Version October 2023
INTRODUCTION — The conditions grouped together under Mendelian susceptibility to mycobacterial diseases (MSMD; MIM #209950) are caused by genetic defects affecting the interactions of mononuclear phagocytes and T helper cells around the synthesis and response to interferon (IFN) gamma and interleukin (IL) 12, often referred to as the type 1 T helper cell (Th1) pathway [1]. These defects were predominantly identified through Bacille Calmette-Guérin (BCG) susceptibility but are unified by problems with the control and killing of intracellular pathogens such as mycobacteria and also include bacteria (eg, Salmonella, Burkholderia), fungi (eg, Histoplasma, Talaromyces), and viruses (eg, herpes simplex virus [HSV], varicella-zoster virus [VZV]) (table 1).
In countries in which BCG is not given, the clinical and infectious manifestations of MSMD may be unrelated to mycobacteria.
This topic reviews specific genetic defects that are considered forms of MSMD (table 2). An overview topic reviews pathogenesis, typical presentation, and general approach to diagnosis and management. (See "Mendelian susceptibility to mycobacterial diseases: An overview".)
IL12RB1 DEFICIENCY — The functional interleukin (IL) 12 receptor requires both IL-12 receptor beta 1 (IL12RB1) and IL-12 receptor beta 2 (IL12RB2) chains. Absence of either chain leads to complete deficiency of IL-12 signaling. IL12RB1 is slightly promiscuous; it complexes with IL12RB2 for IL-12 signaling or with IL-23R for IL-23 signaling. Pathogenic variants in IL12RB1, encoded on chromosome 19p13.1, have been identified in patients with disseminated infections, including Salmonella, nontuberculous mycobacteria (NTM), tuberculosis, and Bacillus Calmette-Guérin (BCG) following vaccination [2-10]. Penetrance and expressivity in IL12RB1 deficiency (MIM #614891) are highly variable, with some affected patients asymptomatic, whereas others develop severe disseminated BCG or NTM early in life. Variably formed granulomas are typically present in histopathology and frequently have high numbers of organisms. Despite the variable penetrance, mortality is approximately 30 percent.
All reported patients with IL12RB1 deficiency have biallelic missense or nonsense pathogenic variants in the extracellular domain of the IL12RB1 that usually preclude the surface expression of the IL12RB1 protein [11]. Interferon (IFN) gamma secretion by otherwise healthy T cells and natural killer (NK) cells is impaired as a result of defective IL-12R signaling. Ex vivo studies typically show no IL12RB1 on T lymphoblasts and defective intracellular signal transducer and activator of transcription (STAT) 4 phosphorylation and IFN-gamma secretion in response to IL-12 stimulation [11,12]. Carriers are clinically healthy with normal IL-12 signaling and IFN-gamma production patterns.
In an international study of 141 patients, the first serious disseminated infection occurred on average at 2.4 years in the 102 probands and was caused by BCG (64 percent), nontyphoidal Salmonella (22 percent), NTM (9 percent), or M. tuberculosis (4 percent) [11]. Mild chronic mucocutaneous candidiasis (CMCC) was reported in 23 percent of all patients, possibly reflecting impaired IL-23-dependent IL-17 production, whereas invasive candidiasis was uncommon [13]. BCG disease was inversely associated with subsequent infection with NTM. Twenty-seven percent of genetically affected siblings were asymptomatic. However, the overall mortality rate was approximately 30 percent, with a mean age at last follow-up visit of 12.7 years (range 0.5 to 46.4 years). Patients with NTM infection had the worst prognosis.
IFN-gamma therapy, initiated at the standard doses used in chronic granulomatous disease (CGD), may provide benefit in patients for whom antimycobacterials alone have been incompletely successful. The dose can be escalated based upon the patient's tolerance and response, with monitoring for an overexuberant inflammatory reaction. There is limited hematopoietic cell transplantation (HCT) experience, and so its role remains undefined, but it has been successful in rare refractory cases. (See "Chronic granulomatous disease: Treatment and prognosis", section on 'Immunomodulatory therapy with interferon-gamma' and 'Autosomal dominant partial IFNGR1 deficiency' below.)
