High yield of surveillance in patients diagnosed with constitutional mismatch repair deficiency

Abstract

BackgroundConstitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessively inherited syndrome that is caused by biallelic pathogenic variants of the mismatch repair genes. It is characterised by the development of multiple tumours in the first and second decade of life including brain, gastrointestinal and haematological tumours often resulting in early death. In order to improve the prognosis of these patients, the European collaborative group ‘care for CMMRD’ developed a surveillance programme in 2014 and established a registry of patients with CMMRD in Paris. The aim of the study was to evaluate the outcome of this programme.MethodsTwenty-two patients with a definitive diagnosis of CMMRD and with at least one follow-up study were selected from the registry. Medical data on the outcome of surveillance were collected from these patients.ResultsDuring a mean follow-up of 4 years, the programme detected eight malignant tumours including three brain tumours, three upper gastrointestinal cancers and two colorectal cancers. Most tumours could successfully be treated. In addition, many adenomas were detected in the duodenum, and colorectum and subsequently removed. Seven patients developed a symptomatic malignancy, including two brain tumours, one small bowel cancer and four haematological malignancies. At the end of the follow-up, 16 out of 22 patients (73%) who participated in the surveillance programme were still alive.ConclusionThe study suggests a beneficial effect of surveillance of the digestive tract and brains.

Genomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach

“…Biallelic variants in MLH1 or MSH2 variants resulted in an earlier onset of malignancy than PMS2 or MSH6 variants [100]. The main hallmark of CMMRD is multiple tumor development in brain, gastrointestinal, and hematological tumors, developing in the first and second decade of life [101] (Table 1). Familial neuroblastoma-Neuroblastoma (NB) is the most commonly occurring malignant extracranial solid childhood tumor and accounts for nearly 15% of all cancer-related pediatric cancer mortality between the ages of 1 and 5 years [102][103][104].…”

“…Biallelic variants in MLH1 or MSH2 variants resulted in an earlier onset of malignancy than PMS2 or MSH6 variants [ 100 ]. The main hallmark of CMMRD is multiple tumor development in brain, gastrointestinal, and hematological tumors, developing in the first and second decade of life [ 101 ] ( Table 1 ).…”

“…Genes involved in germline cancer predisposition syndromes of various cancer types (adapted from Pizzo and Poplack's Pediatric Oncology, 8th edition[77,100,101]). …”

Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants

“…Current guidelines for the management of CMMRD recommend intensive surveillance starting in early childhood [13][14][15] . These surveillance recommendations are highly effective for brain and intestinal tract tumours, whilst little benefit was seen for haematological malignancies 16,17 . However, applying these guidelines to late onset CMMRD patients, assuming they have a distinct phenotype caused by hypomorphic variants, would give relatively low yields, particularly for brain tumours, given their delayed disease onset and LS-like tumour spectrum, whilst exposing young patients to often invasive and stressful interventions.…”

“…LS carriers are recommended 1-5 yearly gastrointestinal and gynaecological surveillance from age 20 years or older, depending on which MMR gene is affected and the specific guidelines [8][9][10][11][12] . In contrast, individuals with CMMRD are recommended annual gastrointestinal surveillance from as early as 6 years, annual brain magnetic resonance imaging (MRI) from initial diagnosis or at latest aged 2 years, and annual clinical examination, among other interventions [13][14][15][16][17] . Genetic counselling and psychological impact will also be considerably different between CMMRD and LS.…”