DAVID Syndrome and NFKB2 Deficiency

Autosomal dominant immunodeficiency of the non-canonical NF-κB pathway, in which hypogammaglobulinaemia with a common variable immunodeficiency phenotype is associated, in variants of the C-terminal domain, with adrenocorticotrophic hormone deficiency, alopecia, trachyonychia and neutralising autoantibodies against type I interferon.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

AD: autosomal dominant; AR: autosomal recessive; ACTH: adrenocorticotrophic hormone; IgG, IgA, IgM and IgE: immunoglobulins of classes G, A, M and E; IUIS: International Union of Immunological Societies. Numbers, codes and inheritance correspond to the entries and sources consulted on 31 October 2026 [1–13].

0.1. Entities and subtypes covered in this article

The autosomal recessive entities of the same pathway — NIK deficiency (MAP3K14, OMIM 620449) and RELB deficiency (RELB, OMIM 617585), from the group of alternative NF-κB pathway defects — share the thymic mechanism and anti-interferon autoantibodies, but have a combined immunodeficiency phenotype and are covered in the differential diagnosis [4, 6, 7, 14].

1. Introduction

The association between anterior pituitary insufficiency and humoral immunodeficiency was defined as a distinct entity in 2012 by Quentien, Delemer, Papadimitriou, Brue and colleagues, from the French multicentre GENHYPOPIT network: among twenty-two unrelated patients with adrenocorticotrophic hormone (ACTH) deficiency without an identified TBX19 variant, three (13.6%) had common variable immunodeficiency (CVID), and the study brought together four patients from three unrelated families, including a sibship with two affected members [15]. ACTH deficiency manifested between 5 and 15 years of age, always with symptomatic hypoglycaemia, and the immunodeficiency had been diagnosed earlier, between 2 and 8 years, because of recurrent infections; three of the four patients had a hypoplastic pituitary and one had low insulin-like growth factor 1 (IGF-1) with a subnormal growth hormone (GH) response to stimulation [15]. As anti-pituitary autoantibodies were negative in all and sequencing of the candidate genes of the time (LIF, IKZF1, IKZF4) revealed nothing, the authors proposed the acronym DAVID, for deficit in anterior pituitary function and variable immune deficiency, arguing that the coincidence of two rare diseases in four patients from three independent pedigrees was not fortuitous [15].

The molecular cause emerged the following year, through two independent routes. Chen, Kumánovics, Hill and colleagues, in Utah, sequenced the exome of a family with childhood-onset autosomal dominant CVID and found the heterozygous variant c.2564del, p.(Lys855SerfsTer8) in NFKB2; targeted screening of NFKB2 in thirty-three other patients with CVID identified c.2557C>T, p.(Arg853Ter) in a sporadic case, the only one of the thirty-three with known central adrenal insufficiency [16]. In the four affected patients, hypogammaglobulinaemia of all three classes, poor antigen responses and ACTH deficiency coexisted, and functional studies in Epstein–Barr virus-transformed B-cell lines showed that the variants impair phosphorylation and proteasomal processing of the p100 precursor, with reduced nuclear translocation of p52 [16]. In parallel, Brue, Quentien, Samuels and colleagues sequenced the exomes of the original French families and found that NFKB2 was the only gene with a rare variant shared by the three probands: p.(Ala867Val), p.(Asp865Gly) and p.(Arg853AlafsTer30), to which they added p.(Arg853Ter) in a fourth family by Sanger sequencing of the two C-terminal exons [17]. De novo origin was demonstrated in the three families in which both parents could be studied, and two of the six families ascertained had no variant in the C-terminal region of the gene, which led the authors to accept genetic heterogeneity of the clinical syndrome [17].

The name used depends on the specialty seeing the patient, which explains the apparent multiplication of names for the same disease. In medical genetics nomenclature the entity is "common variable immunodeficiency 10" (OMIM 615577), a designation reflecting the context of its discovery; in Orphanet it is "deficit in anterior pituitary function–variable immunodeficiency syndrome" (ORPHA:293978), with "DAVID syndrome" as a synonym and assignment to code E23.0 of the International Classification of Diseases, tenth revision [3]. In the International Union of Immunological Societies (IUIS) classification of inborn errors of immunity, updated in 2024, the entity appears as "NFKB2 deficiency", autosomal dominant, in the group of predominantly antibody deficiencies with a CVID phenotype, characterised by low serum IgG, IgA and IgM with low B-cell counts, and by recurrent sinopulmonary infections, alopecia and endocrinopathies [4]. Orphanet classifies it among the rare endocrine diseases, and the three designations coexist in the literature [3, 4].

The history of the following fifteen years is that of an entity that proved broader than the acronym. The cohort of Klemann, Grimbacher and colleagues, published in 2019, brought together fifteen new patients from eleven families and all thirty-five cases published up to September 2018, totalling fifty carriers from thirty-two families with seventeen different variants, and showed that ACTH deficiency affects 44% of carriers, whereas early immunodeficiency affects 92% [5]. The study established that the disease exceeds the usual clinical spectrum of CVID, with clinical signs of T-cell dysfunction, predominantly T-cell-mediated autoimmunity and non-negligible mortality [5]. In 2023, Le Voyer, Casanova, Puel and colleagues reclassified the disease in functional terms: studying seventy-three patients from fifty families with twenty-eight rare variants, they distinguished three autosomal dominant inborn errors of NF-κB2 and showed that only one of them, the one in which unprocessed p100 accumulates and exerts excessive inhibitory activity, is associated with anterior pituitary deficiencies, ectodermal dysplasia, neutralising autoantibodies against type I interferon and a risk of severe viral disease [7]. In 2025, Meissner, Fliegauf, Grimbacher and Klemann brought together one hundred and thirty-eight carriers from the literature and organised the genotype–phenotype correlation into three types of protein defect, confirming that ACTH deficiency and trachyonychia occur exclusively with variants of the C-terminal domain [6].

This article covers the complete class of diseases caused by germline NFKB2 variants, not only the presentation with pituitary deficiency, because the correlation between variant position, protein defect and phenotype is now the framework that organises diagnosis and follow-up. DAVID syndrome corresponds to the subset of patients with a C-terminal domain defect who develop symptomatic ACTH deficiency; patients with the same type of defect without pituitary involvement have the same molecular disease and the same need for endocrine surveillance, and patients with early or central truncations have a milder phenotype, with partial penetrance and no described endocrinopathy [6, 7]. The autosomal recessive disorders of other components of the same pathway, NF-κB-inducing kinase (NIK, encoded by MAP3K14) and RELB, share with the dominant form of NFKB2 the thymic mechanism and anti-interferon autoantibodies, and are covered here in the differential diagnosis [4, 7]. Combined congenital hypopituitarism, in which NFKB2 is listed as a cause with involvement of other systems, isolated ACTH deficiency due to TBX19, inborn errors of immunity in general, Tregopathies with a CVID phenotype and activated PI3Kδ syndrome are part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The gene and the protein

NFKB2 (OMIM 164012; HGNC:7795) is located at 10q24.32 and encodes the transcription factor NF-κB2, synthesised as a 900-amino-acid cytoplasmic precursor p100, also called p49/p100 in the older literature and LYT-10 in haemato-oncology studies [2, 18]. The MANE Select reference transcript is NM_001322934.2, with protein NP_001309863.1; the clinical and functional literature uses NM_001077494.2 or NM_001077494.3, isoform a, whose nucleotide and amino acid numbering coincides with that of the MANE transcript for the pathogenic variants described, as confirmed variant by variant in VariantValidator [8]. The protein has the Rel homology domain in the N-terminal half, which contains the nuclear localisation signal and mediates dimerisation and DNA binding, the ankyrin repeat domain, a death domain and, at the C-terminal end, between amino acids 760 and 900, the processing domain with the NIK-responsive sequence [6, 7]. The mature p52 form corresponds to amino acids 1 to 405 [7].

The gene was mapped to 10q24 by Liptay and colleagues in 1992, by fluorescence in situ hybridisation, and it was confirmed that NFKB2 corresponds to LYT10 isolated from a lymphoma t(10;14)(q24;q32) translocation [2]. OMIM stresses that p100 and p105 (the product of NFKB1) are not merely precursors: they have their own regulatory functions, which is precisely the key to the pathophysiology of this disease [2].

2.2. The non-canonical NF-κB pathway

The NF-κB network is activated by two interconnected pathways. The canonical pathway, dependent on NF-κB1, responds to a variety of immune receptors and organises rapid, broad inflammatory responses; the non-canonical pathway, dependent on NF-κB2, is triggered by specific stimuli and regulates lymphoid organ development, B-cell maturation including germinal centre reactions, T-cell differentiation, thymic selection and innate antiviral immunity [5, 6]. The receptors that trigger it include the lymphotoxin beta receptor, the B-cell activating factor receptor (BAFF-R), RANK and CD40 [2, 17].

The sequence of molecular events is as follows. The stimulus activates NF-κB-inducing kinase (NIK, the product of MAP3K14), which activates the kinase IKKα (the product of CHUK); this phosphorylates p100, preferentially bound to RelB, at serines 866, 870 and 872, and phosphorylated p100 is polyubiquitinated at lysine 855 by the βTrCP ubiquitin ligase complex [6, 19]. The proteasome then removes the C-terminal half, generating p52, which dimerises with a Rel protein — mainly RelB, but also RelA and c-Rel — and migrates to the nucleus, where the p52–RelB heterodimer activates transcription of target genes [5, 7]. p52–p52 homodimers, lacking a transactivation domain, are transcriptional repressors [5]. In resting cells, unprocessed p100 homomultimerises through its IκB-like domain and forms high-molecular-weight complexes, the kappaBsomes, whose inhibitory activity is termed IκBδ and which retain almost all NF-κB subunits in the cytoplasm, including those of the canonical pathway [6, 7]. The work of Basak and colleagues, cited by OMIM, showed that p100 functions as a true IκB inhibitor in the non-canonical pathway, inhibiting DNA binding of RelA–p50 and RelB–p50 dimers [2].

2.3. Three types of protein defect and their functional consequences

The position of the variant within the gene determines which of these mechanisms is disrupted, and the classification into three types of protein defect, proposed by Meissner and colleagues, now organises the genotype–phenotype correlation [6].

The table summarises data on one hundred and thirty-eight carriers gathered by systematic review of the literature, ClinVar and the Human Gene Mutation Database, of whom 106 had a C-terminal domain defect, 24 a central truncation and 8 an early truncation [6]. The C-terminal domain defect is the most common in the literature; early truncations are rare in NFKB2, unlike NFKB1, where they are the most frequent defect, suggesting that a simple halving of the p100 and p52 dose is weakly pathogenic, possibly even haplosufficient, and that the dominant defect is the presence of unprocessable p100 with sustained inhibitory activity [6].

The functional characterisation by Le Voyer and colleagues translates the same principle into assay terms: of twenty-eight rare variants studied by overexpression, luciferase assays, immunoblotting and confocal microscopy, three categories emerged — p52 loss of function with IκBδ gain of function (p52LOF/IκBδGOF, 57 patients), p52 loss of function with IκBδ loss of function, corresponding to true haploinsufficiency (4 patients), and p52 gain of function with IκBδ loss of function (6 patients) [7]. Only the first group prevented nuclear translocation of p52 and RelB and the formation of p52–RelB heterodimers in patients' fibroblasts, and only in this group were ectodermal dysplasia and anterior pituitary deficiencies described [7]. This distinction cannot be deduced from the position of the variant with absolute certainty, so the functional assay remains the arbiter when the clinical classification is doubtful [7].

Chen and colleagues favoured functional haploinsufficiency as the mechanism, because in patients' cells p52 translocation was reduced but not abolished, and because assays of toll-like receptors 1 to 8 were normal, suggesting a preserved canonical pathway [16]. Brue and colleagues, by contrast, described the variants as generating an unprocessable "super-repressor", with a dominant effect, and in their conclusions spoke of a dominant gain-of-function effect, which explains the "gain of function" label that Orphanet retains for the gene–disease association [3, 17]. The murine work of Wirasinha and colleagues resolved the apparent contradiction: in mice with mutations of the p100 degron, resistance to degradation is graded, and only severe resistance, from a highly resistant allele or from two subclinical alleles, causes thymic medullary hypoplasia and autoimmunity, whereas complete absence of p100 and p52 does not, indicating that autoimmunity results from the IκB function of degradation-resistant p100 and mainly in non-haematopoietic cells [20]. The two mechanisms therefore coexist in the same variant: there is too little p52 to activate transcription and too much p100 inhibiting it.

2.4. Thymic mechanism and central tolerance

The link between a lymphocyte signalling pathway and a pituitary deficiency remained unexplained for more than a decade. The initial hypothesis of a direct role for NFKB2 in pituitary development, suggested by pituitary hypoplasia in the first patient, lost ground as normal magnetic resonance scans accumulated and because the Lym1 mouse, carrying the p.(Tyr868Ter) variant in the same domain, has a histologically normal pituitary, TPIT-labelled corticotrophs (TPIT being the product of TBX19), pro-opiomelanocortin expression and adrenal glands [2, 5, 17].

The alternative was a breakdown of central tolerance. NFKB2, downstream of the lymphotoxin beta receptor, regulates AIRE expression in medullary thymic epithelial cells, and Nfkb2−/− mice develop organ infiltration by activated T cells and autoantibodies, with a phenotype similar to Aire−/−, Ltbr−/−, Nik aly/aly and Traf6−/− mice; bone marrow transplantation experiments showed that autoimmunity arises from the radiation-resistant stromal compartment, not the haematopoietic compartment [2]. Le Voyer and colleagues confirmed this in human tissue: thymic volume was smaller in eleven patients aged 4 to 16 years than in age-matched controls, and thymic biopsies from a patient with p.(Pro850Serfs*36) and from a patient with complete recessive RELB deficiency showed a dysplastic organ, disorganised corticomedullary architecture, an atrophic medulla, scarce medullary epithelial cells and absence of AIRE and of Hassall's corpuscles [7].

The most striking immunological consequence of this failure is narrow and specific: patients produce neutralising autoantibodies against the twelve subtypes of interferon alpha and against interferon omega, and little else. In fifty-six patients with p52LOF/IκBδGOF variants, 33 (59%) had high titres of anti-interferon alpha-2 IgG, compared with 41 of 45 (91%) in autoimmune polyendocrinopathy type 1 due to AIRE deficiency, and none of the patients in the other two functional groups [7]. The autoantibodies neutralised interferon alpha-2 in 36 of 57 (65%) and interferon omega in 30 of 57 (53%) at high concentrations, and in 43 of 57 (75%) and 44 of 57 (77%) at low concentrations, with 47 of 57 (82%) neutralising one or the other [7]. Unlike autoimmune polyendocrinopathy type 1, organ-specific autoantibodies are lacking: 26 of 30 patients (87%) did not have the tissue autoantibodies typical of that syndrome, and screening of about twenty thousand human proteins detected no pituitary or skin autoantigens [7]. This absence is the strong argument against antibody-mediated autoimmune hypophysitis as the cause of ACTH deficiency, and points to a T-cell-mediated mechanism, consistent with the lymphocytic organ infiltrations described in half of patients [5, 7].