IL12RB2 AND IL-23 RECEPTOR DEFICIENCIES — There are rare reports of homozygous defects in both interleukin 12 receptor beta 2 (IL12RB2) and IL-23 receptor (IL-23R) causing variable susceptibility to Bacillus Calmette-Guérin (BCG), nontuberculous mycobacteria (NTM), and tuberculosis. In the two reported families with these defects, chronic mucocutaneous candidiasis (CMCC) was not seen compared with the CMCC susceptibly seen with IL12RB1 deficiency [14].
IFN-GAMMA RECEPTOR DEFICIENCIES
Role of IFN-gamma — Interferon (IFN) gamma is the type II IFN produced primarily by T and natural killer (NK) cells, while type I IFNs (eg, IFN-alpha, IFN-beta, IFN-omega) are produced by epithelial cells, dendritic cells, T cells, monocytes/macrophages, and neurons, among others. IFN-gamma is critical to both innate and adaptive immunity, functioning as the primary activator of macrophages in addition to NK cells and neutrophils, and for the control of many intracellular pathogens.
Types of defects — The functional IFN-gamma receptor (IFNGR) requires both the IFNGR1 and IFNGR2 chains. The absence of either chain leads to complete receptor failure. Pathogenic variants in both IFNGR chains have been identified and characterized [15-22]:
●IFN-gamma receptor 1 deficiency (IFNGR1, gene encoded on chromosome 6q23-q24)
●IFN-gamma receptor 2 deficiency (IFNGR2, gene encoded on chromosome 21q22.1-q22.2)
Autosomal recessive (AR) defects in IFNGR1 and IFNGR2 result in complete or partial deficiencies. Autosomal dominant (AD) inheritance resulting in partial deficiencies is also observed for both genes [1,23].
Autosomal recessive complete IFNGR1 or IFNGR2 deficiencies — Patients with AR complete IFNGR1 (MIM #209950) or IFNGR2 (MIM #614889) deficiency tend to develop severe disseminated mycobacterial disease in infancy or early childhood, requiring long-term antimycobacterial therapy. By contrast, AD mutations retain residual signaling and are generally milder. In one large series, affected patients with biallelic AR IFNGR1 pathogenic variants had more frequent mycobacterial disease episodes (mean of 19 per 100 person-years), more disseminated disease (mean of four organs per infection), and shorter mean disease-free intervals (mean 1.6 years) compared with patients with AD disease [24]. Although infection with mycobacteria and Salmonella are predominantly associated with these genetic defects [24], the phenotype also includes increased susceptibility to cytomegalovirus (CMV), varicella-zoster virus, Listeria monocytogenes, and respiratory viruses such as respiratory syncytial virus (RSV) and parainfluenza virus [20,25,26]. The typical histopathologic feature in areas of infections is failure to form well-circumscribed tuberculoid granulomas [24].
AR pathogenic variants in IFNGR1 or IFNGR2 that lead to complete loss of protein expression map to the extracellular domains of the receptor proteins [16,21]. Flow cytometric analyses of peripheral blood mononuclear cells (PBMCs) show significantly decreased or absent cell surface expression of IFNGR1 or IFNGR2. Thus, signaling via the IFNGR is defective, which is detected as absent intracellular staining for phosphorylated signal transducer and activator of transcription (STAT) 1 protein [27] after IFN-gamma stimulation. Detection of pathogenic variants at the molecular level confirms the diagnosis. (See "Flow cytometry for the diagnosis of primary immunodeficiencies".)
Patients with this defect typically require aggressive treatment with antimycobacterial antibiotics for disseminated mycobacterial disease followed by transplantation. (See "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children", section on 'Antimycobacterial therapy'.)
IFN-gamma cytokine replacement therapy has no value in patients with AR complete defects of IFNGR1 and IFNGR2 since a functional IFNGR is absent. Adjuvant IFN-alpha along with antimycobacterial antibiotics has been used to treat disseminated Mycobacterium avium complex (MAC) in patients with complete IFNGR1 defects, with the goal of turning on shared downstream transcription factors, such as STAT1, through the IFN-alpha receptor [28].
