Inborn Errors of Immunity: General Approach

Approach to patients with suspected inborn errors of immunity (formerly “primary immunodeficiency”), emphasising B- and T-cell defects: the 2024 IUIS classification, warning signs, staged laboratory evaluation, genetic testing and its limitations, anti-infective prophylaxis and immunoglobulin replacement, with comparison of US and European Union labels.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Inborn errors of immunity comprise several hundred monogenic diseases that are individually rare but collectively represent a substantial health burden [2]. The current name replaced “primary immunodeficiencies” because the description of genetic defects presenting mainly with autoimmunity and inflammation, with or without infection susceptibility, demonstrated that the immune phenotype extends beyond infection [1]. The IUIS definition is genetic: an IEI is caused by deleterious germline variants in a single gene, while diseases caused by somatic variants or neutralising anticytokine autoantibodies are classified separately as phenocopies [2].

The field's clinical history begins with Bruton's description of agammaglobulinaemia in 1952; its X-linked inheritance pattern was recognised shortly afterwards [11, 12]. Since 1970, an international committee of paediatric and adult immunologists, clinical researchers and basic immunology researchers, initially under the World Health Organization and now IUIS, has published periodic updates on genetic causes of immunodeficiency and immune dysregulation, aiming to review them every two years [2]. Classification has evolved with expanding knowledge: the 2017 Oxford Desk Reference chapter, still based on the 2014 IUIS classification, listed more than 180 monogenic defects across eight groups (combined immunodeficiencies, well-defined syndromes with immunodeficiency, predominantly antibody deficiencies, immune dysregulation disorders, congenital defects of phagocyte number and function, innate immunity defects, autoinflammatory diseases and complement deficiencies) [13], whereas the 2024 update lists 508 genes and organises conditions into ten tables [2].

American guideline evolution illustrates the same expansion: the first primary immunodeficiency practice parameter, in 1995, comprised 13 pages and 47 references and limited treatment to intravenous immunoglobulin and bone marrow transplantation; the 2005 and 2015 versions comprised 63 and 98 pages, with 530 and 768 references, while the 2025 version introduces genetic evaluation, SCID newborn screening and precision medicine as central elements [1]. For the clinical geneticist, IEI is now a disease in which molecular diagnosis guides counselling, surveillance and, in an increasing number of conditions, selection of mechanism-directed therapy [1, 2].

This article addresses IEI as a general finding, focusing on B- and T-cell defects. Its purpose is to systematise clinical recognition, the investigation sequence, selection and interpretation of genetic tests, and therapeutic measures common to many conditions. SCID, XLA, 22q11.2 deletion syndrome and ataxia-telangiectasia are discussed only insofar as required for diagnostic reasoning.

2. Molecular Genetics and Pathophysiology

2.1. Molecular mechanisms and inheritance patterns

IEI-causing variants alter the gene product by abolishing (null allele) or reducing (hypomorphic allele) protein expression, decreasing or increasing intrinsic protein function (loss of function, LOF; gain of function, GOF), or acquiring a new function (neomorphic) [2]. Mechanisms depend on variant type and inheritance: monoallelic variants cause disease through haploinsufficiency, dominant-negative effects or GOF; biallelic lesions (homozygous or compound heterozygous) cause AR disorders through loss of expression, LOF, GOF or neomorphic function; X-linked recessive diseases result from hemizygous LOF or GOF variants in males or homozygous variants in females [2].

This diversity has practical consequences. Different variants in the same gene can cause clinically distinct diseases: STAT1 and STAT3 appear in different tables because LOF and GOF produce opposite phenotypes; CARD11 has three entries across three tables; IRF4 has an AD combined immunodeficiency entry for a neomorphic variant and two table 6 entries (Whipple disease through haploinsufficiency and antibody deficiency through another neomorphic variant); in the 2024 update, more than 40 genes have multiple entries [2]. Gene dosage also modulates severity: biallelic RAG1 LOF variants cause SCID, but hypomorphic biallelic variants may present later as combined immunodeficiency or mild immune dysregulation, depending on residual RAG activity [2]. These observations challenge the idea that IEI are inevitably ultrarare, severe and confined to childhood [2].

2.2. Incomplete penetrance, monoallelic expression and mosaicism

Several IEI have incomplete penetrance (e.g. JAK1 GOF, PLCG2 LOF, NLRC4 and PTPN2 GOF), so healthy relatives may carry the same variant; monoallelic expression has been identified as an important contributor to incomplete penetrance [2]. PTCRA provides an extreme example: most individuals with hypomorphic variants remained healthy between ages 2 and 65 years, whereas others developed severe infection, lymphoproliferation or autoimmunity in adolescence or adulthood [2]. Variable penetrance is also described in CTLA-4 haploinsufficiency and STAT1 GOF, supporting offers of testing to asymptomatic relatives for surveillance [1].

