Mendelian Susceptibility to Mycobacterial Disease (MSMD)

Inborn errors of interferon gamma-mediated immunity: deficiencies of the IL-12/IL-23–IFN-γ pathway

Literature and regulatory information updated: 7 November 2026.

0. Initial Reference Table

1. Introduction

Mendelian susceptibility to mycobacterial disease designates a group of inborn errors of immunity in which individuals with no other immunological abnormality fall ill with mycobacteria of low virulence, mainly the vaccine strains of bacille Calmette-Guérin and environmental non-tuberculous mycobacteria, and in which the molecular lesion invariably lies in the production of interferon gamma or in the response to it [17, 48]. Orphanet defines the entity as a rare immunodeficiency syndrome characterised by a narrow vulnerability to poorly virulent mycobacteria and by severe recurrent infections, disseminated or localised [17]. The designation is, on its own terms, incomplete: patients are equally predisposed to salmonellosis, candidiasis and tuberculosis, and more rarely to other intramacrophagic bacteria, fungi, parasites and some viruses, so that the name of the syndrome describes the historical reason for its recognition and not the totality of the infectious risk [48].

The historical background begins before molecular biology. Engbaek described in 1964 three fatal cases of Mycobacterium avium infection in the same family, and Uchiyama and colleagues reported in 1981 fatal disseminated atypical mycobacteriosis in two Mexican-American sisters, with different serotypes in the two, suggesting a congenital defect of monocyte microbicidal activity; Fischer and colleagues documented in 1980 deficient monocyte function in a 12-month-old child with fatal disseminated BCG infection [9]. In 1995, Levin and colleagues gathered six children with disseminated atypical mycobacterial infection without a recognised immunodeficiency, four of them from a village in Malta and two siblings of Greek Cypriot origin, with fever, weight loss, lymphadenopathy and hepatosplenomegaly, isolation of Mycobacterium fortuitum, Mycobacterium chelonae and four strains of the Mycobacterium avium intracellulare complex, failure of multiple antibiotic therapy and improvement associated with interferon gamma; three died and the three survivors remained chronically infected [9]. In the same year, Holland and colleagues published the first open therapeutic trial in this field, with seven patients without HIV infection and refractory disseminated non-tuberculous mycobacteriosis, three of them from a family predisposed to M. avium complex infections, treated with subcutaneous interferon gamma 25 to 50 µg/m² two to three times a week in combination with antimycobacterial drugs, with marked clinical improvement in all in the first eight weeks [49].

The year 1996 marks the molecular birth of the entity. Newport and colleagues studied four Maltese children with unexplained genetic susceptibility to mycobacteria, mapped by microsatellites a homozygous region on 6q, where the interferon gamma receptor 1 gene lies, demonstrated absence of the receptor on leucocytes by immunofluorescence and identified a nonsense mutation at nucleotide 395, generating a truncated protein lacking the transmembrane and cytoplasmic domains, with a functional defect in tumour necrosis factor alpha induction by macrophages [50]. In the same issue of the same journal, Jouanguy and colleagues described interferon gamma receptor deficiency in an infant with fatal BCG infection [51]. In 1997, the same team defined partial IFN-γR1 deficiency in a family in which one child had curable BCG disease with tuberculoid granulomas, and an unvaccinated sibling developed clinical tuberculosis; the cellular dose-response to interferon gamma separated the three states, because cells from healthy individuals respond to 10 international units per millilitre, those from a complete deficiency do not respond to 10,000 international units per millilitre and those from a partial deficiency respond only to high concentrations [52].

In 1998, two groups simultaneously published IL-12Rβ1 deficiency, showing that the beta-1 chain of the interleukin 12 receptor was absent in otherwise healthy individuals with mycobacterial and Salmonella infections, with premature stop codons in the extracellular domain, reduced interferon gamma secretion by activated T and NK cells and, unlike interferon gamma receptor deficiency, well-formed mature granulomas [53, 54]. In 1999 the concept of dominant inheritance in this syndrome emerged, with the description of a hotspot of small deletions in IFNGR1: eighteen patients from twelve unrelated families, with twelve independent mutational events at the same site, whose alleles encode a surface receptor lacking the intracytoplasmic domain that binds interferon gamma normally but neither signals nor recycles, exerting a dominant-negative effect [55]. In 2001, Dupuis and colleagues described the first heterozygous loss-of-function STAT1 variant, which abolishes activation of gamma-activated factor but preserves that of interferon-stimulated gene factor 3, resulting in a disease that is dominant for antimycobacterial immunity and recessive for antiviral immunity [56]. In the same year a simple diagnostic test became available: children with complete interferon gamma receptor deficiency have very high plasma levels of this cytokine, unlike the other predisposing genetic defects [38].

The last decade and a half has multiplied the genes. In 2006 the X-linked form due to variants of the leucine zipper of IKBKG was described, with a defect of CD40-dependent interleukin 12 production [57]; in 2007 and 2011, the X-linked form due to CYBB variants that affect only macrophages [58, 59]; in 2011, IRF8 deficiency with dendritic cell immunodeficiency [7]; in 2012, ISG15 deficiency [60]; in 2015, RORγ/RORγT deficiency and complete TYK2 deficiency [61, 62]; in 2016, partial JAK1 deficiency due to biallelic loss-of-function variants [63]; in 2018, SPPL2a deficiency and homozygosity for the common TYK2 P1104A allele as a frequent monogenic cause of tuberculosis [64, 65]; in 2020, complete deficiency of interferon gamma itself and T-bet deficiency [66, 67]; in 2021, ZNFX1 deficiency [68]; in 2023, IL-23R, IRF1 and MCTS1 deficiencies [69–71]; in 2024, CCR2 deficiency, in which BCG disease accompanies pulmonary alveolar proteinosis and polycystic lung disease [72]. In 2026, two publications extended the picture: homozygosity for rare or common hypomorphic IL23R variants predisposes to tuberculosis [73] and complete and partial forms of MCTS1 deficiency were described [74].

The gene count tells the history of the field and explains the difficulty of comparing publications from different periods. Al-Muhsen and Casanova described in 2008 six genes and thirteen distinct disorders, with about half of the patients without an identified aetiology [75]; Bustamante and colleagues listed in 2014 nine genes and eighteen disorders [48]; the 2024 systematic review catalogued variants in 21 genes associated with the syndrome [4]; a 2024 review lists 21 genes and the 2024 IUIS classification keeps ZNFX1 in the viral susceptibility table and includes CCR2 among the phagocyte defects [1, 2]. Successive reviews have followed this expansion, with syntheses devoted to recent discoveries in the field and to how the collapse of interferon gamma-driven immunity explains the heterogeneity of infections [76–78]. Half of the patients with a compatible clinical phenotype still have no molecular diagnosis, a proportion that has remained stable since 2008 and is now attributed to genes not yet described, to deep intronic variants and to structural variants [33, 37].

A nomenclature distinction organises the whole group. Isolated MSMD refers to susceptibility restricted to mycobacteria and related organisms, and syndromic MSMD to cases in which the same genetic defect adds manifestations of another kind, such as chronic mucocutaneous candidiasis, viral susceptibility, intracranial calcification or ectodermal dysplasia. Genes of the isolated form are IFNGR1, IFNGR2, IFNG, STAT1, IRF8, IL12RB1, IL12RB2, IL23R, IL12B, SPPL2A, TYK2, IKBKG and CYBB, and genes of syndromic forms are STAT1, IRF8, ZNFX1, TYK2, JAK1, ISG15, RORC and TBX21, with several genes appearing in both lists because the phenotype depends on the allele [33]. A complementary and more operational classification separates the defects by their point in the pathway: genes whose loss impairs interferon gamma production (IFNG, IL12B, IL12RB1, IL12RB2, IL23R, ISG15, MCTS1, RORC, TBX21, TYK2), genes whose loss impairs the response to this cytokine (CYBB, JAK1, IFNGR1, IFNGR2, IRF1, STAT1, USP18) and genes that affect both (IRF8, IKBKG, SPPL2A) [2]. This separation is not taxonomic: it decides whether recombinant interferon gamma has any chance of working in the individual patient.

The scope of this article is the whole class, with the entities defined one by one. It includes complete and partial IFN-γR1 and IFN-γR2 deficiencies, the three STAT1 disorders linked to the interferon pathway, IL-12p40 and IL-12Rβ1 deficiencies, IL-12Rβ2 and IL-23R deficiencies, deficiencies of interferon gamma, IRF1, IRF8, SPPL2a, ISG15, RORγT, T-bet, complete TYK2 and homozygous TYK2 P1104A, partial JAK1, MCTS1 and ZNFX1, macrophage MSMD due to CYBB and X-linked mycobacteriosis due to hypomorphic IKBKG variants. Hereditary chronic mucocutaneous candidiasis, including STAT1 gain of function and the candidiasis component of RORγT deficiency, chronic granulomatous disease, incontinentia pigmenti, ectodermal dysplasias with immunodeficiency, GATA2 deficiency, type I interferonopathies, which include USP18 deficiency, and monogenic predisposition to severe viral infections due to IFNAR1 and IFNAR2 deficiencies enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The IL-12/IL-23–IFN-γ pathway and its point of failure

Interferon gamma is the type II interferon, produced mainly by T lymphocytes and natural killer cells, and is the cytokine that activates the macrophage to kill the microorganisms it has ingested [2]. Its induction depends on interleukin 12 and interleukin 23, produced by dendritic cells and macrophages after contact with the mycobacterium. Interleukin 12 is a heterodimer of p35 and p40, the latter encoded by IL12B, and binds to a receptor composed of the IL-12Rβ1 and IL-12Rβ2 chains; interleukin 23 shares the p40 subunit and uses a receptor formed by IL-12Rβ1 and IL-23R [2, 69]. The beta-1 chain, encoded by IL12RB1, is therefore common to both receptors, so that its loss simultaneously abolishes interleukin 12 and interleukin 23 signalling. Downstream, TYK2 and JAK2 phosphorylate STAT4 and induce IFNG transcription; the catalytic activity of TYK2 is required for interleukin 23 signalling but not for interleukin 12 signalling, and MCTS1 is required for JAK2 translation [65, 71].

On the response side, interferon gamma binds to the alpha chain IFN-γR1, associated with JAK1, which recruits the beta chain IFN-γR2, associated with JAK2; IFN-γR1 is the ligand-binding chain and IFN-γR2 is the transducing chain, unable to bind the cytokine but indispensable for signalling [2]. Phosphorylation of STAT1 gives rise to the homodimer known as gamma-activated factor, which translocates to the nucleus and activates interferon-stimulated genes, among them IRF1, which is in turn required for the antimycobacterial programme of the mononuclear macrophage [2, 70]. The final microbicidal activity includes the oxidative burst, which in the particular case of the macrophage CYBB variants is impaired only in macrophages [59]. This architecture explains two clinical facts. First, the severity of each form follows the residual interferon gamma activity: complete autosomal recessive deficiencies of IFN-γR1, IFN-γR2, STAT1, IRF1 and interferon gamma are the most severe forms and most patients die before the age of ten without transplantation [2, 4]. Second, the position of the defect determines the therapeutic usefulness of the cytokine: when the lesion lies in production, supplying exogenous interferon gamma bypasses the block; when it lies in the response, there is benefit only if residual receptor exists [33].

2.2. Table of the entities in the class

The associations of IL12RB2, IL23R and loss-of-function JAK1 deficiency appear in the 2024 IUIS classification but have no Mendelian phenotype number of their own in OMIM, and those of IFNG and TBX21 are recorded with the question mark that OMIM uses for provisional relationships [1, 79]. The number 618999, which some databases associate with MSMD due to partial JAK1 deficiency, corresponds in OMIM to autoinflammation, immune dysregulation and eosinophilia, an autosomal dominant disease due to gain-of-function JAK1 variants, clinically distinct and treated with JAK inhibitors; confusion between the two entities of the same gene has opposite therapeutic consequences and must be resolved in the laboratory report [63, 79].

2.3. Defects of interferon gamma production

IL-12Rβ1 deficiency is the most frequent genetic cause, with 41% of 830 published patients [4]. The beta-1 chain is shared by the interleukin 12 and interleukin 23 receptors, so its absence abolishes both pathways, with failure of interferon gamma induction and, through loss of the IL-23–IL-17 axis, mild mucocutaneous candidiasis in a minority of patients [34]. About two thirds of the disease-causing variants create premature stop codons, through nonsense, frameshift or splice-site mutations, and practically all disease-causing alleles completely inactivate the protein, so that a residual response to IL-12 should prompt review of the genotype or a search for another gene [80]. A locus-specific database supports the interpretation of new variants [80]. The most frequently cited recurrent variant is NM_005535.3:c.1791+2T>G, with an effect on splicing; in the Indian cohort of 50 patients the most frequent variant was NM_005535.3:c.962C>A, p.(Ser321Ter), found in seven patients, five of whom died [3, 81].

IL-12p40 deficiency, due to biallelic IL12B variants, removes the shared subunit and with it both cytokines: neither interleukin 12p70 nor free interleukin 12p40 is detectable, and interferon gamma production is low [82]. In the largest series, of 49 patients from 30 families from India, Iran, Pakistan, Saudi Arabia and Tunisia, there were only nine mutant alleles, all loss-of-function, and all patients were homozygous with complete deficiency; four of these alleles were recurrent and accounted for 25 of the 30 families, owing to founder effects [82]. The variant NM_002187.3:c.315_316insT, p.(Lys106Ter), accounts for about 35% of the described alleles of the gene [3, 4], and the Tunisian founder allele was dated to about 1100 years ago [83].

IL-12Rβ2 and IL-23R deficiencies dissect the two pathways that IL-12Rβ1 deficiency abolishes together. In patients with biallelic IL23R variants, interleukin 23 proved necessary for interferon gamma production, basal and mycobacteria-induced, in at least two lymphocyte subsets, Vδ2+ γδ T lymphocytes and mucosal-associated invariant T cells, whereas induction of interleukin 17A by this cytokine is restricted to the latter; this asymmetry explains why all published patients have mycobacterial disease and only some have candidiasis [69]. The series is small and precise: two children from one family with isolated disseminated BCG disease, a 48-year-old man homozygous for NM_144701.3:c.1141C>T, p.(Arg381Ter), with disseminated non-tuberculous mycobacteriosis and almost absent membrane IL-23R, and six patients from four families homozygous for one of four loss-of-function alleles, of whom only two had candidiasis [3, 36, 69]. In 2026 it was shown that homozygosity for four hypomorphic IL23R alleles is enriched in a tuberculosis cohort; three are rare and the fourth is NM_144701.3:c.1142G>A, p.(Arg381Gln), the rs11209026 allele that protects against Crohn's disease, with an allele frequency of 0.056 in gnomAD v4 and 2622 homozygotes recorded, so that homozygosity for this common variant indicates partial predisposition to tuberculosis and not an inborn error of immunity [3, 73].

Complete TYK2 deficiency degrades two arms at once: responses to interleukin 12 and interleukin 23, which reduce interferon gamma induction, and responses to interferon alpha and beta, which weaken antiviral defence; responses to interleukin 10 are also impaired, without evident clinical consequence, and responses to interleukin 21, interleukin 27, interferon gamma itself, interferon lambda and leukaemia inhibitory factor are normal [62]. Two points require care because older descriptions are misleading. The first patient described had a clinical diagnosis of hyper-IgE syndrome, with atopic dermatitis, raised serum IgE and staphylococcal abscesses, and OMIM still summarises immunodeficiency 35 in these terms; when seven additional patients from five families and four ethnic groups were characterised, none had hyper-IgE syndrome and their cells responded normally to interleukin 6, so that a deficient response to this cytokine and the hyper-IgE phenotype do not appear intrinsic to human TYK2 deficiency [62, 84]. The second is that candidiasis is not a reliable feature: the seven later patients had impaired responses to interleukin 23 with normal proportions of interleukin 17-producing T cells and no apparent mucocutaneous candidiasis [62]. A patient homozygous for a nonsense variant had severe viral respiratory infections, Epstein-Barr virus-associated Burkitt-like lymphoma and Jamestown Canyon virus infection, and the cellular defect was not pharmacologically correctable, so the authors proposed transplantation or gene therapy [85]. The common allele NM_003331.5:c.3310C>G, p.(Pro1104Ala), is a distinct case: the protein docks correctly on cytokine receptors and is phosphorylated but has no catalytic activity, and because this activity is required for interleukin 23 signalling and not for interleukin 12 signalling, the deficiency is confined to the interleukin 23 arm; homozygosity is more frequent in patients with tuberculosis from endemic areas than in ethnicity-matched controls, and the allele frequency in Europeans fell from about 9% to 4.2% over the last 4000 years, consistent with purging by endemic tuberculosis [3, 65].

RORγ and RORγT deficiency has two immunological consequences, one expected and one not. Interleukin 17A- and 17F-producing T cells fail to develop, which removes the mucocutaneous antifungal axis; and interferon gamma production in response to mycobacteria is profoundly impaired in γδ T lymphocytes and in the CD4+CCR6+CXCR3+ αβ T subset, which explains the mycobacterial susceptibility [61]. The combination that should prompt testing of this gene is therefore chronic mucocutaneous candidiasis with disseminated BCG disease or environmental mycobacteriosis in the same child, an association that the more common causes of each isolated syndrome do not produce [61]. T-bet deficiency has been described in a single patient, the child of Moroccan cousins, homozygous for an insertion-deletion in TBX21, with very low counts of mycobacteria-reactive NK, iNKT, MAIT and Vδ2+ γδ T cells and scant interferon gamma production by them, while CD8+ T cells and non-classical CD4+ TH1* T cells produced the cytokine normally without being able to compensate for the deficit [67]. In the same patient, upper airway inflammation and eosinophilia were attributed to excessive production of interleukin 5 and interleukin 13 by CD4+ T cells [86].

