Clinical and genetic characteristics in a series of haemophagocytic lymphohistiocytosis patients without perforin defects

Aim

Haemophagocytic lymphohistiocytosis (HLH) is characterised by T cell and macrophage activation and excessive production of inflammatory cytokines. Genetic diagnosis is required to discriminate between primary forms (familial HLH, FHL), due to mutations in genes involved in cytolysis, and secondary forms. We aimed to analyse the genes coding for Munc13-4 (UNC13D) and syntaxin-11 (STX11) proteins in search of mutations that might explain HLH in 5 patients without perforin defects.

Materials and methods

Perforin expression was evaluated by flow cytometry, sCD25 was measured by ELISA and NK activity was investigated by the conventional functional assay. Coding regions and exons surroundings were sequenced for PRF1, UNC13D and STX11 genes.

Results

P1 and P2 developed severe early-onset HLH, P1 died at 6 months. P3, with a sister who died after HLH, responded well to treatment (HLH-2004), and had a second HLH episode two years later. P2 developed HLH at year 7 while in complete remission after lymphoblastic leukaemia. P4 and P5 were brothers who died at 5 and 6 years old due to an HLH and EBV mononucleosis infection. XLP was discarded because P4 was a girl. P1 and P3 showed mutations in UNC13D previously described as pathogenic. There were no changes in STX11.

Conclusions

UNC13D mutations were found in 50% of the HLH families without perforin defects and STX11 defects were not detected. These results agree with published series in which mutations in UNC13D explain up to 50% of FHL without PRF1 mutations, supporting a heterogeneous genetic background for this disease.