Somatic mosaicism is recognised in several diseases. VEXAS syndrome (UBA1) exists only as a somatic disease, while FAS/FASLG autoimmune lymphoproliferative syndrome may be germline or somatic; somatic variants reproducing the germline phenotype have been found in several AD autoinflammatory diseases (NLRP3, NOD2, TNFRSF1A, TNFAIP3, NLRC4, MEFV) [2]. The IUIS committee emphasises the need to consider low-allele-frequency variants potentially pathogenic and for laboratories to report them [2]. The American parameter lists genes with described mosaicism including CYBB, FAS, IL6ST, JAK1, KRAS, NOD2, NRAS, NLRP3, NLRC4, PIK3R1, STAT3, STAT5B, TNFRSF1A, TMEM173, TLR8 and UBA1 [1].

2.3. IUIS criteria for accepting a gene as an IEI cause

IUIS does not include every published candidate gene. Criteria require a monogenic candidate genotype absent in individuals without the phenotype (acknowledging incomplete penetrance), experimental studies demonstrating altered gene-product expression or function, and confirmation of causality through a relevant cellular phenotype, ideally with rescue of the functional defect [2]. These criteria may be met by several cases from unrelated families with detailed immunological data or, exceptionally, a single case with convincing mechanistic data; the committee warns that accumulating evidence may refute causality for some genes and that criteria for removing genes or inheritance patterns from the list are being developed [2]. The phenotypic classification marks diseases with fewer than 10 reported cases or families with one asterisk, and those known from a single case or family with two [9].

2.4. Pathophysiology of B- and T-cell defects

Severe T-cell defects prevent lymphocyte maturation and, through loss of T–B cooperation, also compromise humoral immunity. In X-linked SCID, the common γ chain is a component of five cytokine receptors required for T- and NK-cell development; JAK3 acts in the same signalling pathway; V(D)J recombination defects (RAG1, RAG2, Artemis) prevent expression of functional T- and B-cell receptors, and partial deficiency may cause Omenn syndrome, with erythroderma, lymphadenopathy and hepatosplenomegaly; complete SCID and Omenn syndrome may coexist in the same pedigree [13]. In CD40 ligand deficiency (XL), absent or dysfunctional CD40L on activated T cells prevents the T–B interaction required for isotype switching and also produces a functional T-cell defect [13].

DNA repair defects link immunodeficiency to genomic instability because double-strand break repair proteins participate in joining V, D and J segments of immunoglobulin and antigen receptor genes [14]. Non-homologous end joining (NHEJ) is impaired in radiosensitive SCID (ligase IV, Artemis, DNA-PKcs) and Cernunnos deficiency; damage recognition and signalling are altered in ataxia-telangiectasia, ataxia-telangiectasia-like disorder (MRE11), Nijmegen breakage syndrome (NBN) and RIDDLE syndrome (RNF168), all radiosensitive [14].

Several inborn errors of metabolism directly affect lymphocytes. In adenosine deaminase 1 (ADA1) deficiency, adenosine and 2′-deoxyadenosine, normally undetectable, accumulate and induce premature death of lymphoid progenitors, compromising T-, B- and NK-cell generation; in purine nucleoside phosphorylase (PNP) deficiency, intracellular deoxyguanosine triphosphate accumulation, particularly in the thymus, inhibits ribonucleotide reductase and explains the predominantly T-cell defect [15]. Mitochondrial adenylate kinase 2 deficiency, involving the only isoform expressed in neutrophils, T lymphocytes and the inner ear, causes presentations ranging from reticular dysgenesis (SCID with severe neutropenia and sensorineural hearing loss) to less severe immunodeficiencies [15]. Activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG) are class-switch enzymes, and their deficiency causes hyper-IgM syndromes with low IgG and IgA and normal or elevated IgM [15].

In predominantly antibody deficiencies with a CVID phenotype, identifiable monogenic aetiology accounts for approximately 30% of cases [1]; involved pathways include PI3K signalling (PIK3CD GOF and PIK3R1 LOF in activated PI3Kδ syndrome, APDS), regulatory T-cell control (CTLA4 haploinsufficiency and biallelic LRBA deficiency, both reducing CTLA-4 expression), and NF-κB and IKAROS transcription factors [1, 2]. In APDS1, p110δ GOF maintains uncontrolled AKT–mTOR pathway activation independent of receptor control, with senescent CD8+ effector T cells, expanded follicular helper T cells, increased transitional B cells, defective class switching (elevated IgM with reduced IgG and IgA) and weak vaccine responses [16]. This mechanistic understanding supports PI3Kδ inhibitor use, which would act in the wrong direction in biallelic p110δ LOF deficiency, an AR condition classified in the agammaglobulinaemia subtable [2, 16].

Heterozygotes for TNFRSF13B (TACI) variants warrant separate mention: these variants have been detected in healthy individuals, and IUIS considers them probably modifiers rather than causal [2]. In an exome study of 161 patients with antibody deficiency and rare TNFRSF13B variants, approximately 1% of the healthy population carried one such variant, and 16% of patients with a heterozygous variant also had a pathogenic variant in another IEI gene [17].