The pituitary organoid model has, however, reopened the possibility of a direct developmental effect. Mac, Barlier, Castinetti, Brue and colleagues differentiated organoids from CRISPR/Cas9-edited human induced pluripotent stem cells and found that NFKB2 D865G/D865G organoids had altered expression of genes of pituitary progenitors (HESX1, PITX1, LHX3), hypothalamus-secreted factors (BMP4, FGF8, FGF10), epithelial–mesenchymal transition, lineage precursors (TBX19, POU1F1) and terminal corticotroph differentiation (PCSK1, POMC), with a marked reduction in corticotroph numbers; the same system reproduced the reduction in corticotrophs with the homozygous TBX19 K146R allele (published protein designation, p.(Lys146Arg), OMIM 604614.0005; ClinVar records it only under this designation, without a mapped c. notation), used as a positive control [21]. The study is preclinical and uses homozygous genotypes, which do not occur in patients, but it supports a direct contribution of NFKB2 to human pituitary differentiation, possibly additive to the immunological mechanism [21].

2.5. Inheritance, penetrance and expressivity

Inheritance is autosomal dominant in all cases described with NFKB2 variants, and OMIM classifies the entity as common variable immunodeficiency 10, autosomal dominant [1, 3]. Variants frequently arise de novo: in the French families, de novo origin was confirmed in the three in which both parents could be studied, and in one of them two siblings were affected although the parents were negative in peripheral blood DNA, which the authors attributed to premeiotic germline mosaicism with clonal expansion [17]. Vertical transmission is also well documented, as in the Utah family, in which the mother and two of her children were affected, with maternal grandparents free of infections and with normal immunoglobulins [16].

Expressivity is markedly variable, even within the same family. Of the fifty carriers gathered in 2019, two were asymptomatic, one had only isolated ACTH deficiency and one only rheumatoid arthritis with onset at 48 years [5]. In French family A, one son had clinical immunodeficiency and the other only a moderate immunoglobulin deficiency without clinical features, which the authors interpreted as variable penetrance or late onset [17]. With variants of the ankyrin repeat domain, penetrance is even lower: three relatives with p.(Arg611Ter) had expansion of B-cell subsets, reduced plasmablasts and low IgG without meeting the criteria for common variable immunodeficiency, and the authors proposed surveillance because of the possibility of late manifestation [22]. With the N-terminal variant p.(Trp270Ter), which causes true haploinsufficiency through messenger RNA decay and absence of mutant protein, clinical penetrance is likewise incomplete [23], and the same applies to the Rel homology domain missense variant p.(Arg261Trp), described in a German family with mild antibody deficiency and recurrent respiratory infections [24].

2.6. Variant spectrum

Pathogenic variants cluster in exons 22 and 23, which encode the C-terminal end, and the p.(Arg853Ter) variant is recurrent: it accounted for eight of the fifteen new patients in the German cohort, distributed across four families, and appears in patients from Utah, France, Portugal, Ireland and New Zealand, corresponding to independent mutational events at an arginine residue encoded by CGA, susceptible to C>T transition [5, 16, 17, 19, 25, 26]. The following table lists the variants with correspondence verified in VariantValidator on the MANE Select transcript, with the nomenclature used in the original articles, which in some cases differs from the standardised notation.

The correspondences between nucleotide, protein and genomic notation were confirmed in VariantValidator on GRCh38, without validation warnings, and translation between the NM_001077494 transcript used in the literature and the MANE Select transcript NM_001322934.2 is direct for these variants [8]. In ClinVar, c.2557C>T is classified as pathogenic with criteria provided and multiple submitters without conflicts, last evaluated on 26 January 2026; c.2594A>G as pathogenic or likely pathogenic, without conflicts, evaluated on 28 September 2025; c.2564del as pathogenic, with no assertion criteria provided, since 7 November 2013; and c.2600C>T with conflicting classifications of pathogenicity, evaluated on 29 December 2025 [35]. This divergence for p.(Ala867Val) deserves comment, because it is the variant of the French patients with confirmed ACTH deficiency and also the one carried by seven of the ten patients without anti-interferon autoantibodies in the international cohort [7, 17]. The variants of the French families were submitted to ClinVar under accession numbers SCV000172085 to SCV000172088 [17].

Two nomenclature notes prevent misreading. The article by Brue and colleagues writes "p.R253X" for the variant of patient D1, which is p.(Arg853Ter), an evident typographical error given the context and the gene figure [17]. And the somatic rearrangements and translocations of the NFKB2 locus described in B-cell lymphomas, some generating fusion proteins, are acquired tumour events: they do not constitute the germline disease, and a somatic NFKB2 rearrangement on a lymphoma panel says nothing about inherited immunodeficiency, just as the excess of malignancies in patients with a germline variant is a consequence of the immune defect and not of those rearrangements [18].

2.7. Cellular consequences

The cellular signature is twofold: defective B-cell differentiation and depletion of regulatory and helper T-cell subsets, with preserved overall T-cell numbers. In the fifty patients of 2019, switched memory B cells were reduced in 25 of 26 assessed (96%), marginal zone or non-switched memory cells in 19 of 25 (76%) and naive B cells increased in 14 of 22 (63%), while the total number of B cells was low in 25 of 42 (60%) [5]. FoxP3-positive regulatory T cells were decreased in all nine patients investigated, circulating follicular helper T cells in all fourteen investigated, and Th17 cells in four of six; NKT cells and mucosal-associated invariant T cells were reduced in the patient in whom they were measured [5]. Studies by Min and colleagues in naive B cells from patients showed intrinsic defects: decreased survival, impaired activation and reduced differentiation into CD27+IgD− cells and plasmablasts, with preserved class-switch recombination [36]. In a child with a novel variant, receptor-mediated T-cell proliferation was also impaired, which led the authors to classify the condition as combined immunodeficiency [37]. The reduction in circulating follicular helper T cells, confirmed in several series, explains poor germinal centre formation: the non-canonical pathway regulates expression of inducible T-cell costimulator ligand on B cells, and a patient who underwent lymph node excision had very small germinal centres [5, 27, 38].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and age at onset

The disease usually manifests in early childhood, with infections, and the endocrine deficiencies arrive years later. In the cohort of fifty carriers assembled in 2019, the mean age at symptom onset was 5.9 years, with a standard deviation of 8.7 years, a median of 4.0 years and a range of 0.1 to 48 years, and 26 of 45 patients with information (57%) had disease onset before 5 years of age [5]. Primary immunodeficiency was the initial diagnosis in 46 of the 50 (92%); of the remaining four, two were asymptomatic carriers, one had isolated ACTH deficiency and one only rheumatoid arthritis from 48 years of age [5]. The most common presenting symptom was respiratory infection, in 30 patients (66%), followed by alopecia, in 8 (18%); three patients presented with endocrine abnormalities without initial signs of immunodeficiency, two with severe herpesvirus infection, and one each with meningococcal meningitis, nephritis, arthritis, secondary haemophagocytic lymphohistiocytosis, panniculitis or autoimmune hepatitis [5]. In the group with immunodeficiency, 33 of 46 (71%) received a formal diagnosis of common variable immunodeficiency, at a mean age of 10.5 years (standard deviation 9.1; median 6.5), and the rest had hypogammaglobulinaemia without meeting the criteria [5].

The frequency of manifestations depends on the type of protein defect, and the two available datasets must be read with this in mind. The 2019 cohort comprises fifty carriers, 43 with a C-terminal domain defect and 7 with a proximal truncation, and gives percentages of the number of patients with information available for each item [5]. The 2025 review comprises one hundred and thirty-eight carriers and separates the three groups, also with denominators that vary by item [6]. Both are aggregates of published cases, with publication and selection bias: the 2019 cohort was recruited mainly in immunology centres, and the authors themselves predicted that endocrinology cohorts would identify patients with pituitary dysfunction and few apparent immunological abnormalities [5].

The 2019 percentages are calculated on patients with information available for each item, so the denominator varies (for example, bronchiectasis in 13 of 23 assessed) [5]. Those of 2025 are calculated on the total of each group [6]. The difference between the two datasets for bronchiectasis, gastrointestinal manifestations and organ infiltration mainly reflects this difference in denominator, not a change in the disease.

3.2. Respiratory system and bacterial infections

Recurrent sinopulmonary infections dominate the presentation and are the usual reason for the first assessment. Among patients with immunodeficiency in the 2019 cohort, 38 of 41 with information (93%) had upper respiratory infections, including recurrent otitis media, chronic sinusitis and pharyngitis, and 32 of 39 (82%) lower respiratory infections, with repeated pneumonia [5]. Bronchiectasis, confirmed by imaging, occurred in 13 of 23 assessed (57%) in the 2019 cohort and in 20 of 106 carriers with a C-terminal defect in the 2025 review (19%), and appears as early as childhood and adolescence [5, 6]. Orphanet classifies recurrent upper respiratory infections, recurrent bronchitis, recurrent pneumonia, recurrent sinusitis and pharyngitis and recurrent otitis media as very frequent manifestations, present in 80 to 99% of patients, and bronchiectasis as frequent, in 30 to 79% [3].

Invasive bacterial infections are less common but severe: three patients in the 2019 cohort had bacterial meningoencephalitis and another three septic arthritis or septicaemia [5]. One of the Greek Cypriot siblings presented at 5 months with meningococcal meningitis, and the diagnosis of common variable immunodeficiency was made only at 7 years [1]. Giardiasis was described in three patients and salmonellosis in one [5].

3.3. Viral and fungal infections: the feature that distinguishes it from typical common variable immunodeficiency

Susceptibility to viruses is the feature that sets this disease apart from pure antibody deficiency, and it is all the more striking because T-cell numbers and proliferation are usually normal or increased [5]. Skin infections affected 19 of 31 patients assessed (61%) in the 2019 cohort, mostly due to herpesviruses (13 patients), but also bacterial (3) and severe molluscum contagiosum (2) [5]. Candida oesophagitis was described in two patients and susceptibility to cutaneous or nail candidiasis in four; opportunistic infections included Pneumocystis jirovecii pneumonia in two patients, mycobacterial disease in one, chronic cytomegalovirus viraemia in three and Epstein–Barr virus infection in two [5].

The work of Le Voyer and colleagues quantified the viral risk in the p52LOF/IκBδGOF functional subgroup: severe or recurrent viral disease in 31 of 57 patients (54%), with recurrent mucocutaneous herpes simplex type 1 lesions in 21 (37%), severe influenza in 7 (12%), five of whom required oxygen and one of whom had acute respiratory distress syndrome and encephalitis, and recurrent or severe varicella in 4 patients, all hospitalised, one with encephalitis and one with extensive skin disease requiring aciclovir [7]. Of the nine unvaccinated patients infected with SARS-CoV-2, six developed hypoxaemic COVID-19 pneumonia (grades 5 to 8 on the eight-level National Institutes of Health scale), three were admitted to intensive care at 17, 23 and 39 years of age and two of these, aged 23 and 39 years, died [7]. None of the patients in the functional groups without p100 accumulation had severe viral disease [7]. The factor linking genotype to risk is neutralising autoantibodies against type I interferon: all 31 patients with severe viral infection had them, and 31 of 47 patients with these autoantibodies (66%) had at least one episode of severe or recurrent viral disease, compared with none of those without them [7]. In two patients, samples collected up to sixteen years before SARS-CoV-2 infection already neutralised interferons, demonstrating that the autoantibodies precede infection [7].

Individual reports illustrate the breadth of this susceptibility. A girl with p.(Gln871Ter) had cytomegalovirus pneumonia at 9 years of age, treated with ganciclovir, and at 12 years systemic reactivation with progressive nephrotic syndrome, whose proteinuria tracked the viral titres, with focal segmental glomerulosclerosis on renal biopsy, dying at 13 years of multiorgan failure after Pneumocystis jirovecii pneumonia and pulmonary fungal infection [1, 32]. A patient with p.(Pro850Serfs*36) died of enteroviral encephalomyelitis, with Coxsackievirus A16 identified in brain tissue post mortem after multiple negative tests in cerebrospinal fluid, and assessment of lymphoid tissues showed complete absence of B cells and germinal centres [39]. A 7-year-old Mexican child with p.(Gln871Ter) presented with disseminated coccidioidomycosis with pulmonary, soft tissue, skin, bone and joint involvement [33], and one patient developed severe facial herpes vegetans with herpes simplex viraemia, with detection of neutralising anti-cytokine autoantibodies [40, 41]. A 17-year-old adolescent with a loss-of-function variant was hospitalised for two weeks with COVID-19, seven days on mechanical ventilation, and recovered with biological therapy for the hyperinflammatory response [42]. In 2026, disseminated molluscum contagiosum was described in a child as a manifestation of an NFKB2 variant [43].

3.4. Endocrine system

ACTH deficiency is the most dangerous manifestation and the most easily missed. It occurred in 21 of 48 carriers assessed (44%) in the 2019 cohort, with a mean age at manifestation of 8.2 years (standard deviation 4.2; median 7.0; range 4 to 15 years), and in all but two it was preceded by immunodeficiency [5]. In the review of 138 carriers, ACTH deficiency occurred in 37 of 106 patients with a C-terminal domain defect (35%) and in none of the 32 patients with early or central truncation, so all patients with DAVID syndrome have a defect in this domain [6]. The review of the 28 published cases of DAVID syndrome with ACTH deficiency showed that, in 79%, ACTH was the only pituitary deficiency, and that the mean age at diagnosis of ACTH deficiency was 8.6 years, placing it as the third manifestation after sinus and pulmonary infections (82%, mean age 3 years) and alopecia (mean age 4.7 years) [30].

The presentation is almost always symptomatic hypoglycaemia, often with seizures. Orphanet classifies recurrent hypoglycaemia, hypoglycaemic coma, hypotension, hyponatraemia, decreased circulating ACTH, decreased cortisol, adrenal insufficiency due to ACTH deficiency and fatigue as very frequent manifestations [3]. Hyperkalaemia is marked as excluded, which corresponds to preservation of the mineralocorticoid axis in secondary insufficiency [3, 11]. Anti-pituitary autoantibodies were negative in all patients tested, both in the original French series and in the six patients assessed in the 2019 cohort [5, 15].

Other anterior pituitary deficiencies occurred in 8 of 22 patients assessed (36%) in the 2019 cohort: five growth hormone deficiencies, four cases of hypothyroidism and one hyperprolactinaemia [5]. In the 2025 review, other endocrine abnormalities affected 18 of 106 patients with a C-terminal defect (17%) [6]. One of the French patients had ACTH deficiency, growth hormone deficiency and, on reassessment, central hypothyroidism, which broadened the phenotype beyond the corticotroph axis [1, 17]. Posterior pituitary involvement has been described once: a boy with a de novo variant identified at 1 year of age, with hypogammaglobulinaemia and alopecia totalis, developed central diabetes insipidus at 3 years and central adrenal insufficiency at 4 years, without growth hormone or thyrotropin deficiencies at 7 years, and exome sequencing excluded other known causes [44].

Pituitary imaging is inconsistent. In the 2019 cohort, magnetic resonance imaging showed pituitary hypoplasia in three patients and a normal pituitary in eight [5]; in the 2025 review, hypoplasia confirmed by magnetic resonance imaging was described in 5 of 106 patients with a C-terminal defect (5%) [6]. Three of the four patients in the original French series had a hypoplastic pituitary [15]. Orphanet classifies abnormal pituitary size as a frequent manifestation, in 30 to 79% [3]. A normal scan does not exclude hormone deficiency, and the diagnosis is biochemical.

