title: Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies.
abstract: BACKGROUND
  Interferon gamma receptor 1 (IFNgammaR1) deficiency is a primary immunodeficiency with allelic dominant and recessive mutations characterised clinically by severe infections with mycobacteria. We aimed to compare the clinical features of recessive and dominant IFNgammaR1 deficiencies.
  
  
  METHODS
  We obtained data from a large cohort of patients worldwide. We assessed these people by medical histories, records, and genetic and immunological studies. Data were abstracted onto a standard form.
  
  
  RESULTS
  We identified 22 patients with recessive complete IFNgammaR1 deficiency and 38 with dominant partial deficiency. BCG and environmental mycobacteria were the most frequent pathogens. In recessive patients, 17 (77%) had environmental mycobacterial disease and all nine BCG-vaccinated patients had BCG disease. In dominant patients, 30 (79%) had environmental mycobacterial disease and 11 (73%) of 15 BCG-vaccinated patients had BCG disease. Compared with dominant patients, those with recessive deficiency were younger at onset of first environmental mycobacterial disease (mean 3.1 years [SD 2.5] vs 13.4 years [14.3], p=0.001), had more mycobacterial disease episodes (19 vs 8 per 100 person-years of observation, p=0.0001), had more severe mycobacterial disease (mean number of organs infected by Mycobacterium avium complex 4.1 [SD 0.8] vs 2.0 [1.1], p=0.004), had shorter mean disease-free intervals (1.6 years [SD 1.4] vs 7.2 years [7.6], p<0.0001), and lower Kaplan-Meier survival probability (p<0.0001). M avium complex osteomyelitis was more frequent in dominant than in recessive patients (22/28 [79%] vs 1/8 [13%], p=0.002), and this disorder without other organ involvement arose only in dominant patients (9/28 [32%]). Disease caused by rapidly growing mycobacteria was present in more recessive than dominant patients (7/22 [32%] vs 1/38 [3%], p=0.002).
  
  
  CONCLUSIONS
  Recessive complete and dominant partial IFNgammaR1 deficiencies have related clinical phenotypes, but are distinguishable by age at onset, dissemination, and clinical course of mycobacterial diseases. A strong correlation exists between IFNGR1 genotype, cellular responsiveness to interferon gamma, and clinical disease features.
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, CRC B3-419, 10 Center Drive, MSC 1684, Bethesda, MD 20892-1684, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Dorman
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: David
authors.initials: D
authors.lastname: Lammas
authors.forename: Klaus
authors.initials: K
authors.lastname: Heyne
authors.forename: Jaap T
authors.initials: JT
authors.lastname: van Dissel
authors.forename: Richard
authors.initials: R
authors.lastname: Baretto
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Rosenzweig
authors.forename: Melanie
authors.initials: M
authors.lastname: Newport
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
authors.forename: Dinakantha
authors.initials: D
authors.lastname: Kumararatne
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
mesh_terms: D001500:BCG Vaccine; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D009154:Mutation; D009165:Mycobacterium Infections, Nontuberculous / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014376:Tuberculosis / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000096743:Interferon gamma Receptor
chemical_list: D001500:BCG Vaccine; D007371:Interferon-gamma; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor