A 42-year-old female with a suspicion of "immunodeficiency" came to the immunology clinic. The reason at the time was a present active infection by atypical mycobacteria that affected the skeleton with multiple defects of the spine (Th and L vertebrae), skin, and subcutis of the face, lymph nodes, knee joints, calva, paranasal sinuses, and nose. Immunological investigation revealed normal IgG, IgG subclasses, IgM, and IgA levels. Antibody titres to protein (tetanus, diphtheria) and polysaccharide (pneumococcal) vaccine antigens were normal. The patient had normal lymphocyte subset values, and an oxidation test was normal. A summary of laboratory findings on her first visit to our hospital is presented in Table 1.
The patient's history was long, with the onset of clinical problems in childhood. The chronology of the patient's clinical manifestations is included in Table 2. BCG vaccination in the first month of her life did not cause any immediate complications; however, at 5 years of age, tuberculosis of the lymph node developed, and conventional antituberculous therapy was initiated, i.e., isoniazid and rifampicin were administered. The therapy, which lasted 8 months, was successful and was followed by a long period of remission without any clinical manifestations. The patient was free of clinical complaints until 16 years of age, when an interstitial lung disease was diagnosed. After an erroneous diagnosis of sarcoidosis, the patient was treated with systemic glucocorticoids. During this therapy, dysbacteriosis was clinically manifested. It affected the skin, skeleton, and soft tissues. NTM species were identified using microbiological cultivation methods and subsequently treated according to the proven sensitivity. HIV infection was excluded. From that time, the patient was treated continuously with orally and then parenterally administered antituberculosis drugs (rifampicin, isoniazid, pyrazinamide, streptomycin, and ethambutol) for Mycobacterium lentiflavum infection that affected the nasal wings and nasal septum. Th8, Th11, L1, L3, and L5 discitis were etiologically caused by Mycobacterium kansasii. The knee joints were affected with Mycobacterium kansasii and Mycobacterium avium intracellulare.
In view of the clinical picture, we suspected a diagnosis of MSMD. Whole-exome sequencing performed on the NextSeq Illumina platform uncovered a frameshift variant NM_000416.2:c.819_822delTAAT; p.Asn274Hisfs * 2 in the heterozygous state in exon 6 of the IFNGR1 gene coding IFN-gamma receptor 1, which was confirmed using Sanger sequencing. In addition, a heterozygous sequence variant NM_052813.4; c.1434 + 1G > C in the CARD9 gene was detected. The patient was also submitted to the following laboratory tests: The ability of the proband's CD4 + and CD8 + T cells to produce IFN-gamma after nonspecific stimulation with phorbol myristate acetate (PMA) was undisturbed. The proband showed markedly increased expression of IFNgammaR1 on monocytes, myeloid dendritic cells, and plasmacytoid dendritic cells compared with a healthy control. STAT1 phosphorylation (pSTAT1, Tyr701) assay after IFN-gamma stimulation was performed to assess IFNgammaR1 downstream signalling. The pSTAT1 response was decreased but not absent, compared with a healthy control. Thereafter, the patient was treated with rhIFN-gamma and showed significant clinical improvement. rhIFN-gamma (Imukin, Boehringer Ingelheim) was started at a dose of 200 mug/m2 subcutaneously three times per week. The IFN-gamma-1b therapy was continued, together with antituberculous treatment. The patient's clinical status stabilized. In the last 4 months, she has been in this therapy without the need for antibiotic treatment.