3.5. Autoimmunity

Autoimmune manifestations affected 40 of 50 carriers (80%) and their profile is characteristic: T-cell-mediated autoimmunity predominates and the usual hallmarks of common variable immunodeficiency are lacking [5]. Alopecia was present in 16 of 42 patients assessed (38%), totalis in twelve, with a mean age at manifestation of 4.4 years (standard deviation 5.1; median 4.0; range 2 to 19 years), and it was the initial manifestation, before any sign of immunodeficiency, in half of these patients [5]. Trachyonychia, or twenty-nail dystrophy, occurred in 9 of 43 carriers (21%), and the complete triad of trachyonychia, ACTH deficiency and alopecia in seven patients, with at least two of these manifestations in ten [5]. Both are exclusive or almost exclusive to C-terminal domain defects: alopecia in 40 of 106 (38%) in that group compared with 1 of 24 (4%) in central truncations and none in early truncations, and trachyonychia only in the C-terminal group (21 of 106, 20%) [6].

Autoimmune cytopenias, which in other forms of common variable immunodeficiency account for two thirds to three quarters of all autoimmunity, affected only 5 of 50 patients (10%) [5]. Gastrointestinal manifestations occurred in 12 patients and arthritis in 7 [5]. The unexpected finding was the frequency of lymphocytic organ infiltration, in 15 of 29 patients assessed (52%), mainly of the central nervous system (6) and lung (5) [5]. Other manifestations described include atopic eczema (3), psoriasiform dermatitis (2), vitiligo (2), nephritis (2), rosacea (2), urticaria (2), primary sclerosing cholangitis, lichen planus pigmentosus, panniculitis and granulomatous bone marrow disease; asthma was reported in ten patients [5]. Autoantibodies, mainly anti-thyroid peroxidase, were detected in 12 of 25 patients investigated [5], and the 2025 review recorded autoantibodies against the thyroid, against interferons or against glutamic acid decarboxylase in 42 of 72 patients with a C-terminal defect (58%), compared with 2 of 13 in central truncations (15%) and none in early truncations [6]. Orphanet classifies alopecia, nail dystrophy and periungual abnormalities as frequent, and vitiligo, autoantibody positivity and thyroiditis as excluded, which reflects the initial description based on few cases and diverges from the data of later cohorts [3, 5].

Individual reports add diverse autoimmune and inflammatory conditions: relapsing polychondritis with saddle nose and tracheal stenosis in a 56-year-old woman [5], autoimmune hepatitis with gluten-sensitive enteropathy [5], nephrotic syndrome with focal segmental glomerulosclerosis [32], nephrotic syndrome with hypertensive emergency and progression to chronic kidney disease on dialysis in a 2-year-old child with an N-terminal variant [45], refractory eosinophilic granulomatosis with polyangiitis in a 9-year-old Chinese child [46], neutrophilic dermatosis, generalised pustular psoriasis, and mycosis fungoides as the sole manifestation in three members of one family [47].

3.6. Nervous system

Neurological involvement is more frequent than the name of the disease suggests. In the 2025 review, neurological manifestations such as encephalitis, meningitis or seizures occurred in 27 of 106 patients with a C-terminal defect (25%) [6]. Aseptic meningitis was described in 5 of 50 patients in the 2019 cohort, optic neuritis in 2 and encephalitis in 1, with isolated reports of developmental delay, epilepsy, absence seizures, Bell's palsy and depression [5]. Chiari type 1 malformation appeared as an incidental finding in two unrelated patients in the cohort and also in the Utah family, where both the affected patient and the healthy father had it, suggesting coincidence rather than part of the phenotype [5, 16]. Two cases illustrate inaugural neurological presentations: the fatal enteroviral encephalomyelitis already described [39] and pseudotumour cerebri in a 4-year-old girl, with sixth cranial nerve palsy and papilloedema, in whom intracranial hypertension coexisted with adrenal crisis and responded to hydrocortisone and acetazolamide, recurring when acetazolamide was stopped [26]. One of the Cypriot siblings developed, as a young adult, inflammatory central nervous system disease with maculoretinopathy, gait disturbance, spasticity, hypomania and dysphagia [1].

3.7. Lymphoproliferation and malignancies

Lymphoproliferation is modest, unlike in other monogenic forms of common variable immunodeficiency. It was reported in 6 of 18 patients with information (33%), mainly mild splenomegaly, with rare lymphadenopathy; lymph nodes were present in all patients in the cohort, but the architecture was disrupted, with very small germinal centres in the patient who underwent biopsy [5].

Malignancies occurred in 4 of 50 patients (8%) in the 2019 cohort and in 8 of 106 patients with a C-terminal defect (8%) in the 2025 review, with similar proportions in the other groups [5, 6]. The cases described are T-cell large granular lymphocytic leukaemia with basal cell carcinoma at 22 years, Epstein–Barr virus-negative non-Hodgkin lymphoma at 23 years, urothelial carcinoma at 37 years and acute myeloid leukaemia at 29 years, the latter fatal owing to pulmonary aspergillosis after the first cycle of chemotherapy [5]. The 2025 review adds mycosis fungoides to the spectrum [6, 47]. Given the young age of several of these patients, cancer surveillance is part of follow-up.

3.8. Treated and untreated natural history

The distinction between natural history and treated disease is documented indirectly, because practically all published patients received immunoglobulin replacement after diagnosis. In the 2019 cohort, 33 of 38 patients with immunodeficiency (84%) were on immunoglobulin, several having later switched from the intravenous to the subcutaneous route, and clinical stability on treatment is repeatedly described, with several patients "alive and well" at 24, 27, 52, 56 and 58 years [5]. Bronchiectasis, on the other hand, develops before diagnosis or with insufficient replacement, and is the sequela that determines respiratory prognosis [5, 48]. T-cell dysfunction is not corrected by immunoglobulin, so chronic and opportunistic viral infections persist despite adequate treatment of the antibody deficiency [5, 18]. The B-cell compartment may deteriorate over time: in a patient without autoimmunity, early impairment of B-cell development in the bone marrow with progressive peripheral B-cell deficiency was documented [49]. ACTH deficiency, once treated, no longer causes hypoglycaemia or crisis, but untreated it is potentially fatal during an infection or surgery [5, 18].

4. Clinical Recognition and Warning Signs

The disease reaches the clinician through three distinct doors, and each has its blind spot. The most frequent door is immunological: a child with recurrent sinopulmonary infections and hypogammaglobulinaemia, who is diagnosed with common variable immunodeficiency and remains on immunoglobulin replacement without the pituitary–adrenal axis being assessed. The second is endocrinological: a child with symptomatic hypoglycaemia, often with seizures, in whom secondary adrenal insufficiency is documented and immunoglobulins are not measured. The third is dermatological: a child with alopecia areata or totalis and dystrophic nails, in whom the systemic significance of these signs goes unnoticed.

The list of warning signs follows directly from the cohorts. In any child or adult with hypogammaglobulinaemia or a diagnosis of common variable immunodeficiency, the following suggest NFKB2: onset before 4 or 5 years of age, alopecia areata or totalis, trachyonychia, recurrent or severe herpesvirus infections, cutaneous or nail candidiasis, Pneumocystis jirovecii pneumonia, chronic cytomegalovirus viraemia, recurrent aseptic meningitis, lymphocytic organ infiltration and a family history of hypogammaglobulinaemia or alopecia [5, 6]. The simultaneous presence of two manifestations of the triad of trachyonychia, alopecia and ACTH deficiency has particular value, because it occurred in ten of the fifty carriers and the complete triad in seven [5].

In any child with ACTH deficiency, even isolated and without a history of infections, immunological assessment is indicated. The clearest argument comes from the case of a previously healthy 7-year-old boy, with no clinical history of immunodeficiency, who presented with profound hypoglycaemia and seizures, had secondary adrenal insufficiency with negative anti-pituitary autoantibodies, and in whom assessment unexpectedly revealed hypogammaglobulinaemia of all three classes with moderately reduced pneumococcal responses, with growth hormone deficiency appearing later; exome sequencing identified, six years after presentation, the de novo variant p.(Ser866Arg) [29]. In the original French series, three of twenty-two patients with ACTH deficiency without a TBX19 variant had common variable immunodeficiency [15], and one patient in the 2019 cohort had isolated ACTH deficiency as the only manifestation [5].

In prepubertal children with pseudotumour cerebri, cortisol should be measured. The recommendation stems from the case of a 4-year-old girl with headaches, vomiting, diplopia, right sixth cranial nerve palsy and papilloedema, whose ketotic hypoglycaemia and hypocortisolaemia revealed ACTH deficiency, with hypogammaglobulinaemia diagnosed later and the p.(Arg853Ter) variant confirmed; the association between adrenal insufficiency and intracranial hypertension is rare and, in this case, hydrocortisone was part of the effective treatment [26].

The emergency signs are those of adrenal crisis and severe infection. In a child or adult with a known NFKB2 variant, or with the combination of hypogammaglobulinaemia and alopecia still without a molecular diagnosis, hypoglycaemia, hypotension, hyponatraemia, vomiting, prostration and lethargy during an intercurrent illness should be treated as an adrenal crisis, with immediate parenteral hydrocortisone; blood for cortisol, ACTH, urea, electrolytes and glucose is drawn beforehand, but without delaying treatment [10, 11]. The absence of hyperkalaemia and normal renin and aldosterone do not exclude a crisis, because in secondary insufficiency the mineralocorticoid axis is preserved [3, 11]. Progressive neurological deterioration in a patient with antibody deficiency justifies a low threshold for brain biopsy and an increase in the immunoglobulin dose, because of the possibility of enteroviral encephalitis with negative cerebrospinal fluid tests [39].

There is no neonatal screening for this disease. Neonatal screening by quantification of T-cell receptor excision circles, implemented for severe combined immunodeficiency, does not detect predominantly antibody deficiencies such as this one, because T-cell lymphopenia is not the initial abnormality; in this disease T-cell counts are usually normal or increased [5, 6]. Early detection therefore depends on clinical recognition and targeted genetic testing, and in families already identified on cascade testing [18].

An incidental laboratory finding may be the first clue in an unexpected context. In screening for anti-interferon alpha-2 autoantibodies in 168 children with severe COVID-19, 199 with paediatric multisystem inflammatory syndrome and 45 with mild SARS-CoV-2 infection, only one had high titres, and exome sequencing revealed an NFKB2 ankyrin domain missense variant with impaired p100 cleavage; notably, the autoantibodies were not detectable in patients who had received intravenous immunoglobulin before sampling, which limits the value of this screening in patients already treated [50].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Initial immunological assessment

Assessment of a suspected antibody deficiency begins with a full blood count with differential, quantification of the immunoglobulins IgG, IgA, IgM and IgE, lymphocyte subsets and assessment of responses to protein and polysaccharide antigens, and should be carried out in liaison with clinical immunology before any molecular study [9, 51]. Responses to protein vaccines, such as tetanus and diphtheria toxoids, and to polysaccharides are measured before and three to four weeks after a booster, with an increase of at least fourfold for protein antigens considered normal; for anti-pneumococcal antibodies, thresholds of 1.3 µg/mL after polysaccharide vaccine and 0.35 µg/mL after conjugate vaccine are used, measured in the same laboratory, because results vary between laboratories [9].

The immunological pattern of this disease has features that distinguish it from common CVID. Hypogammaglobulinaemia is practically constant: in the 2019 cohort, IgG was low in 34 of 36 patients (94%) and IgM and IgA in 40 of 41 (98%), with no patient having elevated IgE [5]; in the review of 138 carriers, among patients with a C-terminal domain defect, IgG was low in 85 of 94 (90%), IgA in 90 of 96 (94%), IgM in 92 of 96 (96%) and IgE in 23 of 25 (92%), with clearly lower proportions in central truncations (low IgG in 7 of 13, 54%) and early truncations (4 of 5, 80%) [6]. Specific responses are frequently absent but not universally so: in the C-terminal group, titres were lacking against tetanus in 16 of 32 (50%), against Haemophilus influenzae type b in 7 of 14 (50%), against pneumococcus in 13 of 24 (54%) and against diphtheria in 14 of 17 (82%) [6]. This partial preservation of responses in more than half of the patients tested is clinically relevant, because it conflicts with one of the diagnostic criteria for common variable immunodeficiency [5].

B-cell differentiation is the most constant abnormality, rather than the total number of B cells. In the 2019 cohort, switched memory B cells (CD27+IgD−) were reduced in 25 of 26 patients assessed (96%), non-switched memory or marginal zone B cells (CD27+IgD+) in 19 of 25 (76%) and naive B cells (CD27−IgD+) increased in 14 of 22 (63%), while the total number of B cells was low in 25 of 42 (60%) [5]. In the 2025 review, switched memory was reduced in 30 of 31 patients with a C-terminal defect (97%) [6]. The T-cell compartment, by contrast, is quantitatively spared: T cells were low in 4 of 37 patients, normal in 10 and elevated in 23, mainly due to CD4+ expansion (20 of 42), and the T-cell receptor repertoire was normal in 12 of 14 studies [5]. In central truncations the profile is different, with low CD3+ in 4 of 11 (36%), CD4+ in 4 of 9 (44%) and CD8+ in 4 of 9 (44%), proportions much higher than in the C-terminal group (2%, 6% and 15%) [6]. NK cells were low in 11 of 37 patients (30%) in the 2019 cohort and in 10 of 49 (29%) in the C-terminal group of the review [5, 6].

Assessment of extended subsets adds characteristic information, although it is not available in all laboratories: FoxP3-positive regulatory T cells were decreased in all nine patients investigated, circulating follicular helper T cells in all fourteen, Th17 cells in 4 of 6, and NKT cells and mucosal-associated invariant T cells in the patient in whom they were measured [5]. Functional proliferation tests gave divergent results between series: proliferation to mitogens was reduced in two patients and normal in nine, stimulation with anti-CD3 alone gave a decreased response in 4 of 9, and proliferation against Candida antigen was reduced in all six patients investigated, compared with three of nine with a normal response to tetanus [5]. NK cell cytotoxicity, described as deficient in early reports, was normal in the patients tested by Klemann and colleagues, with one near-normal value [5, 32, 52].

5.2. Clinical criteria for common variable immunodeficiency and their limitations in this disease

The joint practice parameter of the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology and the Clinical Immunology Society, published in 2025, recommends with strong strength and high certainty that common variable immunodeficiency be diagnosed in patients with low serum IgG and low IgA and/or IgM, with impaired antibody response to infection or immunisation and exclusion of other causes of hypogammaglobulinaemia [9]. The IUIS phenotypic classification, updated in 2024, organises the approach based on the clinical and laboratory pattern and places this disease in the group of antibody deficiencies [53]. The European Society for Immunodeficiencies registry criteria, whose mandatory application reclassified 176 of 1704 patients registered as common variable immunodeficiency (10.3%), also require an age at diagnosis above 4 years [54].

In this disease, both sets of criteria fail in some patients, and this should not prevent genetic testing. Thirteen of the fifty carriers had antibody deficiency before 4 years of age, which contradicts the European definition, and in more than half of the patients tested the ability to mount a specific response was at least partially preserved, which contradicts another criterion [5]. A formal diagnosis of common variable immunodeficiency was assigned to 33 of 46 patients with immunodeficiency (71%), the rest having hypogammaglobulinaemia without meeting the criteria [5]. The practical conclusion is that hypogammaglobulinaemia with reduced switched memory B cells, even without meeting all the criteria for common variable immunodeficiency, justifies genetic testing when there is early onset, alopecia, trachyonychia, severe viral infections, endocrinopathy or a family history [5, 6].

5.3. Endocrine assessment

Assessment of the pituitary–adrenal axis is mandatory in any carrier of a pathogenic NFKB2 variant, at diagnosis and repeated over time, including in relatives identified by cascade testing, and not only when symptoms appear [5, 18]. The sequence is morning cortisol with paired ACTH, followed by dynamic testing when the baseline value is indeterminate, plus assessment of the other anterior pituitary hormones, including growth hormone, and pituitary imaging when the deficiency is confirmed [18].

