NF-κB1 Deficiency and Defects of the Alternative NF-κB Pathway (NIK, IKK-α, RelB, TRAF3)

Inborn errors of immunity of the NF-κB family: NF-κB1 haploinsufficiency, the most frequent monogenic cause of common variable immunodeficiency in Europeans, and the recessive and dominant defects of the alternative pathway (NIK, IKK-α, RelB and TRAF3), which combine combined or humoral immunodeficiency, hypoplasia of the lymphoid organs, immune dysregulation and neutralising autoantibodies against type I interferon.

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

0.1. Entities of the class and related conditions

For clinical purposes, the family of inborn errors of NF-κB is divided into defects of the canonical pathway (NEMO, IκB-α, IKK-β, RelA, c-Rel, the CARD11–BCL10–MALT1 complex, the LUBAC complex, OTULIN, A20) and defects of the alternative pathway, whose core is formed by NIK, IKK-α, RelB and NF-κB2, negatively regulated by TRAF3 and activated by a restricted set of receptors (BAFFR, LTβR, CD40, RANK) [5]. NF-κB1 belongs to the canonical pathway, but shares with the alternative pathway the phenotype of common variable immunodeficiency with dysregulation and is grouped with it. NF-κB2 deficiency and DAVID syndrome (OMIM 615577) [27], common variable immunodeficiency as a whole, incontinentia pigmenti and IKBKG defects, and ectodermal dysplasia with immunodeficiency due to NFKBIA enter the differential diagnosis.

1. Introduction

1.1. Historical overview

The history of NF-κB1 deficiency begins before the gene was identified. In 2001, Nijenhuis and colleagues described a Dutch family with six people affected by common variable immunodeficiency over three generations, with transmission compatible with autosomal dominant inheritance; one of the patients had respiratory and gastrointestinal infections before the age of 2 years, and the others were diagnosed only in adulthood, with symptoms from the fourth decade [1]. In 2006, Finck and colleagues linked the disease in that family to the long arm of chromosome 4, with a multipoint lod score of 3.38 [1]. In 2015, Fliegauf and colleagues identified, in that family and in two others (German and New Zealand), three heterozygous NFKB1 variants causing functional haploinsufficiency of the p50 subunit, and the original family came to include 11 patients with common variable immunodeficiency and 9 with hypogammaglobulinaemia [1, 28]. In 2018, genome sequencing of 846 unrelated patients with primary immunodeficiency from the British NIHR BioResource placed NFKB1 as the gene most likely to be associated with disease: 16 loss-of-function variants explained 4% of the 390 patients with common variable immunodeficiency, which made NF-κB1 the most frequent monogenic cause of this syndrome in Europeans [19]. In 2020, the worldwide cohort of Lorenzini and colleagues brought together 157 carriers of 56 pathogenic variants and characterised the phenotype as a disease of immune dysregulation rather than an isolated antibody deficiency [1, 20]. In October 2026, Armbruster and colleagues published the compilation of 333 confirmed carriers, with classification of the variants into eight classes and genotype-phenotype correlation analysis [12].

The alternative NF-κB pathway was described in the mouse long before any human patients were known. The first inborn error of a member of the REL/NF-κB family to abolish protein function was recessive RelB deficiency, published in 2015 by Merico and Sharfe in a consanguineous family of Irish ancestry with three affected boys [5, 7]. In 2014, Willmann and colleagues described two Turkish female cousins with a homozygous variant in the kinase domain of NIK and immunodeficiency with bacterial, viral and Cryptosporidium infections [29]. NF-κB2 deficiency, in 2013, and DAVID syndrome completed the picture of defects of the core of the pathway [5]. IKK-α deficiency was first recognised as a cause of Cocoon syndrome, a lethal fetal malformation, and only later as a cause of combined immunodeficiency with ectodermal dysplasia [5]. TRAF3 emerged in 2010 as a cause of susceptibility to herpes simplex encephalitis, in a single patient with a dominant-negative variant [30], and in 2022 Rae and colleagues described a second phenotype, haploinsufficiency with B-cell hyperactivity, infections, autoimmunity and risk of B-cell neoplasia [13]. In 2023, Le Voyer and colleagues showed that patients with NIK and RelB defects and with processing-resistant NF-κB2 variants produce neutralising autoantibodies against type I interferon, through failure of AIRE-dependent central tolerance in the thymus [21]. The 2026 review by the same group summarises the class [5].

1.2. Nomenclature and classification

The nomenclature of these diseases is heterogeneous. OMIM designates NF-κB1 deficiency as common variable immunodeficiency 12 with autoimmunity (CVID12), NIK deficiency as immunodeficiency 112, RelB deficiency as immunodeficiency 53 and the two TRAF3 phenotypes as immunodeficiency 132A and 132B [1, 3, 7, 9, 10]. Orphanet prefers "NFKB1-related immune dysregulation", recognising that the picture goes beyond an antibody deficiency [2]. In the recent literature, the term "NF-κB1 insufficiency" is used by the Freiburg group to cover haploinsufficiency due to loss of expression and variants with a less predictable effect on the protein [12, 31]. In the 2024 classification of the International Union of Immunological Societies (IUIS), NF-κB1 appears among the predominantly antibody deficiencies with a common variable immunodeficiency phenotype, whereas NIK and RelB deficiencies are among the combined immunodeficiencies [32]. The most recent compilation classifies NFKB1 variants into eight classes of protein defect (early, central and late truncations, early and late in-frame deletions, missense in the N-terminal half, missense in the C-terminal half and large genomic deletions) [12].

1.3. Definition of the entities in scope

NF-κB1 deficiency is defined by the presence of a heterozygous loss-of-function variant in NFKB1 in a patient with hypogammaglobulinaemia, specific antibody deficiency or manifestations of immune dysregulation, with the caveat that many carriers are asymptomatic [1, 12]. NIK deficiency is a recessive combined immunodeficiency with hypoplasia of the secondary lymphoid organs and anti-interferon autoantibodies [5]. IKK-α deficiency covers a spectrum ranging from lethal Cocoon syndrome to Bartsocas-Papas syndrome and to a combined immunodeficiency with ectodermal dysplasia and clefts [5, 6]. RelB deficiency is a recessive combined immunodeficiency, complete or partial, with autoimmunity, candidiasis and severe viral infections [5]. TRAF3 deficiencies comprise the dominant-negative form with herpes simplex encephalitis or mycobacterial disease (IMD132A) and haploinsufficiency with immune dysregulation centred on B lymphocytes (IMD132B) [9, 10].

2. Molecular Genetics and Pathophysiology

2.1. The NF-κB family and the two pathways

The human NF-κB family has five transcription factors: NF-κB1 (precursor p105, mature subunit p50), NF-κB2 (p100 and p52), RelA (p65), RelB and c-Rel, which act as homodimers or heterodimers; all are strongly expressed in blood, spleen and lymph nodes, with maximal levels in T and B lymphocytes, and NF-κB2 and RelB are also highly expressed in medullary thymic epithelial cells (mTEC) [5]. In the canonical pathway, T- and B-cell antigen receptors, receptors of the IL-1/Toll family and tumour necrosis factor receptors activate the IKK complex (IKK-α, IKK-β and NEMO/IKK-γ), which phosphorylates IκB-α and p105; these are ubiquitinated and degraded in the proteasome, and p50/RelA or p50/c-Rel dimers enter the nucleus; the response is rapid and transient [5]. Each Rel protein has an N-terminal Rel homology domain (RHD) of about 300 amino acids containing the sequences for DNA binding, dimerisation, interaction with IκB proteins and nuclear entry [19].

The alternative (non-canonical) pathway is slow and sustained and responds to few receptors of the TNF receptor superfamily: the TWEAK receptor and the lymphotoxin β receptor (LTβR), mainly in stromal cells, and BAFFR, RANK and CD40, mainly in leucocytes [5]. At rest, TRAF3, together with TRAF2 and the ligases cIAP1 and cIAP2, continuously degrades the NIK kinase and prevents spontaneous activation of the pathway; when one of these receptors is activated, NIK is stabilised and phosphorylates IKK-α, which in turn phosphorylates p100, which is processed into p52 and forms with RelB the p52/RelB heterodimer that enters the nucleus [5, 23]. Studies in mice showed that BAFFR is required for B-cell development beyond the T2 transitional stage and for germinal centre initiation, that the CD40–CD40L axis is required for class switching and T-dependent responses, that stromal LTβR organises the lymph nodes and Peyer's patches, and that CD40 and RANK on mTEC are required for the maturation of these cells and for the expression of AIRE, the regulator of negative selection of autoreactive thymocytes [5].

Three pathophysiological consequences common to the defects of the alternative pathway follow from this: failure of terminal B-cell differentiation and of the germinal centre (hypogammaglobulinaemia, lack of memory B cells); hypoplasia of the secondary lymphoid organs due to a stromal defect (absence of lymph nodes and tonsils); and failure of central tolerance through loss of AIRE+ mTEC, which in humans translates mainly into the production of neutralising autoantibodies against type I interferon [5, 21]. The last two defects reside in non-haematopoietic cells, which explains why HSCT does not correct them [5, 23].

2.2. NFKB1 and the mechanism of NF-κB1 insufficiency

NFKB1 is located at 4q24 and encodes the precursor p105, processed during translation into p50, the DNA-binding subunit; the dimers kept inactive in the cytoplasm by IκB proteins control genes of inflammation, immunity, lymphocyte differentiation and apoptosis [6]. The disease mechanism is haploinsufficiency: in cells from patients with truncating variants, p105 and p50 levels fall to about half, and the mutant protein is usually not detected [14, 19]. The Lorenzini compilation distinguished three functional groups (haploinsufficiency due to nonsense, frameshift or splicing variants; "precursor skipping" variants, with lack of p105 and expression of a p50-like protein that enters the nucleus normally; and missense), and the Armbruster compilation expanded them to eight classes [1, 12]:

Source: Armbruster and colleagues, 2026 [12].

The functional consequence is a progressive defect in the formation of immunoglobulin-producing B cells, with reduced class-switched memory B cells and expansion of the CD21low population; all carriers studied by Tuijnenburg had a demonstrable defect of B-cell differentiation, even without clinical disease [6, 19]. p50 haploinsufficiency is also accompanied by inflammatory dysregulation: monocytes derived from induced pluripotent stem cells carrying a frameshift variant produced more IL-1β and inflammatory genes, but only in the patient's own genetic background, which points to modifiers [33]. In a regional American study, patients with common variable immunodeficiency and an NFKB1 variant had higher plasma cytokines than patients without a genetic cause, and the effect was greater with frameshift or nonsense variants than with missense variants [34].

2.3. MAP3K14 (NIK)

MAP3K14 is located at 17q21.31 and encodes NIK, the kinase that initiates the alternative pathway by phosphorylating IKK-α and p100 [5, 6]. The published biallelic variants (numbering on the MANE transcript NM_003954.5, protein NP_003945.2) affect, except for p.(Val345Met), the kinase domain (amino acids 390 to 660), by truncation (p.(Cys306ValfsTer2)), deletion (NM_003954.5:c.1552+217_1972+716del) or missense (p.(Pro565Arg)) [5]. p.(Pro565Arg) has no kinase activity and p.(Val345Met) is hypomorphic [3, 5]. In the patients' immortalised B-cell lines, processing of p100 into p52 after BAFF is almost abolished; the B-cell response to CD40L with IL-4 is little affected, but proliferation with CD40L and IL-21 and ICOSL induction are reduced [5, 29]. In fibroblasts, p100 processing, p52 translocation and induction of VCAM1 and CCL20 after lymphotoxin fail, and canonical activation downstream of LTβR is also partially impaired [5]. CD40 on myeloid cells is required for IL-12 production and for antimycobacterial immunity, which probably explains the susceptibility to BCG [5]. The patients' thymus has few AIRE+ mTEC, and the patients produce autoantibodies against type I interferon [5, 21]. ClinGen classifies the gene-disease relationship as moderate (July 2025) [6].

2.4. CHUK (IKK-α)

IKK-α has NIK-dependent and NIK-independent roles. Biallelic null variants (numbering on the MANE transcript NM_001278.5, protein NP_001269.3), such as p.(Gln422Ter) found in two homozygous fetuses, abolish the protein and cause Cocoon syndrome, with large cranial cysts, an abnormal brain and hypoplastic limbs enclosed under the skin, similar to the Ikka-null mouse; this component reflects the essential, NIK-independent role of IKK-α in keratinocyte differentiation and epithelial development [5]. Hypomorphic variants, homozygous (p.(Gly167Arg), p.(Tyr580Cys), NM_001278.5:c.934-2A>G) or compound heterozygous (p.(His142Arg)/p.(Pro190Leu); p.(Arg457AspfsTer6)/p.(Thr463Lys)), cause ectodermal dysplasia and combined immunodeficiency; kinase domain variants lose activity and binding to NIK and p100, and p.(Tyr580Cys) retains kinase activity but does not bind NIK [5]. Fibroblasts have markedly reduced p100 processing and, in part, a canonical defect after TNF [5]. ClinGen classifies the relationship with Bartsocas-Papas syndrome 2 as moderate, and OMIM marks both phenotype entries as provisional; two de novo heterozygous variants in patients with an EEC/AEC-like phenotype and immunodeficiency do not establish a dominant form [6].

2.5. RELB

RELB is located at 19q13.32 and encodes a subunit that acts exclusively in the alternative pathway, in RelB–p50 or RelB–p52 dimers; it does not bind DNA on its own or form dimers with RelA or c-Rel [6]. With numbering on the MANE transcript NM_006509.4 (protein NP_006500.2), homozygous variants (p.(Gln72ThrfsTer152), p.(Tyr397Ter), p.(Pro364Leu), p.(Gln135dup)) and one compound heterozygous combination (p.(Glu145Lys)/p.(Pro364Leu)) have been described; the first two are loss-of-function variants (complete deficiency, three patients from two families) and the rest are severe hypomorphic variants (partial deficiency, five patients from three families) [5]. In fibroblasts, lymphotoxin induces neither NFKB2 mRNA nor p100/p52, the defect is corrected by transduction of normal RELB, and canonical responses to TNF and IL-1β are intact [35]. Unlike NIK deficiency, processing of p100 into p52 is preserved, but the nuclear p52/RelB heterodimer is missing [5]. The p.(Pro364Leu) variant in the dimerisation domain reduces the protein and no longer restrains RelA-dependent genes, with overexpression of inflammatory cytokines after stimulation, which is associated with the forms with severe autoimmunity [7, 36]. The patients' thymus has a malformed medulla, without Hassall's corpuscles or AIRE+ mTEC [5]. The patients' T lymphocytes produce little IL-17A and IL-22, which contributes to chronic mucocutaneous candidiasis [5, 35].

2.6. TRAF3

TRAF3 is located at 14q32.32 and encodes an E3 ligase that modulates NF-κB, MAP kinases and interferon regulatory factors downstream of TNF receptors, Toll-like receptors and cytosolic RIG-I-like sensors; it is required for TLR3-dependent type I interferon induction and restrains the alternative pathway [5, 6]. There are two mechanisms and two phenotypes (numbering on the MANE transcript NM_145725.3, protein NP_663777.1). The variant NM_145725.3:c.352C>T p.(Arg118Trp), in the zinc finger domain, is a loss-of-expression and dominant-negative variant: in the index case, the protein was at about 17.5% of control and the TLR3 response (IFN-β, IFN-λ, IL-6) was reduced, without being abolished [9, 30]. The same variant, however, has a frequency of about 1/200 to 1/250 in Europeans, and in the UK Biobank 2383 heterozygotes and 4 homozygotes had no documented herpes simplex encephalitis; the estimated risk was non-significant (odds ratio 4.17; 95% CI 0.59–30.2), so it is not a highly penetrant cause of encephalitis, although at population level it is associated with higher immunoglobulins, bacterial infections, lupus and B-cell neoplasms [13]. The second dominant-negative variant, p.(Arg338Trp) in the coiled-coil domain, was described in a woman with pulmonary Mycobacterium abscessus disease [9, 37].

Truncating TRAF3 variants (NP_663777.1: p.(Gln114Ter), p.(Arg163Ter), p.(Ser356ProfsTer6), p.(Gln407Ter), p.(Tyr425Ter)) cause haploinsufficiency: in blood lymphocytes, TRAF3 falls to about 20% of control and rises to 50% with the proteasome inhibitor MG132, indicating accelerated proteasomal degradation of the normal allele; B cells show increased NIK, spontaneous processing of p100 into p52, increased transcripts of MAP3K14, CHUK, NFKB2 and RELB, an exaggerated response to BAFF, to B-cell receptor stimulation with IL-4 and to TLR9, and greater mitochondrial respiration [5, 13]. TRAF3 is one of the alternative-pathway genes with somatic variants, copy-number changes or translocations in B-cell and plasma cell neoplasms (about 30% of these neoplasms have alterations in NFKB2, MAP3K14 or TRAF3), and somatic loss of TRAF3 occurs in about 20% of myelomas [5, 13].

2.7. Inheritance, penetrance and expressivity

NF-κB1 deficiency is autosomal dominant with incomplete penetrance. In the compilation of 333 confirmed carriers, 262 (78.7%) were affected at the last assessment and 71 (21.3%) were not; in the subgroup with a known protein defect, penetrance was 74%, and in the subgroup with an uncertain defect 83% [12]. Penetrance varied by class, from 67% in central truncations to 100% in large deletions, and was stable across age groups [12]. Estimates from other series are similar or lower: about 60% in the Tuijnenburg series, 70% in the Lorenzini series and 52% in a Japanese series of 21 carriers, in which, nevertheless, all 9 asymptomatic carriers tested had immunological abnormalities [1, 20, 38]. Expressivity varies even within families and with the same variant, and the absence of a clear genotype-phenotype correlation leads the authors to postulate genetic, epigenetic or environmental modifiers [12]. Ascertainment bias is likely, because families without affected members are not published [12].

NIK, IKK-α and RelB deficiencies are autosomal recessive and, in most published families, occurred in children of consanguineous parents [5]. The heterozygous parents of patients with RelB deficiency had no disease, and RELB heterozygotes did not produce anti-interferon autoantibodies [7, 21]. TRAF3 deficiencies are autosomal dominant; truncating variants arose de novo or were inherited from affected parents, with complete clinical penetrance in the published families, whereas p.(Arg118Trp) has very low penetrance for herpes simplex encephalitis [5, 13].

2.8. Variant spectrum and reference variants

The following variants were normalised in VariantValidator, on GRCh38, with the MANE Select transcripts indicated [11]:

The OMIM description of the RELB c.1091C>T variant refers at one point to "P346L", but the correct numbering, confirmed in VariantValidator, is p.(Pro364Leu) [7, 11]. Some NFKB1 variants in the literature were described on earlier versions of the transcript (NM_003998.3); the c. numbering of the variants above is unchanged in the MANE version [11, 14].

2.9. Modifiers, common variants and related diseases

An ATTG insertion/deletion polymorphism in the NFKB1 promoter has been studied as a susceptibility factor for ulcerative colitis, with conflicting results across populations; this is a common-variant association and not a Mendelian disease [14]. Likewise, common TRAF3 variants that reduce gene expression are associated with higher immunoglobulins, bacterial infections, lupus and risk of myeloma and non-Hodgkin lymphoma [13]. In one published case, a variant of uncertain significance in AP3D1 accompanied the NFKB1 variant and was considered unrelated to the clinical picture, which illustrates the need to interpret the exome as a whole [39]. Large deletions including NFKB1 may involve contiguous genes: 7 of 14 patients with a clinical report had syndromic features (global developmental delay, dysmorphism, intellectual disability) [12].

