X-Linked Agammaglobulinaemia (Bruton Disease) and Autosomal Agammaglobulinaemias

Congenital defects of early B-cell development with absent or profoundly reduced circulating B cells and all immunoglobulin classes; BTK deficiency is the prototypical form, with clinically overlapping autosomal recessive and dominant forms.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

X-linked agammaglobulinaemia is the prototype of predominantly antibody deficiencies and one of the best-documented inborn errors of immunity (IEI) [12]. Ogden C. Bruton, a paediatrician at Walter Reed Army Hospital, published the foundational article in 1952, describing an 8-year-old boy with recurrent bacterial infections from age 4 whose serum lacked the gamma fraction on protein electrophoresis [12, 13]. Bruton administered subcutaneous Cohn fraction II, derived from pooled healthy donor plasma; the patient's gamma fraction increased to 4.6% and recurrent infections ceased, demonstrating that this fraction, subsequently identified as immunoglobulin G (IgG), contained protective antibodies [12]. Although ataxia–telangiectasia, Wiskott–Aldrich syndrome and severe congenital neutropenia had been described earlier, Bruton's work is regarded as the first laboratory diagnosis and first treatment of an IEI [12]. Bruton called the disease “agammaglobulinaemia” despite low concentrations of immunoglobulins, and X-linked inheritance was recognised shortly afterwards; congenital agammaglobulinaemia, familial hypogammaglobulinaemia and infantile agammaglobulinaemia were also used from the 1950s to the 1970s [1].

Two independent groups identified the gene in 1993 [12]. Tsukada and colleagues described a cytoplasmic tyrosine kinase, termed BPK (B cell progenitor kinase), expressed throughout the B lineage and in myeloid cells, mapped within 100 kb of the polymorphism most closely linked to XLA. Messenger RNA, protein and kinase activity were reduced or absent in patients' pre-B and B-cell lines [14]. Through positional cloning, Vetrie and colleagues isolated a src-family tyrosine kinase gene expressed in B cells and mutated in affected families, naming it ATK; this was the first demonstration that mutations in a src-related gene cause human disease [15]. Concordant location (Xq21.3–Xq22), structure and function led to renaming it Bruton's tyrosine kinase (BTK), honouring the original description [12].

Therapeutic history followed immunoglobulin development: after initial subcutaneous administration, intramuscular delivery predominated in the 1960s, with pain and volume limitations maintaining low IgG levels. Intravenous preparations emerged in the 1970s, enabling higher doses and better infection control; subcutaneous administration returned in Scandinavia and the United Kingdom in the early 1990s and became widespread in the 2000s [12]. Prognosis improved markedly through earlier diagnosis, liberal antibiotic use and preparations allowing normal IgG concentrations; nevertheless, approximately 10% have significant infections despite adequate therapy, and many develop chronic pulmonary abnormalities [1].

Autosomal forms were identified from 1996 onwards, initially through μ heavy-chain defects in recessively inherited families and in patients presumed to have XLA without BTK mutations [16], then through defects in other pre-B receptor components and their signalling [17–21]. These forms are clinically and immunologically indistinguishable from XLA on routine testing [1, 22]. More recently, dominant forms (TCF3, SPI1, TOP2B) and recessive forms with extra-immunological manifestations (SLC39A7, FNIP1) have been described [23–27]. The introduction of kappa-deleting recombination excision circle quantification (KREC, kappa-deleting recombination excision circles) into newborn screening has begun to change the age at diagnosis and has revealed that some forms, such as IGLL1 deficiency, are more frequent and more heterogeneous than previously thought [10, 28]. This article covers XLA and the autosomal agammaglobulinaemias; the general approach to IEI, including the overall framework for immunoglobulin therapy, appears only as context.

2. Molecular Genetics and Pathophysiology

2.1. The BTK gene and protein

BTK is located at Xq22.1 and encodes BTK tyrosine kinase, expressed in haematopoietic progenitors, myeloid cells, platelets and the B lineage [1]. Despite expression in several cell types, BTK is principally required for B-cell antigen receptor (BCR) signalling; its downstream substrate is phospholipase Cγ2 (PLCγ2), which, among other effects, activates the NF-κB pathway necessary for B-cell survival [1]. GeneGuidance curation adds that, after BCR engagement, BTK is recruited to the membrane and, with adaptor BLNK, phosphorylates PLCG2, triggering calcium mobilisation and protein kinase C activation; it also participates in Toll-like receptor signalling and NLRP3 inflammasome assembly [3]. BTK loss arrests B-cell maturation at the pre-B stage; Table 3 of the International Union of Immunological Societies (IUIS) classification records normal pro-B-cell numbers in XLA [3, 4]. The MANE Select reference transcript is NM_000061.3, encoding NP_000052.1 [5].

2.2. Variant spectrum

More than 1,000 different pathogenic BTK variants have been described; two-thirds are premature stop codons, splicing defects or frameshift variants that prevent messenger RNA processing, so cytoplasmic BTK messenger RNA is not identified [1]. By February 2025, more than 2,400 variants had been submitted to the Leiden Open Variation Database (LOVD). In published series, missense variants account for 20–37%, deletions 17–38%, nonsense variants 12–23%, splicing variants 0–20% and insertions 3–8%, predominantly downstream of exon 1 (corresponding to exon 2 in historical nomenclature), whereas 5′ untranslated region (5′-UTR) variants upstream of exon 1 account for only 1% [12]. The disease mechanism is loss of function [1].

Non-coding variants have increasing diagnostic importance [12]. The promoter contains PU.1 and Sp1 binding sites: one variant (5′-UTR-58G>A) changes the core PU.1 site sequence and reduces promoter activity; a four-base-pair deletion (AAAG) in the PU.1 region reduces transcription despite BTK expression remaining detectable by flow cytometry; and c.-193A>G was associated with neutropenia and a mild phenotype, with 1% B cells and IgG 300–450 mg/dL [12]. Exon −1 and intron −1 variants (e.g. c.-31G>A at the exon −1 donor site, described in the Netherlands) produce aberrant splicing products or alter transcriptional regulation [12]. Several deep intronic variants have been described, including c.840-272G>T, creating a donor site and abnormal splicing between exons 8 and 9, with residual monocyte BTK expression; these escape exome sequencing [1, 12].

2.3. Contiguous deletions and Mohr–Tranebjærg syndrome

Approximately 3–5% of individuals with a pathogenic BTK variant have a large deletion extending to neighbouring TIMM8A (also termed DDP) and sometimes TAF7L and DRP2, resulting in XLA with deafness–dystonia–optic neuropathy syndrome (DDON, Mohr–Tranebjærg syndrome) [1]. TIMM8A lies 770 bp centromeric to BTK; the largest described deletion, from BTK to DRP2, spans 196 kb. The contiguous syndrome was described in a family in 1996 and subsequently identified in more than 20 patients [12]. In an isolated case, XLA coexisted with Klinefelter syndrome, both X chromosomes carrying the same maternal variant, suggesting non-disjunction during the second meiotic division of oogenesis [12]. GeneGuidance also links BTK to OMIM 307200 (agammaglobulinaemia with isolated growth hormone deficiency), without additional clinical data in consulted sources [3].

2.4. Genotype–phenotype correlation and expressivity

There is no strong correlation between variant and severity; however, amino acid substitutions or splicing defects at conserved but non-invariant positions are associated with later diagnosis, higher IgM and slightly more B cells [1]. Approximately 10% of hemizygous males remain unrecognised before age 10, some until adulthood; immunoglobulins may be higher than expected, but all have very low B-cell numbers [1]. The 2015 US practice parameter reports discordant sibling phenotypes with identical variants and cases with immunoglobulin levels suggesting common variable immunodeficiency (CVID) or specific antibody deficiency [29].

2.5. Heterozygous women

Heterozygous women are almost always unaffected; two women with XLA have been described, both preferentially using the variant-bearing X chromosome, indicating extremely skewed X-inactivation [1]. A heterozygote with the phenotype warrants investigation for skewed inactivation, but agammaglobulinaemia in a woman should initially suggest an autosomal form [1].

2.6. Autosomal agammaglobulinaemias: genes and mechanisms

Non-X-linked forms result from defects in other genes required for normal B-cell development [1, 22]. The pre-B receptor comprises a rearranged μ heavy chain, a surrogate light chain consisting of λ5 (encoded by IGLL1) and VpreB, and the signalling chains Igα and Igβ (CD79A, CD79B); adaptor BLNK connects this receptor to downstream signalling [3, 17]. Table 1 summarises genes, inheritance, ClinGen-curated association validity and distinguishing findings.

Table 1. Genes associated with non-X-linked agammaglobulinaemias. ClinGen: antibody deficiency panel classification [31]. AR, autosomal recessive; AD, autosomal dominant.

Before identification of PIK3R1, TCF3 and more recent genes, mutations in BTK, μ chain, surrogate light chain, Igα and BLNK explained 85–90% of agammaglobulinaemia patients [18, 20], and approximately 90% of isolated agammaglobulinaemia involved pre-B receptor and BCR signalling genes [23]. The underlying defect remains unknown in a small proportion [1]. The 2025 ClinGen curation, assessing 65 antibody deficiency genes and 74 gene–disease relationships, upgraded SPI1 and FNIP1 from strong to definitive, relevant to panel interpretation [31].

2.7. Pathophysiology and consequences

B-cell developmental arrest prevents plasma cell formation and therefore production of antibodies of all isotypes, including mucosal secretory IgA; cellular immunity is preserved [1, 3]. Immunoglobulin replacement restores only IgG; uncorrected mucosal IgA deficiency compromises intestinal defence and permits dissemination of enteric organisms such as non-pylori Helicobacter [35]. BTK is also expressed in innate immune cells, including microglia, and regulates the NLRP3 inflammasome and NK-cell activation. These functions have been invoked to explain enterovirus susceptibility, neurodegeneration and certain inflammatory manifestations, although evidence is controversial [12, 36]. Resolution of chronic norovirus infection after transplantation, before humoral reconstitution, suggests a non-humoral immunodeficiency component [37].