The interpretation thresholds, according to the Brazilian hypopituitarism guideline, are as follows: morning cortisol, drawn between 8 and 9 a.m., below 100 nmol/L (3 µg/dL) is strongly predictive of secondary adrenal insufficiency, values above 15 µg/dL exclude it, and values between 3 and 15 µg/dL require dynamic testing [11]. In the insulin tolerance test, considered the reference standard, a cortisol peak below 500 nmol/L (18 µg/dL) confirms the diagnosis, this cut-off falling to about 350 nmol/L (12 µg/dL) with the more recent immunoassays calibrated by mass spectrometry; the test is contraindicated in epilepsy, arrhythmias and cerebrovascular disease, and glucagon stimulation is the alternative, with lower sensitivity and specificity [11]. In the 250 µg tetracosactide stimulation test, with cortisol at 30 and 60 minutes, a peak below 500 nmol/L confirms the diagnosis, with false negatives in the first four weeks after pituitary injury and in partial forms [11]. In the patients described, cortisol during the hypoglycaemic crisis was very low, with inappropriately low ACTH and no response to stimulation with synthetic ACTH [16, 25]. The values of one illustrative case, with cortisol below 0.1 µg/dL and ACTH of 4.4 ng/L during hypoglycaemia, show the magnitude of the deficiency [25].

5.4. Genetic testing and its limitations

The definitive diagnosis is molecular. The usual approach is a next-generation sequencing panel of inborn errors of immunity genes or exome or genome sequencing, which were the methods used in all published series [5, 16, 51]. In families already characterised, Sanger sequencing targeted to exons 22 and 23 of NFKB2 is sufficient and was used to confirm the variants in the French and German series [5, 17].

The report should state the gene, the reference transcript with version — NM_001322934.2, the MANE Select transcript, without losing the correspondence with NM_001077494 used in the literature —, Human Genome Variation Society (HGVS) nomenclature for the nucleotide and protein, the zygosity and the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [8]. For variants of uncertain significance, family segregation studies and, particularly in this disease, functional assays are decisive: an edited pituitary organoid made it possible to reclassify as pathogenic a variant previously of unknown clinical significance [21], and luciferase assays, immunoblotting and confocal microscopy distinguish the three functional groups with different phenotypes [7].

The test has four limitations. First, the position of the variant in the gene guides but does not reliably determine the phenotype: C-terminal domain variants are associated with the full phenotype, central and early ones with milder pictures and partial penetrance, but the functional groups overlap partially with topography and only the assay separates them [6, 7]. Second, penetrance is incomplete: asymptomatic carriers have been described in several families, and a positive genetic finding in a relative does not predict disease, although it requires surveillance [5, 22, 23]. Third, a negative NFKB2 result does not exclude the clinical syndrome: two of the six families with the DAVID phenotype ascertained by the French group had no variant in the C-terminal region, and in one of them whole-exome sequencing, with good coverage of all coding exons of the gene, was negative, which led the authors to propose genetic heterogeneity [17]. Fourth, exome sequencing does not reliably detect deep intronic variants, structural variation or low-level mosaicism, and in the parents of an apparently de novo case next-generation sequencing detects mosaicism that Sanger sequencing misses [17].

The proportion of detectable variants in a gene is not equivalent to the clinical sensitivity of the test. Among patients with common variable immunodeficiency, about 30% now have an identifiable genetic aetiology [9], and NFKB1 and NFKB2 are the largest known monogenic subgroups [5]; the proportion of patients with the DAVID phenotype in whom an NFKB2 variant is found is high, but not total [17].

5.5. Autoantibodies against type I interferon as a biomarker

Detection of neutralising autoantibodies against type I interferon is, in this disease, both a diagnostic marker of functional group and a risk marker. They are present in 33 of 56 patients tested with p52LOF/IκBδGOF variants (59%) by detection of anti-interferon alpha-2 IgG, and the neutralising capacity of plasma reaches 47 of 57 patients (82%) for interferon alpha-2 and/or interferon omega; no patient in the other functional groups had them [7]. They are more frequent with truncating than with missense variants, independent of age and sex, and seven of the ten patients without autoantibodies carried p.(Ala867Val) [7]. Their presence identifies patients at risk of severe viral disease and persists after transplantation, so testing for them has practical consequences for prophylaxis and vaccination [7]. The limitation is that intravenous immunoglobulin given before sampling makes the autoantibodies undetectable [50].

5.6. Diagnostic algorithm

5.7. Prenatal and preimplantation diagnosis

There are no published reports of prenatal or preimplantation diagnosis in this disease, and the topic is not addressed in the cohorts. With a known familial variant, prenatal diagnosis by fetal DNA analysis and preimplantation genetic testing are technically possible, as in any monogenic disease with a characterised variant, but the decision is confronted with incomplete penetrance and with the existence of effective treatment for the two main manifestations [5, 9]. In inborn errors of immunity in general, when prenatal diagnosis has not been performed, cord blood can be sent for immunophenotyping or another targeted study, arranged in advance with obstetrics and the immunology laboratory [48].

6. Differential Diagnosis

The differential diagnosis is organised on three levels: other monogenic causes of a common variable immunodeficiency phenotype, other diseases of the alternative NF-κB pathway, and causes of secondary adrenal insufficiency and hypopituitarism lacking the immunological component.

6.1. Distinguishing from NF-κB1

The most likely confusion is with NF-κB1 haploinsufficiency, which shares dominant inheritance, hypogammaglobulinaemia and incomplete penetrance, and is the most frequent monogenic cause of common variable immunodeficiency in Europeans [5, 57]. The systematic review of 397 patients, 257 with NFKB1 variants and 140 with NFKB2 variants, showed that both entities present predominantly with a common variable immunodeficiency phenotype (81.8% for NFKB1 loss-of-function variants and 62.5% for NFKB2 p52LOF/IκBδGOF variants), but differ in their complication profile: NFKB1 variants are more associated with haematological autoimmune diseases, whereas NFKB2 variants are associated with other autoimmunity, with viral infections with a statistically significant difference (p<0.001), with ectodermal dysplasia and with pituitary involvement [58]. Low CD19+ B cells and reduced memory B cells are more frequent with NFKB2 variants [58]. The IUIS classification reflects this separation, attributing to NFKB1 chronic obstructive pulmonary disease, Epstein–Barr virus proliferation, autoimmune cytopenias, alopecia and autoimmune thyroiditis, and to NFKB2 recurrent sinopulmonary infections, alopecia and endocrinopathies [4]. Testing for autoantibodies against type I interferon separates them clearly: they were absent in the eight patients with NF-κB1 haploinsufficiency and in thirty-two patients with defects in ten canonical pathway genes, and present in most patients with NFKB2 p52LOF/IκBδGOF variants [7].

6.2. Distinguishing from the recessive forms of the same pathway

The autosomal recessive NIK and RELB deficiencies are diseases of the same pathway, with the same thymic mechanism and the same anti-interferon autoantibodies, but a combined immunodeficiency phenotype: they present earlier, with opportunistic infections, disseminated BCG disease and cryptosporidiosis in NIK deficiency, and with severe viral and fungal infections with impaired thymopoiesis in RELB deficiency [4, 59, 60]. The clinical distinction matters because haematopoietic stem cell transplantation has been performed successfully in patients with NIK deficiency, whereas in dominant NFKB2 variants the published results are poor [6, 59]. Detection of anti-interferon autoantibodies does not distinguish these entities, because it is present in all three groups: in the two patients with complete NIK deficiency and in seven of eight patients with RELB deficiency [7].

6.3. Distinguishing from autoimmune polyendocrinopathy type 1

The clinical similarity to APECED is striking and has a mechanistic explanation: alopecia areata or totalis, nail dystrophy, susceptibility to Candida, vitiligo and adrenal insufficiency coexist in both diseases, because both impair AIRE expression in medullary thymic epithelial cells, one through a variant of the gene itself and the other through failure of the pathway that regulates it [5, 7]. Three elements separate them. First, adrenal insufficiency is primary in APECED, with elevated ACTH, and secondary in NF-κB2 deficiency, with low or inappropriately normal ACTH [5, 61]. Second, hypoparathyroidism, a cardinal component of APECED, is not part of the NFKB2 phenotype [9]. Third, the autoantibody profile differs decisively: in APECED there are abundant organ-specific autoantibodies and anti-IL-17A and anti-IL-17F autoantibodies that explain chronic mucocutaneous candidiasis, whereas in patients with p52LOF/IκBδGOF variants the breakdown of tolerance is narrow, restricted almost exclusively to the interferon alpha subtypes and interferon omega, with 26 of 30 patients (87%) lacking the tissue autoantibodies typical of APECED and no pituitary or skin autoantigens detectable in a screen of about twenty thousand proteins [7]. Inheritance also differs: APECED is classically autosomal recessive, although OMIM also records dominant transmission through variants with a dominant-negative effect, whereas NF-κB2 deficiency is dominant [7, 62].

6.4. Distinguishing from purely endocrine causes

When the presentation is endocrine, the differential diagnosis runs through the genes of pituitary development and the corticotroph axis. In isolated congenital ACTH deficiency due to biallelic TBX19 variants, hypoglycaemia is severe and neonatal, there is prolonged cholestatic jaundice, seizures occur in about half of cases and ACTH does not respond to corticotrophin-releasing hormone, but immunoglobulins are normal [61]. In combined congenital hypopituitarism, short stature due to growth hormone deficiency dominates the presentation, with midline, cervical spine, eye or limb anomalies depending on the gene, and NFKB2 is listed among the causes with involvement of other systems [21]. Chen and colleagues explicitly excluded causal variants in PROP1, POU1F1, TBX19, POMC, CRH, HESX1, OTX2, LHX3, LHX4, SOX3, CRHR1, CRHR2, NR0B1 and AIRE in their patients before attributing the phenotype to NFKB2 [16]. Measurement of serum immunoglobulins is the simplest and most cost-effective discriminating test at this crossroads, which is why immunological assessment is recommended in all patients with early-onset ACTH deficiency [29].

6.5. Secondary causes and other pitfalls

Before concluding primary antibody deficiency, it is mandatory to exclude secondary causes of hypogammaglobulinaemia, which overall are more prevalent than inborn errors of immunity, especially in adults: anatomical causes, epithelial barrier defects, malnutrition, infections affecting immune cells, immunosuppressive drugs including rituximab and corticosteroids, protein loss, lymphatic malformations, malignancies and the extremes of age [9]. In patients with hypogammaglobulinaemia and thymoma, the diagnosis is Good syndrome [9]. In adults with elevated IgM, monoclonal gammopathy of undetermined significance should be considered [9]. It is also important not to confuse somatic rearrangements of the NFKB2 locus, described in B-cell lymphomas, with the germline disease: they are acquired tumour events and have no hereditary implications [18].

7. Treatments and Risk Management Strategies

There is no specific guideline for NF-κB2 deficiency, nor any clinical trial directed at this disease; treatment combines that of a severe antibody deficiency, that of secondary adrenal insufficiency and that of the autoimmune manifestations, with the particularity that T-cell dysfunction is not corrected by immunoglobulin replacement [6, 18, 63]. The evidence has two levels: category guidelines, for antibody deficiency and for adrenal insufficiency, and disease-specific observational evidence, namely the cohorts of fifty and of one hundred and thirty-eight carriers and the case reports [5, 6, 18].

7.1. Immunoglobulin replacement

Immunoglobulin replacement is the mainstay of treatment and is lifelong. In the 2019 cohort, 33 of 38 patients with immunodeficiency (84%) were on immunoglobulin, several having switched from the intravenous to the subcutaneous route and remaining stable [5]; in the 2025 review, it was given to 79 of 106 patients with a C-terminal domain defect (75%), 6 of 24 with central truncation (25%) and 4 of 8 with early truncation (50%) [6]. The indication follows recommendation 8.1 of the 2025 parameter, strong and with high certainty, for replacement in any inborn error of immunity with IgG antibody deficiency; the authors of the 2025 review stress that, in C-terminal domain defects, replacement should be prompt, given the severity of the phenotype [6, 9].

The dose reference is that of the guideline, 400 to 600 mg/kg per month with an IgG target above 800 mg/dL, and the European label is cited for comparison: the minimum of 6 g/L in the summary of product characteristics is the regulatory threshold common to all replacement indications, whereas the target of the American and British guidelines incorporates data on biological trough and pneumonia [9, 64, 71]. The British consensus calculates the dose by ideal body weight and sets 400 to 500 mg/kg per month, diverging slightly from the American range [71]. The quantitative basis for the target is a meta-analysis of studies with intravenous immunoglobulin: the incidence of pneumonia fell by 27% for each 100 mg/dL increase in IgG trough, and was five times higher with a maintenance trough of 500 mg/dL than with 1000 mg/dL (0.113 versus 0.023 cases per patient-year), with no additional benefit above 1000 mg/dL [9]. The trough required varies between patients — the concept of the biological trough —, and in a study with doses of 200 to 1200 mg/kg per month patients with common variable immunodeficiency needed troughs between 500 and 1700 mg/dL to remain free of bacterial infections [9]. Faced with intercurrent infections despite a trough above 8 g/L, the British consensus recommends first optimising antibiotic prophylaxis and respiratory physiotherapy before increasing the dose [71].

The route is chosen according to tolerance and patient preference (recommendation 8.7, conditional, moderate certainty): the subcutaneous route has fewer systemic adverse effects, greater flexibility and is preferred in children, pregnant women and patients with difficult venous access, requiring in return more frequent administration and autonomy; the intravenous route is preferred by those with reduced manual dexterity or who prefer less frequent treatment [9]. Several patients in the series switched from the intravenous to the subcutaneous route while remaining stable [5], and a French patient switched to subcutaneous immunoglobulin during the COVID-19 pandemic, to reduce hospital visits [30]. Low or absent serum IgA, frequent in this disease, does not contraindicate replacement (recommendation 8.6, strong, moderate certainty); when there are systemic symptoms, the subcutaneous route or an IgA-depleted product is used [9]. Privigen® is contraindicated in hyperprolinaemia, because it contains L-proline, and in IgA deficiency with anti-IgA antibodies and a history of hypersensitivity [65].

Adverse effects and their management are well characterised: reactions during intravenous infusion in 5 to 15% of administrations, usually mild and rate-related, with fever, chills, headache, myalgia, nausea, back pain, paraesthesiae and changes in blood pressure, which are controlled by reducing or stopping the infusion for fifteen to thirty minutes and resuming at the last tolerated rate; premedication one hour beforehand with ibuprofen or paracetamol and an antihistamine, with or without hydrocortisone, prevents recurrent reactions, and prior oral or intravenous hydration prevents hypotension [9]. Serious events are uncommon and include acute kidney injury, thrombosis, aseptic meningitis, haemolytic anaemia, arrhythmia and transfusion-related acute lung injury; the thrombotic risk increases with pre-existing cardiovascular disease, diabetes, dehydration, age over 65 years, sepsis, paraproteinaemia, hyperviscosity, hypercholesterolaemia and hypertension [9]. Haemolysis is more frequent in blood groups A and AB, which justifies monitoring of the blood count [9]. Products are not interchangeable and switching should involve the prescribing physician, with reactions described in 15 to 18% of switches, although a review of 802 switches due to supply problems recorded only twelve reactions, none requiring hospital admission [9]. Central venous catheters placed solely to administer immunoglobulin are not recommended, because of thrombotic and infectious risks, and the subcutaneous route is preferred in patients with difficult access [9].

