Mendelian susceptibility to mycobacterial diseases: Specific defects

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, often referred to as the type 1 T helper cell (Th1) pathway [1]. Infections in these conditions are almost exclusively extrapulmonary and disseminated, reflecting the failure of the innate immune system to keep organisms limited to the gut or respiratory tract. These defects are typically unified by problems with the control and killing of intracellular pathogens such as mycobacteria. However, despite the name, infections with pathogens other than mycobacteria occur in this set of disorders, such as Salmonella and endemic fungi, and may be more frequent than the mycobacterial infections, depending on exposures.

The majority of MSMD disorders were recognized through infections related to the administration of Bacille Calmette-Guerin (BCG), the live-attenuated tuberculosis vaccine still in use in very early infancy in many countries around the world. In countries in which BCG is not given, the clinical and infectious manifestations of MSMD will differ. Infectious agents in MSMD tend to be weakly virulent environmental organisms including mycobacteria (the nontuberculous mycobacteria [NTM], BCG, and occasionally Mycobacterium tuberculosis); bacteria (salmonellae, some Burkholderia, Listeria); fungi, especially the dimorphic molds (Histoplasma, Coccidioides, Blastomyces), as well as the opportunistic fungi Cryptococcus, Aspergillus, and Talaromyces (Penicillium) marneffei; and the intracellular parasite Leishmania. In addition, in some defects, herpesvirus infections are more common and can be severe, including herpes simplex virus (HSV) types 1 and 2, cytomegalovirus (CMV), and Epstein-Barr virus (EBV), the last of which can cause EBV+ neoplasms.

This topic reviews specific forms of MSMD due to known genetic defects. An overview topic reviews pathogenesis, typical presentation, and general approach to diagnosis and management. (See "Mendelian susceptibility to mycobacterial diseases: An overview".)

IFN-GAMMA RECEPTOR DEFICIENCIES

Role of IFN-gamma — Interferon (IFN) gamma is a cytokine produced primarily by T cells. It is critical to both innate and adaptive immunity, functioning as the primary activator of macrophages in addition to natural killer (NK) cells and neutrophils. IFN-gamma is critical 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 [2-9]:

●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 [1,10].

Autosomal-recessive complete IFN-gamma receptor 1 or 2 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. In one large series, affected patients with 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 [11]. Although infection with mycobacteria and Salmonella are predominantly associated with these genetic defects [11], 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 [7,12,13]. The typical histopathologic feature in areas of infections is failure to form well-circumscribed tuberculoid granulomas [11].

AR pathogenic variants in IFNGR1 or IFNGR2 that lead to complete loss of protein expression map to the extracellular domains of the receptor proteins [3,8]. 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 [14]. Detection of pathogenic variants at the molecular level confirms the diagnosis. (See "Flow cytometry for the diagnosis of primary immunodeficiencies".)

Serum IFN-gamma levels have been proposed as diagnostic markers for AR complete IFNGR1 deficiency [15] since the receptor that binds and internalizes IFN-gamma, thereby removing it from the circulation, is absent. However, levels are elevated only during active infection and are better viewed as surrogate markers for infection control. A normal IFN-gamma serum level (low) does not exclude AR complete IFNGR1 deficiency or any other MSMD. Conversely, an elevated IFN-gamma serum level suggests active infection or inflammation.

Patients with this defect typically require aggressive treatment with antimycobacterial antibiotics for disseminated mycobacterial disease [16,17]. 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 chemotherapy 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 and genes with IFN-gamma, but through the IFN-alpha receptor [18].

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 [19]. 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. Complications of HCT have included fatal graft-versus-host disease (GVHD), severe generalized granulomatous response after engraftment, failure to clear infection, and gram-negative sepsis. 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 [20]. Other patients were successfully transplanted after myeloablative conditioning from matched unrelated or related donors [21,22]. 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 [23]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

