title: Hemophagocytic lymphohistiocytosis due to germline mutations in SH2D1A, the X-linked lymphoproliferative disease gene.
abstract: The hemophagocytic lymphohistiocytoses (HLH) comprise a heterogeneous group of disorders characterized by dysregulated activation of T cells and macrophages. Although some patients with HLH harbor perforin gene mutations, the cause of the remaining cases is not known. The phenotype of HLH bears a strong resemblance to X-linked lymphoproliferative disease (XLP), an Epstein-Barr virus (EBV)-associated immunodeficiency resulting from defects in SH2D1A, a small SH2 domain-containing protein expressed in T lymphocytes and natural killer cells. Here it is shown that 4 of 25 male patients with HLH who were examined harbored germline SH2D1A mutations. Among these 4 patients, only 2 had family histories consistent with XLP. On the basis of these findings, it is suggested that all male patients with EBV-associated hemophagocytosis be screened for mutations in SH2D1A. Patients identified as having XLP should undergo genetic counseling, and be followed long-term for development of lymphoma and hypogammaglobulinemia.
authors.affiliation: Department of Pediatrics, IRCCS Policlinico S. Matteo, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Arico
authors.forename: S
authors.initials: S
authors.lastname: Imashuku
authors.forename: R
authors.initials: R
authors.lastname: Clementi
authors.forename: S
authors.initials: S
authors.lastname: Hibi
authors.forename: T
authors.initials: T
authors.lastname: Teramura
authors.forename: C
authors.initials: C
authors.lastname: Danesino
authors.forename: D A
authors.initials: DA
authors.lastname: Haber
authors.forename: K E
authors.initials: KE
authors.lastname: Nichols
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000175:diagnosis; D005091:Exons / Q000235:genetics; D018740:Genetic Heterogeneity; D018095:Germ-Line Mutation; D015616:Histiocytosis, Non-Langerhans-Cell / Q000175:diagnosis / Q000209:etiology / Q000235:genetics* / Q000821:virology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008232:Lymphoproliferative Disorders / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D017384:Sequence Deletion; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D014960:X Chromosome / Q000235:genetics*; D018909:src Homology Domains
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein