Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders - 03/02/22

Doi : 10.1016/j.jaci.2021.07.015

Lisa R. Forbes, MD ^a,^b,^c, Olive S. Eckstein, MD ^a,^b,^d, Nitya Gulati, MD ^a,^b,^d, Erin C. Peckham-Gregory, PhD, MPH ^a,^d, Nmazuo W. Ozuah, MD ^a,^b,^d, Joseph Lubega, MD, MPH ^a,^b,^d, Nader K. El-Mallawany, MD ^a,^b,^d, Jennifer E. Agrusa, MD ^a,^b,^d, M. Cecilia Poli, MD, PhD ^a,^b,^e, Tiphanie P. Vogel, MD, PhD ^a,^b,^f, Natalia S. Chaimowitz, MD, PhD ^a,^b,^c, Nicholas L. Rider, DO ^a,^b,^c, Emily M. Mace, PhD ^g, Jordan S. Orange, MD, PhD ^g, Jason W. Caldwell, DO ^h, Juan C. Aldave-Becerra, MD ⁱ, Stephen Jolles, MD, PhD ^j, Francesco Saettini, MD ^k, Hey J. Chong, MD, PhD ^l, Asbjorg Stray-Pedersen, MD, PhD ^m, Helen E. Heslop, MD ^a,^b,ⁿ, Kala Y. Kamdar, MD ^a,^b,^d, R. Helen Rouce, MD ^a,^b,^d,ⁿ, Donna M. Muzny, MS ^o,^p, Shalini N. Jhangiani, MS ^o,^p, Richard A. Gibbs, PhD ^o,^p,^q, Zeynep H. Coban-Akdemir, PhD ^p,^q, James R. Lupski, MD, PhD ^a,^b,^o,^p,^q, Kenneth L. McClain, MD, PhD ^a,^b,^d, Carl E. Allen, MD, PhD ^a,^b,^d,^⁎ , Ivan K. Chinn, MD ^a,^b,^c,^⁎
^a Department of Pediatrics, Baylor College of Medicine, Houston, Tex
^b Texas Children’s Hospital, Houston, Tex
^c Division of Pediatric Immunology/Allergy/Retrovirology, Texas Children’s Hospital, Houston, Tex
^d Division of Pediatric Hematology/Oncology, Texas Children’s Hospital Cancer Center, Houston, Tex
^e Universidad del Desarrollo, Clínica Alemana de Santiago, Santiago, Chile
^f Division of Pediatric Rheumatology, Texas Children’s Hospital, Houston, Tex
^g New York Presbyterian Morgan Stanley Children’s Hospital, Columbia University College of Physicians and Surgeons, Department of Pediatrics, New York, NY
^h Section of Pulmonary, Critical Care, Allergic and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, NC
ⁱ Division of Allergy and Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru
^j Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom
^k Department of Pediatric Hematology, Fondazione MBBM, University of Milan-Bicocca, Monza, Italy
^l Division of Pediatric Allergy and Immunology, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pa
^m Department of Pediatric and Adolescent Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway
ⁿ Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Tex
^o Human Genome Sequencing Center, Baylor College of Medicine, Houston, Tex
^p Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Tex
^q Baylor-Hopkins Center for Mendelian Genomics, Houston, Tex

^∗Corresponding author: Carl Allen, MD, PhD, Texas Children’s Hospital, Feigin Center, Suite 730.06, 1102 Bates St, Houston, TX 77030.Texas Children’s HospitalFeigin CenterSuite 730.061102 Bates StHoustonTX77030^∗∗Ivan Chinn, MD, Texas Children’s Hospital, Feigin Center, Suite 330, 1102 Bates St, Houston, TX 77030.Texas Children’s HospitalFeigin CenterSuite 3301102 Bates StHoustonTX77030

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.

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Key words : Lymphoproliferation, pediatric, whole exome sequencing, genomic, Epstein-Barr virus

Abbreviations used : ALPS, CAEBV, EBV, EBV-PLPD, HGSC, HLH, HSCT, IUIS, LPD, PIDD, PIRD, PLPD, WES

Plan

Methods

Subject enrollment

Clinical data and study criteria

WES and data analysis

Statistical analysis

Results

Characteristics of PLPD Cohort

Genetic findings

Discussion

Clinical and genomic landscape of PLPD

PLPD risk stratification

Increased mortality in patients with EBV-PLPD and no genetic explanation

Genetic diagnoses yield treatment opportunities

HSCT in PLPD

Conclusions

	The first 2 authors contributed equally to this article, and both should be considered first author. The last 2 authors contributed equally to this article, and both should be considered senior author.
	Funded in part by the HistioCure Foundation (Texas Children’s Hospital Histiocytosis Program) and the Fayez Sarofim Lymphoma Program; grant support from St Baldrick’s Foundation (NACHO Consortium to C.E.A. and K.L.M.; Innovation Award to C.E.A.; International Scholar Award to J.L. and N.W.O.; and Fellow Award to N.G.); the Leukemia and Lymphoma Society (Translational Research Project to C.E.A.; Career Development Program to E.P.G.); the American Society of Hematology Scholar Award in Clinical Research (to E.P.G.); SPORE in Lymphoma (CA126752 to H.E.H., C.E.A., and E.P.G.); National Institutes of Health K12 (K12CA090433 to O.S.E.); National Institutes of Health–National Institute of Allergy and Infectious Diseases (NIH-R01AI120989 to J.S.O.); Jeffrey Modell Foundation Translational Research Award and Histiocytosis Association Research Award (to I.K.C.); National Institutes of Health-National Human Genome Research Institute/National Heart, Lung, and Blood Institute UM1 HG006542 (to the Baylor-Hopkins Center for Mendelian Genomics); and Fondecyt 1118222 (to M.C.P.).
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 149 - N° 2

P. 758-766 - février 2022 Retour au numéro

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Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders - 03/02/22

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