ISG15 deficiency corrected a prediction made in the mouse. Work in animal models had led to the expectation of an antiviral phenotype mediated by ISGylation; human patients have no abnormal viral susceptibility and their cells did not prove susceptible to the viruses tested [60]. Instead, leucocytes, especially granulocytes, secrete ISG15 in response to mycobacteria, and this secreted ISG15 induces interferon gamma production by lymphocytes and NK cells; without it, interferon gamma responses to mycobacteria are impaired [60]. The absence of intracellular ISG15 prevents the accumulation of USP18, a potent negative regulator of interferon alpha and beta signalling, so that type I interferon responses are amplified, with basal ganglia calcification and a picture reminiscent of Aicardi-Goutières syndrome [2, 60]. MCTS1 deficiency operates through a translational mechanism: complete loss of this translation reinitiation factor impairs the synthesis of a subset of proteins, including the kinase JAK2 in all cell types tested, with JAK2 expression low enough to impair responses to interleukin 23 and partially to interleukin 12, but not those to other JAK2-dependent cytokines; deficient responses to interleukin 23 preferentially affect interferon gamma production by MAIT cells and γδ T lymphocytes [71]. Complete interferon gamma deficiency is the most upstream lesion possible: two Lebanese cousins living in Kuwait were homozygous for NM_000619.3:c.354_357del, p.(Thr119IlefsTer4), with loss of expression and function, and their T and NK lymphocytes produced no detectable amounts of the cytokine; population genetic analyses show that IFNG is under stronger purifying selection than IFNGR1 or IFNGR2, which explains the relative rarity of this deficiency [3, 66]. A second patient, Turkish and the child of consanguineous parents, was homozygous for NM_000619.3:c.224T>C, p.(Phe75Ser), with intracellular production of the cytokine but without correct folding or secretion [3, 87].

2.4. Defects of the response to interferon gamma

The two IFNGR1 disorders carry different recurrence risks and distinct clinical courses, which is why this gene appears with two modes of inheritance. In the defining comparison, of 22 patients with complete recessive deficiency and 38 with partial dominant deficiency, the recessive patients were younger at the first environmental mycobacterial infection, with a mean of 3.1 years versus 13.4 years, had more episodes of mycobacterial disease, 19 versus 8 per 100 person-years, more organs involved by the M. avium complex, 4.1 versus 2.0, much shorter disease-free intervals, 1.6 versus 7.2 years, and lower Kaplan-Meier survival; disease due to rapidly growing mycobacteria clustered in them, 32% versus 3%, and all nine vaccinated recessive patients developed disease due to the vaccine strain [5]. The hallmark of the dominant form is multifocal osteomyelitis due to the M. avium complex, present in 22 of 28 dominant patients versus 1 of 8 recessive patients, and isolated bone disease without involvement of other organs occurred only in the dominant patients, in 9 of 28; the bone tropism is attributed to loss of the brake that interferon gamma exerts on osteoclast differentiation and bone resorption [5]. Granulomas are lepromatoid and poorly formed in complete deficiency and tuberculoid and well differentiated in partial deficiency [5, 52]. Most dominant alleles arise in a single hotspot of small deletions: eighteen patients from twelve unrelated families carried one of several overlapping small frameshift deletions, generated by twelve independent mutational events at the same site, and the truncated receptor reaches the surface without the intracytoplasmic domain, binds the cytokine normally but neither signals nor recycles, with a dominant-negative effect [55]. The classic variant of this hotspot is NM_000416.3:c.819_822del, p.(Asn274HisfsTer2), written in the older literature as 818del4 and in recent catalogues as c.819_822delTAAT, and accounts for about 40% of the described variants of the gene [3, 4]. There is a third, partial recessive form, described in 14 patients from 11 families with the founder alleles NM_000416.3:c.260T>C, p.(Ile87Thr), found in the homozygous state in nine patients from Chile, Portugal and Poland, and NM_000416.3:c.188T>G, p.(Val63Gly), in five patients from the Canary Islands; the most recent common ancestors of the carriers were dated to about 1600 years ago for the first allele and 500 years ago for the second, the mean age at onset of the first environmental mycobacterial disease was 11.25 years and the outcome was favourable, with 13 of the 14 patients alive and up to ten free of infection without any prophylaxis [3, 88]. The 2017 mutation update counted 40 distinct variants in 135 individuals from 98 families, 60% of which create a premature stop codon and 28% are amino acid substitutions, all deposited in a locus-specific database [89]. As the cytokine is not consumed by the receptor, circulating interferon gamma rises to very high levels in infected patients with complete deficiency, a finding with diagnostic value of its own [38].

IFN-γR2 deficiency reproduces the picture, with the particularity that the beta chain does not bind the ligand. The complete form expresses no functional receptor at the surface, abolishes the cellular response and manifests in the neonatal period or early childhood with severe disease [11]. The partial forms have two distinct mechanisms. In the first, hypomorphic alleles produce misfolded proteins with abnormal N-glycosylation, largely retained in the endoplasmic reticulum, of which a small fraction reaches the surface and functions; the cellular response to interferon gamma in these patients is enhanced by chemical modifiers of N-glycosylation in cellular assays [90]. In the second, variants of the initiation codon or the second codon, NM_005534.4:c.1A>G, p.(Met1?), and NM_005534.4:c.4del, p.(Arg2AspfsTer46), allow the production of small amounts of normal-length receptor through translation initiation at non-AUG codons located between the second and ninth codons of the 21-amino-acid signal peptide, giving rise to a purely quantitative form of partial recessive deficiency; in these patients residual signalling levels were very low, which explains a more severe clinical phenotype than that of partial forms with a dysfunctional receptor at the surface [3, 91]. There is also a dominant form due to haploinsufficiency: a single loss-of-function allele, without a dominant-negative effect, can cause the syndrome mainly in lymphoid cells, which express less IFN-γR2 than myeloid cells, with incomplete clinical penetrance; Epstein-Barr virus-transformed B cells from ten heterozygous relatives of patients with complete deficiency responded poorly to interferon gamma, in some cases as poorly as those of the index patient [6]. A heterozygous IFNGR2 finding in a symptomatic patient therefore deserves functional assessment and not automatic dismissal as carrier status [6].

The three STAT1 disorders are distinguished by the direction of the functional change, not by the presence of a variant. Dominant-negative heterozygous variants cause autosomal dominant partial deficiency with mycobacterial susceptibility, in which multifocal osteomyelitis is a representative manifestation; the described alleles lie in the tail segment, with NM_007315.4:c.2117T>C, p.(Leu706Ser), in the DNA-binding domain, with p.(Glu320Gln) and p.(Gln463His), and in the SH2 domain, with NM_007315.4:c.1909A>G, p.(Lys637Glu), and NM_007315.4:c.2018A>G, p.(Lys673Arg) [3, 8, 56]. The first of the latter is hypomorphic and impairs tyrosine phosphorylation, whereas the second is null and affects phosphorylation and DNA binding; both are dominant-negative and impair STAT1-mediated cellular responses to interferon gamma and interleukin 27, while responses to interferon alpha and interferon lambda 1 remain normal, which explains the selectively mycobacterial and not viral susceptibility of this form [8]. Biallelic loss-of-function or hypomorphic variants cause complete or partial recessive deficiency, with vulnerability to intracellular bacteria, especially mycobacteria, and also to viruses [13]. Gain-of-function variants, clustered in the coiled-coil domain, act through impaired dephosphorylation, not increased phosphorylation, and cause chronic mucocutaneous candidiasis with autoimmunity, a picture in which mycobacterial disease occurs in only 6% of an international cohort of 274 patients from 167 families in 40 countries [92]. The distinction is not academic: JAK inhibition is rational in gain of function and would be expected to worsen loss of function [13].

Downstream of STAT1, IRF1 deficiency shows that the antimycobacterial programme of the macrophage depends on this transcription factor. Children with complete deficiency had multiple, potentially fatal diseases due to poorly virulent mycobacteria and related intramacrophagic agents, with no history of severe viral disease despite exposure to many viruses, including SARS-CoV-2; in stimulated leucocytes and fibroblasts, IRF1-dependent responses to interferon gamma are quantitatively and qualitatively much stronger than those to interferon alpha and beta, and deficient mononuclear phagocytes do not control mycobacteria when stimulated with interferon gamma, whereas interferon alpha- and beta-dependent intrinsic immunity to nine viruses remains almost normal in fibroblasts [70]. Partial JAK1 deficiency was described in a patient with recurrent atypical mycobacteriosis and early-onset metastatic bladder carcinoma, homozygous for two variants, with reduced phosphorylation of JAK1 and of STAT proteins after stimulation, reduced induction of interferon-regulated genes and dysregulated cytokine production, including that of interferon gamma [63].

2.5. Defects affecting both pathways and genes of uncertain placement

IRF8 variants produce two immunodeficiencies of very different severity, separated by zygosity. Complete biallelic deficiency, immunodeficiency 32B, is characterised by absence of circulating monocytes and dendritic cells, with myeloproliferation and neutrophilia and normal lymphoid counts; the child in whom the disease was defined presented at ten weeks with failure to thrive, oral candidiasis and early disseminated BCG disease, with a profound deficit of tissue and blood dendritic cells, improved with antimycobacterial and antibacterial drugs, deteriorated at six months and received haematopoietic cell transplantation, being well twelve months later; she was homozygous for NM_002163.4:c.322A>G, p.(Lys108Glu), in the DNA-binding domain, and none of the other family members, all vaccinated with BCG, fell ill [3, 7, 14]. Partial heterozygous deficiency, immunodeficiency 32A, due to NM_002163.4:c.238A>G, p.(Thr80Ala), selectively depletes CD11c+CD1c+ dendritic cells and preserves monocytes; the two individuals originally described were healthy adults with a childhood history of disseminated but curable BCG disease [3, 7]. A fourth patient with complete deficiency, compound heterozygous for c.55del and p.(Arg111Ter), had severe pulmonary alveolar proteinosis, disseminated BCG disease and cerebral calcifications, and died at ten months of refractory proteinosis; the c.55del allele allows translation reinitiation from a downstream methionine, but both alleles were loss-of-function in a luciferase assay [93]. Biallelic IRF8 mutations also impair NK cell maturation and function, with an increase in CD56 bright cells and a decrease in CD56 dim cells, which helps to explain the susceptibility to Epstein-Barr virus documented in a family followed since 1982 [14, 94].

Hypomorphic variants of IKBKG, which encodes the nuclear factor kappa B essential modulator, cause an X-linked immunodeficiency that affects only males and that, depending on the domain affected, may or may not be accompanied by ectodermal dysplasia. Two variants of the leucine zipper domain, NM_001099857.5:c.944A>C, p.(Glu315Ala), and NM_001099857.5:c.956G>A, p.(Arg319Gln), both predicted to disrupt a salt bridge, were identified in three families with the X-linked recessive form of the syndrome; the mutant proteins are produced in normal amounts, but the patients' monocytes have an intrinsic defect of T cell-dependent interleukin 12 production, with deficient interferon gamma secretion by these cells, owing to a specific failure of CD40 signalling mediated by NEMO and by nuclear factor kappa B and c-Rel, whereas CD40-dependent proliferation and immunoglobulin class switching remain normal and the cells respond to other activators of the pathway, such as tumour necrosis factor alpha, interleukin 1 beta and lipopolysaccharide [3, 57]. In an American family, four boys developed disseminated M. avium complex disease between the ages of 5 and 14 years without having been vaccinated with BCG, and several had recurrent bacteraemias due to Haemophilus influenzae and Enterobacter [15]. In general, variants affecting the C-terminal zinc finger domain give a more severe course with ectodermal dysplasia, whereas those of the leucine zipper or of the more N-terminal coiled-coil domains give a less severe course, usually without dysplasia, although isolated hypodontia and conical incisors may be present [15]. In four adults from three families with disseminated mycobacteriosis diagnosed between the ages of 26 and 38 years, the variants lay in the 5' untranslated region, with NM_001099857.5:c.1-16G>C at the last base of the first untranslated exon in one case and a change in the adjacent intron in another; the resulting splicing abnormality leaves about 30% of the transcript and protein, the cells do not upregulate cytokines in response to Toll-like receptor agonists, and three of the four patients died of the mycobacterial infection [15, 35]. These untranslated region variants escape exome sequencing [35]. The same hypomorphic IKBKG variants give rise, in other alleles, to anhidrotic ectodermal dysplasia with immunodeficiency and to the form with osteopetrosis and lymphoedema, described in atlases of skeletal dysplasias with anhidrosis, delayed tooth eruption and conical teeth, sparse hair, multiple bacterial infections, failure to thrive, malabsorption, hyperpigmented rash and lymphoedema, mild bone sclerosis and a bone-within-bone appearance, with X-linked dominant inheritance and mothers with incontinentia pigmenti [32, 95, 96].

SPPL2a deficiency operates through accumulation of a toxic fragment. Without this transmembrane protease, the N-terminal fragment of CD74, the invariant chain of the HLA class II complex, accumulates in cells expressing that complex and selectively depletes type 2 conventional dendritic cells, CD1c+, which produce interleukin 12 and interleukin 23, and their circulating progenitors; mycobacteria-specific memory TH1* T cells then no longer produce interferon gamma in vitro, while the receptor pathway for this cytokine remains intact [64]. The first three patients were Moroccan twin girls and a Turkish boy, from two consanguineous families, homozygous for essential splice-site variants, all with BCG disease after vaccination and axillary mycobacterial lymphadenitis in early childhood, with acid-fast bacilli on biopsy and necrotising granulomatous inflammation; leucocyte subsets were normal and one patient had low IgG. The twins' hereditary spastic paraplegia was due to a distinct homozygous variant of AP4E1 and is not part of SPPL2a deficiency [64].

ZNFX1 deficiency is the member of the class whose placement remains open. Four patients from two unrelated families had intermittent monocytosis and mycobacterial disease, including BCG-osis and disseminated tuberculosis, without any known inborn error of the interferon gamma pathway; they were homozygous for predicted loss-of-function variants, p.(Ser959Ter) and p.(Glu1606ArgfsTer10), and there are no homozygotes for equivalent variants in public databases [68]. The protein is a conserved, broadly expressed helicase, recruited to stress granules and able to induce them; the patients' lymphocyte subsets were normal and produced interferon gamma normally, and haematopoietic and non-haematopoietic cells responded normally to this cytokine, so the mechanism of mycobacterial susceptibility does not go through the canonical pathway [68]. The 2024 IUIS classification places the gene in the table of predisposition to severe viral infections, with severe early inflammation of the liver, brain, kidneys and lungs, virus-triggered inflammatory episodes, hepatosplenomegaly and lymphadenopathy, and the review devoted to interferon gamma notes that the effect of the gene in the syndrome is uncertain [1, 2]. CCR2 deficiency, in turn, is a lung disease before it is a mycobacterial immunodeficiency: nine children from five families with autosomal recessive complete deficiency had pulmonary alveolar proteinosis, progressive polycystic lung disease and recurrent infections, including BCG disease, with raised blood levels of the ligand CCL2, which serve as a screening test, preserved immunity mediated by interferon gamma and by granulocyte-macrophage colony-stimulating factor, and an alveolar macrophage count reduced to about half [72].

The macrophage CYBB variant is the clearest example of how a known gene can hide a different disease. Two French families, with four and three maternally related men, presented recurrent mycobacterial disease with X-linked recessive inheritance: in the first, three with recurrent BCG disease and one with recurrent tuberculosis, aged 32 to 55 years at the time of the report, with lymph node tropism and granulomas with caseous necrosis without acid-fast bacilli, all responding to antibiotics or surgical excision; in the second, three men aged 36 to 41 years with BCG disease after neonatal vaccination [16, 58]. The variants identified were NM_000397.4:c.532A>C, p.(Thr178Pro), and NM_000397.4:c.692A>C, p.(Gln231Pro); all clinically affected men were hemizygous and the eleven obligate carriers tested were heterozygous [3, 59]. The decisive finding was functional: NADPH oxidase activity was normal in circulating neutrophils and monocytes, unlike classic chronic granulomatous disease and its variants, but in vitro differentiation of monocytes into macrophages in the presence of macrophage colony-stimulating factor revealed impaired oxidase activity and reduced capacity to control BCG growth, with CYBB expression much more reduced in macrophages than in neutrophils and monocytes and impaired production in lymph node macrophages [59]. The GeneReviews chapter on chronic granulomatous disease explicitly notes that the dihydrorhodamine test is normal in this form, so a normal result does not exclude it [31].

2.6. Penetrance, expressivity and genotype–phenotype correlations

Penetrance varies by entity in a way that shapes counselling. It is described as complete in complete recessive IFN-γR1 deficiency and in complete deficiencies of IFN-γR2, interferon gamma and IRF1, and as low as 0.5% in partial dominant IFN-γR1 and IFN-γR2 deficiencies [4]. In IL-12Rβ1 deficiency, of 29 genetically affected siblings identified by family screening, 20 were symptomatic and 8, that is 27%, remained entirely asymptomatic [34]; in the original series of 41 patients, seven of the twelve affected siblings excluding the probands never had an infection meeting the case definition [97]. In IL-12p40 deficiency, one third of the genetically affected relatives of index cases had no symptoms [82]. This incomplete penetrance is why cascade screening, and not waiting for the first symptom, is what protects the next sibling before vaccination [34, 82].

In genes with complete and partial forms, the correlation between genotype, cellular response to interferon gamma and clinical picture is strong, and it is this correlation that makes the cellular dose-response an examination with prognostic and therapeutic value [5, 52]. In the Indian cohort the same relationship was observed for IFN-γR1 deficiency, with absent or markedly reduced CD119 expression and higher circulating interferon gamma levels in the complete forms, with a more severe phenotype, and greater expression in the partial forms; for IL-12Rβ1 deficiency there was no correlation between protein expression, cytokine data and clinical severity, as patients with normal expression had severe disease [81]. Among the frequent variants, analysis of symptoms by gene showed osteomyelitis to be common in dominant STAT1 deficiency, in 62%, and dominant IFN-γR1 deficiency, in 54%, fever frequent in STAT1 deficiency, in 79%, and IFN-γR2 deficiency, in 63%, and lymphadenopathy rarer in NEMO deficiency, in 20%, and TYK2 deficiency, in 19% [4]. The microbiological pattern also points to the gene: the association of mycobacterial disease with cytomegalovirus infection suggests complete recessive IFN-γR1 or IFN-γR2 deficiency or complete recessive STAT1 deficiency; salmonellosis, especially due to non-typhoidal Salmonella, suggests complete IL-12Rβ1 or IL-12p40 deficiency; chronic mucocutaneous candidiasis suggests IL-12Rβ1, IL-23R or RORγT deficiency; the combination of cerebral calcification with mycobacterial disease suggests ISG15, USP18 or ZNFX1 deficiency; and multifocal osteomyelitis is strongly associated with dominant IFN-γR1 and STAT1 deficiencies and with X-linked MCTS1 deficiency [4].

