Predictive Genetic Testing in Children: Constitutional Mismatch Repair Deficiency Cancer Predisposing Syndrome

Abstract

Biallelic germline mutations in mismatch repair genes predispose to constitutional mismatch repair deficiency syndrome (CMMR-D). The condition is characterized by a broad spectrum of early-onset tumors, including hematological, brain and bowel and is frequently associated with features of Neurofibromatosis type 1. Few definitive screening recommendations have been suggested and no published reports have described predictive testing. We report on the first case of predictive testing for CMMR-D following the identification of two non-consanguineous parents, with the same heterozygous mutation in MLH1: c.1528C > T. The genetic counseling offered to the family, for their two at-risk daughters, is discussed with a focus on the ethical considerations of testing children for known cancer-causing variants. The challenges that are encountered when reporting on heterozygosity in a child younger than 18 years (disclosure of carrier status and risk for Lynch syndrome), when discovered during testing for homozygosity, are addressed. In addition, the identification of CMMR-D in a three year old, and the recommended clinical surveillance that was proposed for this individual is discussed. Despite predictive testing and presymptomatic screening, the sudden death of the child with CMMR-D syndrome occurred 6 months after her last surveillance MRI. This report further highlights the difficulty of developing guidelines, as a result of the rarity of cases and diversity of presentation.

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

“…Thus, the lack of clinical consequences in children, combined with their right not-to-know, and potential harm due to anxiety and other issues (eg, potential difficulty in acquiring insurance) highlight that a diagnosis of Lynch syndrome is undesirable in a minor 49. Further considerations on this topic can be found in the study by Bruwer et al , who offered predictive CMMRD testing to children of parents both carrying familial MLH1 mutations 50. The situation is more complex for MSH6 and even more so for PMS2 .…”

The psychological impact of genetic information on children: a systematic review

“…11 In some cases, it might be appropriate to consider timing testing to avoid overlapping with the often difficult transition into adolescence. In fact, some of the developmental processes that occur during adolescence (for example, desire for independence and wanting to "fit in" with peers) may make genetic testing at this time particularly difficult.…”

“…10 Screening resources can be preserved and focused on those at highest risk for the disease, eliminating unnecessary surveillance in those who are mutation-negative. 11 Noted disadvantages of genetic testing include possible anxiety, worry, guilt, and depression (at least in the short term) following disclosure of a positive test result. 12,13 Patients may also receive an uncertain result, whereby the significance of the genetic alteration is unclear, which can adversely impact psychological functioning.…”

“…In familial adenomatous polyposis (FAP), for example, genetic testing enables clinicians to offer treatment and potentially life-saving interventions for children who test positive while sparing those identified as mutation-negative from unnecessary surveillance and anxiety. 11 The possibility of a medical benefit of genetic testing is one of the most important justifications for performing genetic testing in a minor. 18 Genetic testing in childhood may also allow the opportunity for early psychological adjustment and the ability to alert other family members (i.e., siblings, parents, cousins) to hereditary risk.…”

Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair‐deficiency and Lynch syndrome

“…Roughly 200 cases have been described worldwide, with an, however, increasing number of patients to be diagnosed due to intensified screening. Patients show characteristics of neurofibromatosis type 1, such as café‐au‐lait macules, skin hypo‐pigmentation, Lisch nodules, and neurofibromas along with a complex cancer phenotype of brain tumors, hematological malignancies, and gastrointestinal cancers with different molecular features . This wide tumor spectrum is a consequence of the loss of MMR function in all tissues already throughout embryogenesis and results in continuous accumulation of additional genetic defects throughout development .…”