Kalene van Engelen1, Anita Villani2,3, Jonathan D Wasserman3,4, Laura Aronoff2,5, Mary-Louise C Greer6, Marta Tijerin Bueno6, Bailey Gallinger1,7,8,9, Raymond H Kim7,10, Ronald Grant2,3, M Stephen Meyn1,3,7,9, David Malkin1,2,3, Harriet Druker2,8,9. 1. Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. 2. Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada. 3. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. 4. Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario, Canada. 5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 6. Department of Diagnostic Imaging, The Hospital for Sick Children, Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada. 7. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada. 8. Department of Genetic Counselling, University of Toronto, Toronto, Ontario, Canada. 9. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. 10. Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND: To expand the current knowledge of DICER1 syndrome and to propose criteria for genetic testing based on experience at a pediatric tertiary care center. PROCEDURE: This study involved a retrospective chart review of the 78 patients (47 probands and 31 family members) seen in the Cancer Genetics Program at The Hospital for Sick Children (SickKids) who were offered genetic testing for DICER1. RESULTS: Of 47 probands offered genetic testing for DICER1, 46 pursued testing: 11 (23.9%) carried a pathogenic variant and one proband (2.1%) carried a missense variant of uncertain significance with evidence for pathogenicity. Thirty-one family members of variant-positive probands were offered testing: eight of the 25 who agreed to testing carried their familial variant (32.0%). Overall, 20 patients were identified to have a variant in DICER1 (eight males, 12 females). Of these, 13 (65.0%) presented with clinical manifestations associated with the syndrome. The most common lesions were pleuropulmonary blastoma (PPB) (five of 20 patients, 25.0%) and pineoblastoma (three of 20 patients, 15.0%). The average age at which individuals were diagnosed with a primary neoplasm was 5.2 years (range 0.8-20 years, median 3.0). Surveillance at our institution, with a median follow-up time of 23 months, has identified PPB in two asymptomatic individuals. These lesions were identified at early stages, thus potentially reducing treatment-related morbidity and mortality. CONCLUSION: This study further delineates the DICER1 syndrome phenotype and demonstrates the feasibility of a DICER1 syndrome surveillance protocol for the early detection of tumors.
BACKGROUND: To expand the current knowledge of DICER1 syndrome and to propose criteria for genetic testing based on experience at a pediatric tertiary care center. PROCEDURE: This study involved a retrospective chart review of the 78 patients (47 probands and 31 family members) seen in the Cancer Genetics Program at The Hospital for Sick Children (SickKids) who were offered genetic testing for DICER1. RESULTS: Of 47 probands offered genetic testing for DICER1, 46 pursued testing: 11 (23.9%) carried a pathogenic variant and one proband (2.1%) carried a missense variant of uncertain significance with evidence for pathogenicity. Thirty-one family members of variant-positive probands were offered testing: eight of the 25 who agreed to testing carried their familial variant (32.0%). Overall, 20 patients were identified to have a variant in DICER1 (eight males, 12 females). Of these, 13 (65.0%) presented with clinical manifestations associated with the syndrome. The most common lesions were pleuropulmonary blastoma (PPB) (five of 20 patients, 25.0%) and pineoblastoma (three of 20 patients, 15.0%). The average age at which individuals were diagnosed with a primary neoplasm was 5.2 years (range 0.8-20 years, median 3.0). Surveillance at our institution, with a median follow-up time of 23 months, has identified PPB in two asymptomatic individuals. These lesions were identified at early stages, thus potentially reducing treatment-related morbidity and mortality. CONCLUSION: This study further delineates the DICER1 syndrome phenotype and demonstrates the feasibility of a DICER1 syndrome surveillance protocol for the early detection of tumors.
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