As regards the variant spectrum across the whole class, the systematic review of 830 patients catalogued 299 unique variants in 21 genes: 100 missense (34%), 80 frameshift insertions or deletions (27%), 53 nonsense (18%), 35 essential splice-site (12%), 10 in-frame insertions or deletions (2.7%), 6 insertion-deletions (2%) and 15 large deletions or duplications; the variants are distributed relatively evenly along the genes, without mutational hotspots, with the two exceptions already mentioned, c.819_822delTAAT of IFNGR1 and c.315_316insT of IL12B [4]. Dominant-negative mechanisms are described in IFN-γR1, STAT1 and IRF8, and haploinsufficiency in IFN-γR2 [4].

3. Clinical Spectrum and Manifestations by System

3.1. Common picture and cohort data

The unifying feature is selective vulnerability: previously healthy children, with normal blood count and routine immunological assessment, fall ill with microorganisms that the general population tolerates [37, 48]. The systematic review of 830 patients with a genetic diagnosis, from 581 families and 63 countries and published up to 2024, is the broadest numerical reference: 436 male (52.5%), 369 female (44.5%) and 25 of unstated sex, with a positive family history in 347 (45.5%) and a mean age of 10.41 years, plus or minus 0.42 years standard error of the mean, with cases between 14 days and 62 years [4]. The countries with the most published patients were Iran with 114, Turkey with 107, India with 63, Saudi Arabia with 54 and France with 51 [4]. At the time of each publication's report, 597 patients were alive (71.9%), 177 had died (21.3%) and 56 had no information; the mean age at death was 8.68 years, with a standard error of 1.00 year [4].

The initial presentation, documented in 417 patients, was lymphadenopathy in 195 (46.8%), isolated fever in 59 (14.1%), BCG disease in the form of BCG-osis or BCG-itis in 27 (6.5%), osteomyelitis in 24 (5.7%), fever with involvement of at least one organ in 17 (4.1%) and anorexia or cutaneous manifestations in 14 (3.4%) each [4]. Over the course of the disease, lymphadenopathy affected 378 patients (45.5%), isolated and axillary in 106 (28%), cervical in 23, peripheral subcutaneous in 19, abdominal in 11, mediastinal in nine and at multiple sites in 134 (35.4%) [4]. Fever occurred in 251 (30.2%), organomegaly in 206 (24.8%), with splenomegaly in 78, hepatomegaly in 66 and hepatosplenomegaly in 62, and at least one episode of sepsis in 171 (20.6%) [4]. Abscesses in at least one episode appeared in 85 patients (10.2%), in lymph nodes in 17, in a paravertebral location including the psoas muscle in 15, hepatosplenic in 13, cutaneous in eight and in the chest wall in five [4].

Osteomyelitis occurred in 117 patients (14.1%) and was multifocal, defined as involvement of at least two bones at distinct sites, in 67 of these cases (57.3%); there was isolated vertebral disease in eight, lower limb disease in seven, hip joint disease in five, rib disease in two, skull disease in one and upper limb disease in another, with the site undetermined in 26 [4]. In 38 of the 117 cases of osteomyelitis there was mixed bacterial and mycobacterial infection, in 38 infection by the tuberculosis complex and in 31 by non-tuberculous mycobacteria, with one case of isolated Salmonella osteomyelitis and nine aseptic cases or of undetermined cause [4]. Cutaneous manifestations affected 118 patients (14.2%), with maculopapular rashes in 21, candidiasis and granulomas in 12 each, ulcers in nine, eczema in eight, abscesses and cutaneous vasculitis in six each and erythema nodosum in five [4].

Neurological manifestations were described in 64 patients (7.7%), including 27 with meningitis, seven with facial or limb paralysis or paresis, six with seizures, two with simultaneous seizures and meningitis and two with central nervous system granulomas; twenty had other central manifestations, including encephalitis, brain abscesses and calcifications, and seven developed abscesses or infectious infiltration of the brain [4]. Rheumatological conditions occurred in 23 patients (2.8%), with Henoch-Schönlein purpura in eight, vasculitis in eight, classified as leucocytoclastic vasculitis of the skin in three, arthritis in five and other manifestations in two [4]. Neoplasms were recorded in 17 patients (3.4%), including five cases of haemophagocytic lymphohistiocytosis and three of B-cell lymphoma, and at least one allergic reaction in 13 (2.6%) [4]. Among gastrointestinal findings, there was weight loss in 51 patients (6.1%), with a mean loss of 12 kilograms and a standard error of 5.01, and failure to thrive in 31 (3.7%) [4].

3.2. Microbiological spectrum

Bacterial infection was reported in 727 patients (87.6%), of whom 209 (28.7%) had mixed infections with at least two different bacteria [4]. Infections by the tuberculosis complex affected 560 patients (67.5%), due to Mycobacterium bovis BCG in 491 (87.7%), to Mycobacterium tuberculosis in 44 (7.9%), to both in 23 (4.1%) and to Mycobacterium africanum in two [4]. Infections by non-tuberculous mycobacteria occurred in 188 patients (22.7%), and the mean number of mycobacterial episodes per patient was 1.75, with a standard error of 0.16 [4]. The species described in these infections include Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium mageritense, Mycobacterium peregrinum, Mycobacterium smegmatis, Mycobacterium scrofulaceum, Mycobacterium intracellulare, the M. avium complex and Mycobacterium kansasii [33].

Salmonella infections were described in 152 patients (18.3%), localised in 13, disseminated in 34 and of undetermined extent in the remainder; the species identified were Salmonella enteritidis in 39 cases, Salmonella typhimurium in 14, Salmonella paratyphi in eight, Salmonella typhi in three and Salmonella dublin in two, with concomitant infections by at least two types in 14 patients and undetermined species in 60; the mean age at Salmonella infection was 4.71 years, with a standard error of 0.55 [4]. Besides mycobacteria and salmonellae, the spectrum includes other intramacrophagic bacteria, such as Listeria monocytogenes and Burkholderia species [33].

Severe viral infections were reported in 107 patients (12.9%), with isolated cytomegalovirus in 22, isolated varicella-zoster virus in 20, isolated herpes simplex virus in six, isolated Epstein-Barr virus in six, isolated coronavirus in three and human herpesvirus 8, respiratory syncytial virus and influenza or parainfluenza virus in two each; there were mixed viral infections in 38 patients (35.5% of those with viral infection) [4]. Fungal infections affected 136 patients (16.4%), with candidiasis in 120 (88.2%), histoplasmosis in ten, aspergillosis in three and one case each of coccidioidomycosis, paracoccidioidomycosis and pneumocystosis [4]. Thirteen patients (1.6%) had protozoal infections, with toxoplasmosis in six, leishmaniasis in four, giardiasis in two and cryptosporidiosis due to Cryptosporidium parvum in one [4].

3.3. Disease associated with BCG vaccination

In 571 patients (68.8%) there was a history of BCG vaccination and most of these, 484 (84.8%), had an abnormal reaction to the vaccine; the infection was limited to the injection area in 146 (30.2%), was disseminated in 289 (59.7%) and of undetermined extent in 49 [4]. The mean time between vaccine exposure and the adverse reaction was 4.54 months, with a standard error of 0.37, and the mean age at onset of the reaction was 0.97 years, with a 95% confidence interval of 0.42 to 1.52 years [4]. BCG-itis designates localised infection, which manifests as a local abscess, severe ulcer at the injection site or involvement of the ipsilateral regional lymph nodes with suppuration, fistulisation or both; BCG-osis designates disseminated, potentially fatal infection, with involvement of distant lymph nodes, skin, lungs, bone, liver, spleen and central nervous system [37]. The adverse reaction usually appears in the first six months or after twelve, and also depends on the strain used, vaccine storage, dose and injection technique; strains in use worldwide include the Brazilian Moreau or Rio de Janeiro, the Danish Copenhagen-1331, Pasteur-1173, the Japanese Tokyo-172-1, the Russian Moscow-368, the Bulgarian Sofia-SL222, Connaught, Mérieux, Shanghai and TICE [37]. In countries with routine vaccination, the proportion of patients with vaccine complications ranges from 35% to 100%, with adenitis between 8% and 40% and severe BCG-osis between 25% and 85% [37].

The signs that should raise suspicion of BCG-osis are systemic manifestations such as fever, anaemia, weight loss or failure to thrive, enlarged lymph nodes beyond the vaccine site, including epitrochlear, axillary, cervical or inguinal nodes, skin lesions or abscesses outside the vaccinated region, hepatosplenomegaly, bone pain or swelling reflecting underlying osteomyelitis and signs of meningeal involvement [33].

3.4. Differences by entity

In IL-12Rβ1 deficiency, the international survey of 141 patients from 102 families in 30 countries describes the first infection at a mean age of 2.4 years; in 78 of the 102 probands the initial infection was mycobacterial, caused by BCG in 65, by environmental mycobacteria in nine and by M. tuberculosis in four, and 22 of the remaining 24 probands presented with extraintestinal non-typhoidal salmonellosis [34]. BCG disease recurred in 15 patients, environmental mycobacteriosis in three and salmonellosis in 22, so recurrence is more characteristic of salmonellosis than of mycobacteriosis; BCG disease strongly protected against subsequent disease due to environmental mycobacteria [34, 97]. Ninety of the 132 symptomatic patients had infections by a single microorganism and 40 had multiple infections, with combined mycobacteriosis and salmonellosis in 36; candidiasis was documented in 33 patients (23%) [34]. Where BCG is not used, as in North America, the disease presents with other bacterial or fungal infections and is easily overlooked [98]. In the Indian cohort of 50 patients, 30 had IL-12Rβ1 deficiency and one IL-12p40 deficiency, with a median age at presentation of four months; 20 (65%) presented with localised BCG adenitis and ten (32%) with BCG-osis, with left axillary lymphadenopathy ipsilateral to the vaccine site in practically all, axillary and cervical lymphadenopathy in five and multifocal lymphadenopathy in six [81]. Six patients with this deficiency had diarrhoea or other gastrointestinal manifestations, three of whom had a diagnosis of inflammatory bowel disease on colonoscopy and histology, which is consistent with IL-12Rβ1 deficiency being a recognised monogenic cause of this disease [81].

In IL-12p40 deficiency, the figures from the series of 49 patients show the relevance of the vaccine: 40 of the 41 vaccinated patients (97.5%) developed disease due to the vaccine strain; recurrent salmonellosis, in 36.4%, was more common than recurrence of mycobacterial disease, in 25%, the two coexisted in nine patients and infection by more than one mycobacterial species was rare, in only three; a minority had chronic mucocutaneous candidiasis, nocardiosis or klebsiellosis [82].

In the response defects, the complete recessive form of IFN-γR1 deficiency begins before three years of age, with disseminated disease and a continuous course, and BCG and environmental mycobacteria are the most frequent agents; the plasma of these patients usually contains large amounts of interferon gamma and their cells do not respond to this cytokine in vitro [9]. Salmonellosis is present in about 5% of patients with recessive or dominant IFN-γR1 deficiency [9]. The partial dominant form runs with moderately severe recurrent infections by environmental mycobacteria or BCG and has unifocal or multifocal osteomyelitis due to the M. avium complex as its clinical signature [10]. A published case illustrates the familial transmission of this form: a 13-month-old girl presented with pneumonia and her 33-year-old mother with hip pain, both with heterozygous IFN-γR1 deficiency and disseminated Mycobacterium genavense infection, the mother having progressive osteomyelitis [10, 99]. The partial recessive form was described in patients whose diseases were disease due to the vaccine strain in six, environmental mycobacteriosis in six and tuberculosis in one, with disseminated salmonellosis in three, one of whom without mycobacteriosis, and with a highly variable age at onset of the first environmental mycobacterial disease [88].

In complete IFN-γR2 deficiency, the picture overlaps with that of complete IFN-γR1 deficiency, with early manifestation and severe and frequently fatal infection, and the agents most often found are BCG, M. avium and M. fortuitum [11]. Patients with partial forms, by contrast, may have controllable disease: of two siblings from a consanguineous Turkish family with an initiation codon variant, one had local lymphadenitis at nine months with relapse at 18 months, cervical lymphadenopathy, deep cervical abscesses and cervical bone lesions at five years and cervical, thoracic, lumbar and sacral osteomyelitis due to M. bovis BCG at seven years, successfully treated with antibiotics and subcutaneous interferon gamma, and the sister post-vaccination suppurative lymphadenitis, likewise treated with antibiotics and interferon gamma; a boy from a consanguineous Indian family, vaccinated at ten days of life, had swelling of the left axillary lymph node at three months with acid-fast bacilli in peripheral blood, inguinal and axillary lymphadenitis with hepatosplenomegaly at 11 months and Mycobacterium chelonae in lymph node culture, and died at five years of persistent disseminated disease [11, 91]. A Saudi boy has been described who presented at two months with Streptococcus viridans bacteraemia and severe cytomegalovirus viraemia, with anaemia, thrombocytopenia, splenomegaly and lymphadenopathy and criteria for haemophagocytic lymphohistiocytosis, with cytomegalovirus and Mycobacterium abscessus in the bone marrow, and whose inheritance was digenic, with a homozygous loss-of-function IFNGR2 variant explaining the mycobacterial disease and a homozygous IFNAR1 variant explaining the atypical viral component [11].

In X-linked mycobacteriosis due to hypomorphic IKBKG variants, severe infections are early and usually caused by pneumococcus, Haemophilus influenzae and atypical mycobacteria, although other agents have been detected; immunological assessment shows variable or normal abnormalities, including dysgammaglobulinaemia with hypogammaglobulinaemia, decreased IgG2, aberrant IgM and IgA levels, reduced class-switched memory B cells, weak and variable vaccine responses, particularly to pneumococcal polysaccharides, impaired NK cytotoxic function, impaired cytokine production after stimulation with interleukin 1 beta or tumour necrosis factor alpha, and decreased interleukin 6, interleukin 12 and interferon gamma [15]. Hypohidrotic ectodermal dysplasia is generally absent, although some patients have conical teeth or isolated hypodontia [15]. A Polish patient followed in Germany illustrates the spectrum: from 15 months he had multiple episodes of disseminated M. avium disease, with mainly lymph node and bone involvement, bronchiectasis due to H. influenzae and Streptococcus pneumoniae at seven years, extraintestinal Salmonella enteritidis disease at 11 years, severe autoimmune haemolytic anaemia at 12 years and death from herpes simplex virus 1 meningoencephalitis; he had low IgA and IgG, markedly raised serum IgM and low interferon gamma, without antibodies against diphtheria and tetanus toxoids despite complete vaccination, low titres against H. influenzae and absent memory B cells [15].

Haemophagocytic lymphohistiocytosis deserves emphasis because it diverts the diagnosis. In complete interferon gamma deficiency, the first patient described had BCG-osis and developed suspicion of this picture fourteen months later, with relapse that led to transplantation; the second, Turkish patient presented at six months with high fever, hepatosplenomegaly, generalised maculopapular rash and left axillary lymphadenopathy, with hypofibrinogenaemia, hypertriglyceridaemia, hyperferritinaemia, severe anaemia, thrombocytopenia and leucocytosis, without an infectious agent identified on serology and blood cultures, and responded favourably to etoposide, dexamethasone and ciclosporin before the genetic aetiology was established [2, 87]. In the review of 830 patients, five of the 17 neoplasms recorded were in fact cases of haemophagocytic lymphohistiocytosis [4]. The risk of this picture is also relevant under treatment, because patients with IL-12Rβ1 deficiency treated with interferon gamma may develop a haemophagocytic-type response [33].

3.5. Initial misdiagnoses and gaps in recognition

The initial diagnosis was something other than the syndrome in 23 patients (2.8%) in the systematic review. The initial diagnosis was a neoplastic disease in five, more than half of whom had Langerhans cell histiocytosis, sarcoidosis in four, chronic granulomatous disease, acquired immunodeficiency syndrome and primary tuberculosis in three each, and chronic recurrent multifocal osteomyelitis in two [4]. In countries with high tuberculosis endemicity, infection by non-tuberculous mycobacteria is underdiagnosed owing to a lack of means for species identification: the molecular assays in routine use target the tuberculosis complex and do not detect non-tuberculous mycobacteria, and in the Indian cohort of 50 patients these were identified in only two, with recurrence of tuberculosis in ten patients, confirmed as multidrug-resistant in three [37, 81].

4. Clinical Recognition and Warning Signs

Suspicion arises from the organism and the context, not from the severity of an isolated symptom. Any child with disseminated BCG disease or infection by environmental mycobacteria should be investigated for this syndrome, and the gene to consider first is IL12RB1, as it accounts for 41% of published cases [4, 34]. In countries with universal neonatal vaccination, even localised BCG adenitis deserves to be treated as a warning sign of an inborn error of immunity when it requires therapeutic intervention: in an earlier Indian series from the same team, about 58% of children with localised BCG disease requiring treatment had an inborn error of immunity, this syndrome being the most frequent [81].

The clinical recommendations of the African Society for Immunodeficiencies propose operational criteria that organise the suspicion [33]. Essential criteria are the identification of a pathogenic germline variant described in the syndrome and the presence of at least one of the clinical features, and desirable criteria are a history of predominantly mycobacterial or bacterial, though also fungal or viral, infections and disseminated BCG disease. The clinical features are organised under the acronym for severe, persistent, unusual or recurrent infections. The severity category includes uncontrolled or complicated tuberculosis, such as tuberculous empyema, tuberculous pericarditis, tuberculous meningitis, spinal tuberculosis, osteoarticular tuberculosis at multiple sites and disseminated or miliary tuberculosis. The persistence category includes the need for longer antituberculous therapy or lack of response to a correct regimen with good adherence, with an intensive phase required for more than two months. The unusual infection category includes the agent, when it is BCG or a non-tuberculous mycobacterium, and the site, when the disease is extensive or disseminates to atypical sites, such as the ear or brain, or when there is osteoarticular tuberculosis at an unexpected site, such as the skull or facial bones. Bacterial infection is considered disseminated when it affects two or more non-contiguous sites by the lymphohaematogenous route, and recurrent when more than one episode occurs, separated by at least one year, between the ages of 5 and 15 years, in the absence of an evident secondary cause or without response to therapy [33].

The signs of disseminated non-tuberculous mycobacterial disease are non-specific and include fever, weight loss, diarrhoea, generalised lymphadenopathy, generalised skin lesions, diffuse abdominal pain, hepatosplenomegaly and ascites, with the picture reflecting the main sites affected, such as the bone marrow, the lymphoreticular system, the gastrointestinal tract and the lungs [33]. Partial deficiencies, such as partial dominant IFN-γR1 deficiency, present with more limited disease, typically osteomyelitis due to non-tuberculous mycobacteria, and appear later in childhood or even in adulthood [33]. Skin lesions are common in patients with disseminated disease [33].

