title: Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH.
abstract: Familial hemophagocytic lymphohistiocytosis (HLH) is a rare primary immunodeficiency disorder characterized by defects in cell-mediated cytotoxicity that results in fever, hepatosplenomegaly, and cytopenias. Familial HLH is well recognized in children but rarely diagnosed in adults. We conducted a retrospective review of genetic and immunologic test results in patients who developed HLH in adulthood. Included in our study were 1531 patients with a clinical diagnosis of HLH; 175 patients were 18 years or older. Missense and splice-site sequence variants in PRF1, MUNC13-4, and STXBP2 were found in 25 (14%) of the adult patients. The A91V-PRF1 genotype was found in 12 of these patients (48%). The preponderance of hypomorphic mutations in familial HLH-causing genes correlates with the later-onset clinical symptoms and the more indolent course in adult patients. We conclude that late-onset familial HLH occurs more commonly than was suspected previously.
authors: Division of Human Genetics, Children's Hospital Medical Center, University of Cincinnati College of Medicie, Cincinnati, OH 45229, USA. kejian.zhang@cchmc.org
authors: Kejian
authors: K
authors: Zhang
authors: Michael B
authors: MB
authors: Jordan
authors: Rebecca A
authors: RA
authors: Marsh
authors: Judith A
authors: JA
authors: Johnson
authors: Diane
authors: D
authors: Kissell
authors: Jarek
authors: J
authors: Meller
authors: Joyce
authors: J
authors: Villanueva
authors: Kimberly A
authors: KA
authors: Risma
authors: Qian
authors: Q
authors: Wei
authors: Peter S
authors: PS
authors: Klein
authors: Alexandra H
authors: AH
authors: Filipovich
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D051938:Munc18 Proteins / Q000235:genetics* / Q000502:physiology; D009154:Mutation / Q000502:physiology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D051938:Munc18 Proteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; C497940:STXBP2 protein, human; C507969:UNC13D protein, human; D054353:Perforin