7.2. Antimicrobial prophylaxis

Antibiotic prophylaxis is added when bacterial infections persist despite an optimised immunoglobulin dose, and it was required on a continuous basis in at least three patients in the 2019 cohort and in 5 of 106 patients with a C-terminal defect in the 2025 review [5, 6]. In the presence of bronchiectasis, azithromycin is the antibiotic of choice because of its antimicrobial and anti-inflammatory properties, and pulmonary infection with non-tuberculous mycobacteria should be excluded first, so as not to induce resistance; the regimens used are 250 mg on three days per week, as in the randomised trial in patients with primary antibody deficiency and chronic lung disease, 500 mg on three days per week, or 250 mg daily [9]. The alternatives are amoxicillin and trimethoprim–sulfamethoxazole [9].

Antiviral prophylaxis has a specific rationale in this disease, because susceptibility to herpesviruses results from T-cell dysfunction and is not corrected by immunoglobulin [7, 18]. Aciclovir or valaciclovir is recommended in inborn errors of immunity with recurrent or severe herpes simplex or varicella-zoster infections [9]. The dose in the 2025 parameter, with the correction published in September 2026, is aciclovir 12.5 mg/kg twice daily orally for herpes prophylaxis, rising to 20–40 mg/kg (maximum 400 mg) twice daily in combined immunodeficiencies with a severe T-cell defect [72]. One patient in the 2019 cohort was on prophylactic aciclovir for recurrent genital and labial herpes [5], and the Irish patient treated with baricitinib simultaneously received aciclovir 400 mg orally twice daily, with no opportunistic infections over eighteen months [19]. Prophylaxis against Pneumocystis jirovecii pneumonia is not routinely indicated in antibody deficiencies, but two patients in the cohort had it, and in combined immunodeficiencies trimethoprim–sulfamethoxazole 5 mg/kg of trimethoprim (maximum 160 mg) two to three times per week or twice daily is used depending on the severity of the T-cell defect [5, 9].

After exposure to varicella, susceptible patients may receive specific varicella-zoster immunoglobulin or, alternatively, immunoglobulin 400 mg/kg within the following ten days if not already on replacement, or aciclovir or valaciclovir for seven days starting from the seventh to tenth day [9]. After exposure to measles, the European label indicates 0.4 g/kg within the following six days, or an extra dose in patients already on intravenous immunoglobulin, and recommends increasing maintenance to at least 0.53 g/kg if the usual dose is below this value in patients at risk of future exposure [64].

7.3. Vaccination

Live attenuated vaccines are contraindicated while there is a significant T-cell deficiency, and in this disease T-cell dysfunction, despite normal counts, warrants caution [5, 9]. Human papillomavirus vaccine is recommended from 9 to 45 years of age in all inborn errors of immunity, including in patients on immunoglobulin, in three doses, because immunoglobulin preparations do not contain sufficient antibodies and viral clearance depends on CD4+ T cells [9]. Vaccination against influenza and SARS-CoV-2 takes on particular importance in this group, because of the neutralising autoantibodies against type I interferon and the fatal cases of COVID-19 pneumonia and influenza described: of the nine unvaccinated patients infected with SARS-CoV-2 in the international cohort, six developed hypoxaemic pneumonia and two died, whereas there was no severe disease in the functional groups without autoantibodies [7]. None of the patients in that cohort had received the live attenuated yellow fever vaccine, and the authors point out the risk of live viral vaccines in this context [7]. Patients who no longer need immunoglobulin should receive catch-up live viral vaccines at least six to eight months after the last infusion [9].

7.4. Glucocorticoid replacement in ACTH deficiency

Once ACTH deficiency is confirmed, hydrocortisone replacement is mandatory and lifelong, and does not require mineralocorticoid, because the renin–angiotensin–aldosterone axis is preserved in secondary insufficiency [11]. Hydrocortisone is the glucocorticoid of choice because it has the profile closest to endogenous cortisol and less effect on growth and bone [11]. The 2016 Endocrine Society guideline on hormone replacement in adult hypopituitarism frames replacement in adults, and the doses presented here follow the British paediatric consensus and the Brazilian guideline [10, 11, 73].

The dose reference is that of the guidelines; where the national label differs, the divergence is made explicit. The summary of product characteristics of Hidrocortisona Roussel, the only one with an express indication for adrenal insufficiency of pituitary origin in Portugal, proposes 12 to 20 mg/m² per day in children, above the 8 to 10 mg/m² range of current paediatric guidelines and the Alkindi® label, so the dose to use is that of the guideline [10, 74, 76]. In the published Portuguese case, hydrocortisone was started at 7 mg/m² per day with a good clinical response [25]. The generic Hidrocortisona Generis 10 mg tablets has an approved indication only for congenital adrenal hyperplasia from 12 years of age, so its use in this disease is off-label, unlike Hidrocortisona Roussel [76]. In Brazil, availability of oral hydrocortisone is limited and compounded preparations are not recommended, so the national guideline prescribes prednisone or prednisolone 2.5 to 5.0 mg once daily in the morning, with an equivalence of 1 mg of prednisone to 4 mg of hydrocortisone; registered hydrocortisone exists (Ariscorten®, Blau; hydrocortisone EMS) as does generic hydrocortisone sodium succinate, with Solu-Cortef® inactive and Alkindi® not registered [11, 80].

Patient and family education is part of treatment, not an accessory: sick-day dose rules, an emergency card, an identification bracelet or medallion, training for intramuscular administration at home and a written emergency plan [10, 11]. Before a vaccination, one or two sick-day doses may be considered [10]. On long-haul flights, the morning dose is kept every six to eight hours [10]. In secondary insufficiency, cortisol deficiency reduces free water clearance and contributes to hyponatraemia, which matters in the interpretation of electrolytes and in fluid therapy [10]. When central hypothyroidism coexists, levothyroxine is started only once cortisol secretion is ensured or the patient is already on hydrocortisone, because acceleration of cortisol metabolism may trigger a crisis [81]. For growth hormone deficiency, somatropin was used in patients in the series, and the dosing and monitoring rules are those of combined congenital hypopituitarism [5, 17].

7.5. Treatment of autoimmune and inflammatory manifestations

Thirteen of the fifty carriers in the 2019 cohort required immunosuppression for autoimmune manifestations: mainly corticosteroids, with four courses of anti-CD20 antibody (rituximab), one of cyclophosphamide and one with methotrexate and adalimumab, with mention also of anti-interleukin-1 therapy; arthritis was treated with non-steroidal anti-inflammatory drugs and intra-articular corticosteroid [5]. In the 2025 review, 19 of 106 patients with a C-terminal domain defect (18%) received immunosuppression, with rituximab, azathioprine or corticosteroids [6]. Autoimmune thrombocytopenic purpura was treated with oral corticosteroid and pulses of intravenous immunoglobulin in one patient and with corticosteroids and rituximab in two others [5]. A patient with autoimmune hepatitis and gluten-sensitive enteropathy received ciclosporin, tacrolimus, mycophenolate and prednisolone [5]. Secondary haemophagocytic lymphohistiocytosis in an infant with a proximal truncating variant was treated according to the HLH-2004 protocol, with good tolerance and rapid response, the patient remaining well more than two years after stopping all treatment [5].

The decision to immunosuppress these patients requires redoubled caution, because the baseline infectious risk includes herpesviruses, Candida and opportunistic agents, and because fatal viral disease has been described [7, 39]. The seven patients on immunosuppression in the international cohort did not explain the group's viral susceptibility, which is due to the anti-interferon autoantibodies, but the overlap of the two factors is unfavourable [7].

7.6. JAK inhibitors for alopecia

The alopecia of this disease is a T-cell-mediated autoimmune disease of the hair follicle, and inhibition of the JAK–STAT pathway has established results in severe alopecia areata in general [19]. A 2025 report describes the response in a 5-year-old Irish boy with the de novo p.(Arg853Ter) variant, alopecia universalis that developed over four weeks at 20 months of age, trachyonychia of the finger- and toenails, respiratory infections since the first year and hypogammaglobulinaemia, without endocrine involvement at the time of publication [19]. Immunoglobulin replacement markedly reduced infections, but the alopecia persisted despite topical mometasone 1% and, later, topical tacrolimus 0.1% [19]. With baricitinib 4 mg once daily, accompanied by prophylactic aciclovir 400 mg orally twice daily, there was no regrowth in the first four weeks, sparse regrowth of the occipital scalp, eyelashes and eyebrows appeared at eight weeks, patchy growth with recovery of most of the eyebrows and eyelashes at five months, sustained improvement at one year and, at eighteen months, improvement also of the trachyonychia; there were no adverse effects or opportunistic infections, with quarterly monitoring by full blood count, liver and renal function, lipid profile and polymerase chain reaction testing for cytomegalovirus, Epstein–Barr virus and BK virus [19].

The dose and age used in this report are outside the label conditions. Baricitinib (Olumiant®) is authorised in the European Union for severe alopecia areata in adults and adolescents from 12 years of age, at 4 mg once daily with reduction to 2 mg in patients at higher risk of venous thromboembolism, major adverse cardiovascular events or malignancy, aged 65 years or over, or with a history of chronic or recurrent infections; in the paediatric indications covering younger ages, juvenile idiopathic arthritis and atopic dermatitis from 2 years of age, the dose is 2 mg for weights between 10 and less than 30 kg and 4 mg from 30 kg [82]. In the United States, baricitinib is approved for alopecia areata in adults, and ritlecitinib from 12 years of age [19]. The 2025 parameter guides the use of JAK inhibitors in inborn errors of immunity: start with the dose approved for the labelled indication and titrate every four to six weeks according to response, with baricitinib 2 mg daily rising to 4 mg daily over four to six weeks, and 2 mg daily below 9 years of age; it suggests aciclovir prophylaxis because of the risk of herpesviruses and clinical assessments every four to six months for opportunistic infections, cardiovascular disease, thromboembolism, malignancy and severe liver disease [9]. The evidence in this disease amounts to a single case, and the balance between cosmetic and psychological benefit and the risks of additional immunosuppression in a patient with underlying immune deficiency should be made explicit to the family [19].

7.7. Haematopoietic stem cell transplantation

Transplantation is curative in many inborn errors of immunity, but in this disease the data are scarce and unfavourable. The 2025 review identified four transplantation attempts in patients with NF-κB2 defects: one patient died shortly after the procedure from undisclosed complications, two died after transplantation from unexplained causes and one was alive at the time of publication [6]. One of the deaths in the 2019 cohort was a transplant complication at 8 years of age, and a probably affected relative died at 9 years after bone marrow transplantation [5].

There is also a mechanistic argument against the expectation of cure: the defect affects medullary thymic epithelial cells and the regulation of AIRE, which are of stromal rather than haematopoietic origin, and therefore are not replaced by the graft [6, 7]. Empirical demonstration came from the observation that neutralising autoantibodies against type I interferon persisted up to fourteen years after transplantation with an established graft in a patient with recessive RELB deficiency, a disease of the same pathway [7]. The authors of the 2025 review consider transplantation a last resort in patients with a severe combined immunodeficiency phenotype, noting that established organ damage complicates the decision [6]. This position contrasts with that for the recessive deficiencies of the same pathway: in NIK deficiency, one patient was successfully transplanted [59].

7.8. Pregnancy, perioperative care and transition

Data on pregnancy are limited to a single case: a patient with common variable immunodeficiency diagnosed at 17 years, autoimmune hepatitis and enteropathy became pregnant at 28 years, with improvement in her clinical condition during pregnancy, without infections or urticaria, and had a healthy daughter by caesarean section because of pre-eclampsia [5]. There are no studies of obstetric outcomes in this disease. General rules apply: immunoglobulin replacement is maintained, with monthly IgG monitoring during pregnancy because of changes in volume of distribution [9], and hydrocortisone crosses the placenta poorly because it is inactivated by 11β-hydroxysteroid dehydrogenase type 2, remaining the glucocorticoid of choice [11].

In the perioperative period, the greatest risk is unrecognised adrenal crisis. Any patient with a pathogenic NFKB2 variant who is to undergo surgery should have the pituitary–adrenal axis assessed beforehand, and patients with confirmed deficiency follow the steroid cover protocol, with a sick-day dose for minor procedures and intravenous hydrocortisone at induction followed by an infusion for major procedures [10]. First place on the operating list and fasting of no more than six hours with intravenous fluids containing sodium chloride and glucose reduce the risk [10]. One of the three deaths in the 2019 cohort was due to a haemorrhagic complication after abdominal surgery at 22 years, and another probably affected patient died of surgical complications of gastrostomy placement, which calls for careful assessment before any procedure [1, 5].

Transition to adult care should be planned and involve immunology and endocrinology, because both replacements are lifelong and because pituitary deficiencies may appear de novo in adolescence or young adulthood [5, 9]. The latest age described for onset of ACTH deficiency is 15 years, but endocrine follow-up is not stopped after that age, because denominators are small and there are patients with late presentations of other manifestations, including rheumatoid arthritis presenting at 48 years [5].

7.9. Agents to avoid and precautions

Live attenuated vaccines should be avoided, particularly yellow fever vaccine, given the viral susceptibility associated with anti-interferon autoantibodies [7, 9]. Pharmacological inhibitors of the NF-κB pathway used in oncology deserve attention: Brue and colleagues warned that broad inhibition of these pathways, or specific inhibition of NF-κB2 processing, may have long-term deleterious effects on central endocrine function, and proposed monitoring endocrine function in trials of drugs targeting the NF-κB pathway [17]. Immunosuppression should be used at the minimum necessary and with carefully considered antiviral and antifungal prophylaxis [7]. In patients with hyperprolinaemia, Privigen® is contraindicated because of the L-proline used as a stabiliser [65].

7.10. Clinical trials and recent developments

There is no clinical trial directed at germline NF-κB2 deficiency or DAVID syndrome. Searches for "NFKB2", "DAVID syndrome" and "NF-kB2 deficiency" in the ClinicalTrials.gov application programming interface, performed on 31 October 2026, returned only oncology studies related to somatic NFKB2 rearrangements in myeloma, acute myeloid leukaemia and lymphoma, plus a neuroimaging study unrelated to the disease; a search without results does not prove non-existence, but the absence is consistent with the rarity of the entity and the lack of a directed therapeutic target [63].

Developments in the twelve months preceding this update are all descriptive or preclinical, with no associated regulatory process. In July 2026, the Rel homology domain missense variant p.(Arg261Trp) was described, associated with mild hereditary hypogammaglobulinaemia with incomplete penetrance, in which the primary defect is loss of protein expression, mainly of the mature p52 subunit; the authors recommend screening for NFKB2 loss-of-expression variants in mildly affected patients with recurrent respiratory infections [24]. In 2026 a Turkish series of seven individuals from five families with NFKB1 or NFKB2 variants was also published, confirming clinical and immunological heterogeneity, including marked intrafamilial variability [83], as was a report of disseminated molluscum contagiosum as a manifestation of an NFKB2 variant in a child [43]. The CRISPR/Cas9-edited pituitary organoid model, published in 2024, is preclinical and uses homozygous genotypes, and there are no data on therapeutic application [21]. Regarding guidelines, the American joint parameter was published in 2026 with a corrigendum on 28 September 2026, and the 2024 IUIS classification was published in 2025 [4, 9, 72].

