{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T03:56:36Z","timestamp":1778644596474,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T00:00:00Z","timestamp":1666742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>We describe a patient with constitutional mismatch repair-deficiency (CMMR-D) in whom the syndrome started at age 10 with the development of multiple adenomas in the large bowel. In the successive 25 years, four malignancies developed in different organs (rectum, ileum, duodenum, and lymphoid tissue). The patient had biallelic constitutional pathogenic variants in the PMS2 gene. We speculate that besides the PMS2 genotype, alterations of other genes might have contributed to the development of the complex phenotype. In the nuclear family, both parents carried different PMS2 germline mutations. They appeared in good clinical condition and did not develop polyps or cancer. The index case had a brother who died at age three of lymphoblastic leukemia, and a sister who was affected by sarcoidosis. Tumor tissue showed diffuse DNA microsatellite instability. A complete absence of immunoreactivity was observed for the PMS2 protein both in the tumors and normal tissues. Next-generation sequencing and multiple ligation-dependent probe amplification analyses revealed biallelic PMS2 germline pathogenic variants in the proband (genotype c.[137G&gt;T];[(2174+1_2175-1)_(*160_?)del]), and one of the two variants was present in both parents\u2014c.137G&gt;T in the father and c.(2174+1-2175-1)_(*160_?)del in the mother\u2014as well as c.137G&gt;T in the sister. Moreover, Class 3 variants of MSH2 (c.1787A&gt;G), APC (c.1589T&gt;C), and CHEK2 (c.331G&gt;T) genes were also detected in the proband. In conclusion, the recognition of CMMR-D may sometimes be difficult; however, the possible role of constitutional alterations of other genes in the development of the full-blown phenotype should be investigated in more detail.<\/jats:p>","DOI":"10.3390\/genes13111953","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T09:59:37Z","timestamp":1666778377000},"page":"1953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Biallelic PMS2 Mutations in a Family with Uncommon Clinical and Molecular Features"],"prefix":"10.3390","volume":"13","author":[{"given":"Monica","family":"Pedroni","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41125 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maurizio","family":"Ponz de Leon","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41125 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Reggiani Bonetti","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41125 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppina","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41125 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2804-0840","authenticated-orcid":false,"given":"Alessandra","family":"Viel","sequence":"additional","affiliation":[{"name":"Division of Functional Onco-Genomics and Genetics, Centro di Riferimento Oncologico di Aviano, IRCCS, Via Gallini 2, 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele Damiano Luca","family":"Urso","sequence":"additional","affiliation":[{"name":"Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, Via Giustiniani 1, 25128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0410-1760","authenticated-orcid":false,"given":"Luca","family":"Roncucci","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41125 Modena, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1053\/j.gastro.2014.04.001","article-title":"Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer","volume":"147","author":"Giardiello","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1038\/ajg.2017.212","article-title":"Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management","volume":"112","author":"Kanth","year":"2017","journal-title":"Am. 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