Lisa R Forbes1, Olive S Eckstein2, Nitya Gulati2, Erin C Peckham-Gregory3, Nmazuo W Ozuah2, Joseph Lubega2, Nader K El-Mallawany2, Jennifer E Agrusa2, M Cecilia Poli4, Tiphanie P Vogel5, Natalia S Chaimowitz1, Nicholas L Rider1, Emily M Mace6, Jordan S Orange6, Jason W Caldwell7, Juan C Aldave-Becerra8, Stephen Jolles9, Francesco Saettini10, Hey J Chong11, Asbjorg Stray-Pedersen12, Helen E Heslop13, Kala Y Kamdar2, R Helen Rouce14, Donna M Muzny15, Shalini N Jhangiani15, Richard A Gibbs16, Zeynep H Coban-Akdemir17, James R Lupski18, Kenneth L McClain2, Carl E Allen19, Ivan K Chinn20. 1. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Immunology/Allergy/Retrovirology, Texas Children's Hospital, Houston, Tex. 2. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, Tex. 3. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, Tex. 4. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Universidad del Desarrollo, Clínica Alemana de Santiago, Santiago, Chile. 5. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Rheumatology, Texas Children's Hospital, Houston, Tex. 6. New York Presbyterian Morgan Stanley Children's Hospital, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY. 7. Section of Pulmonary, Critical Care, Allergic and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, NC. 8. Division of Allergy and Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru. 9. Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom. 10. Department of Pediatric Hematology, Fondazione MBBM, University of Milan-Bicocca, Monza, Italy. 11. Division of Pediatric Allergy and Immunology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pa. 12. Department of Pediatric and Adolescent Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway. 13. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Tex. 14. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, Tex; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Tex. 15. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex. 16. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Baylor-Hopkins Center for Mendelian Genomics, Houston, Tex. 17. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Baylor-Hopkins Center for Mendelian Genomics, Houston, Tex. 18. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Baylor-Hopkins Center for Mendelian Genomics, Houston, Tex. 19. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, Tex. Electronic address: ceallen@txch.org. 20. Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Immunology/Allergy/Retrovirology, Texas Children's Hospital, Houston, Tex. Electronic address: chinn@bcm.edu.
Abstract
BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.
BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.
Authors: Paul C Mayor; Kevin H Eng; Kelly L Singel; Scott I Abrams; Kunle Odunsi; Kirsten B Moysich; Ramsay Fuleihan; Elizabeth Garabedian; Patricia Lugar; Hans D Ochs; Francisco A Bonilla; Rebecca H Buckley; Kathleen E Sullivan; Zuhair K Ballas; Charlotte Cunningham-Rundles; Brahm H Segal Journal: J Allergy Clin Immunol Date: 2017-06-09 Impact factor: 10.793
Authors: Joshua D Milner; Tiphanie P Vogel; Lisa Forbes; Chi A Ma; Asbjørg Stray-Pedersen; Julie E Niemela; Jonathan J Lyons; Karin R Engelhardt; Yu Zhang; Nermina Topcagic; Elisha D O Roberson; Helen Matthews; James W Verbsky; Trivikram Dasu; Alexander Vargas-Hernandez; Nidhy Varghese; Kenneth L McClain; Lina B Karam; Karen Nahmod; George Makedonas; Emily M Mace; Hanne S Sorte; Gøri Perminow; V Koneti Rao; Michael P O'Connell; Susan Price; Helen C Su; Morgan Butrick; Joshua McElwee; Jason D Hughes; Joseph Willet; David Swan; Yaobo Xu; Mauro Santibanez-Koref; Voytek Slowik; Darrell L Dinwiddie; Christina E Ciaccio; Carol J Saunders; Seth Septer; Stephen F Kingsmore; Andrew J White; Andrew J Cant; Sophie Hambleton; Megan A Cooper Journal: Blood Date: 2014-10-30 Impact factor: 22.113
Authors: Amanda Rudman Spergel; Kelly Walkovich; Susan Price; Julie E Niemela; Dowain Wright; Thomas A Fleisher; V Koneti Rao Journal: Pediatrics Date: 2013-10-07 Impact factor: 7.124
Authors: Yasodha Natkunam; Dita Gratzinger; Amy Chadburn; John R Goodlad; John K C Chan; Jonathan Said; Elaine S Jaffe; Daphne de Jong Journal: Blood Date: 2018-08-06 Impact factor: 22.113
Authors: Carrie L Lucas; Hye Sun Kuehn; Fang Zhao; Julie E Niemela; Elissa K Deenick; Umaimainthan Palendira; Danielle T Avery; Leen Moens; Jennifer L Cannons; Matthew Biancalana; Jennifer Stoddard; Weiming Ouyang; David M Frucht; V Koneti Rao; T Prescott Atkinson; Anahita Agharahimi; Ashleigh A Hussey; Les R Folio; Kenneth N Olivier; Thomas A Fleisher; Stefania Pittaluga; Steven M Holland; Jeffrey I Cohen; Joao B Oliveira; Stuart G Tangye; Pamela L Schwartzberg; Michael J Lenardo; Gulbu Uzel Journal: Nat Immunol Date: 2013-10-28 Impact factor: 25.606
Authors: Elisabeth Salzer; Svenja Daschkey; Sharon Choo; Michael Gombert; Elisangela Santos-Valente; Sebastian Ginzel; Martina Schwendinger; Oskar A Haas; Gerhard Fritsch; Winfried F Pickl; Elisabeth Förster-Waldl; Arndt Borkhardt; Kaan Boztug; Kirsten Bienemann; Markus G Seidel Journal: Haematologica Date: 2012-07-16 Impact factor: 9.941
Authors: James E D Thaventhiran; Hana Lango Allen; Oliver S Burren; William Rae; Daniel Greene; Emily Staples; Zinan Zhang; James H R Farmery; Ilenia Simeoni; Elizabeth Rivers; Jesmeen Maimaris; Christopher J Penkett; Jonathan Stephens; Sri V V Deevi; Alba Sanchis-Juan; Nicholas S Gleadall; Moira J Thomas; Ravishankar B Sargur; Pavels Gordins; Helen E Baxendale; Matthew Brown; Paul Tuijnenburg; Austen Worth; Steven Hanson; Rachel J Linger; Matthew S Buckland; Paula J Rayner-Matthews; Kimberly C Gilmour; Crina Samarghitean; Suranjith L Seneviratne; David M Sansom; Andy G Lynch; Karyn Megy; Eva Ellinghaus; David Ellinghaus; Silje F Jorgensen; Tom H Karlsen; Kathleen E Stirrups; Antony J Cutler; Dinakantha S Kumararatne; Anita Chandra; J David M Edgar; Archana Herwadkar; Nichola Cooper; Sofia Grigoriadou; Aarnoud P Huissoon; Sarah Goddard; Stephen Jolles; Catharina Schuetz; Felix Boschann; Paul A Lyons; Matthew E Hurles; Sinisa Savic; Siobhan O Burns; Taco W Kuijpers; Ernest Turro; Willem H Ouwehand; Adrian J Thrasher; Kenneth G C Smith Journal: Nature Date: 2020-05-06 Impact factor: 49.962