3. Clinical Spectrum and Manifestations by System

3.1. Natural history and presentation

Boys with XLA are usually well during the first months, protected by transplacental maternal IgG; recurrent bacterial infections develop within the first two years, and immunodeficiency is recognised before age five [1, 22]. Recurrent otitis is the most frequent prediagnostic infection; conjunctivitis, sinopulmonary infections, diarrhoea and skin infections are also common [1]. Approximately 60% are identified only after a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis or septic arthritis [1]. Streptococcus pneumoniae and Haemophilus influenzae predominate before diagnosis and may continue causing sinusitis and otitis after immunoglobulin replacement starts [1, 6]. Some patients are recognised only after age five, and approximately 10% after age ten [1, 6].

In the US registry of 201 patients (2006), infection was the initial presentation in 85%, positive family history occurred in 41% and neutropenia in 11%; mean diagnostic age was 2.59 years with family history and 5.37 years without, and only 34.5% with family history known at birth were diagnosed before symptoms [38]. The proportion experiencing at least one episode was 70% for otitis, 62% pneumonia, 60% sinusitis, 23% chronic or recurrent diarrhoea, 21% conjunctivitis, 18% pyoderma or cellulitis, 11% meningitis or encephalitis, 10% sepsis, 8% septic arthritis, 6% hepatitis and 3% osteomyelitis [38]. In the more recent USIDNET registry (240 patients born between 1945 and 2017), median onset age was 0.8 years and diagnostic age 2 years; 92.5% had recorded infections, including pneumonia in 56.2%, sinusitis in 54.6% and otitis media in 54.2%. Meningitis and bacteraemia/sepsis were the only infections whose prevalence decreased after diagnosis [39].

3.2. Manifestations by system

Table 2. Manifestations by system in XLA. WAO, World Allergy Organization.

3.3. Characteristic infections

Patients with XLA are not vulnerable to most viral infections, but are susceptible to severe chronic enteroviral infections, often presenting as dermatomyositis or chronic meningoencephalitis [1]. Chronic enteroviral infection incidence declined from the mid-1980s with immunoglobulin replacement, although enteroviral encephalitis and neurological deterioration of unknown cause still occur [1]. Risk is now lower than during intramuscular immunoglobulin or no replacement, but has not decreased significantly during the intravenous immunoglobulin era; cerebrospinal fluid detection has low sensitivity and reluctance to perform brain biopsy delays diagnosis [42]. As with all antibody deficiencies, susceptibility is increased to Giardia, persistent mycoplasma infections and unusual organisms such as Flexispira or Helicobacter cinaedi [1]. Non-pylori Helicobacter species (H. cinaedi, H. fennelliae, H. canis, H. bilis) cause cellulitis, pyoderma gangrenosum, bacteraemia and osteomyelitis; immunoglobulin replacement alone does not prevent them. Isolation requires prolonged blood culture and molecular methods (16S ribosomal RNA PCR, mass spectrometry), and skin infections require at least six weeks of antibiotics [12]. Pneumocystis pneumonia or vaccine-strain poliovirus infection occurs rarely [6]. One described XLA patient developed severe tick-borne encephalitis that prior vaccination might have prevented [1].

3.4. Non-infectious complications

Progressive neurodegeneration without identifiable infection was described in 15 patients, with mean XLA diagnostic age 3.25 years and neurological onset age 10.15 years; 13 received immunoglobulin before symptoms and outcomes were fatal in 10 of 13 [12]. In the 2023 USIDNET registry, neurological disease was the most frequent underlying comorbidity among deceased patients [39]. XLA-associated nephritis comprises chronic glomerulonephritis (mesangial proliferation and immune-complex deposits, in atypical or mild phenotypes with good corticosteroid and immunosuppressant responses) and tubulointerstitial nephritis (classical XLA, frequently after more than 10 years of IVIg, with CD8+ infiltration and less favourable prognosis). Post-IVIg IgG peaks have been proposed to contribute to immune complexes, which SC administration might avoid, but evidence of prevention is lacking [12].

Malignancies occurred in 3.7% of the Italian cohort and 1.25% of USIDNET (B-cell lymphoma, angiosarcoma and craniopharyngioma) [39, 40]. More than half of reported solid tumours are gastric and colorectal adenocarcinomas diagnosed at young ages (13 of 15 patients with gastric or colorectal cancer were below 40), attributed to chronic inflammation caused by Giardia, Campylobacter jejuni and H. pylori [12]. H. pylori investigation should use culture and PCR because serology is falsely negative [12]. Acute leukaemias (B-lymphoblastic, myeloid, megakaryocytic) also have prevalence above the general population, with somatic CDKN2A and TP53 alterations and monosomy 7, interpreted through a two-hit model in which germline BTK variation is the first hit [12]. In the WAO series, individually uncommon complications (inflammatory bowel disease, large granular lymphocyte disease and others) collectively occurred in 20.3% [36]. Allergic manifestations (rhinitis, eczema, urticaria) were recorded in 28% of USIDNET patients [39].

3.5. Distinctive features of autosomal forms

Patients with μ-chain deficiency tend to present earlier and have more life-threatening infections than XLA patients, although clinical overlap is substantial [1, 30]. SLC39A7 deficiency involves blistering dermatosis with dermoepidermal junction cleavage, growth retardation and thrombocytopenia in severe cases, and enteropathy, hepatic dysfunction or seborrhoeic dermatitis in others [3, 26]. FNIP1 deficiency includes early-onset hypertrophic cardiomyopathy, ventricular pre-excitation and neutropenia [3, 27]. PU.1 deficiency also reduces conventional and plasmacytoid dendritic cells; the clinical course resembles XLA, and some patients had late onset, occasionally in adulthood [33]. TCF3 haploinsufficiency produces milder disease, with recurrent non-severe infections and incomplete penetrance [32]. IGLL1 deficiency identified through newborn screening spans agammaglobulinaemia to transient hypogammaglobulinaemia [28]. p85α deficiency was associated with colitis [21], and Hoffman syndrome (TOP2B) with facial dysmorphism and limb abnormalities [4].

4. Clinical Recognition and Warning Signs

XLA should be suspected with recurrent otitis, pneumonia, sinusitis and conjunctivitis beginning before five, severe bacterial infection (sepsis, meningitis, cellulitis, empyema), sparse lymphoid tissue (small adenoids, tonsils and lymph nodes), and family history compatible with X-linked inheritance without male-to-male transmission [1]. Absent family history does not exclude diagnosis: half of newly diagnosed boys have none [1, 22]. Absent lymph nodes and tonsils distinguish agammaglobulinaemia from other antibody deficiencies, although small or absent tonsils also occur in some combined immunodeficiencies [6, 29].

Table 3. Warning signs for congenital agammaglobulinaemia.

Diagnostic delay has measurable consequences. In USIDNET, diagnostic age was lower in patients without lower respiratory infection (median 1.5 vs 3.0 years) and in surviving versus deceased patients (1.8 vs 2.7 years); each year's delay in treatment initiation increased lower respiratory infection odds (OR 1.216; 95% CI 1.048–1.411) [43]. In the worldwide WAO series, 34% of centres reported delays exceeding 24 months between first symptoms and diagnosis, and 39% lacked genetic testing [36]. In an international survey of 88 adults and 65 children with agammaglobulinaemia, early-diagnosed patients reported fewer severe infections and admissions and quality of life similar to the general population, whereas late diagnosis was associated with poorer quality of life [44].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

The 2025 US practice parameter recommends diagnosing agammaglobulinaemia in patients with low or undetectable serum immunoglobulins, low or undetectable circulating B cells and normal CD3+ T-cell numbers (strong recommendation, high certainty) [6]. Agammaglobulinaemia typically involves IgG below 100 mg/dL, low or undetectable IgM and IgA and CD19+ B cells below 2%; specific antibody titre measurement is unnecessary when IgG is below 150 mg/dL [6]. The 2015 parameter specified IgM below 20 mg/dL and IgA below 10 mg/dL [29]. GeneReviews describes IgG typically below 200 mg/dL (2 g/L), mostly between 100 and 200 mg/dL with approximately 10% above 200 mg/dL, IgM and IgA typically below 20 mg/dL, and CD19+ cells below 1% [1]. IgM warrants attention: low IgG and IgA occur in constitutional delay of immunoglobulin production, but low IgM with reduced IgA and IgG is almost always associated with immunodeficiency [1].

The European Society for Immunodeficiencies (ESID) registry working criteria for probable clinical agammaglobulinaemia require circulating B cells (CD19 and CD20) below 2%, preferably on two measurements, with normal T-cell numbers (CD3, CD4, CD8); and serum IgG below 200 mg/dL in infants under 12 months or below 500 mg/dL over 12 months, or normal IgG with IgA and IgM below 2 standard deviations; and recurrent infection onset before age 5 or maternal family history of agammaglobulinaemia [45]. For agammaglobulinaemia with normal B cells, ESID suggests unclassified antibody deficiency [45].

Table 4. Agammaglobulinaemia criteria and laboratory thresholds across sources.

XLA diagnosis is established in a male proband with suggestive findings and a hemizygous pathogenic or likely pathogenic BTK variant, or a female proband with suggestive findings and a heterozygous BTK variant [1]. A variant of uncertain significance (VUS) neither establishes nor excludes diagnosis [1]. XLA patients do not produce antibodies to vaccine antigens (tetanus, H. influenzae, pneumococcus) or specific antibodies following SARS-CoV-2 vaccination, but retain normal cellular responses [1]. Serum immunoglobulins are uninformative in newborns or infants because of maternal IgG; B-cell percentage and molecular testing are informative [1].

