cases have been reported in the literature and therefore the full phenotypic spectrum or the expressivity of CMMRD syndrome is not known.…”

Constitutional mismatch repair-deficiency syndrome

“…Péron et al 2 have shown in 3 CMMR-D patients that 15,19,20 . It remains to be seen whether defective IgA and IgG production is a common feature of CMMR-D. Fortunately, severe bacterial infections have not been reported to occur at high frequencies in persons with CMMR-D.…”