Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis

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 ( < .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 ( < .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.

Recommendations for the management of hemophagocytic lymphohistiocytosis in adults

“…3), and TNFRSF1A (12p13.31), as well as CYBB (Xp21.1-p11.4), CYBA (16q24.2), and NCF1 (7q11.23) which encode the phagocyte reduced NAD phosphate oxidase complex affected in chronic granulomatous disease. 13,46,124 in clinical circumstances that strongly support lymphoma (history of B symptoms, weight loss, elevated sCD25/ferritin ratio). 58…”

Genetics and genomics in Peru: Clinical and research perspective

“…Furthermore, Peruvian patients—regarding other autoimmune diseases—from the Hospital Edgardo Rebagliati Martins have been also been included in several multinational reports of primary immunodeficiencies (Stray‐Pedersen et al, ), including STAT1 (OMIM #600555) mutations (Aldave Becerra & Cachay, ; Toubiana et al, ), hemophagocytic lymphohistiocytosis (Chinn et al, ), Wiskott–Aldrich syndrome and X‐linked thrombocytopenia (Crestani et al, ).…”

Limitations of HLH‐2004 criteria in distinguishing malignancy‐associated hemophagocytic lymphohistiocytosis

“…Malignancy‐associated HLH is a well‐known entity in adults, with 48% of published cases being triggered by neoplasms . Neoplasms as triggers of HLH in children have been recognized recently, with studies showing a prevalence of 8% to 11% . The true incidence of malignancy‐associated HLH may even be higher than those estimates, as some patients with immune dysregulation fulfilling the HLH‐2004 diagnostic criteria in the context of malignancy may not have been recognized or reported, especially in pediatrics.…”

“…1 Neoplasms as triggers of HLH in children have been recognized recently, with studies showing a prevalence of 8% to 11%. 2,3 The true incidence of malignancy-associated HLH may even be higher than those estimates, as some patients with immune dysregulation fulfilling the HLH-2004 diagnostic criteria in the context of malignancy may not have been recognized or reported, especially in pediatrics. Malignancy-triggered HLH is associated with increased mortality, with one pediatric series describing a 6-month overall survival of 67% and median overall sur- findings be present to diagnose HLH (Table 1).…”