5.2. BTK protein

Absent BTK protein in monocytes or platelets can be demonstrated by Western blot or flow cytometry [6, 29]. Direct sequencing may be necessary when missense variants permit normal expression of non-functional protein [29]. An intracellular monocyte BTK flow assay validated against 40 patients with pathogenic variants detected abnormal expression in 38 (95% sensitivity and 100% specificity at the selected cut-off), and was proposed as rapid support when genetic results are pending or inconclusive and for carrier evaluation [46]. Normal BTK in a boy with agammaglobulinaemia increases the likelihood of an autosomal form without proving it [3].

5.3. Genetic tests and limitations

GeneReviews proposes targeted testing (BTK sequencing followed by gene-targeted deletion/duplication analysis, or a multigene panel) or comprehensive genomic testing (exome or genome) [1]. Table 5 summarises methods' yields for pathogenic BTK variants.

Table 5. Yield and limitations of molecular tests for BTK.

These percentages describe the distribution of pathogenic variants identifiable by each technique and are not equivalent to clinical sensitivity in a patient with a suggestive phenotype. The 2025 parameter recommends single-gene sequencing when a relative has a known defect or when massively parallel sequencing may not reliably analyse the gene, a panel or exome initially in other cases, genome testing with non-immunological features or suspected non-coding defects, copy number variant (CNV) investigation with suspected deletion, and American College of Medical Genetics and Genomics / Association for Molecular Pathology (ACMG/AMP) variant classification [6]. It also emphasises pre-test probability: in a male infant with agammaglobulinaemia and absent B cells, a BTK variant retains high post-test probability even if classified as VUS, whereas a benign or likely benign variant does not explain disease [6]. This supports further investigation (BTK protein, family studies) without converting a VUS into a pathogenic variant. GeneGuidance highlights two autosomal pitfalls: large IGHM deletions are frequent and sequencing alone may miss diagnosis; in IGLL1, neighbouring pseudogene IGLL3P can confuse short-read variant calling, and pseudogene-derived alleles are genuinely pathogenic [3, 17]. FNIP1 evaluation should include CNVs and uniparental disomy [27]. RNA analyses were required to interpret synonymous and splicing variants in BLNK [3]. A SPI1 nonsense variant missed by a targeted panel was identified only by exome, confirming that a negative panel does not exclude rare forms [3].

Reports should specify gene, versioned transcript (NM_000061.3 for BTK), HGVS (Human Genome Variation Society) coding DNA and protein nomenclature, zygosity (hemizygous, heterozygous, homozygous or compound heterozygous), ACMG/AMP classification and technical limitations (CNVs, intronic regions, mosaicism). For example, NM_000061.3:c.46C>T p.(Gln16Ter), the variant in section 10's case, was confirmed by VariantValidator as NC_000023.11:g.101375239G>A (GRCh38) and recorded as pathogenic in ClinVar (VCV000523855) [5, 47]; NM_000061.3:c.1573C>T p.(Arg525Ter), detected in a Dutch screening study patient, corresponds to NC_000023.11:g.101354688G>A and is pathogenic in ClinVar (VCV000279714) [5, 8, 47].

5.4. Diagnostic algorithm

1. Clinical suspicion (Table 3) → full blood count with differential, IgG, IgA, IgM and lymphocyte immunophenotyping (CD3, CD4, CD8, CD19/CD20, CD16/56), excluding secondary causes [6, 22].
2. Immunoglobulins in the agammaglobulinaemic range + CD19+ <2% + normal T cells → agammaglobulinaemia diagnosis [6, 45].
3. Boy: BTK protein by flow cytometry (if available) and BTK sequencing with deletion/duplication analysis; if hearing loss, CMA first [1, 6].
4. Negative BTK, female sex or consanguinity: IEI panel or exome including Table 1 genes and CNVs; if negative with persistent suspicion, genome or RNA [1, 6, 12].
5. Start immunoglobulin without awaiting genetic results once the immune phenotype is established; first collect baseline immunoglobulins and vaccine titres [1, 3].
6. Initial postdiagnostic assessment: full blood count, C-reactive protein, immunoglobulins and baseline titres, chest and paranasal sinus radiographs, lung function tests if the child can cooperate, and genetic counselling [1].

5.5. KREC newborn screening

KRECs are episomal DNA circles formed during V(D)J recombination of the IGK locus; they do not replicate and indirectly mark bone marrow B-cell production. XLA and other agammaglobulinaemias lacking peripheral B cells can therefore be identified through low or absent dried-blood KRECs [8]. They are measured at low cost alongside T-cell receptor excision circles (TRECs) used for severe combined immunodeficiency screening [8]. The 2025 US parameter recommends TREC screening (strong recommendation) and states in the text that KREC quantification “may be adopted” to identify other IEIs, without formally recommending it [6].

Table 6. KREC newborn screening experience in agammaglobulinaemia.

Known false-positive causes include prematurity, maternal immunosuppression during pregnancy, transfusion, syndromes such as Jacobsen, Wiskott–Aldrich or dyskeratosis congenita, and transient B-cell lymphopenia [8, 48]. In an Italian series of 18 term newborns with isolated low KRECs and confirmed B-cell lymphopenia (CD19+ ≤2%), repeat dried-blood testing already showed above-threshold KRECs in 78%; all normalised B cells around 50 days, without complications over 39.5 person-years. The authors propose repeating KREC before referral [50]. In Russia, analysis of 66 confirmed agammaglobulinaemia patients and 534 false positives proposed a three-step algorithm with thresholds of 100, 250 and 850 copies per 10⁵ cells to improve classical and atypical XLA detection without increasing unnecessary referrals [51]. Intrinsic limitations include missed hypomorphic BTK variants with detectable KRECs and failure of exon NGS to detect deep intronic, copy number and structural variants; Dutch authors therefore propose a “safety net” using immunophenotyping for newborns with the lowest KRECs [8, 10]. A 2026 economic analysis concluded that adding KREC to existing programmes is probably cost-effective [52]; the first international KREC consortium meeting (Tampa, February 2026) prioritised method and reporting harmonisation, false-positive reduction and follow-up pathways [53].

6. Differential Diagnosis

XLA is the most common agammaglobulinaemia cause, accounting for approximately 85% of patients with early infections, panhypogammaglobulinaemia and CD19+ B cells below 2% [1]. Autosomal forms cannot be distinguished by routine clinical or laboratory tests and should be considered in girls with XLA phenotypes, boys without BTK variants and consanguineous families [1]. Severe CVID may produce immunoglobulin and B-cell levels in the agammaglobulinaemic range, making distinction difficult without molecular testing [6, 29].

Table 7. Differential diagnosis of agammaglobulinaemias.

Hearing loss also requires differentiation: in a child with XLA it may result from recurrent otitis, but progressive sensorineural deafness with dystonia suggests contiguous-deletion Mohr–Tranebjærg syndrome [1, 12].

7. Treatments and Risk Management Strategies

7.1. Principles

GeneReviews notes that no XLA-specific clinical practice guidelines exist and that its recommendations reflect author experience [1]; formal guidance derives from general IEI and immunoglobulin therapy guidelines, including the US AAAAI/ACAAI/CIS 2025 parameter and British BSI/UKPIN 2022 consensus, and individual product labels [6, 54]. The 2015 parameter summarised three management pillars: antimicrobials, IgG replacement and attention to pulmonary status [29]. Autosomal forms receive the same treatment, extrapolated from immune phenotype rather than gene-specific evidence, with additional management of extra-immunological manifestations [3].

7.2. Immunoglobulin replacement

Immunoglobulin replacement is the foundation of treatment, delivered intravenously every 2–4 weeks or subcutaneously weekly [1]. The 2025 parameter recommends it for IEIs with IgG antibody deficiency (strong recommendation, high certainty), as continuous therapy (strong, low certainty), with an initial 400–600 mg/kg monthly dose (strong, moderate), adjusted subsequently to clinical efficacy and weight changes exceeding 5%. Serum IgG should remain above 800 mg/dL (strong, high), with route selected according to tolerance and patient preference (conditional, moderate) [6]. Low or absent IgA does not contraindicate replacement [6]. Most US XLA patients receive approximately 400 mg/kg every four weeks; both routes achieve therapeutic levels, no brand has shown superior efficacy or adverse effects, and stable patients do not require IgG measurement at every infusion [1].

Trough targets differ between sources for specific reasons. The BSI/UKPIN consensus explicitly includes XLA and autosomal recessive agammaglobulinaemia as confirmed indications, sets a target of at least 8 g/L (IV trough, any time for SC) for most primary immunodeficiencies, and recognises that XLA may require at least 10 g/L to minimise infections or progressive organ injury [54]. European summaries of product characteristics (SmPCs) specify troughs of at least 6 g/L or within the age-specific reference range, increasing doses if infections persist [55, 56]. The 2025 parameter supports an individual “biological trough”: with doses of 200–1,200 mg/kg/month, XLA patients required troughs of 800–1,300 mg/dL to remain infection-free. An IVIg meta-analysis found pneumonia incidence declined 27% per 100 mg/dL trough increase and was fivefold higher at 500 mg/dL than 1,000 mg/dL (0.113 versus 0.023 cases/patient-year), without benefit above 1,000 mg/dL [6]. In a French cohort of 31 children treated early with IVIg, median trough 700 mg/dL, bacterial infections requiring admission fell from 0.40 to 0.06/patient-year, but enteroviral meningoencephalitis occurred (one fatal), along with bronchiectasis in 6 of 23 assessed and chronic sinusitis in 20 of 23 [57]. In a multicentre European–US study of 81 XLA patients with COVID-19, pre-existing bronchiectasis and IgG troughs below 8 g/L were associated with admission [58].

Table 8. Immunoglobulin replacement doses and targets.

