Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

Autor: Forbes LR; 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., Eckstein OS; 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., Gulati N; 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., Peckham-Gregory EC; Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, Tex., Ozuah NW; 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., Lubega J; 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., El-Mallawany NK; 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., Agrusa JE; 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., Poli MC; Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Universidad del Desarrollo, Clínica Alemana de Santiago, Santiago, Chile., Vogel TP; 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., Chaimowitz NS; 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., Rider NL; 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., Mace EM; New York Presbyterian Morgan Stanley Children's Hospital, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY., Orange JS; New York Presbyterian Morgan Stanley Children's Hospital, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY., Caldwell JW; Section of Pulmonary, Critical Care, Allergic and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, NC., Aldave-Becerra JC; Division of Allergy and Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru., Jolles S; Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom., Saettini F; Department of Pediatric Hematology, Fondazione MBBM, University of Milan-Bicocca, Monza, Italy., Chong HJ; Division of Pediatric Allergy and Immunology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pa., Stray-Pedersen A; Department of Pediatric and Adolescent Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway., Heslop HE; 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., Kamdar KY; 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., Rouce RH; 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., Muzny DM; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex., Jhangiani SN; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex., Gibbs RA; 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., Coban-Akdemir ZH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex; Baylor-Hopkins Center for Mendelian Genomics, Houston, Tex., Lupski JR; 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., McClain KL; 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., Allen CE; 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., Chinn IK; 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.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2022 Feb; Vol. 149 (2), pp. 758-766. Date of Electronic Publication: 2021 Jul 28.
DOI: 10.1016/j.jaci.2021.07.015
Abstrakt: 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.
(Copyright © 2021 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
Databáze: MEDLINE
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