8. Reproductive Options and Family Counselling

Inheritance is autosomal dominant, so an affected parent has a 50% risk of transmitting the variant in each pregnancy, regardless of the sex of the child [1]. Translating this risk into a risk of disease is, however, uncertain, because penetrance is incomplete and expressivity highly variable: of the fifty carriers gathered in 2019, two were asymptomatic, one had only isolated ACTH deficiency and one only rheumatoid arthritis with onset in the fifth decade [5]. In French family A, of the two carrier sons of the affected mother, one had clinical immunodeficiency and the other only a moderate immunoglobulin deficiency without symptoms, illustrating that the same allele in the same family produces different pictures [17]. With variants of the ankyrin repeat domain, penetrance is even lower, with carriers lacking any clinical manifestation [22], and the same applies to N-terminal variants causing true haploinsufficiency [23, 24].

A substantial proportion of cases are sporadic, due to de novo variants. In the French families, de novo origin was confirmed in the three in which both parents could be studied by peripheral blood DNA analysis [17], and the variants described in the Portuguese case, the Irish case, the Mexican child with coccidioidomycosis, the patient of Aird and colleagues and the Chinese child with eosinophilic granulomatosis are likewise de novo [19, 25, 32, 33, 46]. Counselling a couple with an affected child and negative parents cannot, however, assume a zero recurrence risk. In family C of Brue and colleagues, two siblings were affected by the same variant although neither parent had it in peripheral blood, and the authors attributed this to premeiotic germline mosaicism: a variant that arises in a mitotic clone of the germline, in the testis or ovary, and expands, repeatedly giving rise to carrier gametes over the years [17]. The recurrence risk for a couple in this situation has not been quantified for this disease, but it is higher than in the general population, and next-generation sequencing of parental DNA, with sufficient coverage to detect a low allele fraction, detects mosaicism missed by Sanger sequencing [17].

Cascade testing of first-degree relatives has direct clinical consequences and is not merely informative. Any carrier identified, even if asymptomatic, should have immunological assessment with immunoglobulins and lymphocyte subsets and assessment of the pituitary–adrenal axis with morning cortisol and ACTH, repeated over time [5, 18]. The reason is that ACTH deficiency is potentially fatal during an infection or surgery if unrecognised, and appears at a mean age of 8.2 years, many years after the immunodeficiency [5, 18]. Identifying a carrier relative with subclinical hypogammaglobulinaemia also makes it possible to anticipate immunoglobulin replacement when infections begin, and to monitor for the appearance of bronchiectasis [9, 17]. Determining the functional group of the variant, when available, adds information for counselling, because only variants with p100 accumulation are associated with anterior pituitary deficiency, ectodermal dysplasia and a risk of severe viral disease due to anti-interferon autoantibodies [6, 7].

The reproductive options for an affected adult include spontaneous pregnancy with or without prenatal diagnosis, preimplantation genetic testing, gamete donation and adoption. There are no published reports of prenatal or preimplantation diagnosis in this disease, and any of these routes should be discussed recognising three facts: the variant can be reliably identified when known in the family, the phenotype cannot be predicted from the genotype except for the distinction between functional groups, and the two main manifestations have effective and available treatment, immunoglobulin replacement and hydrocortisone [5, 7, 9, 10]. This combination — known variant, variable prognosis and effective treatment — places the decision in the domain of the couple's informed preferences, and the geneticist's role is to set out the real spectrum, from the asymptomatic form to the fatal viral disease described in two young adults [7].

When prenatal diagnosis has not been performed and there is a known risk, cord blood can be sent for immunophenotyping, arranged in advance with obstetrics and the immunology laboratory, which makes it possible to start surveillance from birth [48]. The carrier newborn has no indication for immediate treatment, because maternal hypogammaglobulinaemia transmitted across the placenta protects in the first months and because the phenotype may never manifest, but has an indication for clinical surveillance, measurement of immunoglobulins over the first year and scheduled endocrine assessment [18, 84].

Testing asymptomatic minors in a family with a known variant is justified, unlike in adult-onset diseases without available treatment, because a positive result triggers surveillance with demonstrable benefit: early recognition of ACTH deficiency prevents adrenal crises and timely immunoglobulin replacement prevents bronchiectasis [5, 9, 18]. Parents should be informed that a positive result does not mean disease and that follow-up is the reason for the test [22].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and published numbers

The disease is very rare and its true frequency is unknown. Orphanet places the worldwide point prevalence in the class below 1 per 1,000,000 and recorded, based on the original French article, a count of seven cases [3]. The available numbers are counts of published cases, which grow with the availability of sequencing rather than with incidence: fifty carriers from thirty-two families with seventeen different variants in 2019 [5]; seventy-three patients from fifty families with twenty-eight rare variants in the 2023 international functional cohort [7]; one hundred and thirty-eight carriers gathered by systematic review of the literature, ClinVar and the Human Gene Mutation Database in 2025 [6]. An independent systematic review counted 140 patients with NFKB2 variants and 257 with NFKB1 variants [58]. None of these counts is a prevalence: there is no population denominator, and the three series partly overlap.

The possible epidemiological framework is indirect. Common variable immunodeficiency is perhaps the most frequent symptomatic inborn error of immunity, with an estimated prevalence of about 1 per 30,000, higher in Northern Europe [9], and older estimates placed it between 1 per 10,000 and 1 per 50,000 [5, 16]. About 30% of patients with common variable immunodeficiency now have an identifiable genetic aetiology [9], and NFKB1 and NFKB2 are the largest known monogenic subgroups [5]. In the series of Chen and colleagues, an NFKB2 variant was found in 1 of 33 patients with common variable immunodeficiency screened (3%), and this patient was the only one of the thirty-three with known central adrenal insufficiency [16]. From the endocrinological perspective, the French GENHYPOPIT network found common variable immunodeficiency in 3 of 22 patients (13.6%) with ACTH deficiency without a TBX19 variant [15]. Both proportions describe referral series from specialised centres and cannot be extrapolated to the population.

9.2. Geographical distribution and biases

Published cases come from centres on all inhabited continents, with no identified founder population. In Europe there are series and cases from France, Germany, Italy, the United Kingdom, Ireland, Portugal, Poland, Cyprus and Turkey; in North America, from the United States and Canada; in Latin America, from Mexico; in Asia, from China and India; and in Oceania, from Australia and New Zealand [5, 16, 17, 19, 22, 25, 26, 33, 83, 85]. Two patients in the German cohort were of Kosovan and Indian origin [5]. The recurrent p.(Arg853Ter) variant appears in patients from several of these countries, corresponding to independent mutational events at a CGA codon susceptible to C>T transition rather than a founder effect [5, 19, 25, 26].

The existing data have two relevant biases. The first is selection: the 2019 cohort was recruited mainly in immunology centres, so it over-represents the immunological phenotype, and the authors themselves predicted that endocrinology cohorts would identify patients with pituitary dysfunction and few apparent immunological abnormalities [5]. The second is publication: patients with early and central truncations are under-represented precisely because the milder phenotype reduces the likelihood of their being studied and published, which inflates the proportion of C-terminal domain defects in the series [6].

In Portugal one case has been published, a 9-year-old boy followed at the Centro Hospitalar Universitário de São João, in Porto [25]. In Brazil, the sources consulted do not describe cases with a confirmed NFKB2 variant, and there are no national prevalence estimates in either country; this absence in the sources consulted does not demonstrate an absence of patients or publications. The Brazilian hypopituitarism guideline does not specifically address this entity, but documents a practical limitation relevant in that country: the restricted availability of oral hydrocortisone, with use of prednisone or prednisolone instead [11].

9.3. Special populations

In children, the disease is more severe and earlier in onset than typical common variable immunodeficiency, with 57% of patients developing symptoms before 5 years of age and pituitary deficiencies appearing at a mean age of 8.2 years; scheduled paediatric endocrine surveillance is therefore the measure with the greatest impact in this age group [5]. In adults, diagnosis may be late: one patient was diagnosed with common variable immunodeficiency at 40 years and another at 30, and there are patients whose first manifestation occurred in the fifth decade [1, 5, 16]. Mortality from viral disease was concentrated in young adults, with two deaths from COVID-19 at 23 and 39 years of age [7].

Patients with neutralising autoantibodies against type I interferon form a subgroup with its own prevention needs: vaccination against influenza and SARS-CoV-2, early recognition of viral infection, a low threshold for antiviral therapy and avoidance of live viral vaccines [7]. The autoantibodies persist after transplantation, so these measures accompany the patient for life [7].

9.4. Reference networks and patient resources

The relevant European Reference Network is ERN RITA, dedicated to rare immunological diseases, including primary immunodeficiencies and autoinflammatory and autoimmune diseases [12]. For the endocrine component, Endo-ERN, the European network for rare endocrine conditions, is the second relevant network, and coordination between the two reflects the mixed nature of the disease [13].

The European Society for Immunodeficiencies maintains the European patient registry, which in 2019 included more than twenty-five thousand patients with inborn errors of immunity and is the infrastructure in which this disease can be systematically counted [54, 86]. Enrolling identified patients in this registry is the practical route to improving estimates of frequency and natural history.

For patients and families, the international organisation is IPOPI, which brings together national associations of patients with primary immunodeficiencies and maintains the list of member organisations [87]. In the United States there is the Immune Deficiency Foundation [88]. For the adrenal insufficiency component, the Associação Brasileira Addisoniana provides educational material and emergency kits, referred to by the Brazilian guideline [11, 89]. The websites of two associations cited in older sources, PID UK and the Portuguese primary immunodeficiencies association, did not respond when checked on 31 October 2026, so Portuguese patients should be referred via the IPOPI member list and the national primary immunodeficiency reference centres [48, 87].

10. Illustrative Clinical Case

The case described by Nogueira and colleagues, from the Centro Hospitalar Universitário de São João, in Porto, is the published Portuguese report of this disease and illustrates the typical sequence of presentation [25].

The patient was a 9-year-old boy, with no family history of endocrine or immunological disease, diagnosed with common variable immunodeficiency at 3 years of age. At that time he had had an episode of infectious parotitis followed, two months later, by an extensive varicella-zoster virus infection on the chest, which led to referral to the immunodeficiency clinic. Laboratory assessment showed IgA of 7 mg/dL (reference 22 to 159), IgM of 23 mg/dL (reference 47 to 200) and IgG of 314 mg/dL (reference 441 to 1135), with a normal peripheral B-cell count (CD19+ 18.6%) and no signs of autoimmunity. He started monthly intravenous immunoglobulin and remained stable, without respiratory or other infections [25].

At 9 years of age he had a seizure in the early hours of the morning; the pre-hospital emergency team recorded a capillary blood glucose of 40 mg/dL and administered intravenous dextrose, with rapid recovery of consciousness. On admission to the paediatric emergency department capillary blood glucose was 177 mg/dL, physical examination was unremarkable, urine showed 4+ ketonuria and venous blood gas and other tests were normal; brain computed tomography was also normal. Two months later he returned to the emergency department with a second episode of symptomatic hypoglycaemia, with capillary blood glucose of 24 mg/dL, accompanied by vomiting, diarrhoea and extreme fatigue, also reversed with intravenous dextrose [25].

Endocrine and metabolic investigation during the hypoglycaemic crisis showed serum cortisol below 0.1 µg/dL (reference 6.2 to 19.4) with inappropriately low ACTH, of 4.4 ng/L (reference below 63.3), and cortisol did not rise on the ACTH stimulation test, with a peak of 0.3 µg/dL. Pituitary magnetic resonance imaging described a small anterior pituitary and a thin pituitary stalk, with Chiari type 1 malformation as an incidental finding, visible on the T1-weighted sagittal image in figure 2 of the article [25]. The other pituitary functions were preserved: free thyroxine of 1.16 ng/dL (reference 0.88 to 1.58) with thyrotropin of 1.74 µIU/mL (reference 0.35 to 5.00), IGF-1 of 117 ng/mL (reference 95 to 460), IGF-binding protein 3 of 3.7 µg/mL (reference 2.4 to 8.9), growth hormone of 2.72 ng/mL, follicle-stimulating hormone of 2.05 mIU/mL and luteinising hormone of 2.48 mIU/mL. Primary hyperinsulinism was excluded, with insulin of 0.8 µU/mL (reference 2.6 to 24.9) and C-peptide of 0.29 ng/mL (reference 1.1 to 4.4) [25].

He started hydrocortisone replacement at a dose of 7 mg/m² per day, continuing immunoglobulin, and became asymptomatic; he was prepubertal, with adequate growth on the 10th centile of the Centers for Disease Control and Prevention charts. Exome sequencing identified, in exon 22 of NFKB2, the heterozygous germline nonsense variant c.2557C>T, p.(Arg853Ter), and parental exome sequencing did not identify pathogenic variants in the gene, consistent with de novo origin. The pedigree is shown in figure 1 of the article [25].

The two figure pages of the article were consulted on 31 October 2026: figure 1 shows the pedigree, with the proband marked by an arrow, and figure 2 the midsagittal T1-weighted image with the hypoplastic anterior pituitary indicated by an arrowhead and the Chiari type 1 malformation by an arrow. The legends were read; the images were not visually inspected [25].

The case exemplifies several points of this article. The six-year interval between the diagnosis of common variable immunodeficiency and the manifestation of ACTH deficiency matches the pattern of the cohort of fifty carriers, in which immunodeficiency preceded ACTH deficiency in all but two patients and the mean age at endocrine manifestation was 8.2 years [5]. Hypoglycaemia with seizure as the presenting feature, inappropriately low ACTH and absent response to synthetic ACTH stimulation are the pattern described since the original French series and the molecular discovery [15, 16]. The pituitary hypoplasia placed him among the approximately 5 to 27% of patients assessed with abnormal imaging, the pituitary being normal in most, which reinforces that the diagnosis is biochemical rather than radiological [5, 6]. The Chiari type 1 malformation repeats an incidental finding described in two unrelated patients in the German cohort and in a patient and his healthy father in the Utah family, pointing to coincidence rather than part of the phenotype [5, 16]. And the p.(Arg853Ter) variant is the most frequent in this disease, accounting for eight of the fifteen new patients in the German cohort and described in patients from several countries [5].

Two aspects of management in the report deserve comment because they differ from current recommendations, and should not be read as routine. The starting hydrocortisone dose of 7 mg/m² per day is slightly below the range of 8 to 10 mg/m² per day recommended by the 2023 British paediatric consensus and the European label of hydrocortisone granules, published or updated after the report [10, 74]. And the fact that ACTH deficiency was sought only when symptomatic hypoglycaemia appeared, six years after the immunological diagnosis, is exactly the situation that scheduled assessment of the pituitary–adrenal axis in all carriers of a pathogenic variant aims to prevent [5, 18]. The authors of the report conclude precisely along these lines: symptomatic hypoglycaemia in a child with primary immunodeficiency should raise the suspicion of DAVID syndrome and prompt molecular analysis of NFKB2, to allow timely treatment and genetic counselling, avoiding potentially fatal consequences [25].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Prognosis depends on the type of protein defect, how early the diagnosis is made, the adequacy of immunoglobulin replacement, recognition of ACTH deficiency and the presence of neutralising autoantibodies against type I interferon. In primary antibody deficiencies in general, the long-term prognosis should be good provided diagnosis is not late and treatment and monitoring are optimised [48]; in this disease, however, there are three sources of mortality that immunoglobulin replacement does not cover.