For IV-to-SC conversion, US labels use adjustment factors: weekly dose = previous IV dose (g) ÷ weeks between doses × 1.37 for Hizentra and Gammagard Liquid SC, and × 1.30 for Cuvitru [59–61]; the 2025 parameter reports recommendations of 1.35–1.53 times IV dose [6]. SC peaks occur 3–5 days after infusion and steady state after 4–6 months [6]. Recombinant human hyaluronidase-facilitated therapy (HyQvia®) permits up to fourfold greater volume per site and intervals of 3–4 weeks [6, 62]. SC may be preferable in children, pregnant women and patients with difficult venous access, with fewer systemic effects and improved quality of life through home administration, but requires autonomy, adherence and more punctures [6]. Central venous catheters solely for IVIg are not recommended [6]. The BSI/UKPIN consensus states that replacement should not normally be discontinued or subjected to annual need reassessment with definitive XLA or autosomal recessive agammaglobulinaemia [54]. The documented autosomal exception is IGLL1 deficiency, where two patients discontinued replacement without infections while maintaining immunoglobulins; this case-series observation requires surveillance and cannot be generalised [28].

7.3. Immunoglobulin products: US and EU labels

US indications are class-based (“primary humoral immunodeficiency”), explicitly including but not limited to congenital agammaglobulinaemia and XLA; autosomal agammaglobulinaemia with demonstrated humoral deficiency therefore falls within the approved indication [59, 60, 63]. Centralised EU SmPCs indicate replacement in “primary immunodeficiency syndromes with impaired antibody production” in adults, children and adolescents aged 0–18 [55, 56, 64].

Table 9. Examples of immunoglobulin products indicated for primary immunodeficiency. Non-exhaustive; several European products have national authorisations. Authorisation does not ensure reimbursement or availability in Portugal or Brazil, which were not verified.

μ-chain deficiency and other autosomal agammaglobulinaemias often manifest before two. In the USA, Gammagard Liquid, Hizentra, HyQvia or Cuvitru use below two falls outside the studied labelled age range and constitutes age-related off-label use requiring specialist judgement, whereas consulted European SmPCs cover paediatric use from birth [3, 55, 59, 60].

Table 10. Immunoglobulin registration trials in primary immunodeficiency.

These uncontrolled open-label trials involve mixed populations (predominantly CVID), with the regulatory objective of demonstrating fewer than one serious bacterial infection per patient-year. They cannot compare products or estimate XLA-specific efficacy; numerical rate differences reflect different designs, populations and periods [61–63]. Survival benefit evidence comes from registries: USIDNET patients receiving IgG had median survival of 51 years versus 16 in the 11 without recorded therapy (death hazard ratio 0.11), an observational comparison subject to era and selection biases [39].

7.4. Immunoglobulin adverse effects and management

Infusion effects (fever, chills, headache, myalgia, back pain, flushing, nausea, blood pressure changes, tachycardia, volume overload and, with SC, local reactions) occur in 5–15% of IV infusions, are usually mild and rate-dependent. Slowing or stopping infusion for 15–30 minutes reverses many; 34% of reactions recorded in an Immune Deficiency Foundation survey occurred with the first infusion of a product [6]. In XLA, reactions (headache, chills, back pain, nausea) are more likely with intercurrent viral infection or brand changes and may disappear over time [1]. Premedication (ibuprofen or paracetamol, antihistamine and/or hydrocortisone one hour beforehand) and hydration may prevent recurrence after an initial reaction [6]; the 2026 Spanish Delphi consensus recommended premedication only in selected high-risk patients and considered serial anti-IgA testing of limited utility [67]. Rare serious effects include renal injury (more frequent with sucrose-containing products, no longer marketed in the USA), thrombosis, aseptic meningitis, haemolytic anaemia (more frequent in groups A and AB), arrhythmia and transfusion-related acute lung injury [6]. All US immunoglobulin labels carry boxed thrombosis warnings, and IV products renal dysfunction warnings [59, 63]. In USIDNET, headache was the most frequent reaction, with anaphylaxis in two patients and thrombosis, renal dysfunction and aseptic meningitis in one each [39]. Products are not interchangeable and switching should involve the prescriber, although among 802 shortage-related switches in 2017–2018 only 12 caused reactions, none requiring admission [6]. Privigen and Hizentra contain L-proline and are contraindicated in hyperprolinaemia [59, 63].

7.5. Infection treatment and prevention

Acute infections should be treated promptly for at least twice the duration used in healthy individuals [1]; the 2025 parameter suggests immediate diagnostic testing and longer antimicrobial regimens than in immunocompetent individuals (conditional, low certainty) [6]. Some centres use antibiotic prophylaxis: GeneReviews names amoxicillin–clavulanic acid, co-trimoxazole (sulfamethoxazole–trimethoprim), or ciprofloxacin as a third option, without doses [1]. The 2025 parameter recommends considering prophylaxis when bacterial infections persist despite optimised immunoglobulin dosing, with azithromycin preferred in chronic lung disease after excluding non-tuberculous mycobacterial infection [6]. Its Table 9A gives azithromycin 5 mg/kg/day (maximum 250 mg/day) or 500 mg three days weekly, with amoxicillin or co-trimoxazole alternatives (conditional recommendation, low certainty); the randomised trial in adults with primary antibody deficiency and chronic lung disease used 250 mg three days weekly [6]. This prophylaxis is off-label, supported by the cited guideline, and azithromycin requires QTc monitoring [6]. In XLA, azithromycin also covers some Campylobacter, Helicobacter and Mycoplasma species causing disseminated infections [6]. Non-pylori Helicobacter skin infections require at least six weeks of susceptibility-guided antibiotics [12]. In USIDNET, 24% received prophylaxis without a demonstrated association with fewer infections [39]. Safe drinking water, avoidance of stream and lake water, and hand hygiene reduce giardiasis and Campylobacter risk [6]. Isolated antibody deficiencies do not usually require antibiotic prophylaxis for invasive dental procedures [6].

Enteroviral meningoencephalitis has been treated with high-dose IV immunoglobulin (troughs above 1,000 mg/dL), preferentially using batches with high titres against the virus, and one cure with intraventricular immunoglobulin was reported [29]. Failure remains common, and anti-enteroviral drugs are under development [42]. Lung transplantation achieved initial success in a few end-stage pulmonary cases, experience too limited to generalise [29]; USIDNET also recorded two liver transplants for cirrhosis and portal hypertension [39].

7.6. Vaccination

Live vaccines are contraindicated in antibody deficiencies: all live viral vaccines, live attenuated influenza vaccine, dengue vaccine and live bacterial vaccines (BCG, oral typhoid) [6]. Oral poliovirus vaccine should be avoided in patients, siblings and household contacts, who should receive inactivated vaccine [1, 6]. Contacts may receive other scheduled live vaccines except oral poliovirus and ACAM2000 (mpox/smallpox); after an infant household member receives oral rotavirus vaccine, handwashing after nappy changes is recommended for one month [6]. Non-live vaccines are recommended: they do not induce protective antibodies but probably produce cellular responses [1]. The 2025 parameter recommends COVID-19 vaccination with boosters in patients receiving replacement, human papillomavirus vaccination from 9 to 45 years (three doses), and recombinant zoster subunit vaccine in adults with IEI retaining CD4+ T-cell function [6]. IVIg recipients are probably protected against varicella if infused within three weeks before exposure [6]. The European Privigen SmPC specifies, after measles exposure in primary immunodeficiency receiving regular IVIg, an additional 0.4 g/kg within 6 days; with future exposure risk and maintenance below 0.53 g/kg every 3–4 weeks, a single increase to 0.53 g/kg [55]. Serology cannot assess immunity or previous infection in these patients [3].

7.7. Haematopoietic stem cell transplantation

GeneReviews considers haematopoietic stem cell transplantation (HSCT) non-standard in XLA because of its risks [1]. An international survey of 22 transplant recipients (16 for recurrent or life-threatening infections, 3 for malignancy, 3 for other complications), receiving myeloablative (4), reduced-toxicity myeloablative (10) or reduced-intensity (8) conditioning, found 95% engraftment, 86% overall and 77% event-free survival at 2 years, complete or stable mixed chimerism in 95%, and immunoglobulin discontinuation one year after HSCT in 89% [7]. The 2025 review recommends reduced-intensity regimens (e.g. fludarabine-based), considering HSCT salvage treatment for severe infections, haematological malignancies or other lethal complications, and relatively indicated when replacement is difficult to maintain [12]. A US cost–utility analysis estimated lifetime immunoglobulin costs of $1,512,946 versus $563,776 (matched sibling donor) and $637,036 (unrelated donor), with similar quality-adjusted life-years. However, immunoglobulin prevented at least 2,488 premature deaths per 10,000 microsimulations; below $29,469 annually, it became the cost-effective strategy [68]. Recent reports describe successful HSCT for chronic norovirus with intestinal failure [37], refractory Campylobacter/norovirus enteropathy in an adult [69], and disseminated Helicobacter bilis infection [35]. Autosomal data are sparse: the two most severe SLC39A7 patients underwent transplantation, curing immune abnormalities and improving dermatosis [3].

7.8. Investigational therapies and developments over the last 12 months

No gene therapy is approved for XLA. A 2025 preclinical targeted-editing model (CRISPR-Cas9 with recombinant AAV6 vector) inserts BTK complementary DNA into its endogenous locus; mice transplanted with corrected progenitors showed high engraftment, increased B cells and immunoglobulins, greater BCR diversity and specific antibody production after immunisation [70]. The same year, cell-penetrating-peptide-conjugated splice-modulating oligonucleotides targeting a BTK pseudoexon partially restored the B lineage in a murine model [71]. In BLNK deficiency, ex vivo correction of one patient's progenitors transplanted into immunodeficient mice restored B-cell differentiation, a proof of concept without an identified human trial [3]. ClinicalTrials.gov searches on 6 October 2026 (condition “agammaglobulinemia” and terms “X-linked agammaglobulinemia” and “BTK gene therapy”) identified no XLA gene therapy or gene-editing trials; registered condition-specific trials primarily studied immunoglobulin products, including an ongoing non-recruiting phase 3 paediatric trial of Kedrion 10% IVIg (NCT04944979) [72]. This negative search does not establish absence of unregistered programmes.

