Infections Due to Various Atypical Mycobacteria in a Norwegian Multiplex Family with Dominant Interferon-γ Receptor Deficiency

Heidi Glosli () 2 3 Asbjrg Stray-Pedersen 2 3 Anne C. Brun 2 6 Lena W. Holtmon 2 6 Tone Tnjum 0 1 2 Ariadne Chapgier 2 5 Jean L. Casanova 2 4 5 Tore G. Abrahamsen 0 2 3 0 Medical Faculty, University of Oslo , Oslo 1 Institute of Microbiology, Rikshospitalet University Hospital 2 that give rise to intracellular infections , such as those 3 Department of Pediatrics 4 Unite d'Immunologie et d'Hematologie Pediatriques , Hopital Necker-Enfants Malades, Paris, France 5 Laboratoire de Genetique Humaine des Maladies Infectieuses , INSERM U550, Faculte de Medecine Necker-Enfants Malades 6 Department of Pediatrics, Vestfold Hospital , Tnsberg, Norway Background. Atypical mycobacteria can cause systemic infections in patients with certain types of immunodeficiency. Methods. Clinical samples were decontaminated and cultured to assess the presence of mycobacterial species. Gene sequencing was performed to reveal interferon-g receptor 1 (IFN-gR1) deficiency. Results. The index patient received a diagnosis of dominant IFN-gR1 deficiency during treatment for a serious infection due to atypical mycobacteria. She belongs to a Norwegian multiplex family comprising 3 generations and 5 patients with dominant IFN-gR1 deficiency. Four of these patients have been treated with tuberculostatics because of extensive infection due to atypical mycobacteria, such as Mycobacterium avium-intracellulare, Mycobacterium scrofulaceum, Mycobacterium bovis (bacille Calmette-Guerin), Mycobacterium bohemicum, and Mycobacterium gordonae. Two of the patients have also received subcutaneous injections of IFN-g. One family member with the deficiency has not received treatment and is still healthy at 13 years of age. Conclusions. Serious infection due to atypical mycobacteria should initiate a search for primary immunodeficiencies, particularly IFN-gR1 deficiency. Treatment with IFN-g should be started when serious infection due to atypical mycobacteria is verified and dominant partial IFN-gR1 deficiency is suspected. Infection due to mycobacteria represents a huge and caused by mycobacteria and some Salmonella species. - [25]. Most IFN-gR1 dimers in heterozygous cells are nonfunctional because of the presence of at least one defective molecule. The few wild-type IFN-gR1 dimers that form in response to IFN-g account for the defect being partial rather than complete [6]. Here, we describe a Norwegian family (figure 1) with an autosomal dominant IFN-gR1 deficiency. All 5 family members are alive and doing well, 4 of whom have received appropriate treatment with antimycobacterial Figure 1. Pedigree of the family with autosomal dominant IFN-g receptor 1 deficiency and mycobacterial infections. Squares represent male individuals, and circles represent female individuals. White symbols indicate unaffected individuals, hatching indicates IFN-g receptor 1 deficiency but no infection, and black indicates IFN-g receptor 1 deficiency and infection due to atypical mycobacteria. agents; the 2 youngest patients have also received injections of IFN-g 3 times weekly. Our index patient presented with a prolonged history, disseminated infection due to the atypical mycobacterium Mycobacterium avium-intracellulare, and a family history of similar infections. Clinical samples were investigated for the presence of mycobacteria by the standard methods at the time. Recently, the samples have been cultivated at 37 C in the Bactec MGIT 960 system (Becton-Dickinson). Isolates that were nontuberculous mycobacteria were identified either by GenProbe hybridization (for M. avium-intracellulare) or 16S rDNA PCR sequence analysis (for all other nontuberculous mycobacteria). The sequencing of IFNGR1 was performed as described elsewhere [5]. The findings were confirmed by gel electrophoresis and direct sequencing of genomic PCR products obtained for each exon and flanking intronic region. Biochemical activation of the IFN-g pathway was evaluated by means of electrophoretic mobility shift assay, as described elsewhere [7]. Nuclear protein extracts from the patient and a positive control sample (Epstein-Barr virus type B cells) were incubated with a radiolabeled g-activated sequence DNA probe after several doses of IFN-g. The activation of IFN-g at the cellular level was performed as previously described [8]. In short, a whole blood sample was activated with bacille Calmette-Guerin (BCG) plus either IFNg or IL-12, for investigation of IL-12p40 and IL-12p70 or of IFN-g production, respectively. General findings. Sequencing of chromosome 6 revealed a deletion of 4 nucleotides in exon 6 of IFNGR1, designated 818del4 (OMIM 107470.0006), implying a dominant, partial e24 CID 2008:46 (1 February) Glosli et al. IFN-gR1 deficiency in 5 members of the family. The biochemical activation of IFN-g studied by electrophoretic mobility shift assay showed a partial deficiency in IFN-g response in these patients, compared with control subjects (data not shown), as described elsewhere for 818del4/WT cells from patients [5]. At the cellular level, all of our heterozygous patients showed a partial defect in IL-12p40 and a complete defect in production of IL-12p70 to BCG plus IFN-g, whereas they had normal responses to BCG alone or to BCG plus IL-12 for the production of IFN-g (data not shown), as described elsewhere for 818del4/WT whole blood cells [8]. Patient 1. A 7-year-old girl (born in 1995) (figure 1 and table 1) was admitted to the hospital with an infiltrate in the upper part of the left lung 4 months after having a possible Schonlein-Henoch purpura. Treatment with oral penicillin G and aerosolized salbutamol was given for 10 days. However, 4 weeks after discontinuation of the treatment, a new chest radiograph revealed a confluent infiltrate in the upper part of the left lung. Supplemental pulmonary CT exhibited a single abscess with a diameter of 2 cm and several microabscesses in the same lung, whereas an abdominal CT showed a 3 4 cm abscess in the lateral part of the right liver lobe. Treatment with cefotaxime and, subsequently, metronidazole was started. A tuberculin skin test (Pirquets test) with regular tuberculin for M. tuberculosis yielded positive results (diameter at 2 different test sites, 2 mm and 3 mm). The girl was transferred to the reference hospital for drainage of the liver abscess and further evaluation. She had fever and was pale, with enlarged lymph nodes, especially in the neck region and both sides of the groin. The liver was enlarged, and ultrasound analysis revealed an additional abscess. She had a limping gait. Pus from one of the liver abscess contained M. avium-intracellulare. Scintigraphy revealed massive bone involvement. Treatment was started with oral rifabutin, clarithromycin, and ethambutol and intravenous amikacin. The patients clinical condition improved slightly. However, the mycobacteria isolated were resistant to amikacin, rifabutin, clarithromycin, and ciprofloxacin, whereas they were susceptible to ethambuto (...truncated)