Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene

The hemophagocytic lymphohistiocytoses (HLH) comprise a heterogeneous group of disorders characterized by dysregulated activation of T cells and macro phages, Although some patients with HLH harbor perforin gene mutations, the cause of the remaining cases is not known. The phenotype of HLH bears a st rong resemblance to X-linked lymphoproliferative disease (XLP), an Epstein- Barr virus (EBV)- associated immunodeficiency resulting from defects in SH2 D1A, a small SH2 domain-containing protein expressed in T lymphocytes and n atural killer cells. Here it is shown that 4 of 25 male patients with HLH w ho were examined harbored germline SH2D1A mutations. Among these 4 patients , only 2 had family histories consistent with XLP. On the basis of these fi ndings, it is suggested that all male patients with EBV-associated hemophag ocytosis be screened for mutations in SH2D1A, Patients identified as having XLP should undergo genetic counseling, and be followed long-term for devel opment of lymphoma and hypogammaglobulinemia.