A Nationwide Analysis of the Phenotype/Genotype Landscape of Hemophagocytic Lymphohistiocytosis: UNC13D Associates with Poor Prognosis.

BACKGROUND/OBJECTIVES: Geographic and ethnic differences influence the genetic landscape of hemophagocytic lymphohistiocytosis (HLH) and the frequency of familial HLH (FHL); this in turn can affect outcomes. METHODS: We collected data on 98 patients treated for HLH between 1 January 2001 and 31 July 2024 at four tertiary centers, characterizing the genotype/phenotype correlations. RESULTS: Half of the patients, 51 (52%), were symptomatic by age 1 year and 43 (44%) were diagnosed by that age. Our varied population included 43% Sephardic/Ashkenazi/Ethiopian Jews, 50% Muslim Arabs, and 7% Druze. Molecular analysis was performed on 90.5% of patients and revealed an FHL-related variant in 72%. The genetic variation included biallelic variants in PRF1 (21), UNC13D (12), STXBP2 (15), and STX (1). Eight hemizygous variants were found in X-linked lymphoproliferative disorder-related genes. A RAB27A monoallelic variant in an infant with a severe phenotype was considered pathogenic. The recently described HLH-related gene, ZNFX1, was mutated with varying penetrance in three symptomatic siblings. Overall, of the 94/98 with follow-up, 77% are alive. Strikingly, 5/12 (41.6%) patients with UNC13D variants died while 14/15 (93.3%) patients with STXBP2 variants survived. Logistic regression found poor prognosis associated with young age at diagnosis (p < 0.001), any variant (p = 0.016), UNC13D variant (p < 0.001), poor initial treatment response (p = 0.009), and no BMT (p = 0.005). CONCLUSIONS: Our cohort included an extremely high rate of genetic testing and detection of FHL-related variants. UNC13D variations are associated with exceedingly poor outcomes. Response to initial treatment seems crucial for positive outcomes, as does access to hematopoietic stem cell transplantation. Overall, we report a high survival rate, possibly due to a high index of suspicion and prompt diagnosis.