Adult-onset familial hemophagocytic lymphohistiocytosis has distinct genetic architecture and outcomes: a nationwide multicenter cohort study in China

Familial hemophagocytic lymphohistiocytosis (FHLH) is classically pediatric, but adult-onset disease is increasingly recognized. Whether adult-onset FHLH differs from pediatric/adolescent-onset disease remains incompletely defined. We aimed to characterize age-related differences in a nationwide multicenter cohort of patients with FHLH in China. We conducted a nationwide multicenter retrospective study of 223 patients with FHLH from 27 centers in China. Genetic architecture, central nervous system (CNS) involvement, allogeneic hematopoietic stem cell transplantation (allo-HSCT), and survival were compared by age at onset, with adult-onset disease defined as onset at age ≥ 18 years and pediatric/adolescent-onset disease as onset at < 18 years. In this cohort, adult-onset disease accounted for 54/223 cases (24.2%). In the PRF1/UNC13D subset ( n = 192), higher non-truncating variant burden was associated with adult onset (unadjusted OR per additional recorded variant, 1.95; 95% CI, 1.17–3.39), although the association attenuated after adjustment for gene and zygosity (adjusted OR, 1.58; 95% CI, 0.94–2.75). Epstein–Barr virus (EBV) was the predominant documented trigger in adults. CNS involvement was common across age groups (46.4%), with uncertain prognostic significance. Adults underwent allo-HSCT less frequently (49.1% vs. 70.2%) and were less often in complete response before transplantation (15.4% vs. 46.8%). Adult onset remained associated with poorer overall survival after multivariable adjustment including time-dependent allo-HSCT (HR, 3.74; 95% CI, 1.96–7.12). Post-HSCT survival was also poorer in adults. Adult-onset FHLH was associated with non-truncating variant enrichment and poorer overall and post-HSCT survival. These findings support considering inherited disease despite acquired triggers and careful assessment of disease control and transplant-related risks in adults with FHLH.