Table 11. Investigational therapies and recent developments.

7.9. Particularities of autosomal forms

Management follows congenital agammaglobulinaemia care, with immunoglobulin, early infection treatment and live vaccine avoidance [3, 29]. Additional measures include cardiological assessment and follow-up (hypertrophic cardiomyopathy and pre-excitation) and neutropenia surveillance in FNIP1 deficiency [3, 27]; dermatological and nutritional treatment and consideration of HSCT in severe SLC39A7 deficiency, without zinc supplementation because the defect concerns intracellular redistribution and no source supports supplementation [3]; orthopaedic, urological and craniofacial assessment in Hoffman syndrome [3]; and deciding replacement initiation in TCF3 haploinsufficiency on clinical and immunological findings rather than genotype alone, given incomplete penetrance [3, 32].

8. Reproductive Options and Family Counselling

8.1. XLA: risks to relatives

By definition, XLA follows X-linked inheritance [1]. An affected boy's father is neither affected nor hemizygous and requires no investigation [1]. With more than one affected family member, the mother is an obligate heterozygote; if she has multiple affected sons without other affected relatives and the variant is absent from leucocyte DNA, gonadal mosaicism is most likely [1]. Approximately 50% of affected boys are isolated (simplex) cases; the mother may be heterozygous, the proband's variant may be de novo, or maternal somatic or gonadal mosaicism may be present [1]. In approximately 80–85% of families the mother is heterozygous, and approximately 15–20% of affected individuals have de novo variants. The Oxford Desk Reference adds that most new mutations arise in the maternal grandfather, maternal grandmothers are carriers in fewer than 20% of isolated cases, and carrier risk is therefore below 10% for a woman whose sister has an XLA son without other family history [1, 22]. Maternal molecular testing is recommended [1].

Table 12. XLA recurrence risks.

Carrier detection requires the known familial variant or, if the affected individual is unavailable, sequencing followed by deletion/duplication analysis [1]. Documented maternal gonadal mosaicism explains residual risk even when maternal blood testing is negative [1]. BTK flow cytometry has been proposed to support carrier assessment [46].

8.2. Autosomal forms

In recessive forms (IGHM, IGLL1, CD79A, CD79B, BLNK, PIK3R1, SLC39A7, FNIP1), each affected person's sibling has a 25% risk of being affected, and consanguinity makes these forms more likely than XLA [1]. SLC39A7 heterozygotes had normal immune function and require no immunological follow-up [3]. Dominant-form counselling depends on mechanism: TCF3 p.Glu555Lys was de novo in all four reported patients [23]; TCF3 haploinsufficiency and PU.1 deficiency have incomplete penetrance (estimated 81.8% for SPI1) and variable expressivity, including adult onset [32, 33]. Gene identification changes which relatives require investigation and recurrence risk, making molecular diagnosis necessary even when immediate treatment is unchanged [3].

8.3. Prenatal and preimplantation diagnosis

Once the familial variant is identified, prenatal diagnosis and preimplantation genetic testing are possible; counselling is ideally offered before pregnancy to affected, carrier or at-risk young adults [1]. Mutation analysis is generally possible in chorionic villi when the proband's variant is known; when diagnosis is secure but the variant undefined, prenatal linkage analysis may be possible [22]. Professional and family perspectives vary, and the decision is personal [1]. In an Italian multicentre cohort of 53 XLA adults, 52 mothers and 33 sisters, all sisters received genetic counselling, 40% chose carrier testing and 60% of these underwent invasive prenatal diagnosis. There were 9 XLA diagnoses overall, including 6 live births, and several carriers continued pregnancies after affected-fetus diagnosis or declined testing [73].

8.4. At-risk relatives and newborns

At-risk male relatives' genetic status should be established as soon as possible after birth to initiate immunoglobulin and avoid live vaccines; B-cell percentage and lymphoid tissue examination may be added, but serum immunoglobulins are uninformative because of maternal IgG [1]. In the 2006 US registry, only 34.5% with family history known at birth were diagnosed before symptoms [38]. Without prenatal diagnosis, cord blood should be sent for immunophenotyping, preferably planned beforehand with obstetrics and the immunology laboratory [22]. Affected children's siblings should receive inactivated poliovirus vaccine [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

GeneReviews estimates XLA prevalence at approximately 3–6 per 1,000,000 males across all racial and ethnic groups [1]. Orphanet records validated worldwide point prevalence for XLA (ORPHA:47) of 0.22/100,000, with validated European national figures ranging from 0.03/100,000 (Germany, Romania) to 0.25/100,000 (North Macedonia), including 0.21 in Italy, 0.18 France, 0.08 United Kingdom and 0.06 Spain; US birth prevalence is 0.26/100,000 and point prevalence 0.07/100,000 [2]. European registry figures measure diagnosed patients, not true incidence. The 2006 US registry estimated a birth rate of 1/379,000 during 1988–1997 [38]. Newborn screening, identifying patients before clinical selection, found higher figures: XLA in 1/146,804 Russian live births (0.68/100,000; 95% CI 0.39–1.11) and overall agammaglobulinaemia in 1/86,290 in Japan; the Czech pilot increased estimated agammaglobulinaemia incidence sixfold [9, 10, 49]. GeneGuidance's IGHM curation expresses Orphanet worldwide prevalence as 0.22 per 1,000,000; the correct Orphanet field unit is per 100,000 (class 1–9/1,000,000), correctly used by GeneGuidance in other entries [2, 3].

For autosomal forms, Orphanet records approximately 100 published non-syndromic autosomal agammaglobulinaemia cases, with an unvalidated European prevalence class below 1/1,000,000 [2]. KREC screening changed understanding of IGLL1: pooled biallelic genotype incidence of 1.3/100,000 in Austria, Czechia and Switzerland, almost twice XLA, and 1.32/100,000 in Russia, with many mild or transient cases [10, 28]. These figures measure genotypes in screened newborns, not clinically significant disease.

9.2. Regional and population differences

In the WAO survey of 40 centres in 32 countries (783 patients), survival beyond 20 exceeded 75% in Australia and Europe, and was 75% in North America, 72% South America, 39% Asia and 22% Africa [36]. Vaccine-associated paralytic poliomyelitis (12 cases) occurred only in countries using oral vaccine, with one European and no North American case. Enteroviral meningoencephalitis occurred in 10.7% of South American, 0.54% European and 0% North American patients; arthritis was more frequent in Europe (17.2%), particularly Russia; mycobacterial infections were reported in Argentina and India [36]. Immunoglobulin access was the principal problem reported by centres (16% of responses), and only 61% had SC access [36]. USIDNET included 72.5% white, 11.2% black and 9.8% Hispanic patients, proportions differing from the US census; available data showed no differences between white and non-white patients in diagnostic age, treatment initiation or survival [39].

Portugal participated in WAO through one Lisbon centre; analysis of published series includes a Portuguese series of 9 patients, with median presentation at 13 months and diagnosis at 3.4 years, infection as presentation in 89%, Giardia in 33%, neutropenia in 33%, septic arthritis in 22%, chronic lung disease in 22% and no deaths [36]. Brazil participated through two centres [36]; a 2026 systematic review of next-generation sequencing in Brazilian IEI identified SCID and XLA as the most frequently reported diagnoses, with studies concentrated in the Southeast, Northeast and South and none from the North [74]. A Colombian cohort of 38 patients (2026), with median diagnosis at 16 months, 53% novel variants, bronchiectasis in 34.2% and eight-year survival 71.1%, illustrates Latin American structural sequelae [41]. These hospital series cannot estimate national prevalence. No BTK founder effects were identified in consulted sources; recurrent alternative IGHM splicing site variation occurred across at least three haplotypes, indicating a mutational hotspot rather than founder effect [30]. In SLC39A7 deficiency, patient ethnicity matched the population in which each variant had been described [3].

9.3. Special populations

In women with the phenotype, autosomal forms are more likely than skewed-X-inactivation XLA [1]. During pregnancy in an autosomal agammaglobulinaemia patient receiving replacement, the 2025 parameter recommends more frequent (monthly) IgG monitoring and mentions SC as preferable in pregnant women [6]; the US Privigen label notes absence of human fetal-risk data and increasing placental immunoglobulin transfer after 30 weeks [63]. WAO centres identified adult-care transition as a challenge [36].

9.4. Networks and organisations

The relevant European Reference Network is ERN RITA (European Reference Network on Rare Immunological Disorders) [11]. ESID and US USIDNET registries collect patient data; GeneReviews lists ImmUnity Canada, Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center, ESID and USIDNET as resources [1]. The Oxford Desk Reference cites PID UK as a British support group [22]. International patient organisation IPOPI and the Immune Deficiency Foundation, supporting USIDNET, are active in this area [39, 75]. No specific Portuguese or Brazilian organisations were identified in consulted sources; this does not demonstrate their absence.