Autosomal-dominant partial IFN-gamma receptor 1 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 [24], histoplasmosis [25], coccidioidomycosis [26], or salmonellosis [11]. Most patients with AD IFNGR deficiency develop NTM osteomyelitis, a manifestation that is the hallmark for this genotype in North America and Europe [11]. Histology shows mature-looking paucibacillary granulomas (picture 1), which are occasionally mistaken for malignancy [27]. (See 'Autosomal-recessive partial IFN-gamma receptor 1 or 2 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 [28]. This truncation eliminates the Janus kinase (JAK) 1 and STAT1 binding sites, as well as the receptor recycling domain, impairing the ability of the cell to remove this nonbinding molecule from the cell surface. This pathogenic variant has a "dominant-negative" effect because the mutant molecule over-accumulates on the cell surface and interacts with the normal, wild-type IFNGR1 and IFNGR2 receptor chains, inhibiting their signal ability [6,28]. Mutant chains with intact extracellular domains can still bind IFN-gamma but fail to transduce the signal because the JAK and STAT1 binding motifs are missing. In addition, the mutant chains do not get recycled, because the receptor-recycling domain is deleted [29]. 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 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 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 [16,17] and adjunctive IFN-gamma therapy than do patients with AR complete IFNGR1 deficiency, although they sometimes require a relatively high dose of IFN-gamma [5]. 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 for NTM or BCG, secondary prophylaxis is typically given with a macrolide such as daily azithromycin.

Autosomal-dominant partial IFN-gamma receptor 2 deficiency — AD partial IFNGR2 deficiency has been described in several families [30,31]. The dominant-negative 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 IFN-gamma receptor 1 or 2 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 [8,32-34]. 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 [18]. 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 [16,17].

IL-12 RECEPTOR BETA 1 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 also involved in IL-23R signaling. Pathogenic variants in the gene encoding the IL12RB1 subunit (IL12RB1, encoded on chromosome 19p13.1) have been identified in patients with disseminated infections, including Salmonella, nontuberculous mycobacteria (NTM), and Bacillus Calmette-Guérin (BCG) following vaccination [35-43]. 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 pathology that frequently has high numbers of mycobacteria.

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 [44]. 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 [44,45]. Carriers are clinically healthy with normal IL-12 signaling and IFN-gamma production patterns.

In an international study of 141 patients, the first infection occurred on average at 2.4 years of age in the 102 probands and was caused by BCG (64 percent), nontyphoidal Salmonella (22 percent), NTM (9 percent), or M. tuberculosis (4 percent) [44]. Mild chronic mucocutaneous candidiasis (CMCC) was reported in 23 percent of all patients, whereas invasive candidiasis was uncommon [46]. 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 the role remains undefined but is an option in refractory cases. (See 'Autosomal-dominant partial IFN-gamma receptor 1 deficiency' above.)

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 [47-49]. Neither the IL-12p40 subunit nor the IL-12p70 heterodimer are detectable 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 [50]. The mortality rate in the largest series was 32 percent in symptomatic patients, with a mean age at death of seven years [49]. Similar to those with IL12RB1 deficiency, the penetrance is variable, and some persons with pathogenic variants are asymptomatic.

Treatments of choice are antibiotics and subcutaneous IFN-gamma, as described above for IL12RB1 deficiency. In addition, reduced secretion of IFN-gamma by lymphocytes can be corrected with recombinant IL-12 in vitro. However, mortality remains high. (See 'Autosomal-dominant partial IFN-gamma receptor 1 deficiency' above.)

IL-12 RECEPTOR BETA 2 AND IL-23 RECEPTOR DEFICIENCIES — There are rare reports of homozygous defects in both interleukin 12 receptor beta 2 (IL-12RB2) 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 IL-12RB1 deficiency [51].

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 [35]. 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, hypermorphic-activating pathogenic variants in STAT1 confer dominant gains of function (GOF) and have little clinical overlap with the LOF variants. 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 signal transducer and activator of transcription (STAT) 1 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]. Pathogenic variants reported include missense variants (L600P and Q123H, leading to the in-frame splicing out of coding exon 3), small frameshift deletions (1758_1759delAG), or frameshift insertions (1928insA). The three unrelated patients described with this deficiency all developed disseminated Bacillus Calmette-Guérin (BCG) infection. All died in infancy, one from herpes simplex encephalitis, another from an unidentified viral illness, and the third from multiorgan failure secondary to fulminant Epstein-Barr virus (EBV) infection three months after HCT. Early HCT prior to infection may improve outcomes in patients with AR complete STAT1 deficiency.

Autosomal-recessive LOF STAT1 deficiency — AR loss-of-function (LOF) signal transducer and activator of transcription (STAT) 1 deficiency is caused by hypomorphic missense pathogenic variants that lead to impaired STAT1 expression (loss of function) [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 signal transducer and activator of transcription (STAT) 1 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 disseminated BCG or M. avium 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 IFNGR deficiency. (See 'Autosomal-recessive partial IFN-gamma receptor 1 or 2 deficiencies' above.)