Early mortality occurs without hematopoietic cell transplantation (HCT) in patients with complete IFNGR defects. The success of HCT is mostly related to the patient's overall status, and efforts should be taken to control mycobacterial infection before transplantation. However, patients have been successfully transplanted despite active mycobacterial infection [29]. There was high mortality and graft failure with early attempts at HCT for IFNGR deficiency, especially in those with poor control of disseminated infection. Most transplants have been performed with myeloablative regimens. In a report from 2004, of eight patients who received 11 HCTs, four died, and two had poor engraftment; the two who had full remission had received T cell-replete grafts from matched siblings following full ablation [30]. Other patients were successfully transplanted after myeloablative conditioning from matched unrelated or related donors [31,32]. Another survey reported on 30 transplants in 28 patients, of whom 23 were alive (82 percent overall survival) at a mean of 2.5 years posttransplant [33]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)
Autosomal dominant partial IFNGR1 deficiency — AD partial IFNGR1 deficiency (MIM #615978) is more common than AR complete IFNGR deficiency. The clinical presentation is usually later in childhood or in adolescence with more localized infection. Patients with AD IFNGR1 may present with localized or disseminated Bacillus Calmette-Guérin (BCG) or nontuberculous mycobacterial (NTM) infections [34], histoplasmosis [35], coccidioidomycosis [36], or salmonellosis [24]. Most patients with AD IFNGR deficiency develop NTM osteomyelitis, a manifestation that is the hallmark for this genotype in North America and Europe [24]. Histology shows mature-looking paucibacillary granulomas (picture 1), which are occasionally mistaken for malignancy [37]. (See 'Autosomal recessive partial IFNGR1 or IFNGR2 deficiencies' below.)
AD partial IFNGR1 deficiency is most often due to small frameshift deletions in a deletion hotspot just inside the intracellular domain of the IFNGR1 gene, leading to truncation of most of the intracellular domain [38]. Mutant chains with intact extracellular domains can still bind IFN-gamma but fail to transduce the signal because the Janus kinase (JAK) and STAT1 binding motifs are missing. In addition, the mutant chains do not get recycled off of the plasma membrane, because the receptor-recycling domain is deleted [39]. These abundant mutant receptors compete with wild-type receptors at the cell surface for binding IFN-gamma, but they do not block all signaling, which is why this is a dominant negative (DN) partial defect with retained granuloma formation and localized disease.
Flow cytometric analysis of monocytes from affected patients demonstrates a three- to fivefold increase in cell surface IFNGR1 protein expression compared with healthy control monocytes. However, STAT1 phosphorylation following in vitro stimulation with IFN-gamma is reduced even at 100-fold higher concentrations of IFN-gamma. Diagnosis is confirmed by identification of a pathogenic variant by deoxyribonucleic acid (DNA) sequencing. (See "Flow cytometry for the diagnosis of primary immunodeficiencies".)
Patients with AD partial IFNGR1 deficiency have a much more favorable response to antimycobacterial treatment [40,41] and adjunctive IFN-gamma therapy than do patients with AR complete IFNGR1 deficiency, although they sometimes require a relatively high dose of IFN-gamma [18]. Combination antibiotics should be used based upon the Mycobacterium isolated. IFN-gamma is initially dosed at 50 mcg/m2 (or 1 million international units/m2) for patients whose body surface area is >0.5 m2 and 1.5 mcg/kg/dose for patients whose body surface area is ≤0.5 m2, which is the standard dosing for chronic granulomatous disease (CGD). The dose can then be escalated gradually based upon patient tolerance and response. After completion of treatment with combination antibiotics, if a mycobacterial infection is found, secondary prophylaxis is typically given with a macrolide such as azithromycin dosed at 250 mg daily for adults or 5 mg/kg/day for children (maximum dose 250 mg daily). Some severe cases have undergone successful transplantation [42]. (See "Disseminated nontuberculous mycobacterial (NTM) infections and NTM bacteremia in children", section on 'Antimycobacterial therapy' and "Chronic granulomatous disease: Treatment and prognosis", section on 'Immunomodulatory therapy with interferon-gamma'.)
Autosomal dominant partial IFNGR2 deficiency — AD partial IFNGR2 deficiency has been described in several families [43,44]. The DN pathogenic variant is hypofunctional. IFNGR activity was low in mildly symptomatic or asymptomatic heterozygous family members and absent when in homozygosity. One homozygous patient had NTM osteomyelitis, and the other had disseminated CMV and M. avium infection.
