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.

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Journal
Biomarker Research
Published
2026-10-28
DOI
https://doi.org/10.1186/s40364-026-01026-7
Primary Topic
Autoimmune and Inflammatory Disorders Research
Type
article
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article

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

chengyi wang, Taoli Suo, Yan Han, Gan Fu et al.
Biomarker Research
Autoimmune and Inflammatory Disorders Research
article

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

chengyi wang, Taoli Suo, Yan Han, Gan Fu, Muyuan Ji, Weiyu Kong, Xue Li, Meiling Liao, Jie Bai, Yong Zhang, YunYan He, Sujun Gao, Zhencang Zhou, Haixia Yang, Yu Li, Shilin Liu, Rui Zhang, Yuan Sun, Fei Li, Jia Zhang, Tingting Cui, Rong Liu, Zhao Wang, Yaping Wang, Zebin Luo, Kai Xue, Jing Cao, Ruohan Yang, Dao Wang, Yan Chen, Jiaxu Qi, Jingshi Wang
article en

Abstract

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.

Biomarker ResearchVol. 14(1)
Fujian Medical University (CN), Central South University (CN), Nanchang University (CN), Zunyi Medical University (CN), Shanghai Jiao Tong University (CN), Capital Medical University (CN), Ruijin Hospital (CN), Nanjing Children's Hospital (CN), Kunming Children's Hospital (CN), Shanghai Children's Medical Center (CN), First Affiliated Hospital of Jiangxi Medical College (CN), Second Hospital of Hebei Medical University (CN), Capital Institute of Pediatrics (CN), Children's Hospital of Zhejiang University (CN), Shandong Provincial Hospital (CN), First People’s Hospital of Zunyi (CN), First Hospital of Jilin University (CN), First Affiliated Hospital of GuangXi Medical University (CN), Hunan Children's Hospital (CN), Second Hospital of Tianjin Medical University (CN), Beijing Children’s Hospital (CN), Shanghai Institute of Hematology (CN), Beijing Friendship Hospital (CN), Anhui Provincial Children's Hospital (CN), Shanxi Provincial Children's Hospital (CN), Shenzhen Children's Hospital (CN), Shandong Provincial QianFoShan Hospital (CN), First Affiliated Hospital of Zhengzhou University (CN), Children's Hospital of Chongqing Medical University (CN), Xiangya Hospital Central South University (CN), Qilu Hospital of Shandong University (CN), Aviation General Hospital (CN), Shandong First Medical University (CN), First Affiliated Hospital of Nanchang University (CN), Affiliated Hospital of Zunyi Medical College (CN), State Key Laboratory of Medical Genomics (CN), Zhejiang University (CN), Chongqing Medical University (CN)
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Autoimmune and Inflammatory Disorders Research
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