3. Clinical Spectrum and Manifestations by System

3.1. The cohorts and what they measure

The clinical data on NF-κB1 deficiency come from series with different designs. The British series of Tuijnenburg started from patients with primary immunodeficiency sequenced in the NIHR BioResource (82% European) and measures mainly index patients [19]. The Lorenzini cohort (157 individuals from 68 families, mostly European) includes patients and relatives and was the reference until 2026 [20]. The Armbruster compilation brings together all individuals published in 67 articles and four new Freiburg cases; of the 815 individuals recorded, at least 41.2% had been published more than once, and the analysis separates 241 carriers with a known protein defect from 109 with an uncertain defect [12]. The Japanese series of Moriya (21 carriers) and the American series of Yin (15 patients with common variable immunodeficiency compared with 77 without a genetic cause) add non-European populations and a control group [34, 38]. None of these series is population-based; all over-represent severely affected patients and families with several affected members. For the defects of the alternative pathway, the data are case reports and small series summarised in the Le Voyer review [5].

3.2. NF-κB1 deficiency: overview and age at onset

The mean age at onset in the compilation of 333 carriers was 19 years, ranging from birth to 68 years; in the subgroup with a known protein defect it was 21.2 years, and the mean age at genetic diagnosis was 40 years in women and 37 in men, reflecting a long diagnostic delay [12]. There was no sex predominance [12]. The course is progressive in most affected individuals, with worsening and appearance of new manifestations over time, and two initially healthy carriers became ill later [12]. The frequency of manifestations in the two largest compilations is summarised in the following table.

Sources: Lorenzini 2020 (via OMIM and GeneGuidance) and Armbruster 2026, table 2 [1, 12, 20]. The Lorenzini denominators refer to patients with data; those of Armbruster include unaffected carriers, which lowers the percentages. The differences in autoimmunity and neoplasia between the Armbruster subgroups had p<0.05 in an exploratory analysis without correction for multiple comparisons, and the authors consider a type I error more plausible than a systematic difference [12].

3.3. NF-κB1 deficiency: infections and the respiratory system

Sinopulmonary infections, mainly with encapsulated bacteria, are the most common presentation [1, 20]. Viral, fungal and, more rarely, mycobacterial, CMV and JC virus infections also occur, with cases of progressive multifocal leucoencephalopathy [1]. Opportunistic infections reached 15.7% in the Lorenzini series [20]. Bronchiectasis is frequent and was more common in patients with an NFKB1 variant than in patients with common variable immunodeficiency without a genetic cause in the American study of Yin [34]. Lymphocytic interstitial lung disease and lymphoid interstitial pneumonia appear among the manifestations of dysregulation [1].

3.4. NF-κB1 deficiency: autoimmunity, lymphoproliferation and autoinflammation

Autoimmunity is dominated by autoimmune cytopenias (haemolytic anaemia, thrombocytopenia, neutropenia), followed by alopecia, vitiligo, Hashimoto's thyroiditis, arthritis, hepatitis, pernicious anaemia, type 1 diabetes, vasculitis and Addison's disease [1]. In the American study, any form of autoimmunity affected 80% of patients with an NFKB1 variant versus 36% of patients with common variable immunodeficiency without a genetic cause (p=0.003), and autoimmune cytopenias 60% versus 29% [34]. In the Tuijnenburg series, massive lymphadenopathy affected 24%, unexplained splenomegaly 48% and autoimmune disease 48%, features associated in other studies with a worse prognosis in common variable immunodeficiency [19]. Autoinflammation includes recurrent fever, aphthae, systemic inflammation and pyoderma gangrenosum, the latter present in 11 carriers (3.3%) in the 2026 compilation [12, 40]. Rheumatological diagnoses (rheumatoid arthritis, spondyloarthritis, vasculitis, lupus) were described in 15 carriers [12]. In the Japanese series, two patients had moyamoya disease and one alopecia with rheumatoid arthritis [38].

3.5. NF-κB1 deficiency: gastrointestinal tract, liver and other organs

Non-infectious enteropathy (23.1% in Lorenzini), colitis, inflammatory bowel disease and gastrointestinal infections are frequent [20, 34]. Liver diseases, including gallbladder disease, were recorded in 66 carriers, with frequencies of 16.7% to 21.8% depending on the variant class [12]. Central nervous system manifestations (7–8%) include opportunistic infections and vascular disease [12, 38].

3.6. NF-κB1 deficiency: neoplasia

OMIM summarises that fewer than 20% of affected individuals develop cancer, mainly solid tumours and lymphoma [1]. In the Tuijnenburg series, 28.6% of patients had a neoplasm (parathyroid adenoma, breast cancer and four lymphomas), in the Lorenzini series 16.8%, and in the 2026 compilation 10% in the subgroup with a known defect and 3% in the subgroup with an uncertain defect [1, 12, 20]. These percentages come from different denominators and do not define a lifetime risk.

3.7. NF-κB1 deficiency: large deletions and syndromic forms

The 17 people with large deletions including NFKB1 were all affected, with ages at onset of 0, 5, 12 and 44 years in the 4 with data, and one died at 52 years; half of those described had syndromic features due to involvement of contiguous genes, and 3 (18%) had common variable immunodeficiency or a similar picture [12]. A patient with a deletion or with developmental delay and infections should also be studied for copy-number variation.

3.8. NIK deficiency

The 8 published patients (Iran, Saudi Arabia, South Africa, Turkey) had combined immunodeficiency with recurrent sinopulmonary bacterial infections (7), disseminated BCG (3), CMV (2), norovirus (2), chronic mucocutaneous candidiasis (6) and cryptosporidiosis (2) [5]. Tonsils are absent, and lymphoscintigraphy shows hypoplasia or absence of lymph nodes [5, 23]. The Willmann index cases also had granulomatous hepatitis, tuberculous osteomyelitis after BCG, oral and oesophageal candidiasis, chronic diarrhoea and cholestasis [3]. The South African patient with p.(Val345Met) had a BCG abscess at 2 years, which progressed to treatment-resistant BCG meningitis with severe motor and cognitive sequelae; initially she had increased T, B and NK lymphocytes, which fell progressively [3, 41]. In the laboratory, IgM, IgG and IgA are low in almost all patients (7/8, 7/8 and 8/8), responses to T-dependent vaccines are weak, total T cells and recent thymic emigrants are normal, T follicular helper cells are low, NK cells low or normal and CD27+ memory B cells reduced in all those assessed [5]. Even without organ-specific autoimmune disease, the patients have autoantibodies against type I interferon [5, 21]. After HSCT, seropositive arthritis and autoimmune hepatitis appeared [23].

3.9. IKK-α deficiency

Fetuses with complete loss of the protein have Cocoon syndrome, with encasement, facial defects, apparently absent limbs because they are bound to the trunk and brain malformations; it is lethal [5, 6]. The 7 patients with hypomorphic variants, from five families from Belgium, Canada, Italy, Saudi Arabia and Turkey, had ectodermal dysplasia and/or immunodeficiency: three with syndromic clefts, skeletal malformations, alopecia totalis or areata, sparse eyebrows and eyelashes, hypohidrosis and abnormal enamel; one with Bartsocas-Papas syndrome and two with a Hay-Wells phenotype (ankyloblepharon, ectodermal dysplasia and clefting) [5]. All six assessed developed combined immunodeficiency in the second year of life, with hypogammaglobulinaemia and bacterial infections, viral infections (rotavirus, coxsackievirus, respiratory syncytial virus, SARS-CoV-2, adenovirus, bocavirus, rhinovirus, CMV, epidermodysplasia verruciformis), chronic mucocutaneous candidiasis and salmonellosis [5]. Tonsils and palpable lymph nodes were absent in 5/5, there was chronic hepatitis with periportal lymphocytic infiltration and fibrosis in 5, two liver transplants, autoimmune enteropathy in 2 and one diffuse large B-cell lymphoma; three patients died (two after transplantation and one after chemotherapy), and anti-interferon autoantibodies were present in all 4 tested [5].

3.10. RelB deficiency

The 9 patients from 5 families had infections in the first 3 years of life: bacterial (recurrent otitis media, respiratory infections, salmonellosis), viral (HSV-1, varicella-zoster virus, adenovirus, epidermodysplasia verruciformis, JC virus) and fungal (chronic mucocutaneous candidiasis, Talaromyces marneffei, Cryptococcus neoformans) [5]. In the family of Irish ancestry, the three boys had respiratory infections, one with ecthyma gangrenosum and polyarthritis, and all three underwent HSCT [7]. In the siblings with p.(Pro364Leu), organ-specific autoimmunity due to T-cell infiltration predominated (enteritis with villous atrophy, autoimmune hepatitis with portal fibrosis, lung disease, dermatitis, gastritis, sclerosing cholangitis), with age-dependent deterioration, progressive loss of B lymphocytes and short stature in the more affected sister [7, 36]. The 31-year-old Canadian patient had varicella pneumonia, progressive multifocal leucoencephalopathy, epidermodysplasia verruciformis, chronic candidiasis, central hypogonadism, alopecia, lymphoedema, diarrhoea with lymphangiectasia and disseminated diffuse B-cell lymphoma [7]. The immunological abnormalities include few naïve T lymphocytes and recent thymic emigrants, poor proliferation, normal or high Treg and T follicular helper cells, progressive decline of B cells, low IgG and IgA and transiently high IgM in complete deficiencies, poor responses to conjugate vaccines and few MAIT T cells [5]. Anti-interferon autoantibodies were present in 7 of 8 patients tested [21].