Autosomal recessive partial IFNGR1 or IFNGR2 deficiencies — Rare AR partial defects in both IFNGR1 and IFNGR2, in which IFN-gamma signal transduction is impaired but not abolished, have also been identified [21,45-47]. The clinical phenotype may be milder than that of patients with complete defects. Patients may present later in life with more limited disease. Affected patients can have normal granuloma formation.
AR partial IFNGR defects are often due to homozygous recessive missense pathogenic variants causing amino acid replacements in the extracellular domains or compound heterozygous pathogenic variants allowing a hypomorphic cellular phenotype with some IFN-gamma signaling [28]. Overall, the receptor is expressed on the cell surface, and the response to IFN-gamma is diminished, but not totally abolished, at the cellular level.
Diagnosis is established by detection of the pathogenic variants by DNA sequencing. Flow cytometric evaluation of the receptor may be normal since the dysfunctional receptor may still be expressed on the cell surface at normal amounts. However, IFN-gamma signaling is diminished. (See "Flow cytometry for the diagnosis of primary immunodeficiencies".)
Disseminated infection may occur but is often responsive to antimycobacterial drugs (and adjunctive IFN-gamma, if needed), unlike in patients with AR complete IFNGR defects [40,41].
IL-12 p40 DEFICIENCY — IL-12p40 complexes with IL-12p35 to make IL-12p70, the cytokine referred to as interleukin (IL) 12. IL-12p40 can also complex with IL-23p19 to form the cytokine IL-23. Patients with loss-of-function (LOF) autosomal recessive (AR) pathogenic variants in the gene encoding IL-12p40 (IL12B; encoded on chromosome 5q31.1-33.1) have a clinical phenotype similar to IL-12 receptor beta 1 (IL12RB1) deficiency [48-50]. Neither the IL-12p40 subunit nor the IL-12p70 heterodimer are detectable by enzyme-linked immunosorbent assay (ELISA) in these patients. Residual, IL-12 independent interferon (IFN) gamma secretion pathways persist, as reflected by the capacity to form organized granulomata.
Most patients present in early childhood (mean age one year), typically with disseminated or regional Bacillus Calmette-Guérin (BCG) disease. Disseminated and recurrent Salmonella infections are common. Visceral leishmaniasis has also been described [51]. The mortality rate in the largest series was 32 percent in symptomatic patients, with a mean age at death of seven years [50]. Similar to those with IL12RB1 deficiency, the penetrance is variable, and some persons with biallelic pathogenic variants are asymptomatic.
Treatments of choice are antibiotics and subcutaneous IFN-gamma, as described above for IL12RB1 deficiency. However, mortality remains high. (See 'Autosomal dominant partial IFNGR1 deficiency' above.)
STAT1 DEFECTS
Role of STAT1 — Signal transducer and activator of transcription (STAT) 1 (encoded on chromosome 2q32.2-q32.3) is a critical signal transducer for both the interferon (IFN) gamma receptor and IFN-alpha/beta receptors and is required for responses to IFN-gamma, alpha, and beta [2]. Following IFN-gamma stimulation, STAT1 becomes phosphorylated and homodimerizes to form the gamma-activating factor (GAF). In contrast, following IFN-alpha/beta stimulation, phosphorylated STAT1 combines with both STAT2 and p48, a cytoplasmic protein, to form heterotrimers known as IFN-stimulated gene factor 3 (ISGF3).
Types of defects — STAT1 defects vary in severity and clinical presentation, depending upon the pathogenic variant and its effect on protein expression and function. The types of pathogenic variants include amorphic (no function), hypomorphic (reduced function), and hypermorphic (increased function). Biallelic recessive amorphic loss-of-function (LOF) variants lead to partial or complete deficiency of STAT1. Heterozygous dominant negative (DN) variants in STAT1 lead to impaired, but not fully abolished, responses to IFN-gamma. Finally, heterozygous hypermorphic-activating pathogenic variants in STAT1 confer dominant gains of function (GOF). The presentation of these different forms of STAT1 defects can range from isolated thrush, to disseminated infections, to severe immunodeficiency that is lethal in the first year of life.