The history is as informative as the examination. In the genetics clinic, the recommended approach includes a three-generation family tree, extended on the maternal side when possible, and targeted questions about immunodeficiency, death in childhood, from unexplained or infectious causes, neoplasia and haematological diseases; the proband's postnatal history is documented with the types of infection, the ages at which they occurred and the nature of the agents, distinguishing bacteria from viruses and looking for opportunistic and fungal infections, and recording the vaccination history, including BCG vaccination [100]. On examination, growth parameters are assessed, as failure to thrive is common, and skin changes, lymphadenopathy, presence or absence of tonsils and hepatosplenomegaly are sought [100]. When hypomorphic NEMO deficiency is suspected, dentition and sweating are examined, because hypodontia and conical incisors may be the only extraimmune clue [15].

A set of associations points directly to the gene and should be actively sought. The association of mycobacterial disease with severe cytomegalovirus infection suggests complete interferon gamma receptor deficiency or complete recessive STAT1 deficiency; the association with non-typhoidal salmonellosis suggests IL-12Rβ1 or IL-12p40 deficiency; the association with chronic mucocutaneous candidiasis suggests IL-12Rβ1, IL-23R or RORγT deficiency; the association with cerebral calcification suggests ISG15, USP18 or ZNFX1 deficiency; and multifocal osteomyelitis suggests dominant IFN-γR1 or STAT1 deficiency or X-linked MCTS1 deficiency [4]. Pulmonary alveolar proteinosis with BCG disease points to complete recessive IRF8 deficiency or to CCR2 deficiency, and in the latter progressive polycystic lung disease and a raised blood CCL2 level complete the picture [72, 93]. Intermittent monocytosis with mycobacterial disease points to ZNFX1 deficiency [68].

A warning sign of a different nature, but of high yield, is family history. The existence of a positive family history in 45.5% of the 830 published patients and of asymptomatic genetically affected siblings in about a quarter to a third of cases in IL-12Rβ1 and IL-12p40 deficiencies means that the opportunity for prevention lies before the first symptom in the next sibling [4, 34, 82]. In a family with early death of a sibling from vaccine complications, it is recommended to postpone BCG vaccination until immunological investigations are completed [81]. The Portuguese standard enshrines this logic as a formal contraindication: a newborn who is a first-degree relative of a patient with suspected or confirmed primary immunodeficiency is not vaccinated until immunodeficiency has been excluded in the child [40].

Before declaring the suspicion, secondary causes must be excluded. It is imperative to document the absence of HIV infection and to exclude other secondary immunodeficiency, as well as anatomical risk, such as structural chronic lung disease [33]. In adults presenting later in life, the presence of neutralising anti-interferon gamma autoantibodies and an underlying haematological malignancy must be excluded [33].

There is no newborn screening directed at this syndrome. There is, however, a relevant practical interaction with newborn screening for severe combined immunodeficiency, which leads to postponing BCG vaccination until a negative result is confirmed; in Portugal, Standard 006/2016 was updated accordingly, and the inclusion of this screening in the national programme entailed the corresponding adjustment of vaccination [40]. This screening does not detect defects of the interferon gamma pathway, which do not present with T lymphopenia or with reduced T-cell receptor excision circles, so the diagnosis depends on clinical suspicion and family studies [37]. The systematic review of 830 patients concludes that pre-exposure strategies, including changes to vaccine policy in endemic areas, the creation of a worldwide patient registry and precise follow-up of affected families across generations, are the way to reduce the mortality associated with the syndrome [4].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria and sequence of investigation

The criteria proposed by the African Society for Immunodeficiencies require, as essential elements, confirmation of a pathogenic germline variant described in the syndrome and the presence of at least one compatible clinical feature; as desirable elements, a history of predominantly mycobacterial or bacterial infections and disseminated BCG disease [33]. Investigation follows three levels widely applied in inborn errors of immunity [33]. The first level excludes increased anatomical risk and secondary immunodeficiency, with mandatory recording of a negative HIV result, blood count with differential count of neutrophils, granulocytes, lymphocytes and monocytes to identify cytopenias, peripheral blood smear as a standard request to confirm normal neutrophil morphology and exclude signs of marrow involvement, and bone marrow biopsy with mycobacterial culture when there are persistent cytopenias, especially if the smear shows dacrocytes and leucoerythroblastosis. The second level quantifies immunoglobulins IgG, IgM, IgA and IgE, lymphocyte subsets with CD3+, CD4+ and CD8+ T lymphocytes, CD19 and CD16/56, proliferation studies to mitogens and antigens, the nitroblue tetrazolium test or dihydrorhodamine flow cytometry for neutrophil function, and interferon gamma release assays. The third level, in close consultation with immunology, is molecular testing, ideally targeted panels or, preferably, exome or genome sequencing, carried out in the context of genetic counselling [33].

Before specific tests, acquired and hereditary immunodeficiencies that also confer susceptibility to mycobacteria, such as severe combined immunodeficiency, chronic granulomatous disease and predominantly antibody deficiencies, are excluded, with analysis of lymphocyte subsets, nitroblue tetrazolium test, dihydrorhodamine assay and serum immunoglobulin levels [37]. The nitroblue tetrazolium test is, in resource-limited settings, a cheap and effective tool for excluding chronic granulomatous disease [33].

5.2. Functional tests of the interferon gamma pathway

Cytokine production is the tool that distinguishes a production defect from a response defect [37]. Complete deficiencies of IFN-γR1, IFN-γR2, IL-12Rβ1 or IL-12p40 can be detected by these assays, but CYBB deficiencies and dominant IRF8 deficiency show normal interferon gamma production, and partial defects are not clearly identifiable by this approach [37]. Measurement of baseline interferon gamma in plasma or serum by enzyme immunoassay is a simple technique that identifies complete defects, because these patients have very high levels, unlike the other predisposing genetic defects; patients with partial defects have detectable levels and, as values vary between the acute phase of mycobacterial disease and convalescence, measurement is carried out after resolution of the acute infection [37, 38]. Flow cytometry for the receptors is rapid and useful, with the caveat that non-functional receptors may be expressed at the surface: detection of IL-12Rβ1 expression requires prior stimulation with phytohaemagglutinin, and the available antibodies for surface IFN-γR2 are not optimal [37]. Absence of the IL-12Rβ1 protein at the surface, associated with an abolished cellular response to interleukin 12 and interleukin 23, confirms the functional defect and corroborates the molecular result [80].

The cellular dose-response to interferon gamma is the assay with the greatest therapeutic consequence, because it separates complete from partial deficiencies and predicts whether the cytokine can be used: cells from healthy individuals respond to as little as 10 international units per millilitre, cells from a complete deficiency do not respond even to 10,000 international units per millilitre, and cells from a partial deficiency fail at low and intermediate concentrations but respond at high ones [5, 52]. The readouts used include STAT1 phosphorylation and nuclear translocation, HLA class II induction in fibroblasts and CD64 induction and tumour necrosis factor alpha secretion in monocytes [52]. When STAT1 deficiency is suspected, the functional assay determines the direction of the change and not merely its presence: in dominant-negative SH2 domain variants, STAT1-mediated responses to interferon gamma and interleukin 27 are impaired while responses to interferon alpha and interferon lambda 1 are maintained, and dominant-negative behaviour is demonstrated by co-expression with the normal allele [8]. When IL-23R deficiency is suspected, membrane expression of the receptor is measured, along with interleukin 23-induced STAT3 phosphorylation, interferon gamma secretion induced by this cytokine separately in CD4+ T, CD8+ T and MAIT cells, interleukin 17A production and enumeration of circulating Th17, Th1* and MAIT subsets [36]. When RORγT deficiency is suspected, the absence of interleukin 17A- and 17F-producing T cells is sought by flow cytometry after stimulation, combined with impaired interferon gamma production by γδ T cells and by the CD4+CCR6+CXCR3+ subset in response to mycobacterial antigen [61]. In TYK2 deficiencies, the confirmatory pattern is absence of the protein on immunoblot with impaired responses to interleukin 12, interleukin 23 and type I interferons and preserved responses to interferon gamma and interferon lambda; serum IgE should be measured but serves neither to include nor to exclude the diagnosis [62]. In the macrophage CYBB variant, the dihydrorhodamine test on peripheral blood is normal, because the oxidative burst defect is confined to macrophages, and functional diagnosis requires in vitro differentiation of monocytes into macrophages [31, 59].

Interferon gamma release assays, such as QuantiFERON-TB Gold Plus, T-SPOT.TB or ELISpot, are not validated for this purpose but may serve as a screening test of pathway function in patients with confirmed or suspected tuberculosis [33]. The proposed interpretation is as follows: a positive result indicates normal interferon gamma production in response to tuberculous antigens and the positive control, does not exclude the syndrome and, if clinical suspicion is strong, requires further investigation; a negative result in a patient with current or past confirmed tuberculosis is unusual and indicates a partial production defect; an indeterminate result, with absent production in response to the positive control mitogen, should be repeated to exclude a processing error and, if confirmed, indicates a complete production defect or the presence of anti-interferon gamma autoantibodies, which should be investigated especially in adolescents and adults [33]. In all these scenarios the recommendation is to treat as if the syndrome were present until proven otherwise [33]. In the Indian cohort, negative or indeterminate results with a low response in the mitogen tube were considered useful indicators of a production defect, with the limitation that they need validation in a larger number of patients [81]. Caution is also needed in the opposite reading: interferon gamma production is deficient in many of the genes of the syndrome, which makes QuantiFERON unreliable for excluding active tuberculosis in these patients, and the presence of anti-interferon gamma autoantibodies likewise leads to an indeterminate result [37].

5.3. Microbiological diagnosis

Early identification of the agent is decisive because the therapeutic strategy depends on the type and susceptibility profile of the mycobacterium isolated [37]. Faced with unexplained lymphadenopathy, the 2026 North American review insists on early collection of tissue and blood cultures with targeted testing for mycobacteria and, when the syndrome is suspected, on genetic testing of the IL-12/IFN-γ pathway, which comprises at least 19 genes and hundreds of variants and is indispensable for identifying the defect and guiding therapy [78]. Direct methods include microscopy with acid-fast or fluorescent stains, culture on solid or liquid media, the automated mycobacteria growth indicator tube system being recommended, and molecular nucleic acid amplification platforms; molecular platforms usually target only the tuberculosis complex and may not detect non-tuberculous mycobacteria unless they specifically look for them [37]. Culture is the reference standard among phenotypic tests, because it allows non-tuberculous mycobacteria to be grown and differentiated from the tuberculosis complex, but it has a long turnaround time owing to slow growth [37]. Incubation temperature differs between species, with 28 degrees Celsius plus or minus two for rapidly growing mycobacteria and 42 to 45 degrees for Mycobacterium xenopi, and phenotypic differentiation requires a battery of time-consuming biochemical tests; rapid immunochromatographic tests detect the MPT64 antigen of the tuberculosis complex, and matrix-assisted laser desorption/ionisation mass spectrometry systems allow rapid identification of clinically relevant mycobacteria [37]. With the increasing incidence of resistant tuberculosis, susceptibility testing by culture or detection of the associated mutations has become imperative, and in practice liquid culture followed by molecular methods detects and differentiates most species, including M. bovis BCG strains [37].

Sampling should be targeted. All patients with suspected BCG disease have a chest radiograph to exclude pulmonary tuberculosis, and ultrasound or computed tomography of the chest and abdomen when disseminated disease is suspected [37]. Fine-needle aspiration cytology of the lymph node is performed by non-dependent aspiration with a technique of manipulating the overlying skin by a trained operator, and the aspirate is sent for molecular testing for the tuberculosis complex with detection of rifampicin resistance, microscopy, culture with susceptibility testing and cytological smear; when cytology is inconclusive, excision biopsy is performed, with the same panel of tests plus histopathological assessment [37]. Blood cultures and blood and stool cultures for non-typhoidal Salmonella are taken, and imaging is performed to define the extent of disease [33, 34]. In the dominant forms, imaging directed at multifocal osteomyelitis is indicated, including whole-body imaging, because bone may be the only site involved [5]. Granuloma histology is informative, being lepromatoid and poorly formed in complete deficiency and tuberculoid and well differentiated in partial deficiency [5].

5.4. Molecular confirmation, test limitations and report content

The diagnosis is established by identification of pathogenic variants, by Sanger sequencing or next-generation sequencing, and a panel targeting the known genes may be an option [37]. Exome or genome sequencing is preferable because it is quicker, may be less costly, leads to the discovery of new aetiologies and detects variants that Sanger sequencing does not identify, such as copy number variations [37]. Half of the patients with suggestive clinical signs have no variants in the known genes, and it is estimated that only about half of the patients with a clinical diagnosis have a molecular diagnosis [33, 37].

The limits of the tests should be part of clinical reasoning. A negative molecular result does not exclude the diagnosis, because there are genes not yet described, deep intronic variants and structural variants that escape most panels [37]. Variants in the 5' untranslated region of IKBKG that cause severe disseminated mycobacteriosis in adults may be missed by exome sequencing [35]. Blood count, immunoglobulins and lymphocyte subset panels are characteristically normal, so a normal routine immunological panel does not exclude the diagnosis [33, 34]. A normal dihydrorhodamine test result does not exclude the macrophage CYBB variant [31]. A heterozygous IFNGR2 finding in a symptomatic patient should not be automatically classified as carrier status, as there is a dominant form due to haploinsufficiency with incomplete penetrance [6]. For RORC variants, ClinVar submissions are dominated by variants of uncertain significance, with 134 versus 21 pathogenic and three likely pathogenic, so an isolated heterozygous missense variant found incidentally is of little information and the diagnosis requires biallelic loss of function in a patient with the appropriate phenotype [61]. In ISG15, raw ClinVar counts are inflated by copy number variation records of the 1p36 region, where the gene lies, and a 1p36 deletion should not be interpreted as a cause of ISG15 deficiency, which requires loss of both alleles [60]. In IL23R, a common coding variant, heterozygous or homozygous, is not a diagnosis of an inborn error of immunity, and a homozygous R381Q result should be reported as a risk genotype and not as primary immunodeficiency [73]. In IL12B, all nine alleles described in the largest series were loss-of-function and all patients were homozygous with complete deficiency, so a missense variant of uncertain significance should not be presumed causal without functional evidence [82].

The report should state the gene, the reference transcript with its version, HGVS nomenclature at DNA and protein level, zygosity and classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. The MANE Select transcripts to be used are those given in section 0, and conversions of historical nomenclature should be confirmed in a normalisation tool and not calculated manually: the 818del4 nomenclature of IFNGR1 corresponds to NM_000416.3:c.819_822del, p.(Asn274HisfsTer2), and the common P1104A allele of TYK2 corresponds to NM_003331.5:c.3310C>G, p.(Pro1104Ala) [3]. Locus-specific databases exist for IFNGR1, with all described variants and 287 additional variations, and for IL12RB1, and are the point of reference for interpreting a new change [80, 89]. For variants of uncertain significance, functional validation is the step that distinguishes a pathogenic allele from the many common isomorphic alleles, as was done by back-complementation with the normal allele in the IL23R cases, by luciferase assays in the IRF8 cases and by overexpression in the IFNGR2 cases [36, 91, 93]. Family segregation and parental testing, the parents having been heterozygous in all documented recessive cases, add weight to the interpretation [91, 101].

Prenatal diagnosis and preimplantation genetic diagnosis are technically possible from a known familial variant, and the identification of the IL12B founder mutation in Tunisia was expressly presented as facilitating preventive counselling and prenatal diagnosis in affected families [83]. In practice, the most frequent application of family studies is not prenatal diagnosis but testing of the at-risk newborn before vaccination, which was the procedure that kept asymptomatic the sibling, genotyped at birth, of a patient with MCTS1 deficiency [71].

6. Differential Diagnosis

Exclusion of the major immunodeficiencies is the first step. Severe combined immunodeficiency presents in the first year of life with severe infections and lymphopenia, and the difference in the behaviour of BCG is informative: in this disease and in the interferon gamma receptor deficiencies, infection by the vaccine strain typically causes disseminated disease, whereas in chronic granulomatous disease it causes severe localised disease, with draining lesions at the vaccination site [31, 33]. The recommended work-up includes a blood count with differential and peripheral blood morphology, lymphocyte subsets with T and B lymphocytes and NK cells by flow cytometry, serum IgG, IgA, IgM and IgE levels, proliferative responses to mitogens and antigens, antibody responses to pneumococcal vaccine and to diphtheria and tetanus toxoids, an immunology consultation and molecular testing with a panel of almost 500 known inborn errors of immunity [33].

Chronic granulomatous disease is the closest functional differential and the easiest to exclude. It results from the inability of phagocytes to kill bacteria and fungi owing to failure of the NADPH oxidase complex, and presents with severe and recurrent bacterial and fungal infections of the lung, lymph nodes, liver, bone and skin, with granulomas mainly affecting the bladder and the gastrointestinal tract, and with colitis that may be the only manifestation [31]. Mycobacterial disease in chronic granulomatous disease is largely limited to regional and disseminated BCG infections and tuberculosis, and these patients are less susceptible to non-tuberculous infections than patients with T-cell defects or defects of the interferon gamma and interleukin 12 pathway [31]. The diagnostic assay is dihydrorhodamine by flow cytometry, which resolves three patterns: the complete pattern, with absent or markedly reduced superoxide production; the hypomorphic pattern, with residual production; and the bimodal mosaic pattern characteristic of women heterozygous for the X-linked form; the result is normal in the macrophage CYBB variant, so it does not exclude that form [31].

In adults, the acquired phenocopy due to neutralising autoantibodies against interferon gamma is the decisive differential. In a study of 203 people in Thailand and Taiwan, divided into five groups, high-titre autoantibodies were detected in 81% of the 52 patients with disseminated infection by rapidly or slowly growing non-tuberculous mycobacteria, in 96% of the 45 patients with another opportunistic infection, with or without non-tuberculous mycobacteriosis, in 11% of the nine patients with disseminated tuberculosis, in 2% of the 49 patients with pulmonary tuberculosis and in 2% of the 48 healthy controls; the patients did not have HIV infection, CD4+ T-lymphocyte counts were similar to those of the controls, washed cells had intact cytokine production and response, and it was the plasma of these patients that inhibited interferon gamma activity in normal cells [102]. There was no familial clustering [102]. The 2024 IUIS classification includes this entity among the phenocopies of inborn errors of immunity, with susceptibility to intramacrophagic agents, including mycobacteria, fungi, Talaromyces marneffei and Salmonella, and varicella-zoster infections [1]. The interferon gamma release assay is indeterminate in these patients, which is an accessible clue [33, 37].