3.11. TRAF3 deficiencies

The IMD132A index case is a French girl who at 4 years had persistent high fever, diarrhoea, epilepsy and aphasia due to HSV-1 encephalitis, one to two months after chickenpox; she responded to 3 weeks of intravenous aciclovir and at 18 years was healthy, with no other severe infections [9, 30]. The second case is a 51-year-old Asian woman with recurrent pulmonary M. abscessus infections, cavitating bronchiectasis, lobectomy and death from pneumonia superinfected with Pseudomonas and Aspergillus [9, 37].

Haploinsufficiency (IMD132B) begins in childhood, with recurrent oto-sinopulmonary infections with Streptococcus pneumoniae and Haemophilus influenzae, early bronchiectasis, massive lymphoid hyperplasia and follicular bronchiolitis in lobectomy specimens, lymphadenopathy with granulomatous inflammation without an identified agent and massive splenomegaly with enlarged germinal centres [13]. The dysregulation includes Sjögren syndrome with anti-Ro52 in three patients, ANCA vasculitis with glomerulonephritis, thyroiditis, coeliac disease, systemic juvenile idiopathic arthritis with high ferritin and IL-18, atopy with food and drug allergies and high IgE [10, 13]. Most have polyclonal hypergammaglobulinaemia, but four patients developed common variable immunodeficiency in adulthood, with panhypogammaglobulinaemia; all have a poor response to polysaccharide vaccines [5]. The three patients identified by reanalysis of 800 exomes (a Spanish mother and daughter and an Argentinian man) had been labelled as common variable immunodeficiency and were on immunoglobulin, with bronchiectasis, interstitial disease, epithelioid granulomas, intestinal nodular lymphoid hyperplasia, ileitis and colitis, CMV, oesophageal candidiasis and pyoderma gangrenosum, without clinical autoimmunity [10, 25]. No patient with haploinsufficiency had herpes simplex encephalitis [5].

3.12. Natural history and treated disease

The NF-κB1 series mainly describe patients already treated with immunoglobulin and immunosuppressants, so the frequencies of complications do not represent the untreated natural history [12, 20]. In NIK, IKK-α and RelB deficiencies, almost all published patients received immunoglobulin, prophylaxis and, many, HSCT; transplant-free survival is not systematically documented [5]. In TRAF3 haploinsufficiency, immunoglobulin, antibiotic prophylaxis and lobectomy reduced the infectious burden in one patient [13].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

In infancy and early childhood, a combined immunodeficiency with disseminated BCG, cryptosporidiosis, CMV or candidiasis, especially if tonsils and palpable lymph nodes are absent, should lead to consideration of NIK, IKK-α and RelB deficiencies, alongside the more frequent combined immunodeficiencies [3, 5]. The association of immunodeficiency with ectodermal dysplasia (hypohidrosis, alopecia, abnormal teeth), cleft lip and palate or pterygia points to IKK-α, and in the differential to NEMO and IκB-α [5, 42]. A child with HSV-1 encephalitis should be investigated for defects of the TLR3 pathway, which include TRAF3 [6, 42].

In the older child, adolescent and adult, NF-κB1 deficiency should be sought in all patients with common variable immunodeficiency, particularly if there is a family history of hypogammaglobulinaemia or autoimmune disease, autoimmune cytopenias, splenomegaly, lymphadenopathy, enteropathy, liver disease, pyoderma gangrenosum or neoplasia [12, 19, 22]. Presentations may begin in any specialty, including haematology, rheumatology, gastroenterology and oncology [6]. TRAF3 haploinsufficiency should be considered in the presence of infections with encapsulated bacteria with hypergammaglobulinaemia, poor response to polysaccharides, B-cell lymphoproliferation and Sjögren syndrome, and also in patients labelled as common variable immunodeficiency [13, 25]. The clinical history should include a three-generation pedigree and enquiry about infant deaths from infection, neoplasms and haematological diseases, the chronology and type of infections and the vaccination history, including BCG [42].

4.2. Warning and emergency signs

The following are emergencies: herpes simplex encephalitis (fever, seizures, altered behaviour or language), which requires immediate intravenous aciclovir [9, 24]; BCG disease after vaccination in an infant with immunodeficiency [3]; severe viral pneumonia, including COVID-19 and influenza, in patients with anti-interferon autoantibodies [21]; severe autoimmune cytopenias, such as profound neutropenia with fever [39]; and the appearance of rapidly growing lymphadenopathy, B symptoms or progressive splenomegaly, which require exclusion of lymphoma [12, 22].

4.3. Newborn screening

Newborn screening by T-cell receptor excision circles (TREC) does not reliably identify these diseases: in NIK deficiency TREC were normal [5], and in NF-κB1 deficiency the T-cell compartment is generally preserved in childhood [1]. Low TREC have been described in RelB deficiencies, which may lead to occasional detection [7]. Outside these cases, diagnosis depends on clinical suspicion and genetic testing.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Formal criteria

There are no specific diagnostic criteria for any of these entities, and diagnosis rests on demonstrating pathogenic variants compatible with the phenotype [6]. In NF-κB1 deficiency, patients frequently meet the European Society for Immunodeficiencies (ESID) criteria for probable common variable immunodeficiency: at least one of increased susceptibility to infection, autoimmune manifestations, granulomatous disease, unexplained polyclonal lymphoproliferation or an affected family member with antibody deficiency; marked decrease of IgG and IgA, with or without low IgM, on two measurements (<2 standard deviations for age); at least one of poor vaccine response, low class-switched memory B cells or absent isohaemagglutinins; exclusion of secondary causes; diagnosis after 4 years of age; and absence of profound T-cell deficiency [43]. The 2025 American practice parameter recommends diagnosing common variable immunodeficiency with low IgG and low IgA and/or IgM, a proven deficient response to infection or vaccination and exclusion of other causes of hypogammaglobulinaemia [22]. The ESID criteria include NFKB1 (164011) and NFKB2 (164012) among the genes associated with this entry [43]. Only 44% of carriers with a known protein defect have a diagnosis of common variable immunodeficiency, so a carrier who does not meet these criteria still has the genetic disease [12].

5.2. Immunological assessment

The initial assessment includes a full blood count with differential, serum immunoglobulins, antibody responses to protein and polysaccharide vaccines, lymphocyte subsets with detailed B-cell phenotyping and exclusion of secondary causes [22, 42]. In NF-κB1 deficiency, class-switched memory B cells are reduced in about 60% and the CD21low population is increased, and the combination of the B-cell immunophenotype with the variant distinguishes healthy individuals, asymptomatic carriers and patients [19, 20]. In a Japanese series, 58% had a low T-cell count, 72% an inverted CD4/CD8 ratio, 42% B lymphopenia and 61% low switched memory B cells, including asymptomatic carriers [38]. In NIK, IKK-α and RelB deficiencies, the findings vary: low immunoglobulins, low memory B cells, low (NIK, IKK-α) or normal/high (RelB) T follicular helper cells, low naïve T lymphocytes and reduced proliferation (RelB) and low NK cells (NIK) [5]. In TRAF3 haploinsufficiency there are high immunoglobulins (or low in the common variable immunodeficiency-like form), high naïve B cells, low class-switched memory B cells, normal or high CD21low cells, low naïve T cells and high Treg and T follicular helper cells [5, 13].

5.3. Autoantibodies against type I interferon

Testing for neutralising autoantibodies against IFN-α2 and IFN-ω is useful in NIK, IKK-α and RelB deficiencies: they were found in the 2 patients with complete NIK deficiency tested, in 7 of 8 patients with RelB deficiency and in the 4 patients tested with IKK-α deficiency, and were absent in RELB heterozygotes, in the 8 patients with NF-κB1 haploinsufficiency, in BAFFR deficiency, in CD40L deficiency and in 32 patients with defects of the canonical pathway [5, 21]. Their presence identifies the patients at greatest risk of severe viral disease and persists after HSCT [6, 21].

5.4. Genetic testing and its limits

The American practice parameter recommends as the initial step an inborn errors of immunity gene panel or the exome when there is no known familial variant (strong recommendation, high evidence), the genome if there are non-immunological features or a suspected non-coding variant (conditional), copy-number analysis when a deletion or duplication is suspected (strong), classification by the ACMG/AMP rules and family studies to resolve pathogenicity (strong) [22]. These recommendations apply directly to NF-κB1: 17 of the compiled carriers had large deletions, which a panel without copy-number analysis does not detect, and several pathogenic variants are intronic, such as NM_003998.4:c.730+4A>G and NM_003998.4:c.835+2T>G [12, 14]. A variant of uncertain significance in NFKB1 is frequent on panels; its reclassification may require functional studies (p105/p50 expression by immunoblot, reporter assays, protein localisation) and segregation studies, bearing in mind that segregation is hampered by incomplete penetrance [12, 20]. The composite NFKB1-DAS index showed high values in some patients with variants of uncertain significance, but it is not validated for variant classification [31].

For TRAF3, p.(Arg118Trp) is a common variant in Europeans and should not be interpreted as a sufficient cause of herpes simplex encephalitis; classification requires clinical and functional context [13]. For MAP3K14, CHUK and RELB, assays of p100 processing, p52/RelB translocation and induction of NFKB2 and VCAM1 in lymphotoxin-stimulated fibroblasts are research assays performed in specialised laboratories [5, 6]. The report should state the gene, the MANE transcript with version, the HGVS c. and p. nomenclature, zygosity, the ACMG/AMP classification and, in recessive diseases, confirmation of phase [11, 22].