Autosomal recessive complete STAT1 deficiency — Autosomal recessive (AR) complete STAT1 deficiency (MIM #613796) caused by biallelic amorphic STAT1 alleles is a rare, severe immunodeficiency that leads to increased susceptibility to mycobacterial and viral infections. Patients die in infancy in the absence of hematopoietic cell transplantation (HCT). A complete loss of wild-type protein underlies the observed biologic defect in this form of STAT1 deficiency [52,53]. Survival has been poor due to disseminated Bacillus Calmette-Guérin (BCG) and severe viral infections including herpes viruses. Early HCT prior to infection may improve outcomes in patients with AR complete STAT1 deficiency.
Autosomal recessive partial STAT1 deficiency — AR loss-of-function (LOF) STAT1 deficiency is caused by hypomorphic missense pathogenic variants that lead to impaired STAT1 expression (LOF) [54,55]. GAF-mediated immunity is more impaired than ISGF3-mediated immunity. Patients have a mild MSMD phenotype. Two siblings identified with this defect both presented with recurrent and disseminated Salmonella infections. Other manifestations reported include recurrent herpes simplex virus (HSV) infections, recurrent respiratory syncytial virus (RSV) pneumonitis, and hepatosplenic mycobacterial disease.
Dominant negative LOF STAT1 deficiency — Partial STAT1 deficiency with autosomal dominant (AD) inheritance (MIM #614892) due to heterozygous point pathogenic variants in the STAT1 gene has been described in multiple kindreds [56,57]. These defects typically cause problems with phospho-STAT1 dimer formation or DNA binding, leading to impaired expression of IFN-gamma-directed STAT1-induced genes. However, this AD pathogenic variant interferes less with IFN-alpha-induced ISGF3 formation, thereby sparing IFN-alpha/beta-mediated antiviral activity. Patients with these pathogenic variants have more localized BCG or nontuberculous mycobacteria (NTM) infection in childhood with good responses to therapy. The clinical and cellular phenotypes of these patients are similar to those of patients with AR partial or AD IFNGR deficiency. (See 'Autosomal recessive partial IFNGR1 or IFNGR2 deficiencies' above.)
Autosomal dominant GOF STAT1 deficiency — Gain-of-function (GOF) STAT1 pathogenic variants (MIM #614162) are the most common variants in STAT1. This disease was initially described as causing chronic mucocutaneous candidiasis (CMCC), but the phenotype is now recognized as variable, with broad infection manifestations, autoimmunity, and vasculopathy. [58] Infections range from CMCC to NTM (typically more focal than in STAT1 deficiency), disseminated fungal infections, bacterial infections, and recurrent viral infections including herpes family infections but also severe viral infections, such as JC driven progressive multifocal encephalopathy (PML) [59]. Autoimmunity is common and ranges from isolated thyroid disease to extensive immune dysregulation similar to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) [59,60].
The mucosal disease is likely driven by increased T cells with increased IFN-gamma/STAT1 signaling, but the variable phenotypes remain not well understood. Most cases can be managed with prevention and treatment of infections (often maintenance antifungal therapy and anti-HSV prophylaxis). Janus kinase inhibitor (JAKi or Jakinib) therapy are increasingly used in patients with autoimmune complications and CMCC [61,62], but its long-term efficacy is unknown. Initial outcomes with HCT were poor, but with HCT prior to development of significant disease and with improved control of IFN-gamma signaling prior to HCT, there have been more successes [63]. (See "Chronic mucocutaneous candidiasis", section on 'Signal transducer and activator of transcription (STAT1) dysfunction' and "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)
IRF8 DEFICIENCY — Interferon (IFN) regulatory factor 8 (IRF8; encoded on chromosome 16q24.1) is a transcription factor predominantly in mononuclear phagocytes that regulates myeloid cell function, granulocyte and macrophage differentiation, and dendritic cell development [64-66]. It is also critical for defense against intracellular pathogens, activating antimycobacterial defenses via production of interleukin (IL) 12 in response to IFN-gamma, among other cytokines. It is a key regulator for early response in myeloid cells, including phagosome maturation, antigen processing, and antigen presentation [67].
Autosomal recessive (AR) IRF8 deficiency (MIM #226990) due to homozygous K108E pathogenic variants led to a complete absence of circulating monocytes and dendritic cells along with myeloid hyperplasia [68,69]. One patient identified with this genotype presented in early infancy with disseminated Bacillus Calmette-Guérin (BCG) infection and oral candidiasis. Subsequent reports have also demonstrated viral susceptibility, as well as developmental delay with intracerebral calcifications [70]. This form of IRF8 deficiency likely needs early hematopoietic cell transplantation (HCT).