Among the neighbouring genetic entities, GATA2 deficiency presents in adolescence and early adulthood with myelodysplasia and bone marrow hypoplasia, warts, monocytopenia and reduced NK cells, and requires a bone marrow aspirate with cytogenetics and molecular testing [33]; it is also a cause of primary lymphoedema with myelodysplasia, described as Emberger syndrome, and of susceptibility to mycobacteria, papillomaviruses, histoplasmosis and alveolar proteinosis [1, 103]. Hyper-IgE syndrome due to dominant-negative STAT3 variants is distinguished by cold staphylococcal abscesses, eczema and skeletal features, but about one third of patients have non-tuberculous mycobacteria in sputum [33]. STAT1 gain of function is the allelic disorder most easily confused at the molecular level and least at the clinical level: in the international cohort of 274 patients, 98% had chronic mucocutaneous candidiasis with a median age at onset of one year, 74% had bacterial infection, 38% viral infection, 37% autoimmunity and only 6% mycobacterial disease, due to M. tuberculosis, environmental mycobacteria or BCG [92]. The clinical separation is clear and has consequences, because gain of function presents as candidiasis with autoimmunity and loss of function as mycobacterial and viral susceptibility, and the treatments point in opposite directions [8, 92].

Structural causes of non-tuberculous mycobacterial infection should be excluded before assuming an inborn error of immunity: cystic fibrosis, with viscous secretions and a strong association with bronchiectasis and with pulmonary infection by these mycobacteria, and primary ciliary dyskinesia, an autosomal recessive disorder of ciliary function in which these infections are increasingly recognised [33]. In the context of clinical genetics, the historical classification of primary immunodeficiencies places this syndrome in the group of defects of innate immunity, alongside NEMO defects, and distinguishes it from the groups of combined immunodeficiencies, well-defined syndromes with immunodeficiency, predominantly antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocyte number or function, autoinflammatory diseases and complement deficiencies [100].

A final differential group lies within the class itself. The combination of chronic mucocutaneous candidiasis with mycobacterial disease points to RORγT, IL-12Rβ1 or IL-23R deficiency, and not to the usual causes of isolated candidiasis, which are deficiencies of the interleukin 17 pathway [61, 69]. The coexistence of pulmonary alveolar proteinosis with BCG disease points to complete recessive IRF8 deficiency or to CCR2 deficiency [72, 93]. Intermittent monocytosis points to ZNFX1 deficiency, and the absence of circulating monocytes and dendritic cells to complete recessive IRF8 deficiency [7, 68]. The association with conical teeth or hypodontia, even without complete ectodermal dysplasia, points to hypomorphic IKBKG variants, and the presence of anhidrosis, osteopetrosis and lymphoedema in a boy whose mother has incontinentia pigmenti points to the most severe allelic form of the same gene [15, 95, 96].

7. Treatments and Risk Management Strategies

7.1. Principles and dependence on genotype

Management is organised around three pillars: confirmation of the variant and, when necessary, of the corresponding phenotypic expression; aggressive antimicrobial treatment, with or without prophylaxis; and haematopoietic cell transplantation, curative in some patients [33]. The 2026 North American review summarises the same sequence: combination of several antimicrobials, cytokine therapy in selected cases and consideration of bone marrow transplantation [78]. Management should be multidisciplinary, involve the clinical and laboratory teams and support services, and give the patient age-appropriate responsibility for their own care [33]. Treatment is adapted to the mutation: incomplete deficiencies of the interferon gamma receptor or of STAT1 usually do not require transplantation and may benefit from replacement therapy with the cytokine, whereas complete receptor and STAT1 deficiencies respond poorly to this therapy, have a more severe phenotype and require transplantation to be considered [33]. In all cases, antimicrobial treatment should be aggressive and directed at the microorganism, and the patient should be assessed for tuberculosis at each visit, because slight weight loss is often the first indicator of a new infection [33].

Source of the table: recommendations of the African Society for Immunodeficiencies [33].

7.2. Prevention: BCG vaccine and live vaccines

The intervention with the greatest effect is preventive. The World Health Organization position paper on BCG vaccines, of February 2018, which replaces the 2004 and 2007 documents, maintains the importance of the birth dose in high tuberculosis burden countries and declares the vaccine contraindicated in immunocompromised people and in those receiving immunosuppressive treatment [39]. More than 170 countries administer the vaccine in national immunisation programmes, with one dose for all newborns in high-burden countries and vaccination of risk groups, such as children and health workers with prolonged exposure, in low-incidence countries [37].

In Portugal, Standard 006/2016 of the Directorate-General of Health, of 29 June 2016, replaced universal vaccination with a risk-group strategy, using the vaccine from Japan BCG Laboratory, Tokyo 172 strain, freeze-dried, presented in a multidose ampoule reconstituted from two glass ampoules [40]. Eligible are children under 6 years with no BCG record and no vaccine scar who come from high-incidence countries with a stay of at least three months, who have completed contact screening or a prophylaxis regimen, whose parents, cohabitants or household members have HIV infection, alcohol or drug dependence, birth in a high-incidence country or a history of tuberculosis, who belong to high-risk communities, or who travel to high-incidence countries for a stay of at least three months, shorter stays being considered if the risk of infection is high [40]. From 12 months of age, a tuberculin skin test or interferon gamma release assay is indicated before vaccination, and if there is a history of contact with a case of active tuberculosis the child should be screened, the vaccine being administrable within the three months following a negative test [40]. The contraindications in the standard are hypersensitivity reaction to the active substances or excipients, birth weight below 2000 grams, infants of mothers with HIV infection until infection in the child has been excluded, congenital or acquired cellular immunodeficiency, immunosuppressive treatments and HIV infection, a newborn who is a first-degree relative of a patient with suspected or confirmed primary immunodeficiency until immunodeficiency in the child has been excluded, the pre- and post-transplant period for organs or bone marrow, severe systemic disease and severe acute illness with or without fever, generalised skin disease, treatment with antibiotics with tuberculostatic activity, active tuberculosis or a positive tuberculin skin test or interferon gamma release assay, and severe malnutrition [40]. Among the precautions, strictly intradermal administration is essential, with a 1 millilitre syringe graduated in hundredths and a 25 or 26 Gauge short-bevel needle, because subcutaneous administration increases the risk of suppurative lymphadenitis, with abscess or eschar formation, and no vaccine should be given in the same arm in the following three months [40]. The expected local reactions are a red nodule that progresses to a vesicle and then an ulcer in two to four weeks, resolving in two to five months with a superficial scar of 2 to 10 millimetres in diameter, and enlargement of the axillary lymph nodes two to four months after vaccination, which rarely suppurates [40]. This policy explains why, in Portugal, presentation with vaccine disease is now infrequent, unlike in countries with universal vaccination at birth.

In Brazil, the Manual of the Reference Centres for Special Immunobiologicals of the Ministry of Health, sixth edition of 2023, establishes that, in primary immunodeficiencies, patients with combined deficiencies of cellular and humoral immunity should not receive live-agent vaccines, that patients with severe deficiencies of humoral immunity and with phagocytic deficiencies, such as chronic granulomatous disease, receive the other routine vaccines of the national programme except BCG, and that patients with phagocytic deficiency should not receive live bacterial vaccines such as BCG [41]. The manual further stipulates that newborns of mothers who used immunomodulators in the last two trimesters of pregnancy have BCG vaccination postponed until 6 to 12 months of life [41]. The manual contains no entry devoted to this syndrome; the entities of the class fall within the groups with a defect of cellular or phagocytic immunity, for which the vaccine is excluded [41].

As a consequence of these standards and of cohort data, the practical procedure is twofold: no live vaccine for the patient, and testing of at-risk siblings before the neonatal dose, with vaccination postponed until the diagnosis has been excluded [4, 33, 40]. In a family with a history of early death of a sibling from vaccine complications, vaccination should be postponed until immunological investigations are completed [81]. The logic of risk assessment before vaccination is established in other immunodeficiencies: in 22q11 deletion syndrome, live vaccines, including oral poliomyelitis vaccine and BCG, are not given until immune function has been verified, and BCG is only given after a risk assessment showing that the potential benefit exceeds the risk [104]. Emapalumab, a neutralising antibody against interferon gamma, carries in its prescribing information the instruction not to administer live or live attenuated vaccines to patients receiving it [105].

7.3. Antimycobacterial treatment

There are no trial-based guidelines for the choice of antimicrobial regimen in BCG disease, and decisions are made case by case, within the framework of the World Health Organization tuberculosis treatment guidance and national programmes [37]. Two microbiological facts condition the regimen: the BCG strain is resistant to pyrazinamide, which is therefore not part of the treatment, and low-level resistance to isoniazid has been described in the Danish 1331 strain [37]. Therapy should be started without waiting for genetic confirmation, according to the susceptibility profile of the microorganism [37].

The recommendations of the African Society for Immunodeficiencies propose stratification by extent: for involvement of the ipsilateral axillary lymph nodes, at least three antituberculous drugs, isoniazid, rifampicin and ethambutol, for 24 to 36 months, followed by prolonged prophylactic treatment until complete immune reconstitution; if there is dissemination beyond these nodes, at least four antituberculous drugs, isoniazid, rifampicin, ethambutol and levofloxacin, with or without clarithromycin, for 24 to 36 months until complete recovery, followed by a two-drug prophylactic programme until immune reconstitution [33]. The Indian review proposes shorter durations for BCG-osis, of 9 to 12 months and in some cases up to 18, with early use of second-line drugs, including linezolid, a quinolone such as ciprofloxacin or levofloxacin, an aminoglycoside such as amikacin or streptomycin, and clarithromycin, depending on the degree of dissemination, and two-drug prophylaxis, usually isoniazid and rifampicin, after control of the infection and until transplantation [37]. The divergence between the two sources is real and is not resolved by comparative evidence: the first is a regional consensus that favours prolonged continuity in a setting of high tuberculosis endemicity, and the second is a narrative review based on Indian experience; neither derives from a randomised trial. The Indian review adds that, at the end of therapy, six-monthly follow-up for at least two years may be needed depending on the aetiology, and that treatment failure should be considered if there is no response after five months [37].

For drug-susceptible tuberculosis, the conventional regimen is six months, with an intensive phase of two months of isoniazid, rifampicin, pyrazinamide and ethambutol followed by four months of isoniazid, rifampicin and ethambutol; the World Health Organization recently recommended a shorter, four-month regimen for children over three years with non-severe disease, based on the SHINE trial [37]. As most patients with BCG adenitis present before three months of age, they should be treated promptly with the six-month regimen without pyrazinamide [37]. Some patients with residual lymphadenopathy of less than one year at the end of treatment are considered partial responders, and in these it is recommended to add three months of isoniazid, rifampicin and ethambutol, followed by biopsy for histology and culture if there is no response [37]. When the response is minimal or transient, infection by non-tuberculous mycobacteria should be considered; bedaquiline has in vitro activity against the M. avium complex, Mycobacterium abscessus, Mycobacterium ulcerans and Mycobacterium smegmatis, and in mice lacking the interferon gamma gene and in mice with severe combined immunodeficiency bedaquiline, alone and in combination with clofazimine, reduced the bacterial load in the lung, spleen and liver, which is a preclinical finding [37].

Long-term antibacterial prophylaxis follows two distinct principles depending on the entity. In partial interferon gamma receptor deficiencies, after resolution of the acute episode, lifelong prophylaxis with azithromycin is described as effective in preventing recurrences, and receptor deficiencies are in general severe and require prolonged, aggressive antimicrobial therapy; in defects of the interleukin 12 receptor pathway, as a rule milder, the need for prophylaxis is uncertain, although some patients with IL-12Rβ1 deficiency have recurrent infections [37]. Recurrent salmonellosis, more common in production deficiencies, is treated on its own terms, with a good response described to the combination of ceftriaxone and ciprofloxacin, and secondary prophylaxis is given with co-trimoxazole [37]. Mucocutaneous candidiasis is treated with antifungals, and in RORγT deficiency fluconazole has a licensed indication for oropharyngeal and oesophageal candidiasis, which are the usual manifestations, with the caveat that prolonged azole exposure selects resistant Candida species, so isolates should be cultured and tested rather than treated empirically indefinitely [61].

Before starting prophylaxis it is mandatory to exclude active mycobacterial infection or other infection requiring a treatment regimen, and in the setting of active infection it is imperative to consider other at-risk household members who may need prophylaxis, in particular pregnant women, people living with HIV infection and people with previous tuberculosis [33]. There are three options for prophylaxis of tuberculous infection, weekly isoniazid and rifapentine for three months, daily rifampicin and isoniazid for three months, and daily isoniazid for six or twelve months, the choice depending mainly on weight and on anticipated drug interactions; the rifampicin and isoniazid regimen is preferred in children under 25 kilograms and the weekly fixed-dose combination regimen above 25 kilograms, using isoniazid alone when interactions are anticipated [33]. Ideally, all members of the same household receive the same regimen, to reduce the burden and complexity of therapy, and monitoring of adherence and adverse effects is monthly, with weighing of children at each visit and dose adjustment, active surveillance for symptoms of active infection such as fever, night sweats, weight loss and cough, and duration decided case by case, with a general minimum of three months, particularly in immunocompetent relatives receiving prophylaxis for exposure only [33].

Source of the two prophylaxis tables: recommendations of the African Society for Immunodeficiencies [33].

Surgery has a defined role. In the systematic review, 119 patients (14.3%) underwent surgery, of whom 56 (47.1%) had lymph node resection, 24 (20.2%) drainage of an abscess or empyema and seven transplant-related surgery [4]. Excision of abdominal lymphadenopathy may be necessary, and in IL-12Rβ1 deficiency surgical resection of affected areas, mainly abdominal, was used more rarely than antibiotics and interferon gamma [4, 34]. In patients with SPPL2a deficiency, lymphadenectomy accompanied antimycobacterial therapy [64].

7.4. Recombinant interferon gamma-1b

Interferon gamma-1b is the only therapy directed at the mechanism and is used off-label in all forms of this syndrome. In Portugal the international non-proprietary name is interferão gama-1b, marketed as Imukin® by Clinigen Healthcare B.V., with a marketing authorisation of 8 April 1993, procedure NL/H/0033/001, ATC classification L03AB03, pharmacotherapeutic group 16.3 of immunomodulators and dispensing on restricted medical prescription under subparagraph b; the authorisation was revoked on 30 September 2021, with a sell-off period until 23 February 2022, and there is no marketed presentation or valid price in the country [106]. In the United States it is marketed as ACTIMMUNE® under biologics license application 103836, with a label in force from 30 March 2026 [42]. In the United Kingdom and in European Union countries IMMUKIN® remains available, with a summary of product characteristics revised on 31 August 2022 [107].

The mechanism is that of the cytokine itself: activation of the macrophage to kill intracellular microorganisms, through STAT1 phosphorylation and induction of interferon-stimulated genes [2]. In production defects, exogenous supply bypasses the block, because the receptor is intact; in response defects, benefit depends on the existence of residual receptor [33, 90]. The United States label indicates the medicine only to reduce the frequency and severity of serious infections associated with chronic granulomatous disease and to delay time to progression in severe malignant osteopetrosis, so that use in this syndrome is off-label and should be conducted by a specialist immunology service [42].

The reference dose in the literature on this syndrome is 50 µg/m² subcutaneously three times a week, documented in patients with IL-12Rβ1, IL-12p40, dominant or partial recessive IFN-γR1, partial IFN-γR2, NEMO and interferon gamma deficiencies [2]. In patients with IL-12Rβ1 deficiency and antibiotic-refractory BCG disease, escalation was necessary: in one case the initial dose of 50 µg/m² three times a week for three months was increased to 100 µg/m² and, six months later, to 200 µg/m², with a positive clinical effect only at the highest dose; in other patients 25 µg/m² twice a week was started for 18 months, with clinical remission at nine months in one case and no response and death from dissemination in another, and in another case 25 µg/m² three times a week was increased to 100 µg/m², with clinical improvement at two months [2]. In a cohort of 22 patients with IL-12Rβ1 deficiency, 16 were treated with 50 µg/m² three times a week during infection and then as prophylaxis, with lower mortality among those treated [2]. In dominant STAT1 deficiency, two patients with multifocal BCG osteomyelitis received 1.5 µg/kg three times a week, with resolution of the infection [2]. In partial NEMO deficiency, four patients with M. avium complex infections received 50 µg/m² three times a week, with clinical improvement within eight weeks and fatigue, malaise and myalgia in two [2]. In complete interferon gamma deficiency, the second patient described received 50 µg/m² three times a week from 12 months of age, after six months of two or three antimycobacterial drugs alone, then continuing 30 months of subcutaneous interferon gamma with two antimycobacterial drugs; triglycerides and ferritin normalised, no neutralising antibodies were detected after six months of therapy, there was no relapse of mycobacterial disease or of other related infectious diseases, and at five years of age the patient remained well on the cytokine alone [2, 87].

The label dose coincides with the dose in the literature and serves as a comparison. The United States label recommends 50 µg/m² for patients with a body surface area above 0.5 m² and 1.5 µg/kg per dose for an area of 0.5 m² or less, three times a week, for example Monday, Wednesday and Friday; the corresponding activity is one million international units per square metre, one million international units being equivalent to 50 µg [42]. The presentation is 100 µg, corresponding to two million international units, in 0.5 millilitres of solution in a single-dose vial, preservative-free, for subcutaneous use only, at the optimal injection sites, which are the right and left deltoid and the anterior thigh, and it may be administered by a doctor, nurse, family member or suitably trained patient [42]. The British summary of product characteristics gives the same dose, with administration preferably in the evening, and notes that experience in children is limited [107]. The difference between jurisdictions lies in the indications: in the United States, reduction of the frequency and severity of serious infections in chronic granulomatous disease and delay of progression in severe malignant osteopetrosis; in the United Kingdom, reduction of the frequency of serious infections in both diseases [42, 107]. In neither jurisdiction is the syndrome an approved indication, which means that the doses of 100 and 200 µg/m² used in refractory disease are above what the label allows: the prescribing information states that safety and efficacy have not been established for doses higher or lower than 50 µg/m², that higher doses are not recommended and that the minimum effective dose has not been established [42]. The clinical reference for this condition is therefore the dose documented in the literature on the syndrome itself, with escalation expressly declared as extrapolation beyond the conditions of the label [2].

