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Blood. 2018 Jul 5;132(1):89-100. doi: 10.1182/blood-2017-11-814244. Epub 2018 Apr 9.

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

Chinn IK1,2,3, Eckstein OS1,2,4, Peckham-Gregory EC1,4, Goldberg BR1,2,3, Forbes LR1,2,3, Nicholas SK1,2,3, Mace EM1,2,3, Vogel TP1,2,3, Abhyankar HA2,4, Diaz MI2,4, Heslop HE1,2,4,5, Krance RA1,2,4,5, Martinez CA1,2,4,5, Nguyen TC1,2,6,7, Bashir DA1,2,6,7, Goldman JR1,2,6, Stray-Pedersen A8,9,10, Pedroza LA11, Poli MC1,2,12, Aldave-Becerra JC13, McGhee SA14, Al-Herz W15, Chamdin A16, Coban-Akdemir ZH10,17, Jhangiani SN17,18, Muzny DM17,18, Cao TN1,2,3, Hong DN1,2,3, Gibbs RA10,17,18, Lupski JR1,2,10,17,18, Orange JS1,2,3, McClain KL1,2,4, Allen CE1,2,4.

Author information

Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Department of Pediatrics, Texas Children's Hospital, Houston, TX.
Division of Pediatric Immunology/Allergy/Rheumatology and.
Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, TX.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX.
Division of Critical Care Medicine, Texas Children's Hospital, Houston, TX.
Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veteran Affairs Medical Center, Houston, TX.
Norwegian National Unit for Newborn Screening, Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Baylor-Hopkins Center for Mendelian Genomics, Houston, TX.
Universidad San Francisco de Quito, Colegio de Ciencias de la Salud-Hospital de los Valles, Quito, Ecuador.
Universidad del Desarrollo, Clinica Alemana de Santiago, Santiago, Chile.
Division of Allergy and Immunology, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.
Division of Immunology and Allergy, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA.
Department of Pediatrics, Kuwait University, Kuwait City, Kuwait.
Department of Pediatrics and Human Development, Michigan State University, Lansing, MI; and.
Department of Molecular and Human Genetics and.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.


The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

[Available on 2019-07-05]

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