Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis

Ivan K. Chinn, Olive S. Eckstein, Erin C. Peckham-Gregory, Baruch R. Goldberg, Lisa R. Forbes, Sarah K. Nicholas, Emily M. Mace, Tiphanie P. Vogel, Harshal A. Abhyankar, Maria I. Diaz, Helen E. Heslop, Robert A. Krance, Caridad A. Martinez, Trung C. Nguyen, Dalia A. Bashir, Jordana R. Goldman, Asbjørg Stray-Pedersen, Luis A. Pedroza, M. Cecilia Poli, Juan C. Aldave Becerra, Sean A. McGhee, Waleed Al-Herz, Aghiad Chamdin, Zeynep H. Coban-Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Tram N. Cao, Diana N. Hong, Richard A. Gibbs, James R. Lupski, Jordan S. Orange, Kenneth L. McClain and Carl E. Allen

Key points

  • Whole exome sequencing may identify specific therapeutic opportunities for HLH patients.

  • HLH should be conceptualized as a critical illness phenotype driven by toxic activation of immune cells from different underlying mechanisms.


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 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation below 1 year of age (p < 0.0001). "Digenic" fHLH variants were observed but lacked statistical support for disease association. In 28 of 48 subjects (58%), 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%; increased mortality correlated with HLH triggered by infection or malignancy (p < 0.05). 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 HLH patients, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole exome sequencing, however, may identify specific therapeutic opportunities and impact hematopoietic stem cell transplantation options for these patients.

  • Submitted November 6, 2017.
  • Accepted April 3, 2018.