Mutations causing slight reductions in perforin expression and NK cell function could be the basis of HLH that is dormant until triggered by external Cinoxacin factors such as infection. We identified two patients in our study with X-linked SH2D1A gene sequence abnormalities, one of them was a heterozygous female carrier who experienced onset of HLH clinical symptoms at age 18, associated with T-cell lymphoma. Analysis of her parents revealed that the abnormal X chromosome came from her asymptomatic father. Generally, this mutation is predicted by in-silico analysis to be tolerated. We think that the onset of HLH Mechlorethamine hydrochloride disease in the carrier female may be due to nonrandom X-inactivation or differences in methylation that allow expression of the abnormal SH2D1A gene. Viral infection, particularly EBV infection, is an important predisposing factor in HLH. Studies have shown that individuals with immune deficiencies such as X-linked lymphoproliferative syndrome are usually asymptomatic before EBV infection, and there is no clear genotype/phenotype correlation. The onset and severity of HLH disease may differ among individuals due to varying exposure to triggering factors. In the absence of such triggers, the disease gene carrier may have no clinical manifestations, which may explain the phenomenon we observed in the female X-linked SH2D1A mutation carrier and her father. In the other hand, the HLH in these two patients may also be secondary to EBV infection or lymphoma. In this study, we observed 12 different PRF1 mutations in nine 
patients, most of whom had viral infection at HLH onset. Their diagnosis of secondary HLH was revised to primary HLH after genetic testing. The 7 patients with STX11 mutations also had viral infection that seemed to trigger HLH disease onset. Suppression of life-threatening inflammation must be initiated promptly in cases of both primary and secondary HLH. However, the long-term treatment strategies should focus on the underlying cause of HLH for patients in these two categories. For secondary HLH patients, control of the triggering disease or infection is critical for preventing recurrence. For primary HLH patients, who have a genetic mutation causing an immune deficiency, restoration of the lacking immune system components is vital. Therefore we believe that a clear diagnosis of primary or secondary HLH is important for long term therapy. HLH-related genetic testing can aid in distinguishing HLH types and subsequent treatment. And the functional studies, such as degranulation assays, are of great importance and should be implemented by all laboratories serving as prospective referral. In this study of 252 adolescent and adult HLH patients, the overwhelming majority had no identifiable mutation in the six HLH-related genes sequenced. We identified monoallelic mutation in 11 patients, and biallelic mutation in seven additional patients. Therefore, more than half of patients with identifiable genetic changes carried only one mutation in one of these genes. It is possible that other types of mutations were not detectable by the methodology used in this study, or that these patients possessed mutations in additional genes that have not yet been discovered to be associated with HLH. NK cell activity was lower than normal in each patient, and there was no statistically significant difference between monoallelic mutation group and biallelic mutation group. Our results support that defective cytotoxicity might be involved also in a proportion of HLH without biallelic mutations in the FHL related genes.