Autosomal dominant (AD) IRF8 deficiency (MIM #614893) due to heterozygous T80A pathogenic variants caused selective absence of circulating dendritic cells [68] found in association with disseminated BCG disease. This form of IRF8 deficiency responded well to antimicrobial therapy.
GATA2 DEFICIENCY (MonoMAC SYNDROME) — GATA-binding protein 2 (GATA2; encoded on 3q21.3) is an early hematopoietic transcription factor that is required for myeloid and erythroid development. As such, there are no human cases of complete GATA2 deficiency. GATA2 deficiency is an autosomal dominant (AD) disorder by haploinsufficiency (eg, one allele is not enough). The main clinical manifestations include mycobacterial infections, viral infections, pulmonary alveolar proteinosis, myelodysplasia, and leukemia [71-74]. GATA2 deficiency has been called monocytopenia and MAC (MonoMAC); dendritic cell, monocyte, and B and natural killer (NK) lymphoid deficiency (DCML deficiency); Emberger syndrome; the syndrome of familial myelodysplasia and acute leukemia; and the syndrome of NK cell deficiency. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Autosomal dominant GATA2 deficiency'.)
Most commonly, AD GATA2 deficiency leads to the syndrome of monocytopenia and mycobacterial disease (MonoMAC; MIM #614172), which is characterized by late childhood or adult onset of disseminated nontuberculous mycobacterial (NTM) disease [71-74]. Complete blood count (CBC) with differential and lymphocyte subset analysis in these patients are remarkable for absolute circulating monocytopenia, NK cell cytopenia, and B cell lymphopenia. However, tissue macrophages and plasma cells are present, and immunoglobulin levels are normal to elevated, reflecting the fact that these patients start out life with normal complements of cells and then lose them over time but keep the plasma cells and macrophages derived from them.
Mycobacterial infections are common in late childhood or adulthood in patients with GATA2 deficiency [71-74]. Viral infections beginning in childhood include human papillomavirus, molluscum contagiosum, and herpes virus family including severe herpes simplex virus (HSV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) infections. Invasive fungal infections include histoplasmosis and aspergillosis. Lymphedema, deafness, and myelodysplasia are seen more often with null alleles (stop codons, frame shifts, or deletions) [75]. Myelodysplasia frequently develops over time, associated with cytogenetic abnormalities in the bone marrow (eg, trisomy 8 and monosomy 7). Other presentations of this syndrome include chronic neutropenia, aplastic anemia (AA), acute myelogenous leukemia, acute lymphocytic leukemia, and chronic myelomonocytic leukemia [76-79]. Bone marrow flow cytometry, morphology, and cytogenetics can help distinguish idiopathic AA from GATA2 deficiency [78]. Pulmonary alveolar proteinosis develops over time in approximately one-third of patients but may not have the typical "crazy paving" associated with anti-granulocyte macrophage (GM) colony-stimulating factor (CSF) autoantibodies [80]. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial MDS/AML with mutated GATA2'.)
Diagnosis is suspected based upon infections (persistent warts, mycobacterial infections), abnormal CBC with differential (leukopenia, monocytopenia), and /or family history of leukemia or myelodysplasia. Severe genital warts or cervical dysplasia should also prompt consideration of AD GATA2 deficiency. Sequencing of the GATA2 gene leads to definitive diagnosis. However, intronic variants account for approximately 25 percent of cases, and they may not be detected on typical exome or panel sequencing platforms [74].
Hematopoietic cell transplantation (HCT) for GATA2 deficiency is highly successful and is the treatment of choice [81,82].
ISG15 DEFICIENCY — Interferon (IFN) stimulated gene 15 (ISG15, encoded on chromosome 1p36.33) is a ubiquitin-like protein that becomes conjugated to many cellular proteins upon activation. It induces the production of IFN-gamma by lymphocytes, including natural killer (NK) cells [83].
