Hagit N Baris1,2, Inbal Barnes-Kedar3, Helen Toledano4,5, Marisa Halpern6, Dov Hershkovitz2,7, Alexander Lossos8, Israela Lerer9, Tamar Peretz8, Revital Kariv10, Shlomi Cohen11, Elizabeth E Half2,12, Nurit Magal3, Valerie Drasinover3, Katharina Wimmer13, Yael Goldberg8, Dani Bercovich14, Zohar Levi4,15. 1. The Genetics Institute, Rambam Health Care Campus, Haifa, Israel. 2. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 3. The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel. 4. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 5. Department of Pediatric Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel. 6. Department of Pathology, Rabin Medical Center, Hasharon Hospital, Petach Tikva, Israel. 7. Department of Pathology, Rambam Health Care Campus, Haifa, Israel. 8. Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 9. Department of Human Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 10. Department of Gastroenterology & Liver Disease, Sourasky Medical Center, Tel Aviv, Israel. 11. The Pediatric Gastroenterology Unit, Sourasky Medical Center, Tel Aviv, Israel. 12. Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel. 13. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria. 14. Human Molecular Genetics, Tel Hai College, Israel. 15. Gastroenterology Division, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel.
Abstract
BACKGROUND: Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1. PROCEDURE: We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer. RESULTS: In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified. CONCLUSIONS: CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.
BACKGROUND: Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1. PROCEDURE: We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer. RESULTS: In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified. CONCLUSIONS: CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.
Authors: Victoria K Tesch; Hanna IJspeert; Andrea Raicht; Daniel Rueda; Nerea Dominguez-Pinilla; Luis M Allende; Chrystelle Colas; Thorsten Rosenbaum; Denisa Ilencikova; Hagit N Baris; Michaela H M Nathrath; Manon Suerink; Danuta Januszkiewicz-Lewandowska; Iman Ragab; Amedeo A Azizi; Soeren S Wenzel; Johannes Zschocke; Wolfgang Schwinger; Matthias Kloor; Claudia Blattmann; Laurence Brugieres; Mirjam van der Burg; Katharina Wimmer; Markus G Seidel Journal: Front Immunol Date: 2018-07-02 Impact factor: 7.561
Authors: Maria Barton; Julia Santucci-Pereira; Olivia G Vaccaro; Theresa Nguyen; Yanrong Su; Jose Russo Journal: BMC Cancer Date: 2019-10-23 Impact factor: 4.430
Authors: Euphemia Y Leung; Marjan E Askarian-Amiri; Dean C Singleton; Carole Ferraro-Peyret; Wayne R Joseph; Graeme J Finlay; Reuben J Broom; Purvi M Kakadia; Stefan K Bohlander; Elaine Marshall; Bruce C Baguley Journal: Front Oncol Date: 2018-10-12 Impact factor: 6.244