Monitoring is that of the label: blood count with differential and platelet count, biochemistry with renal and liver function tests, and urinalysis before starting treatment and at three-month intervals; in patients under one year of age, liver function tests should be monthly [42]. If severe reactions occur, the dose is reduced by 50% or treatment is interrupted until resolution [42]. The contraindication is hypersensitivity to interferon gamma, to products derived from Escherichia coli or to any component, and the British summary adds hypersensitivity to closely related interferons [42, 107]. The warnings include possible exacerbation of pre-existing cardiac disease, neurological changes, with dose reduction or discontinuation if decreased mental status, gait disturbance or dizziness appears, bone marrow toxicity, with monitoring for neutropenia and thrombocytopenia especially when combined with other myelosuppressive agents, hepatotoxicity, with raised transaminases, hypersensitivity reactions and renal toxicity [42]. The British summary details that acute and self-limiting cardiac exacerbation was observed in early trials with doses of 250 µg/m² per day or higher, without a demonstrated direct cardiotoxic effect, and that transaminase elevations up to 25 times the upper limit of normal occurred during therapy, with a higher incidence below one year of age, in six of ten patients, in one of whom on the seventh day of treatment; treatment was interrupted in all six and reintroduced at a reduced dose in four, with normalisation of values in all and recurrence in only one [107]. Caution is required in patients with known epilepsy or central nervous system impairment and in patients with severe hepatic or renal impairment, because of possible accumulation [107]. Common adverse reactions, with an incidence of 2% or more, are fever, headache, rash, chills, erythema or pain at the injection site, fatigue and diarrhoea [42]. The African recommendations describe the same profile, with influenza-like effects including fever, headache, chills, myalgia and fatigue, and, among the others, rash, erythema or pain at the injection site, diarrhoea, nausea and leucopenia [33]. Storage is between 2 and 8 degrees Celsius, without freezing, and an unused vial may remain at room temperature for up to 12 hours before use, after which it is discarded [42].

Two clinical restrictions delimit its use. The first is futility in complete receptor deficiencies: the cells of these patients do not respond even to 10,000 international units per millilitre, and administering the cytokine in that context consumes time in a patient at risk of death [33, 52]. Patients with partial IFN-γR2 deficiency should be treated with interferon gamma, unlike patients with complete deficiency, in whom it is useless [90]. The second is that in IRF1 deficiency the response should not be presumed, because this factor acts downstream of the receptor and deficient mononuclear phagocytes do not control mycobacteria when stimulated with the cytokine [70]. In patients with IL-12Rβ1 deficiency a haemophagocytic lymphohistiocytosis-type response may arise under treatment, so close monitoring is required [33]. In settings of irregular access to quality health care or of difficult adherence, patient selection for replacement therapy is part of the decision, which should be discussed in a multidisciplinary team and with the patient [33].

In the systematic review, interferon gamma was prescribed to 168 patients (20.2%) and interferon alpha to 16 (1.9%); among the 127 patients with documented follow-up after treatment with interferon gamma, 97 (76.2%) had a favourable response, with the caveat that the drug was available only in some countries [4]. Antimycobacterial drugs were used in 390 patients (47%), with a documented response in 261 of 325 (80.3%) [4]. The authors recommend that, although there is no approval for this indication, interferon gamma therapy be considered in practice, together with antibiotics, in all patients who do not have a complete absence of cellular response to the cytokine [4]. The unavailability of the therapy in many developing countries leaves few alternatives and is one of the arguments for transplantation in those settings [44].

7.5. Haematopoietic cell transplantation

Allogeneic transplantation is the only therapy that restores responsiveness to interferon gamma and is the only known cure for complete recessive IFN-γR1 and IFN-γR2 deficiencies, but the prognosis described is historically poor [33, 37]. The multi-institutional survey that established the problem assessed eight patients with complete IFN-γR1 deficiency who received, in total, eleven transplants from family donors, ten HLA-identical, five from siblings and five from other relatives, and one haploidentical, with five T-cell-depleted grafts and conditioning regimens of variable intensity; four patients died within the following eight months, two of them from complications specific to the mycobacterial infection, two survivors had no engraftment or engraftment of only 2% donor cells, and only two were in complete remission of mycobacterial disease five years later, these being precisely the two who received non-T-cell-depleted grafts from an HLA-identical sibling after fully myeloablative conditioning [43]. The derived recommendation is optimal control of mycobacterial infection before transplantation and use of a non-depleted graft from an HLA-identical sibling with full myeloablative conditioning [43].

The mechanism of rejection is established in an animal model and has protocol consequences. In mice lacking the Ifngr1 gene, transplantation of normal syngeneic cells engrafted well and restored antimycobacterial immunity in uninfected animals, but animals previously infected with M. bovis BCG rejected the graft and had, like infected human patients, very high serum levels of interferon gamma; administration of a vector expressing the cytokine to uninfected animals also caused rejection, transplantation was successful in double-mutant animals lacking the cytokine gene, even after infection, and efficient antibody depletion of the cytokine in infected animals allowed subsequent engraftment [108]. The high concentration of interferon gamma is therefore necessary and sufficient for rejection in this model, by inhibiting the development of heterologous haematopoietic lineages that express the receptor [108]. As the recipient's haematopoietic cells have no receptor for the cytokine, they gain a selective growth advantage, which leads to autologous reconstitution [44].

The aggregated transplant data in the systematic review describe 39 patients, 23 male, 14 female and two of unstated sex, who underwent one transplant in 34 cases and two in five; most had complete deficiencies of IFN-γR1, in 16 patients (41%), or of IFN-γR2, in eight (20.5%), followed by complete deficiencies of IL-12Rβ1 in five, of IRF8 in four, of STAT1 in two, of interferon gamma in one, of TYK2 in one and partial X-linked NEMO deficiency in two [4]. The median age at first transplant was 4 years, with an interquartile range of 1.25 to 5 years, and the donors were a matched sibling in 11 cases (25%), haploidentical in 11 (25%), matched unrelated in ten (22.7%), a matched relative in seven (15.9%) and mismatched unrelated in three (6.8%) [4]. The conditioning regimen was described in 26 of the 39 procedures and included fludarabine in 16, treosulfan in ten, cyclophosphamide in eleven, antithymocyte globulin in nine, busulfan in ten, thiotepa in six, alemtuzumab in five, rituximab in three, melphalan in two, total body irradiation in three and tacrolimus in one; graft-versus-host disease prophylaxis used ciclosporin in 16 of the 21 patients with information (76.2%), mycophenolate mofetil in eight, methotrexate in seven, a corticosteroid in two, tacrolimus in three and the remaining agents in one case each [4]. Neutrophil engraftment occurred at a median of 16.5 days, with an interquartile range of 12.8 to 19.8, full chimerism was achieved in 12 of 19 patients (63.2%), almost half of the patients with data developed graft-versus-host disease, eight of 18 (44.4%), median follow-up after transplantation was 360 days and mortality was 13 of 39 (33.3%), the most frequent causes being infection or related complications, including septicaemia in four, disseminated mycobacterial infection in three, Epstein-Barr virus-associated lymphoproliferative syndrome in one and cytomegalovirus pneumonia in one, followed by liver disease, multiorgan failure, prolonged seizures and severe graft-versus-host disease in one case each [4]. Neither age at transplantation nor donor type was associated with mortality, but the underlying genetic defect contributed to prognosis in the survival analysis, with statistical significance [4]. Donor selection has an impact on outcomes, with better results for fully matched related or unrelated donors than for haploidentical donors, and the high failure rates in interferon gamma receptor deficiencies are attributed to recurrence of infections and to high serum levels of the cytokine, which inhibit progenitor cell proliferation and haematopoiesis [37].

A recent Indian series proposes conditioning adapted to the pathway affected [44]. Seven children underwent eight transplants, four with defects of the interferon gamma pathway and three of the interleukin 12 pathway, with a male to female ratio of 1.6 to 1 and a median age at transplantation of 4.5 years, between 6 months and 10 years. The three children with an interleukin 12 pathway defect received fludarabine and treosulfan and had favourable engraftment kinetics without relevant early complications; the four with an interferon gamma pathway defect received fludarabine, treosulfan and thiotepa, a decision taken after the first patient had primary rejection with fludarabine and treosulfan conditioning. Five children (62.5%) received a haploidentical transplant and three (37.5%) a transplant from a matched family donor; among the haploidentical ones, three used a T-cell-replete graft and two depletion of alpha-beta T-cell receptor cells and of CD19 cells. The source was peripheral blood in six transplants (75%) and bone marrow in two. Engraftment was achieved in seven of eight transplants (87.5%); one child had primary failure and successfully received a second transplant with a different donor and protocol, and another had secondary failure at three months and died of complications of invasive fungal infection, with transplant-related mortality of 12.5%. In the patient with primary failure and autologous reconstitution, the second attempt used a specific strategy to reduce circulating interferon gamma, with two cycles of pre-transplant immunosuppression with fludarabine and dexamethasone, double-volume plasmapheresis and rituximab, followed by haploidentical transplantation with alpha-beta T-cell depletion from the mother's peripheral blood cells, at a dose of 10 million CD34 cells per kilogram, and engraftment was successful; the strategy succeeded in three of the four children in the interferon gamma pathway defect group [44]. Donor chimerism was checked on days 15, 30, 45, 60 and 90, at 6 months and at one year; two patients with mixed chimerism received donor lymphocyte infusions at graded doses of 100,000, 500,000 and one million cells per kilogram, at two-week intervals, and chimerism increased serially after the third infusion in one of them and full chimerism was achieved with a single infusion in the other [44]. Acute graft-versus-host disease occurred in two children (25%), both grade I to II with skin and gastrointestinal involvement, and the chronic hepatic form in one, after the lymphocyte infusions, treated with corticosteroids, mycophenolate mofetil, ciclosporin, ruxolitinib and five sessions of extracorporeal photopheresis [44]. There was cytomegalovirus reactivation in four children (50%), with viral loads up to 1.9 × 10⁵ copies per millilitre, all responding to ganciclovir and cidofovir and without attributable mortality; one child developed virus-induced nephropathy, treated with an angiotensin-converting enzyme inhibitor and furosemide, with full renal recovery [44]. Overall survival was 87.5%, with follow-up of 2 to 8 years and a median of 4.5 years; antituberculous drugs were maintained for about 18 months after transplantation or until immune reconstitution, whichever came first [44]. One child had persistent neurobehavioural and endocrine sequelae, with multiple hormone deficiencies, attributed to pre-transplant neurotuberculosis [44]. The stated limitations are the retrospective design, the small number of patients and the absence of data on interferon gamma levels before and after the intervention, with a prospective national multicentre trial planned [44].

Control of infection before transplantation is essential for the outcome, although complete control is difficult because severe intercurrent infections with mortality may occur; the described practice is to maintain antituberculous medication before, during and after transplantation, in collaboration with the infectious diseases and paediatric intensive care teams, with local control of infection when necessary [44]. The presence of active or disseminated mycobacterial infection tends not to affect survival, although there is a trend towards longer hospital stay, so transplantation may also be considered in patients with disseminated disease [33]. Normalisation of interferon gamma levels before transplantation is recommended, as they are associated with rejection [4]. Successful transplantation is documented in complete IFN-γR2 deficiency [109], and in IL-12Rβ1, NEMO and IRF8 deficiencies [37]. Complete recessive IRF8 deficiency is severe enough to require transplantation, whereas partial heterozygous deficiency is not an indication, the disseminated BCG disease described in these individuals being curable [7].

7.6. Developments and therapies under investigation

Inhibition of interferon gamma before transplantation, to circumvent the rejection that defeats the procedure in complete receptor deficiencies, is investigational. The rationale lies in the murine model in which antibody depletion of the cytokine allowed engraftment [108]. In 2026 an early phase 1 study opened at Cincinnati Children's Hospital Medical Center, starting on 7 January 2026 with 20 participants planned, testing emapalumab at two doses, 3 mg/kg and 10 mg/kg, in the prevention of graft rejection in high-risk patients, with the explicit hypothesis that rejection after transplantation is driven mainly by interferon gamma and that prophylactic inhibition of the cytokine prevents it; the study also aims to characterise the pharmacokinetics and pharmacodynamics of the antibody in this setting [110]. A second, phase 2 study, open since 15 March 2023 with 39 participants planned, compares emapalumab with the combination of fludarabine and dexamethasone in preparing patients with primary immune dysregulation or autoinflammatory diseases for transplantation, funded by the Office of Orphan Products Development of the United States medicines agency [111]. Neither of these studies has this syndrome as a declared eligible condition, and no product has an approved indication for the prevention of rejection in this disease. Emapalumab is authorised, under the brand GAMIFANT®, under application 761107, with a label in force from 26 March 2026, for the treatment of primary haemophagocytic lymphohistiocytosis that is refractory, recurrent or progressive or with intolerance to conventional therapy, and for haemophagocytic lymphohistiocytosis with macrophage activation syndrome in known or suspected Still disease, with an inadequate response or intolerance to glucocorticoids or with recurrent syndrome; the recommended starting dose in the primary form is 1 mg/kg by one-hour intravenous infusion twice a week, with titration up to a maximum of 10 mg/kg [105]. The label contains the warning directly relevant to this syndrome: the medicine may increase the risk of fatal and serious infections by agents favoured by neutralisation of interferon gamma, namely mycobacteria, varicella-zoster virus and Histoplasma capsulatum, should not be given to patients with infection by these agents before appropriate treatment has been started, requires screening for latent tuberculosis and advises prophylaxis against herpes zoster, Pneumocystis jirovecii and fungi, and prohibits live or live attenuated vaccines during treatment [105]. This is why its use in this syndrome is conceivable only in the peritransplant period and under antimycobacterial cover. In the Indian series, unavailability of the medicine led to protocol modification with pre-transplant immunosuppression using fludarabine, dexamethasone and plasmapheresis [44]. A 2026 review systematises the mechanism, the clinical evidence and the emerging therapeutic applications of interferon gamma neutralisation in hyperinflammatory diseases driven by this cytokine [112].

Gene therapy is the second line of investigation and is at the preclinical stage in this class. The strategy is ex vivo correction of the patient's own haematopoietic stem cells with lentiviral vectors, an approach already applied successfully in other inborn errors of immunity, with the theoretical advantage of avoiding graft-versus-host disease and the rejection imposed by high interferon gamma levels [33, 37]. In the preclinical methodology, lentiviral vectors expressing Ifngr1 constitutively or in a myeloid lineage-specific manner were used to transduce haematopoietic stem cells from mice lacking the gene, with stable receptor expression in macrophages and recovery of their responses to interferon gamma; the genetically corrected macrophages derived from these cells suppressed T-cell activation and restored in vitro antimycobacterial activity against M. avium and M. bovis BCG [113]. Transplantation of the corrected cells into deficient mice before BCG infection prevented the manifestations of severe disease, preserved the integrity of the lungs and spleen, reduced the mycobacterial load in these organs and prolonged the overall survival of the transplanted animals [113]. In parallel, lentiviral vectors expressing human IFN-γR1 constitutively showed stable transgene expression in transduced human haematopoietic cells, without interference with viability or proliferation; in a deficient HeLa cell model, the receptor was stably reconstituted and signalling restored without adverse effect on cellular functions, and transduction of SV40-immortalised fibroblasts and of primary fibroblasts from patients with complete IFN-γR1 deficiency recovered receptor expression and restored type II signalling after stimulation with the cytokine [114]. The results are therefore of restoration of the cellular phenotype and of protection in an animal model, without a completed clinical trial or an authorised product; gene editing with CRISPR/Cas9, including gene disruption, correction and insertion, is described as a route to more precise ex vivo correction, with a potential advantage over integration by viral vectors, but likewise without a trial in this disease [33, 113, 114]. A distinct pharmacological route was explored in hypomorphic IFNGR2 alleles with misfolded protein or with gained glycosylation: chemical modifiers of N-glycosylation, some available for clinical use in other indications, enhanced the cellular response to interferon gamma in the cells of these patients, a cell-assay finding that the authors presented as a potential benefit to be confirmed and not as a therapy [90]. In complete TYK2 deficiency, the cellular defect was not pharmacologically correctable in vitro, and the authors concluded that alternative modalities such as transplantation or gene therapy may be needed, with no established protocol for this gene [85].

A search for registered trials with this syndrome as the condition returns, at the date of this update, no study with an intervention directed at the disease; the results correspond to transplantation studies in other immunodeficiencies [110, 111]. The absence of a registered trial does not mean the absence of scientific activity, but it does mean that there is no trial-level evidence for any of the therapies used, and that all practice rests on case series, international surveys and expert consensus [4, 33].

7.7. Agents to avoid, pregnancy, perioperative care and transition

The agents to avoid are, above all, live vaccines, especially BCG, but also the other live-agent vaccines, according to the national standards already cited [39–41]. Pyrazinamide is not part of the treatment of BCG disease because the strain is resistant [37]. One pharmacological group deserves specific note: antagonists of the interleukin 12 and interleukin 23 pathway and TYK2 inhibitors pharmacologically reproduce the genetic lesion. The label of ustekinumab, a human interleukin 12 and 23 antagonist indicated in moderate to severe plaque psoriasis and active psoriatic arthritis, contains under the heading of theoretical risk for particular infections the warning that serious infections due to mycobacteria, salmonellae and BCG vaccination have been reported in patients genetically deficient in IL-12 and IL-23, advises considering diagnostic testing for these infections according to clinical circumstances, requires assessment for tuberculous infection before starting treatment, avoidance of administration in active tuberculosis and prior treatment of latent tuberculosis, and advises avoiding live vaccines during treatment [115]. Deucravacitinib, a TYK2 inhibitor indicated in moderate to severe plaque psoriasis and active psoriatic arthritis in adults, directs that risks and benefits be weighed before starting in patients with chronic or recurrent infection, with previous exposure to tuberculosis, with a history of serious or opportunistic infection or with predisposing conditions, and advises avoiding live vaccines [116]. A patient with biallelic loss of function of the same target is, in these terms, the opposite of the intended recipient of these drugs, so the class should be considered inappropriate in them.