Autosomal recessive (AR) ISG15 deficiency (MIM #616126) has been reported in three patients from two consanguineous families [83]. The phenotype is similar to interleukin (IL) 12 p40 and IL-12 receptor beta 1 (IL12RB1) deficiencies. The probands both presented with disseminated Bacillus Calmette-Guérin (BCG) infections with fistulizing ulcers and lymphadenopathies. In both patients, the infections resolved after prolonged antimycobacterial therapy. The brother of one of these patients, who also had ISG15 deficiency, had a milder infection with BCG. Three other unrelated patients with ISG15 deficiency presented with idiopathic basal ganglia calcification and seizures; these patients did not have significant infections or mycobacterial disease but did not receive BCG vaccination [84].
An increased susceptibility to viral infections was not observed in the six reported patients [84]. The uncontrolled IFN-alpha/beta amplification leads to autoinflammation and likely accounts for the basal ganglia calcifications, which were seen in patients regardless of mycobacterial infection.
NEMO DEFICIENCY — Nuclear factor-kappa-B (NFkB) essential modulator (NEMO) is a member of a complex of proteins required to ubiquitinate the inhibitor of NFkB (IkB), thereby allowing activation of NFkB-induced genes. It is encoded by IKBKG on the X chromosome (Xq28) and associated with the syndrome of ectodermal dysplasia with immunodeficiency (ED-ID; MIM # 300291). It is closely related to the dominant form of IKB-alpha deficiency, caused by heterozygous pathogenic variants in NFKBIA, which also lead to ectodermal dysplasia and immunodeficiency. NEMO and IkB-alpha are both associated with disseminated mycobacterial infections in addition to bacterial and viral infections. Autoinflammatory disease may be present as well, such as colitis. (See "Syndromic immunodeficiencies".)
MACROPHAGE GP91PHOX DEFICIENCY — Pathogenic variants in the gene encoding gp91phox (CYBB) cause X-linked chronic granulomatous disease (CGD), which is due to an impaired phagocyte respiratory burst and predisposes to bacterial and fungal infections, including Bacillus Calmette-Guérin (BCG) and M. tuberculosis. (See "Primary disorders of phagocyte number and/or function: An overview" and "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis".)
Specific pathogenic variants in the extracellular and transmembrane portions of CYBB lead to an unusual cellular phenotype in which neutrophil and monocyte respiratory burst function is normal (unlike in CGD), but the respiratory burst of differentiated macrophages is severely affected [85]. The seven affected patients from two kindreds in this report presented with BCG disease. The role of gp91phox in NADPH oxidase is discussed in detail separately. (See "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Pathogenesis'.)
TYK2 DEFICIENCY — Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of kinases and is required for signal transduction from surface receptors to signal transducer and activator of transcription (STAT) molecules, making it a critical member of the JAK-STAT pathway. Tyk2 is involved in signaling for alpha and beta interferons (IFNs); interleukin (IL) 6, 10, and 13; granulocyte colony-stimulating factor (G-CSF); and IL-12 and -23. Autosomal recessive (AR) Tyk2 deficiency (MIM #611521) was initially described as a cause of a hyperimmunoglobulin E (hyper-IgE) syndrome with disseminated Bacillus Calmette-Guérin (BCG) [86]. Subsequent cases have demonstrated mycobacterial and viral susceptibility, mostly without IgE elevation. Tyk2 involvement in IL-12 and IL-23 signaling likely explains its role in mycobacterial susceptibility, including disseminated BCG, tuberculosis, and viral infections [87]. Common pathogenic variants in TYK2 (found in 1 to 5 percent of Europeans) have been associated with increased susceptibility to tuberculosis [88].
SPPL2A DEFICIENCY — Signal peptide peptidase-like 2A (SPPL2A) is a transmembrane protease involved in the degradation of the human leukocyte antigen (HLA) invariant chain for antigen-presenting cells. Autosomal recessive (AR) loss-of-function (LOF) pathogenic variants were described in two unrelated families with Bacillus Calmette-Guérin (BCG) infections [89]. Without this degradation, the N-terminal fragment of the HLA invariant chain accumulates, leading to an impaired development of circulating dendritic cells and diminished interleukin (IL) 12 and interferon (IFN) gamma production and signaling, thus predisposing patients to BCG infections.
