Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies

Dorman, Susan E, Picard, Capucine, Lammas, David, Heyne, Klaus, van Dissel, Jaap T, Baretto, Richard, Rosenzweig, Sergio D, Newport, Melanie, Levin, Michael, Roesler, Joachim, Kumararatne, Dinakantha, Casanova, Jean-Laurent and Holland, Steven M (2004) Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet, 364 (9451). pp. 2113-2121. ISSN 0140-6736

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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.

FINDINGS

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).

INTERPRETATION

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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Primary Care and Public Health
Subjects: R Medicine > RC Internal medicine > RC0251 Constitutional diseases (General)
Depositing User: pam Thompson
Date Deposited: 09 May 2014 13:07
Last Modified: 09 May 2014 13:07
URI: http://sro.sussex.ac.uk/id/eprint/48390
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