Mortality documented in the cohorts is as follows. Of the fifty carriers gathered in 2019, forty-seven were alive: the three deaths resulted from a haemorrhagic complication after abdominal surgery at 22 years, from Aspergillus pneumonia after the first cycle of chemotherapy for acute myeloid leukaemia at 29 years, and from a complication of haematopoietic stem cell transplantation at 8 years; two probably affected relatives, without possible genetic confirmation, died at 9 years after bone marrow transplantation and at 68 years from cytomegalovirus colitis [5]. In the international functional cohort, the eight deceased patients with an inborn error of NF-κB2 all carried p52LOF/IκBδGOF variants, and six died of suspected or proven viral disease, including two of COVID-19, at 23 and 39 years [7]. To these are added the deaths described in individual reports: enteroviral encephalomyelitis [39], multiorgan failure at 13 years after cytomegalovirus reactivation, nephrotic syndrome, Pneumocystis jirovecii pneumonia and pulmonary fungal infection [1, 32], respiratory failure in a child with refractory eosinophilic granulomatosis with polyangiitis, Pneumocystis pneumonia and severe COVID-19 [46], and surgical complications of gastrostomy placement in a young adult with inflammatory central nervous system disease [1].

Malignancies occurred in 8% of carriers, with cases described between 22 and 37 years of age: T-cell large granular lymphocytic leukaemia, Epstein–Barr virus-negative non-Hodgkin lymphoma, urothelial carcinoma, acute myeloid leukaemia and mycosis fungoides [5, 6, 47]. The young age at these diagnoses is the argument for integrating cancer surveillance into follow-up.

On the other hand, some patients have a prolonged favourable course on treatment: the 2019 cohort describes patients "alive and well" at 24, 27, 52, 56 and 58 years, including a 58-year-old man who had urothelial carcinoma cured at 37 and has only mild arthritis, and patients stable on continuous immunoglobulin replacement with rare infections [5]. Two carriers were completely asymptomatic and one had only treated isolated ACTH deficiency [5].

The sequelae that determine long-term morbidity are respiratory and endocrine. Bronchiectasis, present in 19 to 57% of patients depending on the series and denominator, results from late diagnosis, insufficient immunoglobulin replacement or intercurrent infections not treated aggressively, and is irreversible [5, 6, 48]. Interstitial lung disease and small airways disease have been described in individual patients [5, 16]. ACTH deficiency, once treated, no longer causes hypoglycaemia, but the risk of adrenal crisis remains during intercurrent illness, surgery or trauma if the sick-day dose is not followed; in European estimates for adrenal insufficiency in general, crises occur at a rate of 5 to 10 per 100 patient-years, with mortality of 0.5 per 100 patient-years [11].

11.2. Surveillance table

11.3. Multidisciplinary follow-up

The patient should be followed by clinical immunology, and follow-up includes paediatric or adult endocrinology, respiratory medicine when there is lung disease, dermatology for alopecia and skin manifestations, and medical genetics for counselling and cascade testing [9, 48]. A multidisciplinary approach in inborn errors of immunity is associated with better outcomes, better quality of life and reduced costs [9]. Coordination between immunology and endocrinology is the particularity of this disease, and failure of this coordination is the mechanism by which ACTH deficiency presents with hypoglycaemia and seizure instead of being detected on a scheduled blood test [5, 25].

Fatigue is a frequent symptom in primary antibody deficiencies, with paediatric prevalences between 19 and 65%, apparently independent of disease activity, and its treatment is not well defined, involving prescription of adapted exercise, optimisation of immunoglobulin replacement and treatment of complications [9]. In this disease there is the additional need to distinguish non-specific fatigue from fatigue due to adrenal insufficiency, which is one of the symptoms classified as very frequent and which responds to hydrocortisone [3, 11].

12. Summary and Concluding Remarks

Heterozygous germline NFKB2 variants cause an autosomal dominant immunodeficiency of the non-canonical NF-κB pathway, in which hypogammaglobulinaemia with impaired B-cell differentiation is constant and the number of T cells is normal or increased. The disease reached the literature through two routes describing the same picture: the endocrinological, which in 2012 defined DAVID syndrome by the association of adrenocorticotrophic hormone deficiency with common variable immunodeficiency, and the immunological, which in 2013 identified the gene in families with childhood-onset common variable immunodeficiency and central adrenal insufficiency. The name now depends on the specialty: common variable immunodeficiency 10 in OMIM, deficit in anterior pituitary function–variable immunodeficiency syndrome in Orphanet, NFKB2 deficiency in the IUIS classification.

The mechanism has two inseparable faces. There is too little p52 to activate p52–RelB-dependent transcription, and too much unprocessable p100, which maintains IκB-like inhibitory activity and retains dimers of both NF-κB pathways in the cytoplasm. The position of the variant determines which of these faces predominates, hence the genotype–phenotype correlation that organises practice: C-terminal domain defects, the most frequent, produce the full phenotype, with immunodeficiency in 96% of carriers, ACTH deficiency in 35 to 44%, alopecia in 38%, trachyonychia in 20% and autoantibodies against type I interferon; central and early truncations give milder pictures, with partial penetrance and no case of ACTH deficiency described. Functional characterisation into three groups — p52 loss of function with IκBδ gain of function, true haploinsufficiency and p52 gain of function — adds precision where topography is not enough.

Failure of AIRE expression in medullary thymic epithelial cells explains the autoimmunity and its peculiar form. Patients with p100 accumulation have a small, dysplastic thymus, without AIRE-positive cells or Hassall's corpuscles, and produce neutralising autoantibodies against the interferon alpha subtypes and against interferon omega, and little else: they lack the organ-specific and anti-interleukin-17 autoantibodies that characterise autoimmune polyendocrinopathy type 1, a disease with which it shares alopecia, nail dystrophy, candidiasis and vitiligo. These autoantibodies are not an inert laboratory finding: they identify patients at risk of severe viral disease, are present in all those who have had severe viral infection, precede infection by years and persist after transplantation. ACTH deficiency has no associated anti-pituitary autoantibodies, and the open hypotheses are T-cell-mediated autoimmunity and a direct contribution of NFKB2 to corticotroph differentiation, suggested by edited pituitary organoids.

Clinical practice comes down to four decisions. First: in any patient with early-onset hypogammaglobulinaemia, especially with alopecia, trachyonychia, severe herpesvirus infections or a family history, request genetic testing, even if the formal criteria for common variable immunodeficiency are not met — thirteen of the fifty carriers had antibody deficiency before 4 years of age and more than half retained partial vaccine responses. Second: in any carrier of a pathogenic variant, including those identified by cascade testing and those who are asymptomatic, assess the pituitary–adrenal axis at diagnosis and repeatedly during follow-up, because ACTH deficiency appears at a mean age of 8.2 years, many years after the immunodeficiency, and is potentially fatal during an infection or surgery. Third: in any child with ACTH deficiency, even isolated and without a history of infections, measure immunoglobulins, because there are cases in which the endocrinopathy preceded any immunological manifestation. Fourth: treat the antibody deficiency with immunoglobulin replacement at a dose of 400 to 600 mg/kg per month, with an IgG target above 800 mg/dL, and add antiviral prophylaxis, because the T-cell dysfunction that explains herpesvirus and opportunistic infections is not corrected by immunoglobulin.

The limitations of knowledge are clear and should be stated to the patient. There is no disease-specific guideline nor any directed clinical trial; all treatment rests on category guidelines and case series. Frequency figures come from counts of published patients — fifty in 2019, one hundred and thirty-eight in 2025 — which are not prevalences and which over-represent severe phenotypes and C-terminal domain defects. Haematopoietic stem cell transplantation does not correct the thymic epithelial cell defect and the four published cases had three deaths. Treatment of alopecia with JAK inhibitors rests on a single favourable report, with use outside the label conditions. There are no data on obstetric outcomes, no reports of prenatal or preimplantation diagnosis and no national prevalence estimates. What is established is nevertheless sufficient for the decision that matters most: two simple tests, serum immunoglobulins and morning cortisol with ACTH, requested in both directions by the immunologist and the endocrinologist, recognise the disease and avoid its two preventable deaths, adrenal crisis and untreated respiratory infection.

