Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD)

Abstract

BackgroundConstitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family.Case presentationThe proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband’s family pedigree displays multiple relatives with cancers including a likely case of ‘true’ Turcot syndrome.ConclusionsConstitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.

An Update on Inherited Colon Cancer and Gastrointestinal Polyposis

“…Nádorové spektrum závisí na tom, který gen je mutován. Pacienti s mutací genu MSH2 nebo PMS2 obvykle onemocní nádorem mozku ve věku do 10 let a více než 40 % pacientů homozygotních pro mutaci v genu PMS2 onemocní druhou primární malignitou [33]. Naopak pacienti homozygotní pro mutace v genech MLH1 a MSH2 mají menší pravděpodobnost rozvoje druhé primární malignity (22 %).…”

Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies

“…Of note, the individuals displayed clinical features reminiscent of neurofibromatosis type 1 (NF1) (tumor formation on nerve tissues), now commonly associated with CMMRD [ 28 ]. Since those studies, close to 200 paediatric and young adult CMMRD cancer cases have been reported in at least one of the MMR genes involved in LS [ 10 , 29 ]. Contrary to traditional LS, CMMRD patients lack expression of the MMR protein(s) in both cancer and normal tissue (27).…”

“…The most frequent CMMRD cancers are brain gliomas (diagnosed at an average age of 9.5 years), non-Hodgkin’s lymphomas (diagnosed at 5 years) and colorectal cancers (CRCs) (diagnosed at 16 years) [ 10 ]. The cancer spectrum is related to the nature of the MMR gene mutated; patients with MSH6 and/or PMS2 mutations develop brain tumours within 10 years of life and over 40% of patients homozygous for PMS2 mutations develop second primary malignancies [ 29 ]. By comparison, patients homozygous for MLH1/MSH2 mutations are less likely to develop second primary malignancies (22%).…”

“…Preventive treatment strategies would represent a major advance for CMMRD therapy and the benefits of novel long-term conventional therapies such as acetylsalicylic acid (aspirin) are emerging [ 58 ]. As CMMRD is rare, information on its optimal therapeutic strategies are limited and current knowledge of treatment regimens and their outcomes are limited to individual case reports, often with variable disease phenotypes [ 29 , 36 , 39 , 42 , 46 , 59 – 70 ]. Chemotherapy remains a frontline treatment, but toxicity is a major issue in children.…”

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).…”