As regards pregnancy and lactation, there are no adequate and well-controlled studies of interferon gamma-1b in pregnant women, and the medicine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus; in primates, doses approximately 100 times the human dose, given from day 20 to day 80 of gestation, increased the incidence of abortion, and a study with subcutaneous doses of 2 to 100 times the human dose showed no teratogenic activity [42]. Safety and efficacy are established in paediatric patients aged one year or more in chronic granulomatous disease and one month or more in severe malignant osteopetrosis, with no data below one month of age [42]. The sources consulted do not describe specific pregnancy data in this syndrome.

In the perioperative period, the most frequent interventions are lymph node excision and abscess drainage, procedures performed under antimycobacterial cover guided by the susceptibility of the isolate, and the collection of material for microbiology and histology should be taken advantage of in any intervention [4, 37]. Before transplantation, local control of infection is part of the preparation, alongside immunosuppression intended to lower circulating interferon gamma [44].

The transition to adulthood gains relevance because prognosis improves with age in several entities and because there are patients diagnosed as adults. In the survey of 141 patients with IL-12Rβ1 deficiency, the mean age at last follow-up was 12.7 years, with cases up to 46.4 years [34]. Patients with partial recessive IFN-γR1 deficiency are described as warranting consideration both in children and in adults with mycobacterial disease of any severity [88]. In adults diagnosed with untranslated region IKBKG variants, the diagnosis was made between the ages of 26 and 38 years [35]. At each contact a high degree of suspicion for new mycobacterial infection should be maintained, with weight and growth monitored in children, because a slight fall in normal weight gain frequently heralds active infection, and with clinical screening for tuberculosis by history and physical examination at every visit [33].

7.8. Regulatory framework and trial status

None of these studies is a randomised controlled trial in this syndrome, so comparisons between them are not valid: the available randomised trial was carried out in chronic granulomatous disease and its relative 70% reduction in infections does not transfer to this class, whose pathophysiology is different and whose absolute infection rates are not known in comparable populations. The transplant series differ in era, genotype, conditioning, donor type and control of infection before the procedure, and the apparent improvement in results between the 2004 survey and the 2026 series is compatible both with the evolution of protocols and with patient selection and small sample sizes. The only therapeutic effect quantified in this syndrome is the proportion of favourable responses in patients treated with interferon gamma, 97 of 127 with documented follow-up (76.2%), which derives from aggregated data from heterogeneous publications and not from a comparison group [4]. No negative trials, suspensions or withdrawals relating to therapies for this syndrome were identified in the sources consulted; the absence of records does not demonstrate the absence of studies.

The recommendations of guidelines and consensus documents converge on four points and diverge on one. They converge on the absolute contraindication of live vaccines [33, 39–41], on the need for prolonged antimycobacterial therapy guided by species and susceptibility [33, 37], on excluding interferon gamma in complete receptor deficiencies and in complete STAT1 deficiency and on its use in production defects and partial response defects [4, 33, 90], and on the need to control infection and to normalise circulating interferon gamma before transplantation [4, 43, 44]. They diverge on the duration of treatment of BCG disease: the African consensus proposes 24 to 36 months followed by prolonged prophylaxis, whereas the Indian review proposes 9 to 12 months, exceptionally 18, followed by two-drug prophylaxis until transplantation [33, 37]. The divergence cannot be resolved by the available evidence and should be decided by the extent of disease, the species and susceptibility of the isolate, the clinical, microscopic and radiological response and the prospect of immune reconstitution, in discussion with microbiology and infectious diseases [33, 37].

8. Reproductive Options and Family Counselling

The recurrence risk depends on the entity and, in genes with two disorders, on the form in question. In the autosomal recessive forms, which account for 79.9% of published patients, the risk for each sibling of a proband is 25%, with a 50% probability of being a healthy carrier; these include deficiencies of IL-12Rβ1, IL-12p40, IL-12Rβ2, IL-23R, interferon gamma, IRF1, ISG15, RORγT, T-bet, TYK2, SPPL2a, ZNFX1, CCR2, complete IFN-γR2 deficiency, partial recessive IFN-γR2 deficiency, complete and partial recessive IFN-γR1 deficiency, recessive STAT1 deficiency, complete recessive IRF8 deficiency and partial JAK1 deficiency [1, 4]. In the autosomal dominant forms, which account for 15.2%, the risk for the offspring of an affected individual is 50%, and assessment of the wider family is mandatory before any vaccination; these include partial dominant IFN-γR1 deficiency, dominant IFN-γR2 deficiency through haploinsufficiency, partial dominant STAT1 deficiency and partial dominant IRF8 deficiency [4–6]. In the X-linked forms, which account for 4.9%, carrier women have a 50% probability of transmitting the allele in each pregnancy, with affected sons and carrier daughters; these include macrophage MSMD due to CYBB, X-linked mycobacteriosis due to hypomorphic IKBKG variants and MCTS1 deficiency [4, 57, 59, 71].

Carrier women deserve specific attention in two situations. In macrophage MSMD due to CYBB, all eleven obligate carriers tested in the two French families were heterozygous and none was described as affected, but in X-linked chronic granulomatous disease carriers are not simply unaffected carriers: they usually produce enough gp91-phox from the normal allele to be protected, but skewed X chromosome inactivation can reduce the proportion of oxidase-positive neutrophils and, below 20%, exposes them to the same infections as affected men, besides a substantial risk of inflammatory disease independent of that proportion, with discoid lupus-like skin lesions, recurrent aphthous stomatitis, photosensitive rashes, alopecia, Raynaud phenomenon, oral ulcers, arthralgia, chorioretinal lesions and usually asymptomatic granulomas, Crohn-like colitis and systemic lupus erythematosus, so longitudinal follow-up is recommended [31, 59]. In IKBKG variants, carrier mothers may have mild manifestations of incontinentia pigmenti or conical teeth, and one of them had a history of recurrent sinorespiratory infections without signs of incontinentia pigmenti, so examination of the mother guides the diagnosis in the child [15]. In MCTS1 deficiency, the heterozygous mother and sister of a patient had normal protein expression in neutrophils and no affected woman has been described [71].

Incomplete penetrance turns cascade screening into a high-yield preventive intervention, and not an informative exercise. Of 29 genetically affected siblings identified in IL-12Rβ1 deficiency, eight, that is 27%, remained entirely asymptomatic, and in the original series seven of twelve affected siblings never had an infection meeting the case definition [34, 97]. In IL-12p40 deficiency, one third of the genetically affected relatives of index cases had no symptoms [82]. The authors of these series explicitly recommend that the diagnosis be sought in the healthy siblings of probands, as well as in selected cases of tuberculosis [34, 97]. The practical value of such screening is documented: the sibling of a patient with MCTS1 deficiency, diagnosed at birth and therefore not vaccinated, remained asymptomatic, whereas five of the six genotyped hemizygotes in that series developed severe BCG disease between three months and one year of life [71].

Counselling differs by form within the same gene and this point should be made explicit to families. In complete IFN-γR1 deficiency, inheritance is recessive, with a 25% risk for siblings, whereas in partial dominant deficiency the risk is 50% for the offspring of an affected individual and justifies testing the wider family before any vaccination, since the disease runs through several generations and an apparently healthy parent may be a carrier [5, 55]. The published case of a 13-month-old girl with pneumonia and her 33-year-old mother with hip pain, both with heterozygous IFN-γR1 deficiency and disseminated Mycobacterium genavense infection, illustrates the simultaneous diagnosis of two generations [10, 99]. In the dominant forms with low penetrance, described as 0.5% in partial dominant IFN-γR1 and IFN-γR2 deficiencies, the presence of the variant in a healthy relative does not predict disease, but it does predict the risk associated with live vaccines, which is enough to change management [4].

Germline mosaicism is not documented in this class in the sources consulted. Post-zygotic somatic mosaicism has been described in another disorder of the same JAK1 gene, autoinflammation with immune dysregulation and eosinophilia, in which a patient had the variant only in mosaic form, detected by methods sensitive to low allele fractions, which illustrates that a negative germline result does not exclude involvement of the gene [79]. In incontinentia pigmenti, an allelic disorder of IKBKG, the mutation is de novo in about 65% of cases and the parents of familial cases may be clinically unaffected but have germline mosaicism, which justifies molecular testing of the mother [96].

Consanguinity is a determinant of the epidemiology of this class and therefore of counselling. The incidence is closely related to consanguineous marriage, which increases the risk of autosomal recessive aetiologies, whereas the prevalence of the dominant and X-linked forms does not appear to vary geographically [4]. In the Indian cohort of 50 patients from 44 families, there was consanguinity in 28 families and a family history of an affected sibling in only nine [81]. In a described case of IL-12Rβ1 deficiency, the parents did not declare themselves consanguineous but belonged to the same extended family, which explains the daughter's homozygosity [101]. The identification of founder alleles allows targeted testing and prenatal diagnosis to be offered at reduced cost in specific populations, as was noted for the Tunisian founder mutation of IL12B, dated to about 1100 years ago, and for the IFNGR1 founder alleles from Chile, Portugal, Poland and the Canary Islands [83, 88].

Prenatal diagnosis by fetal DNA analysis and preimplantation genetic diagnosis are possible from a characterised familial variant, and preventive screening with genetic counselling and prenatal diagnosis was expressly identified as a practical consequence of the identification of the Tunisian founder allele [83]. Genetic confirmation is also important for guiding counselling and testing of patients' relatives in countries that offer BCG vaccination, since testing is needed before immunisation [4]. In the Portuguese context, the standard in force dispenses with the genetic result in order to protect the newborn, because being a first-degree relative of a patient with suspected or confirmed primary immunodeficiency is in itself a contraindication until immunodeficiency has been excluded in the child [40].

Counselling of minors and adolescents should incorporate information on prognosis, which is genuinely bimodal in the production forms: in IL-12Rβ1 deficiency the disease typically begins in childhood, is lethal in up to one third of patients, especially in those with disease due to environmental mycobacteria, but the prognosis appears to improve with age and the spectrum ranges from lethal disease in childhood to an entirely asymptomatic adult life [34]. Improvement with age is not a reason to reduce surveillance in a young child, but it is a reason not to present the diagnosis as uniformly fatal [34]. The family should be informed that the patient and their at-risk relatives must never receive live vaccines, that antimycobacterial therapy may be prolonged and maintained until immune reconstitution or transplantation, and that transplantation, when indicated, requires prolonged antituberculous therapy until reconstitution [33, 44]. The patient should be involved in managing the disease, with age-appropriate responsibility, and the family should participate actively [33].

9. Special Considerations: Population Diversity and Epidemiology

There is no population-based study of this syndrome, and published prevalence estimates diverge by a factor of two: a review devoted to interferon gamma gives about 1 in 50,000 individuals worldwide and another review gives 1 in 100,000, neither deriving from population screening [2, 33]. The African recommendations document places the prevalence of inborn errors of immunity in general between 4 and 10 per 100,000 births per year and gives for this syndrome the estimate of 1 in 50,000, noting that the exact prevalence is not known [33]. Orphanet places the individual entities in the class of point prevalence below 1 per 1,000,000 worldwide, which corresponds to less than 0.1 per 100,000; this value is an upper class limit and not a measurement, and the recorded case numbers show it, with about 180 cases described in complete IL-12Rβ1 deficiency, 13 in complete IFN-γR2 deficiency, about eight in TYK2 deficiency, two in partial IRF8 deficiency and two in complete interferon gamma deficiency [18, 20, 25, 27, 29]. The most solid figure available is therefore a count of published cases and not a prevalence: 830 patients with a genetic diagnosis, from 581 families and 63 countries, up to 2024, with 876 patients retrieved from the eligible articles of whom 46 were excluded for lack of a definitive genetic diagnosis [4].

The geographical distribution of published cases reflects consanguinity and vaccination policies, not the true worldwide distribution. The countries with the most published patients were Iran with 114, Turkey with 107, India with 63, Saudi Arabia with 54 and France with 51 [4]. Middle Eastern countries, such as Saudi Arabia, Iraq, Syria, Iran, Turkey and Morocco, have a high frequency of consanguineous marriage which, together with intensive neonatal BCG vaccination policies, results in greater detection of the syndrome during mycobacterial disease in childhood [4]. The small number of cases reported in North America and Australia is attributed to low levels of consanguinity and to a more restricted BCG vaccination policy, and diagnosis rates are intermediate in Latin America, with an increase in the number of patients diagnosed in the last decade; the very small number of patients diagnosed in Africa may result from underreporting, from early death due to infectious disease or from other unrecognised factors [4]. The effect of vaccine policy on presentation is direct: where the vaccine is not used, as in North America, IL-12Rβ1 deficiency presents with other bacterial or fungal infections and is easily overlooked, which was documented in a series that expands the clinical phenotype in that geographical setting [98].

Populations with founder alleles concentrate the risk locally. In IL-12p40 deficiency, four recurrent alleles account for 25 of the 30 published families, with patients coming mainly from India, Iran, Pakistan, Saudi Arabia and Tunisia, and the Tunisian founder allele was dated to about 1100 years ago [82, 83]. In partial recessive IFN-γR1 deficiency, the allele p.(Ile87Thr) was found in the homozygous state in nine patients from Chile, Portugal and Poland, and the allele p.(Val63Gly) in five patients from the Canary Islands, with the most recent common ancestors dated to about 1600 years and 500 years respectively [88]. This is the only specifically Portuguese datum identified in the sources consulted on this class: Portugal lies within the distribution area of an IFNGR1 founder allele associated with the partial recessive form, of better prognosis, which makes this entity worth considering in Portuguese patients with mycobacterial disease of any severity, in children and in adults [88]. The sources consulted contain no prevalence estimates or series of Portuguese patients with this syndrome, nor Brazilian series, and this is a real gap that cannot be resolved by extrapolation.

For Brazil, the information available in the sources consulted is contextual and not about prevalence: the Brazilian vaccine strain Moreau, also designated Rio de Janeiro, is one of the strains in use worldwide for vaccine production, and the country maintains universal vaccination at birth, so the expected presentation is vaccine-associated disease, as in the cohorts from Iran, Turkey and India [37, 41]. The Brazilian standards for special immunobiologicals exclude the vaccine in immunodeficiencies with a defect of cellular or phagocytic immunity [41]. The open data of the Brazilian regulator, consulted in November 2026, contain no registration of interferon gamma-1b, which limits access to the only therapy directed at the mechanism; consultation of the electronic package insert database was not possible, which remains an access limitation.

In Portugal, vaccine policy determines the expected epidemiology. Since Standard 006/2016, BCG vaccination is restricted to children under 6 years belonging to risk groups, in a national situation of low risk of tuberculous infection that meets the international criteria for adopting that strategy, with vaccines produced by Japan BCG Laboratory [40]. The practical consequence is that presentation with vaccine disease is now unlikely in the country and that the diagnosis will be made, as in North America, from non-tuberculous mycobacteriosis, from severe or unusual tuberculosis and from infections by other intramacrophagic agents [40, 98]. There is also the interaction with newborn screening: vaccination is now conditional on confirmation of a negative result of screening for severe combined immunodeficiency, with postponement to up to five weeks of life, which creates an additional safety window for the immunodeficiencies detectable by that screening, but not for this syndrome, which it does not detect [37, 40].

Among the published national cohorts, the largest is the Indian one, with 482 patients referred on suspicion between 2014 and 2024 and 50 genetically confirmed, from 44 families; the median age at symptom onset was 3 months, with a range of 2.4 to 42 months, and the median age at diagnosis 17 months, with a range of 1 to 180 months, which quantifies the typical diagnostic delay [81]. In that cohort, 58% were male, there was consanguinity in 28 families, 48 of the 50 patients received the Danish 1331 strain vaccine at birth, vaccine-related complications were the most frequent infectious manifestation, in 96% of patients, with localised infection in 48% and disseminated infection in 48%, and at follow-up 20 patients had died, 24 were alive and six were lost to follow-up, corresponding to 40% mortality [81]. The genetic distribution in that cohort was 30 patients with IL-12Rβ1 deficiency, one with IL-12p40 deficiency, three with IFN-γR1 deficiency, one with IFN-γR2 deficiency and one with STAT1 deficiency, and biallelic IL12RB1 variants accounted for 60% of the molecularly characterised cases [81]. The proportion of non-tuberculous mycobacteria identified in that cohort was only two patients, attributed to underreporting owing to the limitations of identification methods in a high tuberculosis burden country [81].

The global genetic distribution, measured by published cases, attributes 41% to IL-12Rβ1 deficiency, 20% to IFN-γR1 deficiency, about 9% to IL-12p40 deficiency, about 9% to STAT1 deficiencies and about 6% to IFN-γR2 deficiency, the first two together accounting for 61% [4]. An earlier genetic analysis of a large cohort of 220 patients with defects of the IL-12/IL-23–IFN-γ circuit ranked the genes similarly, with IL12RB1 in 40%, IFNGR1 in 39%, IL12B in 9%, STAT1 in 5%, IFNGR2 in 4% and NEMO in 3%, and data from two Iranian cohorts indicate that IL-12Rβ1 and IL-12p40 defects are the most common in that country [4]. These proportions are measures of cases published in referral centres and not of population incidence, and their interpretation must take account of the detection bias created by BCG vaccination, which makes forms with severe vaccine disease more visible.

Three special populations should be considered. Adults, because the partial forms present late and because diagnosis in an adult requires exclusion of anti-interferon gamma autoantibodies and haematological malignancy [33]. Patients in resource-limited settings, for whom the African recommendations were expressly written and in which irregular adherence or limited regular access to quality care make many patients poorly suited candidates for replacement therapy, a decision that should be discussed in a multidisciplinary team and with the patient [33]. And household members of a patient with active infection, in particular pregnant women, people living with HIV infection and people with previous tuberculosis, who may need prophylaxis [33].

Reference and support resources are European and international. ERN RITA is the European reference network for rare immunodeficiency, autoinflammatory and autoimmune diseases, and brings together European centres with expertise in the diagnosis and treatment of these diseases [45]. The European Society for Immunodeficiencies maintains the European registry of inborn errors of immunity, whose most recent report covers 30,628 patients followed between 1994 and 2024, and is the structure that allows longitudinal follow-up of diseases with small numbers per centre [46]. The International Patient Organisation for Primary Immunodeficiencies, based in Brussels, is the reference patient organisation for this field [47]. The reference classification of the entities is that of the Expert Committee of the International Union of Immunological Societies, whose 2024 update was published in 2025 [1]. The creation of a worldwide registry of patients with this syndrome and precise follow-up of affected families across generations have been identified as measures needed to reduce mortality [4].