5.5. Practical algorithm

5.6. Prenatal and preimplantation diagnosis

Prenatal diagnosis by chorionic villus sampling and preimplantation genetic testing are possible when the proband's variant has been identified [42]. In the recessive diseases (NIK, IKK-α, RelB) the indication is straightforward; in NF-κB1 deficiency, incomplete penetrance and variable expressivity make the decision more complex and require detailed counselling [12]. Cocoon syndrome has been described in fetuses with multiple lethal malformations, which makes prenatal diagnosis particularly relevant in couples with an identified CHUK null variant [5, 6].

6. Differential Diagnosis

6.1. Comparative table of the class and the closest differentials

6.2. Separating NF-κB1 from NF-κB2

The two diseases share common variable immunodeficiency with autoimmunity, but NF-κB2 deficiency with C-terminal variants has complete penetrance before 10 years, hypopituitarism, alopecia and trachyonychia and anti-interferon autoantibodies, whereas NF-κB1 deficiency has incomplete penetrance, later onset and more lymphoproliferation and autoinflammation, without anti-interferon autoantibodies [5, 12, 21]. Alopecia also occurs in NF-κB1 deficiency, and diagnosis rests on the gene [1].

6.3. Separating the recessive defects of the alternative pathway

Among the recessive defects, cryptosporidiosis and mycobacterial disease have been described in NIK deficiency and not in RelB or IKK-α deficiency, which suggests a broader role for NIK [5]. Ectodermal dysplasia, clefts and chronic hepatitis point to IKK-α [5]. In RelB deficiency, Treg and T follicular helper cells are normal or high and organ-specific autoimmunity is more prominent, whereas in NIK and IKK-α deficiency they are low [5]. Lymph node aplasia with lymphocyte function preserved in vitro and without anti-interferon autoantibodies suggests LTβR deficiency, whose prognosis with immunoglobulin is more favourable [5, 23].

6.4. Separating the two TRAF3 phenotypes and other causes of herpes simplex encephalitis

Childhood herpes simplex encephalitis has several monogenic causes in the TLR3 pathway (TLR3, UNC93B1, TRAF3 and others), and the overall incidence of herpes simplex encephalitis is about 0.3 per 100,000 per year [18, 42]. TRAF3 haploinsufficiency, by contrast, has not been associated with herpes simplex encephalitis, and manifests as B-cell hyperactivity [5]. The presence of hypergammaglobulinaemia with poor response to polysaccharides distinguishes it from most humoral immunodeficiencies [13].

6.5. Phenocopies and secondary causes

Secondary causes of hypogammaglobulinaemia, such as high-dose corticosteroids (more than 20 mg per day for 14 days, or more than 2 mg/kg in children weighing less than 10 kg), and thymoma with immunodeficiency (Good syndrome, which may have autoantibodies against type I interferon) should be excluded before attributing the picture to a variant of uncertain significance [32, 46].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

There is no specific guideline for any of the entities in this article, nor any approved treatment targeting the genetic disease [6, 47]. Management follows the general recommendations for inborn errors of immunity, above all the 2025 practice parameter of the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI) and the Clinical Immunology Society (CIS), with the 2026 corrigendum [22, 48], the 2016 ICON international consensus on common variable immunodeficiency [46] and the 2022 British BSI/UKPIN consensus on immunoglobulin replacement [49]. The disease involves several specialties and requires lifelong follow-up at an immunology centre, ideally integrated into the European Reference Network ERN RITA [20, 26, 42]. The three fronts of treatment are prevention of infections (immunoglobulin, antimicrobial prophylaxis, appropriate vaccination), control of non-infectious complications (autoimmunity, lymphoproliferation, autoinflammation, enteropathy) and, in selected cases, HSCT [12, 22].

7.2. Immunoglobulin replacement

Immunoglobulin replacement is the mainstay of treatment of the antibody defect, whether in NF-κB1 deficiency, in the recessive deficiencies of the alternative pathway or in the form of TRAF3 haploinsufficiency with hypogammaglobulinaemia [5, 20, 22, 25]. The American practice parameter recommends it in inborn errors with IgG deficiency (strong recommendation, high evidence), with a starting dose of 400 to 600 mg/kg/month adjusted to response (strong, moderate), intravenously every 3 to 4 weeks or subcutaneously weekly or every two weeks, with maintenance of IgG above 800 mg/dL (strong, high), continuous therapy and choice of route according to tolerance and patient preference; low or absent IgA does not contraindicate treatment [22]. The 2026 corrigendum sets the dose range at 400 to 600 mg/kg/month [48]. The British consensus proposes a cumulative dose of 400 to 500 mg/kg/month calculated on ideal body weight, an IgG trough of at least 8 g/L for most primary immunodeficiencies and of 10 g/L when there is organ damage or persistent infections, and optimisation of other measures before increasing the dose in patients with infections despite a trough of 8 g/L [49]. ICON suggests 0.4–0.5 g/kg/month intravenously and 0.4–0.6 g/kg/month subcutaneously, 0.6 g/kg/month with bronchiectasis and 0.6–0.8 g/kg/month with enteropathy or splenomegaly, and an increase of 0.15 g/kg/month after one severe or persistent infection or three moderate infections per year (Oxford group criterion), applicable to children and adults and with no maximum dose defined in the source [46]. In children, a randomised double-blind crossover trial showed that 800 mg/kg every 4 weeks reduced the number and duration of infections compared with 400 mg/kg [46].

The labels set wider ranges and serve for comparison. The US label of Privigen® indicates 200 to 800 mg/kg every 3 to 4 weeks in primary humoral immunodeficiency and states that there are no randomised trials defining the optimal trough; that of Gammagard Liquid® indicates 300 to 600 mg/kg every 3 to 4 weeks from 2 years of age [50, 51]. The European summaries of product characteristics (SmPC) of Privigen® and Kiovig® indicate a starting dose of 0.4 to 0.8 g/kg, followed by at least 0.2 g/kg every 3 to 4 weeks, with a trough target of at least 5 to 6 g/L, which generally requires 0.2 to 0.8 g/kg/month, in adults and children of all ages [52, 53]. The guidelines target higher troughs than the European regulatory minimum [22, 49, 52]. For the subcutaneous route, the initial weekly dose of Hizentra® in the USA is the previous intravenous dose in grams multiplied by 1.37 and divided by the number of weeks between intravenous doses; in the EU, the cumulative monthly maintenance dose is 0.4 to 0.8 g/kg, after a loading dose of at least 0.2 to 0.5 g/kg [54, 55]. HyQvia® (10% immunoglobulin with recombinant human hyaluronidase) allows subcutaneous intervals of 2 to 4 weeks, with initial ramp-up [56, 57].

Acute reactions (headache, nausea, flushing, urticaria, chills, myalgia, low back pain) are associated with rapid infusion, acute infection, treatment-naive patients, long intervals and change of product, and are treated by reducing the rate, antihistamines, paracetamol or anti-inflammatory drugs [46]. US labels for intravenous immunoglobulin carry a boxed warning on thrombosis and on renal dysfunction and failure; those for subcutaneous immunoglobulin on thrombosis [50, 54]. The subcutaneous route is preferable in patients with previous thrombosis, renal failure, risk of hyperviscosity, previous aseptic meningitis or poor venous access [49]. Before starting, the British consensus recommends archiving serum, testing for hepatitis C by PCR and HBs antigen, and performing a full blood count and biochemistry; IgG for dose adjustment is measured after at least 3 months, and monitoring is six-monthly [49].

In Portugal, the normal human immunoglobulin products marketed include Cutaquig®, Flebogamma DIF®, Gamunex®, Hizentra®, HyQvia®, Ig Vena®, Kiovig®, Octagam® and Privigen® [58]; in Brazil, ANVISA has active registrations for several products, including Cuvitru®, Flebogamma®, Gamunex®, Hizentra®, Octagam®, Panzyga® and Xembify® [59].

7.3. Antimicrobial prophylaxis

The practice parameter recommends targeted antimicrobial prophylaxis (strong, high); in antibody deficiencies with infections despite optimised immunoglobulin, it adds azithromycin, amoxicillin or co-trimoxazole, preferring azithromycin in bronchiectasis, after excluding non-tuberculous mycobacteria, with regimens of 250 mg on three days per week (that of the randomised trial), 500 mg on three days per week or 250 mg daily, and monitoring of the QT interval [22]. For inborn errors with recurrent or severe herpesvirus infections, it recommends prophylaxis with aciclovir or valaciclovir; the 2026 corrigendum indicates oral aciclovir 12.5 mg/kg twice daily, and 20 to 40 mg/kg (maximum 400 mg) twice daily in combined immunodeficiencies with a severe T-cell defect [22, 48]. This prophylaxis is especially relevant in NIK, IKK-α and RelB deficiencies, with HSV, varicella-zoster and CMV infections and anti-interferon autoantibodies [5, 21]. The chronic mucocutaneous candidiasis of RelB and NIK deficiencies requires an antifungal [5].

7.4. Vaccination

Live viral vaccines, live attenuated influenza vaccine and the dengue vaccine are contraindicated in antibody deficiencies; household contacts may receive live vaccines, except oral polio vaccine [22]. BCG caused disseminated disease in three patients with NIK deficiency and should be avoided in any infant with suspected combined immunodeficiency or with an affected sibling [3, 5]. Inactivated vaccines, including influenza and COVID-19 vaccines, should be given to patients and household members, because patients with anti-interferon autoantibodies are at high risk of severe viral pneumonia; in the NF-κB2 cohort with processing-resistant variants, 6 of 9 unvaccinated patients had hypoxaemic COVID-19 pneumonia, with 3 intensive care admissions and 2 deaths [21]. The authors recommend reinforcing prophylactic and therapeutic antiviral measures throughout life in these patients [21].

