Immunodeficiency-35 (IMD35) is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to localized or disseminated mycobacterial infection after BCG vaccination. Some patients may have increased susceptibility to infection with other intracellular organisms and/or viral infections. Fungal infections are not observed. Laboratory studies show normal levels of immune cells but defective signaling in specific immunologic pathways (summary by Kreins et al., 2015).

IMD34 results in predisposition to infections by poorly virulent mycobacteria, such as bacillus Calmette-Guerin (BCG) vaccines and nontuberculous environmental bacteria. Affected individuals are also susceptible to the more virulent species Mycobacterium tuberculosis (Bustamante et al., 2007).

Immunodeficiency-31B (IMD31B) results from autosomal recessive (AR) STAT1 deficiency. STAT1 is crucial for cellular responses to IFNA (147660)/IFNB (147640) (type I interferon) and IFNG (147570) (type III interferon). AR STAT1 deficiency affects both the IFNA/IFNB and the IFNG pathways, resulting in susceptibility to mycobacteria, Salmonella, and viruses, with a severe disease course and often fatal outcome (review by Al-Muhsen and Casanova, 2008).

IMD28 is caused by autosomal recessive (AR) IFNGR2 deficiency, a rare molecular cause of susceptibility to mycobacterial disease. The clinical presentation of complete AR IFNGR2 deficiency resembles that of complete IFNGR1 deficiency (IMD27A; 209950). The disease manifests early in life, with severe, often fatal, infection. The most commonly encountered pathogens include M. bovis bacillus Calmette-Guerin (BCG), M. avium, and M. fortuitum. Complete AR IFNGR2 deficiency is characterized by an undetectable cellular response to interferon-gamma (IFNG; 147570). There is also a rare partial form of AR IFNGR2 deficiency, reported in 1 child, who retained a residual cellular response to IFNG and presented with a relatively mild infection by M. bovis BCG and M. abscessus (review by Al-Muhsen and Casanova, 2008).

IMD30 results from autosomal recessive IL12RB1 deficiency and is the most common form of susceptibility to mycobacterial disease. Activated T and natural killer lymphocytes from IMD30 patients do not express IL12RB1 on their surface or, more rarely, express nonfunctional IL12RB1 on their surface. IMD30 patients therefore lack responses to IL12 (see 161560) and IL23 (see 605580). The clinical presentation of IL12RB1-deficient patients is similar to that of IL12B-deficient patients (see IMD29, 614890). Bacillus Calmette-Guerin (BCG) disease and salmonellosis are the most frequent infections. Salmonellosis is present in about half of IL12RB1-deficient patients, and significant numbers of patients present with isolated salmonellosis. Severe tuberculosis has been reported in several unrelated patients, and other infections have been reported in single patients. IMD30 has low penetrance, and patients have relatively mild disease and good prognosis (review by Al-Muhsen and Casanova, 2008).

Immunodeficiency-27B (IMD27B) results from autosomal dominant (AD) IFNGR1 deficiency. Patients with AD IFNGR1 deficiency commonly present with recurrent, moderately severe infections with environmental mycobacteria or bacillus Calmette-Guerin (BCG). In contrast with patients with complete autosomal recessive (AR) IFNGR1 deficiency (IMD27A), cells from patients with AD IFNGR1 deficiency display residual responses to IFNG in vitro, indicating that the deficiency in IFNGR1 is partial. The clinical features of AD IFNGR1 deficiency are usually less severe than those in children with complete AR IFNGR1 deficiency, and mycobacterial infection often occurs later (mean age of 13.4 years vs 1.3 years), with patients having longer mean disease-free survival. In patients with AD IFNGR1 deficiency, M. avium tends to cause unifocal or multifocal osteomyelitis. Salmonellosis is present in about 5% of patients with AR or AD IFNGR1 deficiency, and other infections have been reported in single patients (review by Al-Muhsen and Casanova, 2008).

IMD38 predisposes individuals to severe clinical disease upon infection with weakly virulent mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccines (Bogunovic et al., 2012). Patients do not experience severe disease in response to viral infection. Affected individuals have intracranial calcification (Zhang et al., 2015).