10. Illustrative Clinical Case

The case described by Dolikhani and colleagues in 2026 documents a gastrointestinal presentation of IL-12Rβ1 deficiency and the typical course of diagnostic delay [101]. It concerns an Iranian girl, born to apparently non-consanguineous parents, who received the BCG vaccine at three months of age according to the vaccination record. Two months later, at five months, she was admitted with signs of BCG-itis, with an abscess and lymphadenopathy in the left axilla and on the left side of the neck. She underwent surgery for removal of the affected nodes and drainage of the abscess, and histology revealed necrotising granulomatous lymphadenitis with numerous acid-fast bacilli. She then began a 12-month regimen with ethambutol 20 mg/kg, rifampicin 10 mg/kg, isoniazid 15 mg/kg, ciprofloxacin 20 mg/kg and clarithromycin 15 mg/kg. Ultrasound showed a pericardial effusion, splenomegaly of 98 millimetres and mild free abdominal fluid, and computed tomography with and without contrast showed a wedge-shaped hypodense area in the lower portion of the spleen, visible in figure 1 of the article, and several enlarged lymph nodes at the hepatic hilum; the tuberculin skin test was negative [101].

At ten months, five months after the first admission, she was readmitted with fever and diarrhoea, with raised transaminases, and SARS-CoV-2 infection was diagnosed by positive polymerase chain reaction, treated with supportive measures alone. Two examinations for acid-fast bacilli, in the buffy coat and in gastric lavage, were negative. Abdominopelvic computed tomography showed a mild left pleural effusion with adjacent subsegmental collapse-consolidation and mild free fluid in the pelvic cavity, and stool examination confirmed Candida infection. Antimycobacterial therapy was temporarily suspended because of the rise in liver enzymes and reintroduced at discharge, after improvement in liver function tests and reassessment by the infectious diseases team. For severe anaemia, with haemoglobin of 5.6 g/dL, she received three units of packed red cells, and endoscopy showed grade 1 oesophageal varices and portal hypertension [101].

Between admissions she remained symptomatic, with intermittent abdominal distension, recurrent diarrhoea, poor oral intake, failure to thrive and insufficient growth, with progressive deterioration. Exome sequencing, performed with a mean coverage of 272-fold, identified a homozygous missense variant in exon 7 of IL12RB1, NM_005535.3:c.635G>A, p.(Arg212Gln), predicted deleterious by the prediction tools used, with a population allele frequency of 0.0004% and no documented homozygotes in gnomAD v4.1, and described in mutation databases as disease-causing [101]. The substitution of an arginine, a positively charged residue, by a glutamine, with a neutral polar side chain, may alter the folding, stability or function of the protein. Both parents were confirmed as heterozygous carriers and, although they did not declare themselves consanguineous, they belonged to the same extended family, which explains the homozygosity; a sister two years older was clinically healthy despite being vaccinated, but was not tested [101]. Normalisation of this variant on the MANE Select transcript confirms NM_005535.3:c.635G>A, p.(Arg212Gln) [3].

At 19 months she was readmitted with persistent abdominal pain, vomiting, insufficient weight gain and continued diarrhoea, with documentation of grade 1 oesophageal varices, portal hypertension, mild ascites, splenomegaly of 98 millimetres, necrotic para-aortic lymph nodes and increased hepatic echogenicity. She developed epistaxis, haematoma and coagulopathy, with a prothrombin time of 38.2 seconds and an international normalised ratio of 3.75, in association with abnormal liver function tests. No microorganism was isolated during that admission and the liver dysfunction was considered multifactorial, possibly related to the physiology of portal hypertension, to chronic inflammatory involvement and to disseminated vaccine-associated disease. She was treated with fresh frozen plasma, intravenous albumin, furosemide and therapeutic paracentesis [101].

At 30 months she was referred to a tertiary centre for progressive ascites and diarrhoea. She weighed 9 kilograms and measured 77 centimetres, with a body mass index of 15.2 kg/m², corresponding to growth failure. Examination showed stable vital signs and marked abdominal distension with tense ascites, documented in figure 2 of the article. Analysis of the ascitic fluid showed a transudate with a high serum-ascites albumin gradient, and direct examination, culture and polymerase chain reaction were negative for bacterial peritonitis. Serology for hepatitis C and B viruses, HIV, Epstein-Barr virus and cytomegalovirus was negative, as was stool culture, and the chest radiograph showed no abnormalities. Gastric lavage identified Mycobacterium bovis BCG susceptible to rifampicin and ethambutol. The chronology of admissions and treatments is presented in figure 3 of the article [101].

Treatment during that admission included levofloxacin 7 to 15 mg/kg, amikacin 15 mg/kg, isoniazid 5 to 10 mg/kg and ethambutol 15 mg/kg, with rifaximin 10 mg/kg added as intestinal decontamination in the setting of severe portal hypertension, recurrent ascites and gastrointestinal symptoms. The ascites was controlled with spironolactone 2 mg/kg, albumin and furosemide. Subcutaneous interferon gamma-1b was given at a dose of 20 µg on alternate days, as immunotherapy adjunctive to susceptibility-guided antimycobacterial therapy, for two doses. Alpha-1 antitrypsin levels and the insulin tolerance test were normal. After marked clinical improvement, reduction of the ascites and improvement in liver function, she was discharged home on spironolactone 5 mg/kg/day, furosemide 2 mg/kg/day, isoniazid 10 mg/kg/day, ethambutol 15 mg/kg/day, levofloxacin 7 mg/kg/day and amikacin 20 mg/kg/day [101].

At the last documented follow-up, at 44 months of age, the ascites was controlled and drug tolerance was acceptable. Shear wave elastography showed a liver of 9.4 centimetres, mean elasticity of 5.9 kilopascals and a fat fraction of 3%, excluding steatosis and significant fibrosis, so the recurrent ascites was attributed to the physiology of portal hypertension, probably related to chronic hepatobiliary or hepatic hilar inflammatory involvement in the setting of BCG-osis, without a defined portal venous anomaly having been documented. Planned long-term management included prolonged susceptibility-guided antimycobacterial therapy, with duration individualised according to clinical response, microbiological findings, drug tolerance and multidisciplinary follow-up [101].

The figures consulted in the open-access full text are available at https://pmc.ncbi.nlm.nih.gov/articles/PMC13504452/figure/fig-0001/ for the wedge-shaped hypodense splenic lesion on abdominal computed tomography, https://pmc.ncbi.nlm.nih.gov/articles/PMC13504452/figure/fig-0002/ for the abdominal ascites during the last admission and https://pmc.ncbi.nlm.nih.gov/articles/PMC13504452/figure/fig-0003/ for the chronology of admissions and treatments [101].

Three aspects of the management in this case should not be taken as routine. The dose of interferon gamma-1b used, 20 µg on alternate days for two doses, corresponds neither to the regimen described in the literature on this syndrome nor to that of the label: the dose documented in the series is 50 µg/m² three times a week, with escalation to 100 or 200 µg/m² in refractory disease, and the label specifies 50 µg/m² or 1.5 µg/kg per dose according to body surface area, three times a week, so the administration described in this report is shorter and at a lower dose than documented practice and its contribution to the improvement cannot be interpreted [2, 42]. The duration of antimycobacterial therapy in this patient, with successive cycles and restarts, also differs from the duration suggested both by the African consensus, of 24 to 36 months followed by prophylaxis, and by the Indian review, of 9 to 12 months, exceptionally 18 [33, 37]. Finally, vaccination took place at three months of age and the disease appeared two months later, which illustrates the described mean interval of 4.54 months between vaccine exposure and the adverse reaction [4]. Gastrointestinal and hepatobiliary involvement with portal hypertension is presented by the authors as a poorly recognised manifestation of IL-12Rβ1 deficiency, and is consistent with the gastrointestinal findings described in the Indian cohort, in which six patients with this deficiency had diarrhoea or other digestive manifestations and three received a diagnosis of inflammatory bowel disease [81, 101].

11. Prognosis and Long-Term Follow-up

Prognosis depends on the genotype and, within each gene, on the existence of residual activity. In the aggregated data of 830 published patients, 597 were alive (71.9%), 177 had died (21.3%) and 56 had no information, with a mean age at death of 8.68 years; among the 153 patients with an identified cause of death, 45 (29.4%) died of mycobacterial infection, 20 (13.1%) of non-mycobacterial sepsis, 13 (8.5%) of respiratory failure unrelated to infectious disease, 11 (7.2%) from central nervous system involvement, five of cancer, five from gastrointestinal involvement, three of graft-versus-host disease and 51 (33.3%) from other causes, including trauma and end-stage renal disease [4]. The high mortality is attributed mainly to poor control of infection [4]. In the Indian cohort of 50 patients, 40% died, which underlines the need for early identification and consideration of transplantation [81].

In the most severe forms, complete autosomal recessive deficiencies of IFN-γR1, IFN-γR2, STAT1, IRF1 and interferon gamma abolish interferon gamma activity and most patients die of severe disseminated mycobacterial infection before the age of ten, so transplantation is the only curative therapy [2, 4]. The overall prognosis of transplantation in these deficiencies is described as poor in the reviews, with mortality of 33.3% in the aggregated series of 39 patients and with the underlying genetic defect contributing in a statistically significant way to prognosis in the survival analysis [4, 33]. In the recent Indian series, with pathway-adapted conditioning, overall survival was 87.5% in eight transplants, with a median follow-up of 4.5 years, a setting that suggests improvement with current protocols but which is not directly comparable with the older series [44].

In the partial forms, the prognosis is considerably better. In partial recessive IFN-γR1 deficiency, thirteen of the fourteen patients described were alive and up to ten were free of infection without any prophylaxis, with one patient dying at seven years nine days after the diagnosis of prolonged M. avium infection and the start of therapy [88]. In partial dominant IFN-γR1 deficiency and partial IFN-γR2 deficiency, clinical penetrance is described as 0.5%, which means that most carriers do not develop disease [4]. In partial IFN-γR2 deficiency penetrance is low and antibiotics are usually sufficient [33]. In partial STAT1 deficiency penetrance is low and the clinical phenotype mild, with a good prognosis for recovery [13]. In partial heterozygous IRF8 deficiency, the disseminated BCG disease described in affected individuals was curable and there is no indication for transplantation [7].

In the production defects, the prognosis is bimodal and improves with age. In IL-12Rβ1 deficiency, ninety-nine of the 141 patients in the international survey (70%) were alive, with a mean age at the last follow-up visit of 12.7 years and a standard deviation of 9.8 years, with cases between 0.5 and 46.4 years; the disease typically begins in childhood and is lethal in up to one third of patients, especially those with disease due to environmental mycobacteria, but the spectrum ranges from lethal disease in childhood to an entirely asymptomatic adult life [34]. The original series of 41 patients concluded that the overall prognosis is good by virtue of broad resistance to infection, low clinical penetrance and the favourable outcome of infections, with only five deaths in childhood and the remaining 36 patients alive and well [97]. In IL-12p40 deficiency, clinical penetrance is high but incomplete, with one third of genetically affected relatives asymptomatic, and the prognosis is poor, with mortality rates up to 28.6% [82]. In the dominant forms, isolated bone disease has a more protracted course, with disease-free intervals of 7.2 years on average, versus 1.6 years in the complete recessive forms [5].

A particular prognostic consequence of IL-12Rβ1 deficiency is cross-protection: BCG disease protected in a statistically significant way against subsequent disease due to environmental mycobacteria, although not against salmonellosis, and both vaccine inoculation and vaccine disease were effective against later environmental mycobacteriosis [34, 97]. The pattern of recurrences differs by organism: mycobacterial disease recurs rarely, with 15 recurrences of BCG disease and three of environmental mycobacteriosis in 141 patients, whereas salmonellosis recurred in 22 [34]. In patients with IL-12Rβ1 deficiency undergoing immunosuppression for another reason, the risk is substantial: a 14-year-old girl who presented with systemic lupus erythematosus developed fatal disseminated infections by mycobacteria and by Candida after immunosuppressive treatment [12].

The intervals in this table correspond to those given in section 7: three-monthly laboratory monitoring and monthly liver function tests below one year of age derive from the interferon gamma-1b label, maintenance of antituberculous drugs for about 18 months after transplantation and verification of chimerism on the days and months indicated derive from the transplant series with adapted conditioning, and six-monthly follow-up for at least two years after completion of antimycobacterial therapy derives from the Indian review [37, 42, 44].

Two follow-up points deserve note for their predictive value. The first is that, in a South African cohort, unexplained weight loss was the sign that stood out most as an indicator of recurrent mycobacterial infection, and that the presentation is frequently subtle and atypical, with isolated fever or lymphadenopathy, so the degree of suspicion should be high at every contact [33]. The second is that assessment of interferon gamma levels before transplantation is proposed as a predictive marker of complications of the procedure, given that high levels are associated with graft rejection and with graft-versus-host disease; in a patient with complete recessive IFN-γR1 deficiency who underwent two unsuccessful transplants, the first attempt failed through graft failure with autologous reconstitution and the second was complicated by graft-versus-host disease, the patient then remaining clinically stable on prednisolone and antituberculous drugs, with poor nutritional recovery [81]. The same patient developed osteomyelitis, a manifestation typically associated with partial dominant deficiency and rarely observed in complete deficiency because of its high mortality; the interferon gamma receptor is expressed on osteoclasts, normally inhibited by this cytokine, and loss of that inhibition explains the bone tropism [81]. Severe lymphopenia with reduced naive T subsets was observed in nine patients in the Indian cohort, a finding not classically considered in this syndrome and which persisted in some patients regardless of therapy, so its interpretation remains open [81].

The documented long-term sequelae include those of infectious cause and those of treatment. In the transplant series, one child had significant neurobehavioural and endocrine sequelae, with multiple hormone deficiencies requiring endocrinology and neurology follow-up, attributed to neurotuberculosis preceding the transplant [44]. In the illustrative case, portal hypertension with oesophageal varices, recurrent ascites and growth failure persisted after microbiological control, with elastography excluding significant fibrosis, and the ascites was attributed to portal hypertension physiology associated with chronic inflammatory involvement [101]. In patients on prolonged antimycobacterial therapy, hepatotoxicity requires interruption and reintroduction of the regimen, as happened in that case and as is described for interferon gamma itself in infants [101, 107].

12. Summary and Final Considerations

Mendelian susceptibility to mycobacterial disease is the clinical name of a group of inborn errors of immunity whose molecular lesion always lies in the production of or the response to interferon gamma, and whose clinical expression is a narrow vulnerability to mycobacteria of low virulence in children whose blood count, immunoglobulins and lymphocyte subsets are normal. That normality of routine tests is the main reason why diagnosis is late, with a median of 17 months in a cohort in which the median age at symptom onset was three months, and is also the reason why a normal immunological panel never excludes the diagnosis.

Recognition begins with the isolated organism and the circumstances of its arrival. Localised or disseminated disease due to the vaccine strain of bacille Calmette-Guérin, infection by environmental mycobacteria, tuberculosis of unusual severity or location, recurrent extraintestinal non-typhoidal salmonellosis and mucocutaneous candidiasis associated with mycobacteriosis are the five pictures that should prompt investigation. Lymphadenopathy is the most frequent manifestation and the most common initial presentation, and multifocal osteomyelitis points to specific dominant forms. In adults, the acquired phenocopy due to neutralising anti-interferon gamma autoantibodies and haematological malignancy are mandatory exclusions, and human immunodeficiency virus infection must be documented as absent in all.

The genetic architecture of the class now comprises more than twenty genes, with autosomal recessive inheritance in the great majority of published patients, autosomal dominant in a substantial minority and X-linked in a small minority, and with two modes of inheritance in the same gene in IFNGR1, IFNGR2 and IRF8. IL-12Rβ1 deficiency and IFN-γR1 deficiency together account for about three fifths of published cases. About half of the patients with a compatible phenotype still have no molecular diagnosis, a proportion stable since 2008, so exome or genome sequencing is preferable to narrow panels, and a negative result leaves the clinical diagnosis open rather than excluding it.

The most consequential clinical distinction is not between genes, but between production defects and response defects, and within the latter between complete and partial forms. That distinction decides three things: whether recombinant interferon gamma has any chance of working, whether transplantation is the only curative option and what prognosis should be communicated to the family. The cellular dose-response to interferon gamma, flow cytometry of the receptors and measurement of plasma interferon gamma are the tests that establish it, and should be requested explicitly and not inferred from the genotype. In IRF1 deficiency, which acts downstream of the receptor, the response to the cytokine should not be presumed.

Prevention remains the intervention with the greatest effect on mortality. No live vaccine should be given to the patient, and at-risk siblings should be tested before the neonatal dose, with vaccination postponed until the diagnosis has been excluded, as established by the Portuguese standard, the Brazilian manual of special immunobiologicals and the World Health Organization position paper. Incomplete penetrance, with a quarter to a third of genetically affected siblings asymptomatic in the production deficiencies, means that waiting for the first symptom in the next sibling is to lose the only opportunity for prevention.

The established treatment is multiple, prolonged antibiotic therapy guided by species and susceptibility testing, without pyrazinamide in BCG disease, with early recourse to second-line drugs in disseminated disease and with continued prophylaxis until immune reconstitution or transplantation. Duration divides the sources, with a regional consensus proposing 24 to 36 months and a review proposing 9 to 12 months, a divergence that the available evidence does not resolve and which should be decided by extent, species, response and the prospect of reconstitution. Interferon gamma-1b is the only therapy directed at the mechanism, is used off-label in all forms of the syndrome, has a reference dose of 50 µg/m² three times a week with escalation documented in refractory disease, and has had no marketing authorisation in Portugal since 2021 and no registration in Brazil, an access limitation that constrains practice in those countries. Allogeneic transplantation is the only cure in complete receptor and STAT1 deficiencies and is hampered by rejection mediated by circulating interferon gamma itself, a mechanism demonstrated in an animal model and countered in practice by intensified conditioning, by pre-transplant immunosuppression aimed at reducing the cytokine and, under investigation, by its pharmacological neutralisation. Gene therapy remains preclinical, with restoration of the cellular phenotype in patients' cells and protection against severe disease in an animal model.

The unmet needs are clear and are stated by the sources themselves: there is no population study of prevalence, no randomised trial of any of the therapies used, no worldwide patient registry, half of the clinically diagnosed patients have no molecular diagnosis and there are no published data from Portuguese or Brazilian series of this class. What does exist, and what underpins practice, are international surveys by entity, a systematic review of 830 patients, national cohorts, regional consensus documents and the periodic classification of the International Union of Immunological Societies, together with a European registry with longitudinal follow-up capacity that is the infrastructure closest to answering these gaps.

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