7.5. Herpes simplex encephalitis

HSV encephalitis is treated with intravenous aciclovir started as early as possible. The FDA label indicates, in herpes simplex encephalitis, 10 mg/kg infused over 1 hour every 8 hours for 10 days in adults and adolescents from 12 years, 20 mg/kg every 8 hours for 10 days from 3 months to 12 years, and 10 mg/kg every 8 hours for 10 days from birth to 3 months; the maximum dose is the equivalent of 20 mg/kg every 8 hours; in obese patients ideal body weight is used; in renal impairment the interval becomes 12 hours with a clearance of 25–50 mL/min/1.73 m², 24 hours with 10–25 and half the dose every 24 hours below 10, with a supplementary dose after haemodialysis; the infusion should last at least 1 hour to reduce renal tubular damage, and renal failure and thrombotic microangiopathy have been described in immunocompromised patients [24]. The index case of dominant-negative TRAF3 received 3 weeks of intravenous aciclovir, with a good response [9]. The label indication is the infection and not the genetic susceptibility; the value of a TRAF3 diagnosis is mainly anticipatory and for counselling [6].

7.6. Autoimmune, lymphoproliferative and autoinflammatory complications

In autoimmune cytopenias, ICON proposes prednisolone 1 to 2 mg/kg/day (or equivalent) in divided doses, with no maximum dose defined in the source, high-dose immunoglobulin of 1 to 2 g/kg, anti-D immunoglobulin and rituximab at standard doses for refractory or relapsing immune thrombocytopenia or haemolytic anaemia, and reserves splenectomy for selected cases [46]. In granulomatous-lymphocytic interstitial lung disease, the practice parameter recommends combined treatment with rituximab and an antimetabolite (mycophenolate mofetil or azathioprine) (strong, moderate), with a typical duration of 12 to 18 months [22]. In the Lorenzini cohort, the treatments used in NF-κB1 deficiency were immunoglobulin and immunosuppressants, including corticosteroids, rituximab and abatacept, according to the summary by Gold and colleagues [20, 39]. The autoinflammatory component of NF-κB1 deficiency can be controlled with anti-TNF-α or anti-IL-1 antibodies, which attenuate the hyperactive canonical pathway [12]; neutrophilic gastritis responded to anti-TNF in a patient studied in an induced pluripotent stem cell model [33]. In TRAF3 haploinsufficiency, ANCA vasculitis was treated with cyclophosphamide and rituximab, systemic juvenile idiopathic arthritis with IL-1 receptor blockade, and systemic autoimmunity with prednisolone, hydroxychloroquine and thalidomide [13]. After HSCT in NIK deficiency, seropositive arthritis responded partially to methotrexate and received rituximab, and autoimmune hepatitis was treated with corticosteroids, rapamycin, mycophenolate and tacrolimus [23]. All these uses are off-label and based on reports and series. For JAK inhibitors, the practice parameter suggests starting with the dose approved for the closest indication and titrating every 4 to 6 weeks, for example baricitinib 2 mg/day, increasing to a maximum of 4 mg/day, and 2 mg/day below 9 years, with aciclovir prophylaxis and clinical assessment every 4 to 6 months for opportunistic infections, thromboembolism, neoplasia and liver disease; there are no studies of these drugs in NF-κB1 deficiency [22].

7.7. Haematopoietic stem cell transplantation

The American practice parameter recommends considering HSCT in immune dysregulation diseases with severe or refractory complications (conditional, moderate) [22]. In NIK, IKK-α and RelB deficiencies, HSCT can correct the haematopoietic defect and the combined immunodeficiency, but not the defects of the stromal cells, which persist: lymph node hypoplasia, anti-interferon autoantibodies and a lifelong risk of severe viral disease [5]. In NIK deficiency, four patients underwent HSCT and two survived with cellular and humoral reconstitution [5]. Long-term follow-up of the Turkish family changed this interpretation: the patient transplanted in 2014 from a 10/10 unrelated donor and the brother of another patient, transplanted at 11 months from his HLA-identical mother after myeloablative conditioning, achieved full chimerism and initial T-cell reconstitution, but retained few central memory T cells and T follicular helper cells, hypogammaglobulinaemia requiring immunoglobulin and absent lymph nodes; both developed autoimmunity (seropositive arthritis, autoimmune hepatitis) and both died of infection, 10 and 3 years after transplantation; a third patient died on day six [23]. The authors conclude that HSCT alone is insufficient in this disease and propose prolonged immunological monitoring, including anti-cytokine autoantibodies, and adjuvant strategies such as thymic regeneration [23]. In RelB deficiency, the three brothers with NM_006509.4:c.1191C>A p.(Tyr397Ter) had good engraftment and reconstitution, and a patient transplanted at 14 years from a matched sibling donor had anti-interferon autoantibodies five years later, which she had not had before transplantation; in another patient the autoantibodies persisted 11 years later [5–7]. No HSCT has been published in IKK-α deficiency [5]. Allogeneic thymus implantation and thymic epithelial cells derived from induced pluripotent stem cells have been proposed, without clinical studies [5].

In NF-κB1 deficiency, HSCT is reserved for patients with a severe and refractory course [12, 20]. A 20-year-old woman with autoimmune neutropenia refractory to weekly immunoglobulin, daily filgrastim and rituximab underwent haploidentical HSCT from her mother, with a good outcome at one year (described in section 10) [39]. According to the summary by those authors, a retrospective multicentre study of HSCT in complicated common variable immunodeficiency had an overall survival of 48%, with deaths from refractory graft-versus-host disease, poor reconstitution and infections, and 92% of survivors had resolution of the immunodeficiency [39]. These figures refer to common variable immunodeficiency in general and not to patients with an NFKB1 variant. The decision is individual and considers severity, age and donor availability; family donors should be tested for the variant, given the incomplete penetrance [12].

7.8. Agents to avoid and precautions

Live vaccines should be avoided in patients with antibody deficiency or combined immunodeficiency, in particular BCG [5, 22]. NF-κB pathway inhibitors used in oncology (proteasome inhibitors, SMAC mimetics, NIK inhibitors in development) could, in theory, aggravate these deficiencies, and there are no clinical data in these patients [5]. In patients treated with rituximab, B-cell recovery may be prolonged, as in the patient with ANCA vasculitis who was left without B lymphocytes [13]. Azithromycin, fluoroquinolones and azoles require monitoring of the QT interval [22].

7.9. Pregnancy, perioperative care and transition

In pregnancy, ICON recommends increasing the immunoglobulin dose in the third trimester and at delivery, by 10% to 50% depending on the authors, and considers subcutaneous administration into the abdominal wall safe [46]. In the dominant diseases, pregnancy raises the question of transmission (section 8). There are no specific perioperative data in these diseases; patients with autoimmune cytopenias, previous splenectomy or bronchiectasis require individual planning [46]. Transition from paediatric to adult care should maintain continuity of immunoglobulin and of surveillance of complications, because the mean age at onset in NF-κB1 deficiency is 19 years and the course is progressive [12, 49].

7.10. Clinical trials and developments in the last 12 months

There are no registered clinical trials targeting NF-κB1, NIK, RelB or TRAF3 deficiency [47]. The developments of the period from November 2025 to October 2026 are summarised in the following table.

The leniolisib trial is the first to include patients with an NFKB1 variant, but the number of patients with this gene is not specified in the press release, there is no control group and the results have not been peer reviewed; the reduction in spleen volume and lymph node lesions is an intermediate endpoint [61]. NIK inhibitors and SMAC mimetics are cited as possible future therapies for inborn errors of the alternative pathway, without any clinical study in these diseases [5]. A negative search of the trial registry does not prove that there are no ongoing studies outside the registry.

8. Reproductive Options and Family Counselling

8.1. General principles

Genetic counselling in this class depends on the gene and the mechanism, because the class brings together autosomal dominant diseases with incomplete penetrance (NF-κB1), autosomal dominant diseases with two distinct mechanisms (TRAF3) and autosomal recessive diseases (NIK, IKK-α, RelB). The general approach to primary immunodeficiencies rests on a three-generation pedigree, extended on the maternal side, recording unexplained infant deaths or deaths from infection, neoplasms and haematological diseases, and counselling is based on the specific molecular diagnosis [42]. Confirmation of the variant in the proband is the prerequisite for cascade testing, prenatal diagnosis and preimplantation genetic testing [22, 42]. The North American practice parameter recommends family testing to resolve the pathogenicity of a variant (strong recommendation, high evidence) and considers it for estimating risk in unaffected relatives (conditional recommendation, low evidence) [22].

8.2. Recurrence risks by gene and scenario

The risk of inheriting the variant is not the same as the risk of disease. In NF-κB1 deficiency, overall penetrance was 78% in the compilation of 333 carriers, with 21% asymptomatic and 4% with mild symptoms; in the subgroup with a known protein defect, penetrance ranged from 67% in central truncations to 88% in missense variants of the Rel homology domain (RHD) and 100% in large deletions [12]. The Japanese series found a clinical penetrance of 52%, but all 9 asymptomatic carriers tested had immunological abnormalities [38]. Age at onset ranges from birth to 68 years, and two initially healthy carriers became ill during follow-up, which precludes regarding an asymptomatic adult carrier as free of risk [12]. These estimates come from published families and are subject to ascertainment bias, because families without affected members are rarely described [12].

8.3. Cascade testing and asymptomatic relatives

In NF-κB1 deficiency, testing first-degree relatives identifies the carriers who benefit from immunological assessment (immunoglobulins, B-cell subsets with class-switched memory and CD21low B cells) and from information about warning signs; in the British series, all carriers, symptomatic or not, had a defect of B-cell differentiation, and the B-cell immunophenotype combined with the variant distinguished healthy individuals, asymptomatic carriers and patients [19]. OMIM records asymptomatic carriers even with hypogammaglobulinaemia [1]. Testing of family donors is necessary before HSCT, so as not to select a carrier sibling or parent without apparent disease [12]. In the recessive diseases, testing siblings identifies affected individuals who are still asymptomatic and heterozygotes; for affected siblings, early HLA typing and cord blood collection at subsequent births are options described for possible HSCT [42]. The population frequency of the TRAF3 p.(Arg118Trp) variant means that finding it in a relative must be interpreted with caution, as a low-penetrance allele and not as a diagnosis [13].