10. Illustrative Clinical Case

Lee and colleagues at the US National Institutes of Health published two cases of disseminated non-pylori Helicobacter infection in XLA in 2026; the first illustrates treated natural history and the current role of HSCT [35]. A young US patient with BTK c.46C>T p.(Gln16Ter) (NM_000061.3; ClinVar pathogenic, VCV000523855) was diagnosed at one year and maintained on immunoglobulin replacement; he had recurrent sinopulmonary infections and biopsy-confirmed hepatic nodular regenerative hyperplasia [5, 35, 47]. At 14, an erythematous plaque appeared on the right leg, followed the next year by the contralateral leg; at 16, erythema, oedema and pain worsened, particularly at the left ankle, with fever after methotrexate prescribed for suspected localised scleroderma [35]. At 17, MRI showed soft-tissue oedema; skin-biopsy review with Steiner staining revealed filamentous bacteria in subcutaneous tissue, plasma cell-free DNA sequencing detected Helicobacter, and blood cultures confirmed Helicobacter bilis [35].

Despite more than 40 days of doxycycline and levofloxacin, with low minimum inhibitory concentrations, blood cultures remained positive (growth on day 12), stool cultures also isolated H. bilis, and minimum inhibitory concentrations increased [35]. Meropenem and doxycycline, followed by tinidazole, produced improvement; stopping meropenem after one year caused relapse with osteomyelitis within six weeks. At 20, new osteomyelitis foci emerged; after switching meropenem to ertapenem, recurrent bacteraemia and right tibial osteomyelitis occurred, and added gentamicin caused ototoxicity [35]. Oral ciprofloxacin, tinidazole, nitazoxanide, rifampicin and subsequently omadacycline rendered blood cultures negative [35]. Article Figure 1A (PubMed Central figure; image) presents an age-based timeline, photographs of erythematous–violaceous leg plaques, MRI STIR hyperintensity and successive antimicrobial bars, from lesion onset (14–16 years) to HSCT (23 years 3 months), all-antimicrobial withdrawal (24 years 5 months) and sustained clinical cure at 25; minimum inhibitory concentrations appear in Table 1 [35].

At 23, with infection refractory to prolonged multidrug therapy, he underwent allogeneic bone marrow HSCT from an HLA-identical non-carrier sister using reduced-intensity conditioning, continuing four antimicrobials during transplantation (rifampicin stopped for interactions) [35]. Infection did not flare; monthly immunoglobulin was stopped one year after HSCT, CD19+ cells normalised with class-switched memory B-cell emergence, and all antibiotics stopped at 14 months after seven consecutive years of treatment; he remained infection-free at 21 months post-transplantation [35]. The second patient, with disseminated Helicobacter cinaedi and c.1844_1851del p.(Arg615GlnfsTer19), responded to meropenem, ciprofloxacin and doxycycline and was being assessed for HSCT [35].

The case demonstrates that replacing only IgG does not correct mucosal defence or prevent non-pylori Helicobacter infection; chronic skin lesions in XLA require targeted investigation (prolonged blood cultures, silver staining, molecular methods) before attribution to inflammatory disease; and HSCT may be considered for refractory infection [12, 35]. These approaches reflect a reference centre's management of two patients and are not routine recommendations; the 2025 review retains immunoglobulin replacement as standard and HSCT as salvage therapy [12].

11. Prognosis and Long-Term Follow-up

11.1. Survival and morbidity

Prognosis has improved markedly over recent decades; most patients lead normal lives, but approximately 10% have significant infections despite adequate therapy and many develop chronic pulmonary abnormalities [1]. Long-term prognosis in primary antibody deficiency should be favourable with timely diagnosis, optimal treatment and surveillance; chronic lung disease with bronchiectasis continues when diagnosis is late, replacement inadequate or intercurrent infections insufficiently treated [22]. Enteroviral meningoencephalitis became less frequent with higher immunoglobulin doses [22].

Table 13. Long-term outcomes in XLA cohorts.

In the Italian cohort, regular replacement reduced invasive infections but did not appear to influence chronic lung disease development [40]. Quality of life approaches the general population without bronchiectasis: a British study found PedsQL scores and SF-36v2 physical component comparable to UK norms, but significantly poorer physical scores with bronchiectasis (47.88 versus 55.14) [76]. In a 2006 survey, 36 of 41 adults worked or studied full-time and had quality of life equivalent to the US male population, although 13 reported chronic lung disease [77]. The 2025 parameter recommends validated quality-of-life instruments, including disease-specific measures, and assessment of fatigue and perceived health at each visit [6].

11.2. Follow-up

Table 14. Recommended surveillance in XLA and agammaglobulinaemias.

Patients should receive follow-up at an experienced centre and with a clinical immunologist [1, 22]. The 2025 parameter suggests specialist clinical immunology consultation and multidisciplinary care, and recommends differential full blood counts, organ assessment, malignancy screening and mental health screening in IEI [6].

12. Summary and Final Considerations

X-linked agammaglobulinaemia, described by Bruton in 1952 and attributed to BTK in 1993, results from Bruton's tyrosine kinase loss of function and B-cell developmental arrest between pro-B and pre-B stages, with absent peripheral B cells and all immunoglobulin classes [1, 13–15]. It accounts for approximately 85% of congenital agammaglobulinaemias; other recessive (IGHM, IGLL1, CD79A, CD79B, BLNK, PIK3R1, PIK3CD, SLC39A7, FNIP1) and dominant (TCF3, SPI1, TOP2B) forms cannot be distinguished routinely and require molecular diagnosis to define recurrence risk [1, 4, 31]. Diagnosis rests on agammaglobulinaemic immunoglobulin levels, B cells below 2% and normal T cells, confirmed by BTK protein and BTK investigation including deletions and, when necessary, RNA or genome analysis, because sequencing detects 92% of pathogenic variants and exome misses deep intronic variants [1, 6, 45]. KREC newborn screening, already integrated into national programmes, advances diagnosis and revealed IGLL1 deficiency frequency, with false positives due to prematurity, maternal immunosuppression and transient B-cell lymphopenia, and potential failure to identify hypomorphic variants [8, 10, 48, 50].

Treatment comprises lifelong continuous immunoglobulin replacement, initially 400–600 mg/kg/month and adjusted to the biological trough, with targets ranging from the European regulatory minimum of 6 g/L through the US parameter's 800 mg/dL to the British consensus's 10 g/L for XLA [6, 54, 55]. Additional measures are early prolonged antibiotics, selected off-label antibiotic prophylaxis, live vaccine avoidance in patients and oral poliovirus avoidance in contacts, and pulmonary, gastrointestinal and neurological surveillance [1, 6]. Despite improved survival, chronic lung disease, enteroviral and Helicobacter infections, neurodegeneration, nephritis and gastrointestinal and haematological malignancies persist [12, 40]. Allogeneic HSCT, with 86% two-year survival and 89% immunoglobulin discontinuation in an international series, is a salvage option for severe complications; gene editing remains preclinical, with no identified registered human trial in October 2026 [7, 70, 72].