Autosomal-dominant GOF STAT1 deficiency — Gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) pathogenic variants (MIM #614162) are the most common causes of the syndrome of chronic mucocutaneous candidiasis (CMCC) [58] but can cause nontuberculous mycobacteria (NTM) infections, disseminated fungal infections, bacterial infections, recurrent viral infections, or immune dysregulation similar to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) [59,60]. In an international survey of 274 patients with this defect, a wide spectrum of disease was seen, ranging from CMCC to disseminated infections, as well as aneurysms and malignancies [59]. Most cases can be managed with prevention and treatment of infections (often maintenance antifungal therapy and anti-HSV prophylaxis). Some patients can have severe disease with oral ulcers, severe infections, and autoimmunity. HCT has been performed in several of these patients, with approximately 50 percent success [61]. Janus kinase inhibitor (JAKi or Jakinib) therapy has been an effective alternative to HCT in some patients with autoimmune complications and CMCC [62,63], but its long-term efficacy is unknown. (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 probably 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 responds 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. All patients have a partial GATA2 deficiency with residual function. Haploinsufficiency of GATA2 causes a broad spectrum of clinical manifestations, including mycobacterial infections, viral infections, bone marrow failure, and leukemia [71-74].

Most commonly, 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, natural killer (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. This syndrome has been called monocytopenia and MAC (MonoMAC), dendritic cell, monocyte, and B and 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'.)

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 aplastic anemia (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'.)

The diagnosis is suspected based upon infections (persistent warts, mycobacterial infections) and abnormal complete blood count with differential (leukopenia, monocytopenia) and is often associated with a family history of relatives with leukemia or myelodysplasia. Sequencing of the GATA2 gene leads to definitive diagnosis. However, intronic variants account for a substantial percentage of cases, and these are not 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 like the other patients [84].

Unlike in the mouse model of this deficiency, an increased susceptibility to viral infections was not observed in the six reported patients [84]. The intact ability to respond to viral infections is due to enhanced IFN-alpha/beta immunity secondary to reduced levels of the negative regulator ubiquitin-specific protease 18 (USP18), which is normally stabilized by ISG15. 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 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. NEMO deficiency is discussed separately. (See "Combined 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 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 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 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 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 1). (See 'Introduction' above and "Mendelian susceptibility to mycobacterial diseases: An overview".)

●IFNGR defects – IFN-gamma receptor (IFNGR) defects can be recessive, which are typically severe and require hematopoietic cell transplantation (HCT), or dominant, which are typically more easily managed medically. Autosomal-recessive (AR) complete IFNGR1- or IFNGR2-deficient patients 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 AR partial IFNGR1 and IFNGR2 deficiencies are rare. (See 'IFN-gamma receptor deficiencies' above.)

●IL12RB1 and IL-12p40 deficiencies – IL-12 receptor beta 1 (IL12RB1) deficiency 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 'IL-12 receptor beta 1 deficiency' above.)

●STAT1 defects – Three types of STAT1 defects have been reported. Recessive complete loss of STAT1 is severe, with mycobacterial and viral infections. Dominant negative (DN) pathogenic variants are milder and 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.)

●IRF8 deficiency – AR IFN regulatory factor 8 (IRF8) deficiency results in a severe immunodeficiency with myelodysplasia with NTM and viral infections, with complete lack of monocytes and dendritic cells. In contrast, the AD form is milder, with selective depletion of circulating dendritic cells. (See 'IRF8 deficiency' 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 pulmonary alveolar proteinosis. (See 'GATA2 deficiency (MonoMAC syndrome)' above.)

●ISG15, RORC, and SPPL2A deficiencies – IFN-stimulated gene 15 (ISG15) deficiency, ROR-gamma-t deficiency, and signal peptide peptidase-like 2A (SPPL2A) deficiencies are rare defects that have only been described in several patients each with disseminated BCG. (See 'ISG15 deficiency' above and 'ROR-gamma-t deficiency' above and 'SPPL2A deficiency' above.)

●gp91phox deficiency – Specific pathogenic variants in CYBB, the gene encoding gp91phox, affect the oxidative burst in macrophages only, resulting in BCG infection. (See 'Macrophage gp91phox deficiency' 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.