8.4. Mosaicism, de novo variants and special situations

De novo variants are documented in NF-κB1 deficiency (for example NM_003998.4:c.139del, published as c.137del, and the NM_003998.4:c.380del variant in the case in section 10, considered probably de novo) and in TRAF3 haploinsufficiency [10, 39, 40]. The sources consulted do not quantify germline mosaicism in any of these diseases; faced with an apparently de novo variant, the risk for siblings is low but higher than that of the general population, because of the general possibility of parental mosaicism. In families with Cocoon syndrome, the lethal prenatal phenotype and the 25% risk per pregnancy make prenatal or preimplantation diagnosis the main reproductive option [5, 6]. De novo CHUK heterozygosity in two patients with an ectodermal dysplasia and immunodeficiency phenotype is not established as a cause of disease [6].

8.5. Prenatal and preimplantation diagnosis and testing of minors

Prenatal diagnosis by chorionic villus sampling and preimplantation genetic testing are possible when the familial variant has been identified; in the absence of prenatal diagnosis, storage and analysis of cord blood are an alternative [42]. In the severe recessive diseases (NIK, IKK-α, RelB) the indication is straightforward. In NF-κB1 deficiency, the decision is more complex: penetrance is incomplete, expressivity varies within the same family and there is no genotype-phenotype correlation that would allow severity to be predicted [12]. Testing of minors is justified in the recessive diseases with onset in childhood and in relatives of patients with NF-κB1 or TRAF3 deficiency when the result changes surveillance (immunoglobulins, vaccination with live vaccines, warning signs), given that manifestations may begin in childhood [12, 22]. Predictive testing of an asymptomatic minor with no immediate consequence for surveillance should be discussed with the parents and deferred when it brings no clinical benefit.

9. Special Considerations: Population Diversity and Epidemiology

9.1. What is known and what each figure measures

There is no population prevalence estimate for any of the entities in the class. Orphanet places NFKB1-related immune dysregulation in the prevalence class below 1/1,000,000, with 173 validated cases in the sources it compiles, NIK deficiency with 2 cases and RelB deficiency with 5 cases, all in the same prevalence class [2, 4, 8]. These figures count published patients, not existing patients. The 2026 review counts 8 patients with NIK deficiency, 7 patients and 2 fetuses with IKK-α deficiency, 9 patients with RelB deficiency and 12 patients from 7 families with TRAF3 haploinsufficiency [5].

NF-κB1 deficiency is the entity with relative frequency data. In the British NIHR BioResource series, with 846 unrelated index patients with primary immunodeficiency (82% of European ancestry), loss-of-function variants in NFKB1 explained 4% of the 390 patients with common variable immunodeficiency, which made NFKB1 the most frequent monogenic gene in this cohort [19]. This value is a proportion within a cohort of referred patients and not a population prevalence. Common variable immunodeficiency has an estimated prevalence of about 1 in 25,000 to 1 in 30,000, higher in northern Europe [19, 22]; applying the 4% proportion to these values would give an approximate but unvalidated order of magnitude, because the proportion of monogenic cases varies with the population studied and with the sequencing strategy. The compilation of 333 carriers showed no sex predilection [12].

9.2. Geographical distribution and founder populations

No founder variant has been described for any of the genes in scope. The concentration of the recessive deficiencies in consanguineous families from the Middle East, Turkey and North Africa reflects the structure of these populations and the origin of the centres that described them, and not a known distribution of the variants. The Japanese NFKB1 series described lower clinical penetrance (52%), two patients with moyamoya disease and absence of a type I interferon signature, but the number of patients is small and does not allow the differences to be attributed to ancestry [38]. The regional North American series compared 15 patients with common variable immunodeficiency and an NFKB1 variant with 77 without a variant and found more autoimmunity (80% versus 36%) [34].

The sources consulted do not include data from Portugal or Brazil for these diseases. The absence of data in these sources does not mean that there are no patients or publications in either country. In Portugal, the replacement immunoglobulins described in section 7 are marketed, and in Brazil ANVISA has active registrations for normal human immunoglobulin [58, 59].

9.3. Special populations

In children, the recessive deficiencies manifest in the first years of life, and BCG vaccination, routine in many countries where these cases were described, caused disseminated disease in three of the eight patients with NIK deficiency [5]. In adults, NF-κB1 deficiency is the most likely scenario, with a mean age at onset of 19 years and genetic diagnosis on average at 37–40 years, which means that many patients reach a molecular diagnosis after years of treatment as common variable immunodeficiency [12]. In pregnancy, the immunoglobulin dose adjustment described in section 7 applies [46]. In consanguineous families, screening of siblings and cousins is part of counselling (section 8).

9.4. Reference networks and patient organisations

The European Reference Network on rare primary immunodeficiency, autoinflammatory and autoimmune diseases (ERN RITA) brings together the European reference centres for these diseases and took part in the European guideline on the diagnosis of granulomatous-lymphocytic lung disease [26, 64]. The International Patient Organisation for Primary Immunodeficiencies (IPOPI) brings together national patient organisations [65]; in Portugal, the Associação Portuguesa de Doentes com Imunodeficiências Primárias (APDIP) [66]. In the USA, the Immune Deficiency Foundation and the Jeffrey Modell Foundation, and in Europe the European Society for Immunodeficiencies (ESID) and its registry, are the resources cited in the international consensus [46]. The public GenIA database (https://www.geniadb.net) brings together the genotypes and phenotypes of published carriers of NFKB1 variants [12]. For Brazil, the sources consulted do not identify a national patient organisation.

10. Illustrative Clinical Case

10.1. NF-κB1 deficiency with refractory autoimmune neutropenia treated with haploidentical HSCT

A 20-year-old woman, with a history of autoimmune alopecia, eczema, a congenital atrophic right kidney and depression, presented to the emergency department with three months of intermittent fever in bouts, malaise, pharyngitis, cervical lymphadenopathy, oral aphthae, diarrhoea and odynophagia, with weight loss of about 2.3 kg (5 pounds) and night sweats; several courses of corticosteroids prescribed by her primary care physician had given only transient improvement [39]. Her mother had renal agenesis and thyroid dysgenesis; her father was healthy; there was no family history of NFKB1 variants [39]. On examination she had a maximum temperature of 38.8 °C, pallor, tender inguinal and fixed submandibular lymphadenopathy, oropharyngeal erythema and a mild axillary rash [39].

The full blood count showed leucocytes 2.23 × 10⁹/L with neutrophils 0.03 × 10⁹/L, haemoglobin 13.9 g/dL with a mean corpuscular volume of 69.3 fL and platelets 151.8 × 10³/µL; immunoglobulins were low (IgG 312 mg/dL, IgA 45 mg/dL, IgM 33 mg/dL) [39]. Computed tomography revealed multiple cervical lymphadenopathy and hepatosplenomegaly. The infectious work-up (Epstein-Barr virus, cytomegalovirus, herpes simplex virus, toxoplasma, hepatitis B, HIV, respiratory and gastrointestinal viral panels, cultures, parasites, QuantiFERON, Bartonella, parvovirus B19) and antinuclear antibodies were negative [39]. Bone marrow biopsy showed trilineage haematopoiesis with myeloid maturation arrest, without dysplasia or excess blasts, with a normal karyotype and negative myelodysplasia sequencing and FISH panels; lymph node biopsies showed reactive changes without neoplasia [39]. Figure 1 of the article shows the lymph node with follicular hyperplasia and T-zone expansion and a reactive subcapsular plasma cell infiltrate, and the marrow with an interstitial infiltrate of CD3+ and CD8+ T lymphocytes, without clonal T-cell receptor rearrangement (https://pmc.ncbi.nlm.nih.gov/articles/PMC12562562/figure/hematolrep-17-00049-f001/) [39].

Genetic testing identified the heterozygous variant NM_003998.4(NFKB1):c.380del, p.(Thr127MetfsTer19), considered probably de novo, and a variant of uncertain significance in AP3D1 without a corresponding phenotype [11, 39]. Prophylaxis with aciclovir, fluconazole and doxycycline was started. Clostridioides difficile colitis followed, and colonoscopy showed active colitis with crypt abscesses and few plasma cells, compatible with common variable immunodeficiency and recent infection [39]. The repeated episodes of fever, aphthae and infections led to escalation of treatment to daily filgrastim and weekly intravenous immunoglobulin, with an IgG target above 1000 mg/dL, because the symptoms coincided with IgG falling below that value; the attempt to reduce to filgrastim twice weekly and immunoglobulin every 3 weeks again caused neutrophils and IgG to fall, and monthly rituximab was added for immune thrombocytopenia [39]. Neutrophils recovered and fell again after a week (0.1 × 10³/mm³ at diagnosis, 0.6 with filgrastim, 3.4 with filgrastim and rituximab, 0 before transplantation) [39].

Because of persistent neutropenic syndromes, the patient underwent haploidentical HSCT with her mother as donor, after conditioning with antithymocyte globulin, fludarabine, cyclophosphamide and total body irradiation, with 3.96 × 10⁸ total nucleated cells/kg [39]. During admission she had herpes labialis due to HSV-2, treated with valaciclovir for 14 days. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide on days +3 and +4 and tacrolimus and mycophenolate from day +5, and cytomegalovirus prophylaxis of letermovir; neutrophil engraftment occurred on day +19, the day of discharge [39]. At one year she was well, with normal counts (neutrophils 6 × 10³/mm³), after an admission for intestinal and cutaneous GVHD treated with tacrolimus, ruxolitinib 5 mg twice daily and budesonide 9 mg/day [39].