13. Bibliographic References

1. Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. In: GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published 5 April 2001; complete update 27 June 2024. NBK1453.
2. Orphanet. Orphadata epidemiology file (en_product9_prev, version dated 23 June 2026): ORPHA:47 (X-linked agammaglobulinemia), ORPHA:33110, ORPHA:229717, ORPHA:183669 and ORPHA:567502 [Internet]. [https://www.orphadata.com/data/xml/en_product9_prev.xml](https://www.orphadata.com/data/xml/en_product9_prev.xml). Accessed 6 October 2026.
3. GeneGuidance. Gene-level curation of BTK, IGHM, CD79A, CD79B, BLNK, IGLL1, PIK3R1, TCF3, LRRC8A, SLC39A7, FNIP1, SPI1 and TOP2B (version of 26 September 2026), with the cited primary references (including Lopez Granados 2002, PMID:12370281; Anzilotti 2019, PMID:30718914; Saettini 2021, PMID:32905580; Knox 2025, PMID:39854693; Boast 2023, PMID:37277074; Cepni 2023, PMID:37068767). User database; accessed 6 October 2026.
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.
5. VariantValidator (version 4.0.1). Validation of NM_000061.3:c.46C>T and NM_000061.3:c.1573C>T on GRCh38 with MANE Select transcript [Internet]. [https://variantvalidator.org](https://variantvalidator.org). Accessed 6 October 2026.
6. 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.
7. Nishimura A, Uppuluri R, Raj R, Swaminathan VV, Cheng Y, Abu-Arja RF, et al. An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia. J Clin Immunol. 2023;43(8):1827-39. doi:10.1007/s10875-023-01551-2. PMID:37454339.
8. Blom M, Duintjer AJ, Pico-Knijnenburg I, Imholz S, Balkassmi S, van Duyvenvoorde HA, et al. Next-generation Sequencing and Other Second Tier Tests in Newborn Screening for (X-linked) Agammaglobulinemia. J Clin Immunol. 2025;45(1):154. doi:10.1007/s10875-025-01927-6. PMID:41203922.
9. Nishinosono T, Muramatsu H, Wakamatsu M, Ishige N, Hanai J, Imaizumi T, et al. Nationwide TREC/KREC-based newborn screening and clinical outcomes in Japan. J Hum Immun. 2026;2(5):e20260083. doi:10.70962/jhi.20260083. PMID:42662969.
10. Marakhonov A, Mukhina A, Efimova I, Balinova N, Ampleeva M, Bobreshova A, et al. First 2-year experience of nationwide newborn screening for severe forms of T and B cell immunodeficiency: 2.3 million newborns analyzed using TREC and KREC in Russia. Front Immunol. 2026;17:1742811. doi:10.3389/fimmu.2026.1742811. PMID:41727503.
11. European Reference Network on Rare Immunological Disorders (ERN RITA). Institutional page [Internet]. [https://ern-rita.org/](https://ern-rita.org/). Accessed 6 October 2026.
12. Kanegane H, Tanita K, Nishimura M, Tomomasa D, Inoue K, Kanamori T, et al. Revisiting X-linked agammaglobulinemia. J Hum Immun. 2025;1(1):e20250020. doi:10.70962/jhi.20250020. PMID:42170232.
13. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722-8. PMID:14929630.
14. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993;72(2):279-90. doi:10.1016/0092-8674(93)90667-f. PMID:8425221.
15. Vetrie D, Vorechovský I, Sideras P, Holland J, Davies A, Flinter F, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361(6409):226-33. doi:10.1038/361226a0. PMID:8380905.
16. Yel L, Minegishi Y, Coustan-Smith E, Buckley RH, Trübel H, Pachman LM, et al. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N Engl J Med. 1996;335(20):1486-93. doi:10.1056/NEJM199611143352003. PMID:8890099.
17. Minegishi Y, Coustan-Smith E, Wang YH, Cooper MD, Campana D, Conley ME. Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia. J Exp Med. 1998;187(1):71-7. doi:10.1084/jem.187.1.71. PMID:9419212.
18. Minegishi Y, Coustan-Smith E, Rapalus L, Ersoy F, Campana D, Conley ME. Mutations in Igalpha (CD79a) result in a complete block in B-cell development. J Clin Invest. 1999;104(8):1115-21. doi:10.1172/JCI7696. PMID:10525050.
19. Minegishi Y, Rohrer J, Coustan-Smith E, Lederman HM, Pappu R, Campana D, et al. An essential role for BLNK in human B cell development. Science. 1999;286(5446):1954-7. doi:10.1126/science.286.5446.1954. PMID:10583958.
20. Ferrari S, Lougaris V, Caraffi S, Zuntini R, Yang J, Soresina A, et al. Mutations of the Igbeta gene cause agammaglobulinemia in man. J Exp Med. 2007;204(9):2047-51. doi:10.1084/jem.20070264. PMID:17709424.
21. Conley ME, Dobbs AK, Quintana AM, Bosompem A, Wang YD, Coustan-Smith E, et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J Exp Med. 2012;209(3):463-70. doi:10.1084/jem.20112533. PMID:22351933.
22. Firth HV, Hurst JA. Immunodeficiency and recurrent infection. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 464–71.
23. Boisson B, Wang YD, Bosompem A, Ma CS, Lim A, Kochetkov T, et al. A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells. J Clin Invest. 2013;123(11):4781-5. doi:10.1172/JCI71927. PMID:24216514.
24. Le Coz C, Nguyen DN, Su C, Nolan BE, Albrecht AV, Xhani S, et al. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. J Exp Med. 2021;218(7):e20201750. doi:10.1084/jem.20201750. PMID:33951726.
25. Broderick L, Yost S, Li D, McGeough MD, Booshehri LM, Guaderrama M, et al. Mutations in topoisomerase IIβ result in a B cell immunodeficiency. Nat Commun. 2019;10(1):3644. doi:10.1038/s41467-019-11570-6. PMID:31409799.
26. Anzilotti C, Swan DJ, Boisson B, Deobagkar-Lele M, Oliveira C, Chabosseau P, et al. An essential role for the Zn2+ transporter ZIP7 in B cell development. Nat Immunol. 2019;20(3):350-61. doi:10.1038/s41590-018-0295-8. PMID:30718914.
27. Saettini F, Poli C, Vengoechea J, Bonanomi S, Orellana JC, Fazio G, et al. Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency. Blood. 2021;137(4):493-9. doi:10.1182/blood.2020006441. PMID:32905580.
28. Soomann M, Bily V, Elgizouli M, Kraemer D, Akgül G, von Bernuth H, et al. Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia. J Allergy Clin Immunol. 2024;154(5):1313-1324.e7. doi:10.1016/j.jaci.2024.08.002. PMID:39147326.
29. Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-205.e1-78. doi:10.1016/j.jaci.2015.04.049. PMID:26371839.
30. Lopez Granados E, Porpiglia AS, Hogan MB, Matamoros N, Krasovec S, Pignata C, et al. Clinical and molecular analysis of patients with defects in micro heavy chain gene. J Clin Invest. 2002;110(7):1029-35. doi:10.1172/JCI15658. PMID:12370281.
31. Nieto-Patlán A, Ross J, Mohan S, Paczosa MK, Soliman R, Sarmento O, et al. Curation of gene-disease relationships in primary antibody deficiencies using the ClinGen validation framework. J Allergy Clin Immunol. 2025;155(5):1647-63. doi:10.1016/j.jaci.2025.01.005. PMID:39826876.
32. Boast B, Goel S, González-Granado LI, Niemela J, Stoddard J, Edwards ESJ, et al. TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies. J Allergy Clin Immunol. 2023;152(3):736-47. doi:10.1016/j.jaci.2023.05.017. PMID:37277074.
33. Knox AVC, Cominsky LY, Sun D, Cruz Cabrera E, Nolan BE, Ofray E, et al. One hundred thirty-four germ line PU.1 variants and the agammaglobulinemic patients carrying them. Blood. 2025;145(22):2549-60. doi:10.1182/blood.2024026683. PMID:39854693.
34. Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S, Fujisaki H, et al. A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest. 2003;112(11):1707-13. doi:10.1172/JCI18937. PMID:14660746.
35. Lee R, Arnold DE, Parta M, Pai SY, Dekker JP, Das S, et al. Pre- and peri-hematopoietic cell transplant management of disseminated non-Helicobacter pylori Helicobacter infection in X-linked agammaglobulinemia: Case series and literature review. Clin Immunol. 2026;284:110685. doi:10.1016/j.clim.2026.110685. PMID:41713716. PMCID:PMC13006914.
36. El-Sayed ZA, Abramova I, Aldave JC, Al-Herz W, Bezrodnik L, Boukari R, et al. X-linked agammaglobulinemia (XLA): Phenotype, diagnosis, and therapeutic challenges around the world. World Allergy Organ J. 2019;12(3):100018. doi:10.1016/j.waojou.2019.100018. PMID:30937141.
37. Shillitoe BMJ, Ponsford M, Slatter MA, Evans J, Struik S, Cosgrove M, et al. Haematopoietic Stem Cell Transplant for Norovirus-Induced Intestinal Failure in X-linked Agammaglobulinemia. J Clin Immunol. 2021;41(7):1574-81. doi:10.1007/s10875-021-01088-2. PMID:34164761.
38. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006;85(4):193-202. doi:10.1097/01.md.0000229482.27398.ad. PMID:16862044.
39. Hernandez-Trujillo V, Zhou C, Scalchunes C, Ochs HD, Sullivan KE, Cunningham-Rundles C, et al. A Registry Study of 240 Patients with X-Linked Agammaglobulinemia Living in the USA. J Clin Immunol. 2023;43(6):1468-77. doi:10.1007/s10875-023-01502-x. PMID:37219739.
40. Lougaris V, Soresina A, Baronio M, Montin D, Martino S, Signa S, et al. Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality. J Allergy Clin Immunol. 2020;146(2):429-37. doi:10.1016/j.jaci.2020.03.001. PMID:32169379.
41. Olaya Hernández M, Triviño Arias J, Arias Valderrama O, Cabrera Guarín V, Patiño JA, Pachajoa HM, et al. Clinical and genetic characterization of X-linked agammaglobulinemia in a Colombian cohort. World Allergy Organ J. 2026;19(9):101441. doi:10.1016/j.waojou.2026.101441. PMID:42733469.
42. Bearden D, Collett M, Quan PL, Costa-Carvalho BT, Sullivan KE. Enteroviruses in X-Linked Agammaglobulinemia: Update on Epidemiology and Therapy. J Allergy Clin Immunol Pract. 2016;4(6):1059-65. doi:10.1016/j.jaip.2015.12.015. PMID:26883540.
43. O'Toole D, Groth D, Wright H, Bonilla FA, Fuleihan RL, Cunningham-Rundles C, et al. X-Linked Agammaglobulinemia: Infection Frequency and Infection-Related Mortality in the USIDNET Registry. J Clin Immunol. 2022;42(4):827-36. doi:10.1007/s10875-022-01237-1. PMID:35288819.
44. Blom M, Duintjer AJ, Jamee M, de Gier M, Bloomfield M, Klocperk A, et al. Self-reported Clinical Outcomes and Quality of Life in Agammaglobulinemia: the Importance of an Early Diagnosis. J Clin Immunol. 2025;45(1):125. doi:10.1007/s10875-025-01904-z. PMID:40853601.