13. References

1. Online Mendelian Inheritance in Man. Immunodeficiency, common variable, 10; CVID10. MIM 615577. Baltimore: Johns Hopkins University. https://www.omim.org/entry/615577
2. Online Mendelian Inheritance in Man. Nuclear factor kappa-B, subunit 2; NFKB2. MIM 164012. Baltimore: Johns Hopkins University. https://www.omim.org/entry/164012
3. Orphanet. Deficiency in anterior pituitary function-variable immunodeficiency syndrome (ORPHA:293978) [Internet]. Paris: INSERM; version of 2 Jul 2026. https://www.orpha.net/en/disease/detail/293978
4. Poli MC, Aksentijevich I, Bousfiha AA, Cunningham-Rundles C, Hambleton S, Klein C, et al. Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. J Hum Immun. 2025;1(1):e20250003. doi:10.70962/jhi.20250003. PMID:41608114. PMCID:PMC12829761.
5. Klemann C, Camacho-Ordonez N, Yang L, Eskandarian Z, Rojas-Restrepo JL, Frede N, et al. Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2. Front Immunol. 2019;10:297. doi:10.3389/fimmu.2019.00297. PMID:30941118. PMCID:PMC6435015.
6. Meissner J, Fliegauf M, Grimbacher B, Klemann C. Type-Specific Impacts of Protein Defects in Pathogenic NFKB2 Variants: Novel Clinical Findings From 138 Patients. J Allergy Clin Immunol Pract. 2025;13(1):192-201. doi:10.1016/j.jaip.2024.10.015. PMID:39447838.
7. Le Voyer T, Parent AV, Liu X, Cederholm A, Gervais A, Rosain J, et al. Autoantibodies against type I IFNs in humans with alternative NF-κB pathway deficiency. Nature. 2023;623(7988):803-813. doi:10.1038/s41586-023-06717-x. PMID:37938781. PMCID:PMC10665196.
8. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: Accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-8. doi:10.1002/humu.23348. PMID:28967166.
9. Orange JS, Chinen J, Horner CC, Kobrynski LJ, Ballow M, Butte MJ, et al. 2025 Inborn errors of immunity practice parameter: Guidance from the Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma & Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the Clinical Immunology Society (CIS). Ann Allergy Asthma Immunol. 2026;136(4):426-493.e1. doi:10.1016/j.anai.2025.10.026. PMID:41936423.
10. Mushtaq T, Ali SR, Boulos N, Boyle R, Cheetham T, Davies JH, et al. Emergency and perioperative management of adrenal insufficiency in children and young people: British Society for Paediatric Endocrinology and Diabetes consensus guidance. Arch Dis Child. 2023;108(11):871-8. doi:10.1136/archdischild-2022-325156. PMID:37045585. PMCID:PMC10646833.
11. Garmes HM, Boguszewski CL, Miranda PAC, Martins MRA, da Silva SRC, Abucham JZ Filho, et al. Management of hypopituitarism: a perspective from the Brazilian Society of Endocrinology and Metabolism. Arch Endocrinol Metab. 2021;65(2):212-30. doi:10.20945/2359-3997000000335. PMID:33905631. PMCID:PMC10065316.
12. European Reference Network on Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA). https://ern-rita.org
13. European Reference Network on Rare Endocrine Conditions (Endo-ERN). https://endo-ern.eu
14. Kuehn HS, Niemela JE, Sreedhara K, Stoddard JL, Grossman J, Wysocki CA, et al. Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. Blood. 2017;130(13):1553-1564. doi:10.1182/blood-2017-05-782177. PMID:28778864. PMCID:PMC5620416.
15. Quentien MH, Delemer B, Papadimitriou DT, Souchon PF, Jaussaud R, Pagnier A, et al. Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections. J Clin Endocrinol Metab. 2012;97(1):E121-8. doi:10.1210/jc.2011-0407. PMID:22013103.
16. Chen K, Coonrod EM, Kumánovics A, Franks ZF, Durtschi JD, Margraf RL, et al. Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013;93(5):812-24. doi:10.1016/j.ajhg.2013.09.009. PMID:24140114. PMCID:PMC3824125.
17. Brue T, Quentien MH, Khetchoumian K, Bensa M, Capo-Chichi JM, Delemer B, et al. Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies. BMC Med Genet. 2014;15:139. doi:10.1186/s12881-014-0139-9. PMID:25524009. PMCID:PMC4411703.
18. GeneGuidance. Record of the NFKB2 gene and the condition Immunodeficiency, common variable, 10 (OMIM 615577; ORPHA 293978) Version of 26 Sep 2026. Accessed 31 Oct 2026.
19. Blokhuis C, Leahy TR, Irvine AD, Browne F, Flinn AM. Baricitinib-Induced Remission of Alopecia Universalis in a Child with NFKB2-Associated Immune Dysregulation. J Clin Immunol. 2025;45(1):62. doi:10.1007/s10875-024-01852-0. PMID:39746888.
20. Wirasinha RC, Davies AR, Srivastava M, Sheridan JM, Sng XYX, Delmonte OM, et al. Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility. J Exp Med. 2021;218(2). doi:10.1084/jem.20200476. PMID:33107914. PMCID:PMC7595743.
21. Mac TT, Fauquier T, Jullien N, Romanet P, Etchevers H, Barlier A, et al. Modeling corticotroph deficiency with pituitary organoids supports the functional role of NFKB2 in human pituitary differentiation. Elife. 2024;12. doi:10.7554/eLife.90875. PMID:39607428. PMCID:PMC11604219.
22. Kotlinowski J, Bukowska-Strakova K, Koppolu A, Kosińska J, Pydyn N, Stawinski P, et al. A Novel Monoallelic Nonsense Mutation in the NFKB2 Gene Does Not Cause a Clinical Manifestation. Front Genet. 2019;10:140. doi:10.3389/fgene.2019.00140. PMID:30863427. PMCID:PMC6399389.
23. Kuehn HS, Bernasconi A, Niemela JE, Almejun MB, Gallego WAF, Goel S, et al. A Nonsense N -Terminus NFKB2 Mutation Leading to Haploinsufficiency in a Patient with a Predominantly Antibody Deficiency. J Clin Immunol. 2020;40(8):1093-1101. doi:10.1007/s10875-020-00842-2. PMID:32813180. PMCID:PMC7567683.
24. Fliegauf M, Gamez-Diaz L, Mrovecova P, God CM, Geiger VF, Camacho-Ordonez N, et al. A Detrimental NFKB2 Missense Variant is Associated with Hypogammaglobulinemia. J Clin Immunol. 2026;46(1). doi:10.1007/s10875-026-02051-9. PMID:42432294. PMCID:PMC13356095.
25. Nogueira M, Pinheiro M, Maia R, Silva RS, Costa C, Campos T, et al. Symptomatic hypoglycemia in a child with common variable immunodeficiency: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome. Clin Pediatr Endocrinol. 2020;29(3):111-113. doi:10.1297/cpe.29.111. PMID:32694887. PMCID:PMC7348627.
26. Price M, Hofman PL, Hsiao K, Jones HF. The search for a unifying diagnosis involving neurological, endocrine and immune dysfunction: a case report of a novel presentation of DAVID syndrome. BMC Pediatr. 2022;22(1):706. doi:10.1186/s12887-022-03760-x. PMID:36494638. PMCID:PMC9733238.
27. Liu Y, Hanson S, Gurugama P, Jones A, Clark B, Ibrahim MA. Novel NFKB2 mutation in early-onset CVID. J Clin Immunol. 2014;34(6):686-90. doi:10.1007/s10875-014-0064-x. PMID:24888602.
28. Lee CE, Fulcher DA, Whittle B, Chand R, Fewings N, Field M, et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood. 2014;124(19):2964-72. doi:10.1182/blood-2014-06-578542. PMID:25237204. PMCID:PMC4321335.
29. Lal RA, Bachrach LK, Hoffman AR, Inlora J, Rego S, Snyder MP, et al. A Case Report of Hypoglycemia and Hypogammaglobulinemia: DAVID Syndrome in a Patient With a Novel NFKB2 Mutation. J Clin Endocrinol Metab. 2017;102(7):2127-2130. doi:10.1210/jc.2017-00341. PMID:28472507. PMCID:PMC11651530.
30. Mac TT, Castinetti F, Bar C, Julia S, Pasquet M, Romanet P, et al. Deficient anterior pituitary with common variable immune deficiency (DAVID syndrome): a new case and literature reports. J Neuroendocrinol. 2023;35(6):e13287. doi:10.1111/jne.13287. PMID:37322808.
31. Baran A, Atılgan Lülecioğlu A, Gao L, Yazıcı YY, Demirel F, Metin A, et al. A Novel Heterozygous NFKB2 Variant in a Multiplex Family with Common Variable Immune Deficiency and Autoantibodies Against Type I IFNs. J Clin Immunol. 2024;45(1):48. doi:10.1007/s10875-024-01843-1. PMID:39579251. PMCID:PMC11821294.
32. Aird A, Lagos M, Vargas-Hernández A, Posey JE, Coban-Akdemir Z, Jhangiani S, et al. Novel Heterozygous Mutation in NFKB2 Is Associated With Early Onset CVID and a Functional Defect in NK Cells Complicated by Disseminated CMV Infection and Severe Nephrotic Syndrome. Front Pediatr. 2019;7:303. doi:10.3389/fped.2019.00303. PMID:31417880. PMCID:PMC6682634.
33. Pérez Cavazos S, De la Cruz Cruz RA, Castillo Bejarano JI, Vaquera Aparicio DN, Mascareñas de Los Santos AH, Zárate Hernández MDC. Disseminated Coccidioidomycosis as the First Presentation of a C-Terminal NFKB2 Pathogenic Variant: A Case Report and Review of the Literature. Pediatr Infect Dis J. 2022;41(2):140-144. doi:10.1097/INF.0000000000003333. PMID:34609106.
34. Tuijnenburg P, Lango Allen H, de Bree GJ, Savic S, Jansen MH, Stockdale C, et al. Pathogenic NFKB2 variant in the ankyrin repeat domain (R635X) causes a variable antibody deficiency. Clin Immunol. 2019;203:23-27. doi:10.1016/j.clim.2019.03.010. PMID:30953794.
35. National Center for Biotechnology Information. ClinVar: NFKB2 records (variations 65385, 65386, 155765, 155766). https://www.ncbi.nlm.nih.gov/clinvar/?term=NFKB2%5Bgene%5D
36. Min Q, Li Y, Wu X, Yu M, Ying W, Zhou Q, et al. Intrinsic functional defects in B cells of patients with NFKB2 mutations. Clin Exp Immunol. 2025;219(1). doi:10.1093/cei/uxae090. PMID:39405181. PMCID:PMC11773609.
37. Lindsley AW, Qian Y, Valencia CA, Shah K, Zhang K, Assa'ad A. Combined immune deficiency in a patient with a novel NFKB2 mutation. J Clin Immunol. 2014;34(8):910-5. doi:10.1007/s10875-014-0095-3. PMID:25205549. PMCID:PMC5705040.
38. Chen Y, Zhou W, Li L, Chen T, Wu Q, Li Q, et al. The impact of NF-κB2 mutations on Tfh cell differentiation and their critical role in immune function. Transl Pediatr. 2025;14(8):1908-1920. doi:10.21037/tp-2025-122. PMID:40949898. PMCID:PMC12433125.
39. Slade CA, McLean C, Scerri T, Giang TB, Megaloudis S, Strathmore A, et al. Fatal Enteroviral Encephalitis in a Patient with Common Variable Immunodeficiency Harbouring a Novel Mutation in NFKB2. J Clin Immunol. 2019;39(3):324-335. doi:10.1007/s10875-019-00602-x. PMID:30927119.
40. Parsons K, Cipriano SD, Rosen LB, Browne SK, Walter JE, Stone BL, et al. Severe Facial Herpes Vegetans and Viremia in NFKB2-Deficient Common Variable Immunodeficiency. Front Pediatr. 2019;7:61. doi:10.3389/fped.2019.00061. PMID:30941333. PMCID:PMC6433840.
41. Ramakrishnan KA, Rae W, Barcenas-Morales G, Gao Y, Pengelly RJ, Patel SV, et al. Anticytokine autoantibodies in a patient with a heterozygous NFKB2 mutation. J Allergy Clin Immunol. 2018;141(4):1479-1482.e6. doi:10.1016/j.jaci.2017.11.014. PMID:29225085.
42. Abraham RS, Marshall JM, Kuehn HS, Rueda CM, Gibbs A, Guider W, et al. Severe SARS-CoV-2 disease in the context of a NF-κB2 loss-of-function pathogenic variant. J Allergy Clin Immunol. 2021;147(2):532-544.e1. doi:10.1016/j.jaci.2020.09.020. PMID:33007327. PMCID:PMC7525247.
43. Yildirimcakar C, Istanbullu MB, Kavukcu Horasan C, Arik Yilmaz E. NFKB2 mutation as a rare cause of disseminated molluscum contagiosum in a child. Pediatr Allergy Immunol. 2026;37(7):e70440. doi:10.1111/pai.70440. PMID:42458766. PMCID:PMC13373328.
44. Nasomyont N, Lindsley AW, Assa'ad A, Dawson DB, Neilson DE, Brady CC, et al. Central Diabetes Insipidus in a Patient With NFKB2 Mutation: Expanding the Endocrine Phenotype in DAVID Syndrome. J Clin Endocrinol Metab. 2019;104(9):4051-4057. doi:10.1210/jc.2019-00469. PMID:31150062.
45. Nagata T, Nakagawa K, Tsurumi F, Watanabe K, Endo T, Hata A. A case of novel NFKB2 variant with hypertensive emergency and nephrotic syndrome leading to CKD 5D. Pediatr Nephrol. 2024;39(9):2637-2640. doi:10.1007/s00467-024-06334-4. PMID:38587560.
46. Lin L, Peng X, Chen L, Dong L, Zhong L. Case report: novel NFKB2 variant associated with pediatric eosinophilic granulomatosis with polyangiitis (EGPA) in the COVID-19 pandemic. Pediatr Rheumatol Online J. 2025;23(1):35. doi:10.1186/s12969-025-01086-3. PMID:40165201. PMCID:PMC11956430.
47. Spangenberg MN, Grille S, Simoes C, Brandes M, Garcia-Luna J, Catalán AI, et al. Case Report: Mycosis fungoides as an exclusive manifestation of common variable immunodeficiency in a family with a NFKB2 gene mutation. Front Oncol. 2023;13:1248964. doi:10.3389/fonc.2023.1248964. PMID:37781189. PMCID:PMC10534963.
48. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 470-1 (Immunodeficiency and recurrent infection: natural history, management, surveillance).
49. Lougaris V, Moratto D, Baronio M, Lorenzini T, Rossi S, Gazzurelli L, et al. Early B cell developmental impairment with progressive B cell deficiency in NFKB2 mutated CVID disease without autoimmunity. Clin Immunol. 2019;205:153-155. doi:10.1016/j.clim.2018.11.014. PMID:30500415.
50. Bodansky A, Vazquez SE, Chou J, Novak T, Al-Musa A, Young C, et al. NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications. J Allergy Clin Immunol. 2023;151(4):926-930.e2. doi:10.1016/j.jaci.2022.11.020. PMID:36509151. PMCID:PMC9733962.
51. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 464-5 (Immunodeficiency and recurrent infection: assessment and investigation).
52. Lougaris V, Tabellini G, Vitali M, Baronio M, Patrizi O, Tampella G, et al. Defective natural killer-cell cytotoxic activity in NFKB2-mutated CVID-like disease. J Allergy Clin Immunol. 2015;135(6):1641-3. doi:10.1016/j.jaci.2014.11.038. PMID:25605273.
53. Bousfiha AA, Jeddane L, Moundir A, Poli MC, Aksentijevich I, Cunningham-Rundles C, et al. The 2024 update of IUIS phenotypic classification of human inborn errors of immunity. J Hum Immun. 2025;1(1):e20250002. doi:10.70962/jhi.20250002. PMID:41608113. PMCID:PMC12829316.
54. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract. 2019;7(6):1763-70. doi:10.1016/j.jaip.2019.02.004. PMID:30776527.
55. Online Mendelian Inheritance in Man. Immunodeficiency 132A; IMD132A. MIM 614849. https://www.omim.org/entry/614849
56. Online Mendelian Inheritance in Man. Immunodeficiency 132B; IMD132B. MIM 621096. https://www.omim.org/entry/621096
57. Online Mendelian Inheritance in Man. Immunodeficiency, common variable, 12, with autoimmunity; CVID12. MIM 616576. https://www.omim.org/entry/616576
58. Fathi N, Nirouei M, Salimian Rizi Z, Fekrvand S, Abolhassani H, Salami F, et al. Clinical, Immunological, and Genetic Features in Patients with NFKB1 and NFKB2 Mutations: a Systematic Review. J Clin Immunol. 2024;44(7):160. doi:10.1007/s10875-024-01763-0. PMID:38990428.
59. Online Mendelian Inheritance in Man. Immunodeficiency 112; IMD112. MIM 620449. https://www.omim.org/entry/620449
60. Online Mendelian Inheritance in Man. Immunodeficiency 53; IMD53. MIM 617585. https://www.omim.org/entry/617585
61. Online Mendelian Inheritance in Man. Adrenocorticotropic hormone deficiency. MIM 201400. https://www.omim.org/entry/201400
62. Online Mendelian Inheritance in Man. Morbid map: Autoimmune polyendocrinopathy syndrome, type I (MIM 240300) and other entries consulted (300755, 615592, 618204, 613493, 240500, 616873, 614700, 615513, 616005, 616100, 609734). https://www.omim.org
63. U.S. National Library of Medicine. ClinicalTrials.gov: searches "NFKB2", "DAVID syndrome" and "NF-kB2 deficiency". https://clinicaltrials.gov
64. European Medicines Agency. Privigen (human normal immunoglobulin, IVIg): Summary of Product Characteristics, sections 4.1–4.2. EMEA/H/C/000831. https://www.ema.europa.eu/en/medicines/human/EPAR/privigen
65. CSL Behring. PRIVIGEN (immune globulin intravenous [human], 10% liquid): prescribing information. DailyMed setid 7e5649da-75be-4a42-8eeb-4aeba562c401. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e5649da-75be-4a42-8eeb-4aeba562c401
66. Takeda. GAMMAGARD LIQUID (immune globulin infusion [human]) 10%: prescribing information. DailyMed setid 9d42adca-0dd7-4df7-864d-5a7feee52130. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d42adca-0dd7-4df7-864d-5a7feee52130
67. European Medicines Agency. Hizentra (human normal immunoglobulin, SCIg 20%): Summary of Product Characteristics, sections 4.1–4.2. EMEA/H/C/002127. https://www.ema.europa.eu/en/medicines/human/EPAR/hizentra
68. European Medicines Agency. HyQvia (human normal immunoglobulin with recombinant human hyaluronidase): Summary of Product Characteristics, sections 4.1–4.2. EMEA/H/C/002491. https://www.ema.europa.eu/en/medicines/human/EPAR/hyqvia
69. European Medicines Agency. Medicines data (medicines-output-medicines_json-report): records of Privigen, Kiovig, Hizentra and HyQvia. https://www.ema.europa.eu/en/documents/report/medicines-output-medicines_json-report_en.json
70. Takeda. HYQVIA (immune globulin infusion 10% [human] with recombinant human hyaluronidase): prescribing information. DailyMed setid 7ca2c26f-4be2-48cd-be5b-486e350654ba. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ca2c26f-4be2-48cd-be5b-486e350654ba
71. Grigoriadou S, Clubbe R, Garcez T, Huissoon A, Grosse-Kreul D, Jolles S, et al. British Society for Immunology and United Kingdom Primary Immunodeficiency Network (UKPIN) consensus guideline for the management of immunoglobulin replacement therapy. Clin Exp Immunol. 2022;210(1):1-13. doi:10.1093/cei/uxac070. PMID:35924867.
72. Orange JS, Chinen J, Horner CC, Kobrynski LJ, Ballow M, Butte MJ, et al. Corrigendum to "2025 Inborn errors of immunity practice parameter: Guidance from the Joint Task Force on Practice Parameters, the American Academy of Allergy, Asthma & Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the Clinical Immunology Society (CIS)". Ann Allergy Asthma Immunol. 2026;137(5):690-2. doi:10.1016/j.anai.2026.08.003. PMID:42808930.
73. Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, et al. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(11):3888-921. doi:10.1210/jc.2016-2118. PMID:27736313.
74. European Medicines Agency. Alkindi (hydrocortisone, granules in capsules for opening): EPAR — Product Information, sections 4.1–4.2. https://www.ema.europa.eu/en/documents/product-information/alkindi-epar-product-information_en.pdf
75. Eton Pharmaceuticals. ALKINDI SPRINKLE (hydrocortisone) oral granules: prescribing information. NDA 213876. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=26c13a5f-7119-4c6a-bf10-fda4e07d7682
76. INFARMED. Resumo das Características do Medicamento: Hidrocortisona Roussel 10 mg comprimidos. Phoenix Labs Unlimited Company. Infomed med_id 571140. https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=571140&tipo_doc=rcm
77. European Medicines Agency. Efmody (modified-release hydrocortisone): EPAR — Product Information, sections 4.1–4.2. https://www.ema.europa.eu/en/documents/product-information/efmody-epar-product-information_en.pdf
78. Pfizer. SOLU-CORTEF (hydrocortisone sodium succinate) for injection: prescribing information. NDA 009866. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=386942d3-c75f-25f1-e063-6394a90a5af2
79. INFARMED. Resumo das Características do Medicamento: Hidrocortisona Generis 100 mg pó para solução injetável. Eugia Pharma (Malta) Limited. Infomed med_id 31554. https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=31554&tipo_doc=rcm
80. Agência Nacional de Vigilância Sanitária (ANVISA). Dados abertos: medicamentos registados no Brasil. https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
81. Persani L, Brabant G, Dattani M, Bonomi M, Feldt-Rasmussen U, Fliers E, et al. 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018;7(5):225-37. doi:10.1159/000491388. PMID:30374425. PMCID:PMC6198777.
82. European Medicines Agency. Olumiant (baricitinib): EPAR — Product Information, sections 4.1–4.2. EMEA/H/C/004085. https://www.ema.europa.eu/en/documents/product-information/olumiant-epar-product-information_en.pdf
83. Sevinç S, İslamoğlu C, Haskoloğlu Ş, Öztürk G, Bal SK, Aslan AD, et al. Nuclear Factor Kappa B (NF-κB)1 and NF-κB2 Deficiency: An Unpredictable Defect With Wide Clinical and Immunologic Phenotype. Scand J Immunol. 2026;104(3):e70142. doi:10.1111/sji.70142. PMID:42625294. PMCID:PMC13494057.
84. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 465-6 (Immunodeficiency and recurrent infection: diagnoses to consider).
85. Shi C, Wang F, Tong A, Zhang XQ, Song HM, Liu ZY, et al. NFKB2 mutation in common variable immunodeficiency and isolated adrenocorticotropic hormone deficiency: A case report and review of literature. Medicine (Baltimore). 2016;95(40):e5081. doi:10.1097/MD.0000000000005081. PMID:27749582. PMCID:PMC5059085.
86. European Society for Immunodeficiencies (ESID). https://esid.org
87. International Patient Organisation for Primary Immunodeficiencies (IPOPI). https://ipopi.org
88. Immune Deficiency Foundation. https://primaryimmune.org
89. Associação Brasileira Addisoniana. https://www.abaddison.org.br