10.2. Reading the case in the light of the guidelines

The case brings together features frequent in NF-κB1 deficiency: onset in young adulthood, previous autoimmunity (alopecia), hypogammaglobulinaemia, reactive lymphoproliferation with hepatosplenomegaly, enteropathy and autoimmune cytopenias [1, 12]. Profound and persistent neutropenia is an uncommon presentation. Some measures diverge from what the guidelines propose as routine: the IgG target above 1000 mg/dL with weekly immunoglobulin is higher than the trough of 800 mg/dL in the American practice parameter and the 8 g/L of the British consensus, which accepts 10 g/L only in selected situations [22, 49]; and HSCT, which the practice parameter recommends only be considered (conditional recommendation) in severe or refractory dysregulation, has high mortality in complicated common variable immunodeficiency [22, 39]. One year of follow-up is short for assessing the long-term outcome, and the report concerns a single case; it does not allow the indication for transplantation to be generalised.

10.3. Complementary case: herpes simplex encephalitis with a dominant-negative TRAF3 variant

The IMD132A index case was a French girl who had herpes simplex encephalitis at 4 years, with fever, diarrhoea, epileptic seizures and aphasia, one to two months after chickenpox; she responded to three weeks of intravenous aciclovir and at 18 years was healthy, with no other severe infections [9, 30]. She was heterozygous for the de novo variant NM_145725.3(TRAF3):c.352C>T, p.(Arg118Trp), with protein expression reduced to about 17.5% and a dominant-negative effect on the production of interferon β, interferon λ and IL-6 after TLR3 stimulation [9, 11, 30]. The same variant was later found in about 1 in 200 to 1 in 250 Europeans, without a strong association with herpes simplex encephalitis in the UK Biobank [13]. The case illustrates the need to interpret a classical variant in the light of its population frequency before considering it a sufficient cause of disease.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis of NF-κB1 deficiency

The course of NF-κB1 deficiency is progressive in most patients, with worsening and the appearance of new manifestations over the years, and individual unpredictability is the rule: there is no clear genotype-phenotype correlation, and penetrance and severity vary within the same family [12]. In the compilation of 333 carriers, 78% were affected at the last assessment, 10% of carriers with a known protein defect had a malignant neoplasm and 44% met the diagnosis of common variable immunodeficiency [12]. Neoplasia estimates vary with the design of the series: 28.6% in the British series of 16 patients, 16.8% in the Lorenzini series and fewer than 20% in the OMIM summary, mainly lymphomas and solid tumours [1, 19, 20]. In the British series, massive lymphadenopathy (24%), unexplained splenomegaly (48%) and autoimmune disease (48%) were frequent, and these manifestations were associated with a worse prognosis in earlier studies of common variable immunodeficiency [19]. None of the series has published survival curves specific to NF-κB1 deficiency; the 2026 compilation records one death at 52 years in the large-deletion group and stresses the scarcity of longitudinal data [12]. In common variable immunodeficiency in general, the prognosis of primary antibody deficiencies is good with early diagnosis and adequate immunoglobulin, and the late complications are bronchiectasis (associated with late diagnosis, insufficient immunoglobulin dosing and poorly treated infections), enteroviral meningoencephalitis (rare with high immunoglobulin doses), autoimmunity, granulomatous disease, lymphoproliferation and neoplasia [42].

The NFKB1-DAS activity index, with 21 parameters, was developed in 2026 to quantify severity; the index value correlated with hospital admission (odds ratio 2.07; 95% confidence interval 1.18–3.62), but external validation is lacking, and the instrument is intended mainly for future trials and for the study of variants of uncertain significance [31].

11.2. Prognosis of the defects of the alternative pathway

In the recessive deficiencies of the alternative pathway, prognosis is determined by the combined immunodeficiency and by the stromal defect that HSCT does not correct. In NIK deficiency, two of the four transplanted patients survived with cellular and humoral reconstitution in the 2026 review [5], but long-term follow-up of the Turkish family showed persistent hypogammaglobulinaemia, absent lymph nodes, autoimmunity and death from infection 3 and 10 years after an HSCT with full chimerism [23]. In IKK-α deficiency, three of the seven patients died (two after liver transplantation for chronic hepatitis and one after chemotherapy for lymphoma) and none underwent HSCT [5]. In RelB deficiency, the transplanted patients had good engraftment, but autoantibodies against type I interferon persisted up to 11 to 14 years after HSCT, with a lifelong risk of severe viral disease [5, 21]. In TRAF3 haploinsufficiency, infections improved with immunoglobulin, prophylaxis and lung surgery, but lymphoproliferation and autoimmunity (Sjögren syndrome, vasculitis, thyroiditis) required immunosuppression in several patients [13]. In the dominant-negative form, the patient with herpes simplex encephalitis was healthy at 18 years [9, 30]; the patient with Mycobacterium abscessus disease died [9, 37].

11.3. Surveillance table

The British consensus measures IgG for dose adjustment only after at least 3 months and repeats it every 6 months, with a full blood count, liver function tests, urea and electrolytes; the same intervals appear in section 7 [49]. The 2026 European guideline recommends screening for granulomatous-lymphocytic lung disease in all adults with common variable immunodeficiency (strong recommendation, low certainty) and in high-risk children, with HRCT as the first examination, does not recommend routine measurement of serum biomarkers and reserves lung biopsy for cases with unclear imaging or suspicion of another diagnosis [64]. The North American practice parameter does not recommend routine screening for organ-specific autoantibodies and recommends a regular full blood count, because the first episode of autoimmune cytopenia may precede diagnosis [22]. Surveillance of transplanted recessive deficiencies continues beyond successful engraftment, because the stromal defects persist [5, 23].

11.4. Transition and quality of life

In NF-κB1 deficiency, the transition to adult care coincides with the mean age at onset (19 years), and should maintain continuity of immunoglobulin, pulmonary surveillance and assessment of autoimmune complications [12, 49]. In the recessive deficiencies transplanted in childhood, follow-up in adulthood includes surveillance for severe viral infections, autoimmunity and late complications of transplantation [23]. The practice parameter recommends assessing quality of life with a validated instrument, such as the CVID-QoL (32 items, adults), and fatigue at each visit [22].

12. Summary and Final Considerations

The NF-κB family transmits, through two pathways, the signals of immune and stromal receptors. The canonical pathway, with a rapid response, depends on the IKK complex with NEMO and on the degradation of IκB-α; the alternative pathway, slow and sustained, depends on the stabilisation of NIK, the phosphorylation of p100 by IKK-α and the formation of p52–RelB dimers, and is kept inactive at rest by the constitutive degradation of NIK by the TRAF3–TRAF2–cIAP complex [5]. The inborn errors of this class affect this machinery at different points and produce phenotypes that overlap, but which are distinguished by inheritance, age at onset and biomarkers.

NF-κB1 deficiency is an autosomal dominant disease due to p50 haploinsufficiency, with a penetrance of about 78% and highly variable expressivity, which presents mainly in young adults as common variable immunodeficiency with autoimmunity, lymphoproliferation, autoinflammation, enteropathy, liver disease and risk of neoplasia; it is the most frequent monogenic cause of common variable immunodeficiency in European cohorts [12, 19]. The recessive NIK, IKK-α and RelB deficiencies are combined immunodeficiencies with onset in childhood, with absence or hypoplasia of lymph nodes and tonsils, bacterial, viral and fungal infections and, in NIK deficiency, mycobacterial and Cryptosporidium infections; IKK-α deficiency adds ectodermal dysplasia and, in the null form, lethal Cocoon syndrome [5]. These three deficiencies share with the processing-resistant form of NF-κB2 deficiency the loss of AIRE+ medullary thymic epithelial cells and neutralising autoantibodies against type I interferon, which persist after HSCT and confer a lifelong risk of severe viral disease [5, 21]. TRAF3 has two dominant phenotypes: the dominant-negative p.(Arg118Trp) variant, described in herpes simplex encephalitis, is now seen as a common low-penetrance allele, and truncating variants cause haploinsufficiency with constitutive activation of the alternative pathway in B cells, hypergammaglobulinaemia with poor response to polysaccharides, infections with encapsulated bacteria, lymphoproliferation and autoimmunity [5, 13].

Diagnosis rests on clinical suspicion, immunoglobulins and lymphocyte subsets, and is confirmed by an inborn errors of immunity gene panel or exome with copy-number analysis; testing for autoantibodies against type I interferon and assessment of lymphoid architecture point to the alternative pathway [21, 22]. There is no approved treatment for any of the entities. Immunoglobulin replacement (400 to 600 mg/kg/month, with IgG above 800 mg/dL), antimicrobial and antiviral prophylaxis, avoidance of live vaccines, inactivated vaccination and immunosuppression targeted at complications form the basis of treatment, according to general guidelines for inborn errors of immunity and common variable immunodeficiency [22, 46, 48, 49]. HSCT corrects the haematopoietic compartment in the recessive deficiencies, but not the thymic and lymph node stroma, and in NIK deficiency long-term follow-up showed that it is insufficient on its own; in NF-κB1 deficiency it is reserved for severe and refractory forms [5, 12, 23]. The new data of recent months (the compilation of 333 carriers, the NFKB1-DAS index and the preliminary results of leniolisib in patients with immune dysregulation, including carriers of NFKB1 variants) have not yet changed the recommendations [12, 31, 61]. Genetic counselling has to deal, in NF-κB1 deficiency, with incomplete penetrance, de novo variants and the absence of a genotype-phenotype correlation, and in the recessive deficiencies with the 25% risk per pregnancy and the option of prenatal and preimplantation diagnosis.

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