45. European Society for Immunodeficiencies (ESID) Registry Working Party. ESID Registry – Working definitions for clinical diagnosis of IEI: Agammaglobulinemia. November 2019 version, p. 4 [Internet]. [https://esid.org/wp-content/uploads/2023/09/ESID-Clin-Crit_omim_orpha_hpo_11_2019fin.pdf](https://esid.org/wp-content/uploads/2023/09/ESID-Clin-Crit_omim_orpha_hpo_11_2019fin.pdf). Accessed 6 October 2026.
46. Igonina M, Malakhova E, Fadeeva M, Vedmedskaia V, Shlyapnikov Y, Musaeva E, et al. Diagnostic workflow for X-linked agammaglobulinemia integrating BTK expression and B-cell maturation analysis by flow cytometry. Cytometry B Clin Cytom. 2026. doi:10.1002/cyto.b.70038. PMID:42116646.
47. National Center for Biotechnology Information. ClinVar: VCV000523855 (NM_000061.3(BTK):c.46C>T, p.Gln16Ter) and VCV000279714 (NM_000061.3(BTK):c.1573C>T, p.Arg525Ter) [Internet]. [https://www.ncbi.nlm.nih.gov/clinvar/variation/523855/](https://www.ncbi.nlm.nih.gov/clinvar/variation/523855/). Accessed 6 October 2026.
48. Soomann M, Prader S, Sluka S, Boucq C, Pachlopnik Schmid J, Trück J, et al. Five Years of Combined Newborn Screening Quantifying TREC and KREC in Switzerland. J Allergy Clin Immunol Pract. 2026;14(1):243-252.e2. doi:10.1016/j.jaip.2025.10.031. PMID:41177434.
49. Bloomfield M, Hlaváčková E, Schneiderová H, Turnovec M, Tichý L, Čech Z, et al. Beyond TREC: Pivotal role of tandem TREC/KREC assay in Czech SCID NBS pilot programme. Pediatr Allergy Immunol. 2025;36(5):e70100. doi:10.1111/pai.70100. PMID:40321024.
50. Valentina G, Enrico D, Caterina P, Silvia B, Francesca S, Monica T, et al. Transient B cell lymphopenia revealed by KRECs newborn screening: Post-screening referral strategies, clinical course, and follow-up. Pediatr Allergy Immunol. 2026;37(7):e70421. doi:10.1111/pai.70421. PMID:42411581.
51. Marakhonov A, Mukhina A, Efimova I, Balinova N, Rodina Y, Zinchenko R, et al. Optimizing Kappa-Deleting Recombination Excision Circles (KREC) Cut-Off Values in Russian Newborn Screening Program: Balancing Sensitivity and False-Positive Rates. Int J Neonatal Screen. 2026;12(3):68. doi:10.3390/ijns12030068. PMID:42647255.
52. Grunebaum E, Tenembaum V, Quinn J, Modell F, Somech R. The cost-benefit of newborn screening for X-linked agammaglobulinemia and related B-cell lymphopenia. Immunol Res. 2026;74(1):111. doi:10.1007/s12026-026-09842-7. PMID:42742808.
53. Suhet PR, Abbott J, Abraham RS, Baker MW, Boyarchuk O, Brigatti KW, et al. Exploiting KREC: Time for newborn screening and beyond—proceedings from the First International KREC Consortium Meeting. J Allergy Clin Immunol. 2026. doi:10.1016/j.jaci.2026.09.003. PMID:42753986.
54. 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.
55. European Medicines Agency. Privigen (human normal immunoglobulin, IVIg): summary of product characteristics, sections 4.1–4.2 [Internet]. EMEA/H/C/000831. [https://www.ema.europa.eu/en/medicines/human/EPAR/privigen](https://www.ema.europa.eu/en/medicines/human/EPAR/privigen). Accessed 6 October 2026.
56. European Medicines Agency. Hizentra (human normal immunoglobulin, SCIg): summary of product characteristics, sections 4.1–4.2 [Internet]. EMEA/H/C/002127. [https://www.ema.europa.eu/en/medicines/human/EPAR/hizentra](https://www.ema.europa.eu/en/medicines/human/EPAR/hizentra). Accessed 6 October 2026.
57. Quartier P, Debré M, De Blic J, de Sauverzac R, Sayegh N, Jabado N, et al. Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr. 1999;134(5):589-96. doi:10.1016/s0022-3476(99)70246-5. PMID:10228295.
58. Stenlander C, Lindahl H, Wahren-Borgström E, Geier CB, Sediva A, Fevang B, et al. Bronchiectasis, Low IgG Levels and Lack of Vaccination are Risk Factors for Covid-19 Hospitalization in X-linked Agammaglobulinemia - A Retrospective Multicenter Study. J Clin Immunol. 2025;45(1):161. doi:10.1007/s10875-025-01962-3. PMID:41240154.
59. CSL Behring. HIZENTRA (immune globulin subcutaneous [human], 20% liquid). Prescribing information. DailyMed setid 7b58f5ff-0316-49a3-b585-1f6003ddb953, version 26, effective 20 April 2023 [Internet]. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b58f5ff-0316-49a3-b585-1f6003ddb953](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b58f5ff-0316-49a3-b585-1f6003ddb953).
60. Takeda. GAMMAGARD LIQUID (immune globulin infusion [human]) 10%. Prescribing information. DailyMed setid 9d42adca-0dd7-4df7-864d-5a7feee52130, version 22, effective 10 December 2025 [Internet]. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d42adca-0dd7-4df7-864d-5a7feee52130](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9d42adca-0dd7-4df7-864d-5a7feee52130).
61. Takeda. CUVITRU (immune globulin subcutaneous [human]) 20%. Prescribing information. DailyMed setid 9aad7ec9-6097-4805-8f1b-898bec35f218, version 19, effective 25 November 2025 [Internet]. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9aad7ec9-6097-4805-8f1b-898bec35f218](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9aad7ec9-6097-4805-8f1b-898bec35f218).
62. Takeda. HYQVIA (immune globulin infusion 10% [human] with recombinant human hyaluronidase). Prescribing information. DailyMed setid 7ca2c26f-4be2-48cd-be5b-486e350654ba, version 23, effective 18 June 2026 [Internet]. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ca2c26f-4be2-48cd-be5b-486e350654ba](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7ca2c26f-4be2-48cd-be5b-486e350654ba).
63. CSL Behring. PRIVIGEN (immune globulin intravenous [human], 10% liquid). Prescribing information. DailyMed setid 7e5649da-75be-4a42-8eeb-4aeba562c401, version 29, effective 4 May 2026 [Internet]. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e5649da-75be-4a42-8eeb-4aeba562c401](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7e5649da-75be-4a42-8eeb-4aeba562c401).
64. European Medicines Agency. HyQvia (human normal immunoglobulin): summary of product characteristics, sections 4.1–4.2 [Internet]. EMEA/H/C/002491. [https://www.ema.europa.eu/en/medicines/human/EPAR/hyqvia](https://www.ema.europa.eu/en/medicines/human/EPAR/hyqvia). Accessed 6 October 2026.
65. European Medicines Agency. Medicines data: report of authorised medicines, Privigen, Kiovig, Hizentra and HyQvia entries [Internet]. [https://www.ema.europa.eu/en/documents/report/medicines-output-medicines_json-report_en.json](https://www.ema.europa.eu/en/documents/report/medicines-output-medicines_json-report_en.json). Accessed 6 October 2026.
66. Kedrion. QIVIGY (immune globulin intravenous, human-kthm) 10%. Prescribing information. DailyMed setid 6f1933e0-240f-48f4-b246-8a30e63a4160, version 6, effective 2 February 2026 [Internet]. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6f1933e0-240f-48f4-b246-8a30e63a4160](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6f1933e0-240f-48f4-b246-8a30e63a4160).
67. Ferranti-Ramos A, Aguilar-Criado M, Avendaño-Monje CL, Díaz Luna MLM, Fusi-Velarde CM, Pons J. Expert consensus recommendations for the prevention and management of immunoglobulin therapy-related adverse reactions in primary and secondary immunodeficiencies: a national Delphi study from the Immunodeficiency Group of the Spanish Society of Immunology. Front Immunol. 2026;17:1901301. doi:10.3389/fimmu.2026.1901301. PMID:42625714.
68. Sun D, Heimall JR, Greenhawt MJ, Bunin NJ, Shaker MS, Romberg N. Cost Utility of Lifelong Immunoglobulin Replacement Therapy vs Hematopoietic Stem Cell Transplant to Treat Agammaglobulinemia. JAMA Pediatr. 2022;176(2):176-84. doi:10.1001/jamapediatrics.2021.4583. PMID:34779842.
69. López-León PT, Cabañero-Navalon MD, Garcia-Bustos V, Giner F, Balastegui Martín H, Asensi Cantó P, et al. Case Report: Hematopoietic stem cell transplantation in an adult patient with X-linked agammaglobulinemia and severe refractory enteropathy. Front Immunol. 2025;16:1662016. doi:10.3389/fimmu.2025.1662016. PMID:40963632.
70. Luthers CR, Mittelhauser A, Colamartino A, Wu X, Cirigliano S, Long JD, et al. Hematopoietic stem cell gene therapy for the treatment of X-linked agammaglobulinemia. Mol Ther Methods Clin Dev. 2025;33(3):101555. doi:10.1016/j.omtm.2025.101555. PMID:40917692.
71. Bestas B, Estupiñán HY, Wang Q, Kharazi S, He C, K Mohammad D, et al. Cell-penetrating peptide-conjugated, splice-switching oligonucleotides mitigate the phenotype in BTK/Tec double deficient X-linked agammaglobulinemia model. RSC Chem Biol. 2025;6(5):761-71. doi:10.1039/d4cb00312h. PMID:40171248.
72. ClinicalTrials.gov. Search for condition “agammaglobulinemia” and terms “X-linked agammaglobulinemia” and “BTK gene therapy” (API v2), including NCT04944979 [Internet]. [https://clinicaltrials.gov/](https://clinicaltrials.gov/). Accessed 6 October 2026.
73. Pulvirenti F, Milito C, Cinetto F, Garzi G, Sardella G, Spadaro G, et al. The dilemma of X-linked agammaglobulinemia carriers. J Allergy Clin Immunol Glob. 2025;4(1):100384. doi:10.1016/j.jacig.2024.100384. PMID:39867744.
74. Dos Santos-Bueno FV, Morgado ES, Agonigi BNDS, Lopes MRG, Pinheiro MO, da Silva LL, et al. Overview of next-generation sequencing to the molecular diagnosis of inborn errors of immunity in Brazil: a systematic review. Front Immunol. 2026;17:1794921. doi:10.3389/fimmu.2026.1794921. PMID:42220512.
75. International Patient Organisation for Primary Immunodeficiencies (IPOPI). Institutional page [Internet]. [https://ipopi.org/](https://ipopi.org/). Accessed 6 October 2026.
76. Shillitoe B, Bourne H, Stroud C, Flood T, Buckland M, Ip W, et al. Quality of life of X-linked agammaglobulinemia patients in the United Kingdom. J Hum Immun. 2026;2(3):e20250198. doi:10.70962/jhi.20250198. PMID:42169998.
77. Howard V, Greene JM, Pahwa S, Winkelstein JA, Boyle JM, Kocak M, et al. The health status and quality of life of adults with X-linked agammaglobulinemia. Clin Immunol. 2006;118(2-3):201-8. doi:10.1016/j.clim.2005.11.002. PMID:16377251.