Whole-Exome Sequencing Uncovers Diverse Genetic Mechanisms Beyond Familial HLH Genes in Pediatric Hemophagocytic Lymphohistiocytosis
Among 122 children meeting HLH-2004 diagnostic criteria, biallelic familial HLH gene defects were found in only 19% by targeted sequencing, while research WES identified likely molecular explanations in 58% of remaining cases, including primary immunodeficiencies and dysregulated immune disorders. Overall survival was 45%, with outcomes driven by trigger type rather than genetic profile, supporting WES over targeted fHLH panels for identifying pathogenic mechanisms and guiding transplant decisions.
The original study
Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.
- Authors
- Chinn IK, Eckstein OS, Peckham-Gregory EC, Goldberg BR, Forbes LR, Nicholas SK, et al.
- Journal
- Blood
- Type
- Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
- PMID
- 29632024
Original abstract
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.