ROR-GAMMA-T DEFICIENCY — The retinoic acid-related orphan receptor member, RORC, encodes ROR-gamma-t, a transcription factor important in CD4 lymphoid development and differentiation to T helper cell type 17 (Th17) cells. Autosomal recessive (AR) loss-of-function (LOF) pathogenic variants were reported in three families in which patients had mucocutaneous candidiasis and disseminated Bacillus Calmette-Guérin (BCG) [90]. As expected from its role in Th17 development, Th17 cells were deficient. Less expected was the defective interferon (IFN) gamma response, predominantly of the gamma-delta T cells and the CD4+CCR6 and CXCR3+ alpha-beta T cells, to mycobacteria.
JAK1 DEFICIENCY — Both interferon (IFN) gamma and IFN-alpha/beta signal via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. IFN-gamma binds to its receptor, which leads to activation of JAK1 and JAK2, allowing phosphorylation of STAT1 and its downstream targets. IFN-alpha/beta binds to its receptors, leading to activation of JAK1 and tyrosine kinase (TYK) 2, followed by phosphorylation of STAT1 and STAT2, allowing activation of IFN-stimulated genes. Thus, disruption of JAK1 impacts both the IFN-gamma and IFN-alpha/beta pathways.
One patient was reported with homozygous missense JAK1 mutations who had early-onset developmental delay and recurrent bacterial infections, viral infections (herpes zoster, warts), fungal infections, and disseminated nontuberculous mycobacteria (NTM) [91]. The patient then developed metastatic bladder cancer in early adulthood. Consistent with the partial JAK1 deficiency, diminished STAT phosphorylation was found. Presumably, full JAK1 deficiency would be lethal in utero or early in life.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY
●Overview – Host defense against Bacillus Calmette-Guérin (BCG), nontuberculous mycobacteria (NTM), as well as Salmonella and other intramacrophagic pathogens, including Mycobacterium tuberculosis, depends upon the interferon (IFN) gamma/ interleukin (IL) 12/signal transducer and activator of transcription (STAT) 1 pathway (figure 1). Genetic defects in this pathway result in mycobacterial and other infections (table 2). It is important to consider that autoantibodies to IFN-gamma can fully mimic MSMD and are most commonly found in people of Southeast Asian origin. (See 'Introduction' above and "Mendelian susceptibility to mycobacterial diseases: An overview".)
●IL12RB1 and IL-12p40 deficiencies – IL-12 receptor beta 1 (IL12RB1) deficiency is the most common cause of MSMD. IL12RB1 and IL-12p40 deficiency have variable presentations but frequently present as disseminated BCG or, in countries without BCG vaccination, with disseminated NTM or with disseminated intracellular bacterial infections such as salmonellosis. (See 'IL12RB1 deficiency' above and 'IL-12 p40 deficiency' above.)
●IFNGR defects – IFN-gamma receptor (IFNGR) defects are one of the most commonly identified causes of MSMD. They can be recessive, which are typically severe and require hematopoietic cell transplantation (HCT), or dominant. Patients with IFNGR2 deficiency tend to develop severe disseminated mycobacterial disease in infancy or early childhood, requiring continuous antimycobacterial therapy and HCT. Autosomal dominant (AD) partial IFNGR1 deficiency usually presents later in childhood or in adolescence with severe localized (ie, multifocal osteomyelitis) or disseminated BCG or NTM infections, disseminated endemic mycoses, or salmonellosis. AD partial IFNGR2 deficiency and autosomal recessive (AR) partial IFNGR1 and IFNGR2 deficiencies are rare. (See 'IFN-gamma receptor deficiencies' above.)
●STAT1 defects – Recessive complete loss of STAT1 is severe, with severe mycobacterial and viral infections and early mortality. Dominant negative (DN) pathogenic variants are milder, predispose to more localized NTM infections, and are medically manageable. Dominant gain-of-function (GOF) STAT1 pathogenic variants often present with mucocutaneous candidiasis and viral and bacterial infections but can also have NTM infections. (See 'STAT1 defects' above.)
●GATA2 deficiency – GATA-binding protein 2 (GATA2) deficiency leads to the syndrome of monocytopenia and mycobacterial disease (MonoMAC), which predisposes to late childhood or adult onset of disseminated NTM disease, viral infections, myelodysplasia and leukemia, and pulmonary alveolar proteinosis. (See 'GATA2 deficiency (MonoMAC syndrome)' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, and Gulbu Uzel, MD, who contributed as Section Editor and author, respectively, to earlier versions of this topic review.
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