2.5. New genes in the 2024 update

The 2024 update added 67 monogenic defects and 2 phenocopies [2]. Combined immunodeficiencies gained IRF4 (AD neomorphic), NFATC1, PRIM1, POLD3 and NUDCD3 (AR LOF), and FOXI3 and PSMB10 (AD LOF); syndromic combined immunodeficiencies gained IKZF2 (dominant-negative), GINS4, SLC19A1, SGPL1, FLT3LG, ITPR3, RECQL4 (AR LOF), PTCRA (AR LOF/hypomorphic), SMAD3 (AD) and STAT6 (AD GOF); B-cell deficiencies gained PAX5, PI4KA and KARS1 (AR LOF) [2]. Almost half of new genes (43%, 29/67) belong to the autoinflammation and immune dysregulation tables, including monogenic lupus causes (TLR7 and UNC93B1 GOF) and arthritis (LACC1), bringing IEI closer to rheumatology [2]. Two observations illustrate IEI as “experiments of nature”: NUDCD3 deficiency sequesters RAG1 in nucleoli and impairs recombination; FLT3L deficiency showed that, unlike mice, humans require this cytokine for monocytes but not NK cells [2].

3. Clinical Spectrum and Systemic Manifestations

3.1. The 2024 IUIS classification as a spectrum map

The 2024 IUIS genotypic classification organises IEI into ten tables with subtables of overlapping phenotypes, classifying each condition by its most consistently described presentation [2]. The 2025 American parameter adopts this structure, assigning tables I and II to T-cell function defects, table III to antibody deficiencies, IV to immune dysregulation, V to neutrophils, VI to innate immunity, VII to autoinflammation and VIII to complement, leaving tables IX (bone marrow failure) and X (phenocopies) outside its detailed scope [1]. The following table reproduces the full structure, with entry counts given in each table's notes; the sum of entries in tables 1 to 9 corresponds to the 559 described conditions [2].

The 2023 French PNDS, aimed primarily at the attending physician, uses a simplified classification into five groups intended to guide genetic testing: combined immune deficiencies (T and B lymphocytes; opportunistic, viral, fungal and bacterial infections), humoral deficiencies (B lymphocytes; ear, nose and throat and pulmonary infections), phagocyte defects (neutrophils and macrophages; fungal and bacterial infections, particularly staphylococcal), immune dysregulation disorders and autoimmune diseases [5]. This scheme does not replace the ten IUIS tables, in which autoinflammatory disorders, complement deficiencies, bone marrow failure and phenocopies have their own place, and the references the PNDS cites for the classification are the 2022 IUIS updates [2, 5].

The table 3 note has direct diagnostic relevance: a minority of patients with X-linked lymphoproliferative disease, WHIM syndrome, ICF syndrome, hepatic veno-occlusive disease with immunodeficiency, thymoma-associated immunodeficiency (Good syndrome) or myelodysplasia first present to an immunologist with recurrent infections and hypogammaglobulinaemia [2]. The table 1 note reminds readers that infants with SCID and maternal T-cell engraftment may have normal T-cell counts without function, and hypomorphic SCID gene variants produce Omenn syndrome, leaky SCID or CID, with more than 300 autologous T cells/µL and reduced but not absent proliferative responses [2].

3.2. Infections: pathogen patterns as indicators of the defect

Infections are the most frequent complication and commonest reason for evaluation; they mainly involve community-prevalent pathogens but have unusual severity, frequency and duration and poor therapeutic response, whereas severe defects are associated with opportunistic pathogens [18]. Up to 26% of children over age 2 years with invasive pneumococcal disease have an identifiable primary immunodeficiency [18].

Antibody deficiencies predominantly involve sinopulmonary infections with encapsulated bacteria (Streptococcus pneumoniae and Haemophilus influenzae), viral respiratory and gastrointestinal infections, and Mycoplasma and Ureaplasma infections, which may cause arthritis [1, 18]. In agammaglobulinaemia, suggestive infections include ECHO enterovirus meningoencephalitis, Helicobacter-associated ecthyma or pyoderma gangrenosum, silent Helicobacter or Campylobacter jejuni bacteraemia, and, rarely, Pneumocystis pneumonia or poliovirus vaccine strain infection [1]. Refractory gastrointestinal Giardia and norovirus infections are common in CVID [1]. T-cell and combined defects predominantly involve viral, fungal and opportunistic infections; SCID usually presents before age 7 months with failure to thrive, diarrhoea, oral candidiasis and Pneumocystis jirovecii pneumonia [13]. CD40L deficiency presents with recurrent bacterial infections or Pneumocystis pneumonia and a high incidence of liver disease [13], and CD40L, DOCK8 and IL-21R deficiencies predispose to chronic cryptosporidiosis with cholangiopathy and portal hypertension [1].

The French PNDS insists on identifying the pathogen before requesting immunological investigation, because the microbiological pattern points to the affected compartment; its indicative, non-exhaustive table is summarised as follows [5]:

The same document adds clinical clues by pathogen [5]:

• Papillomaviruses. Common warts of the hands and feet usually disappear before the age of 20 without recurrence; new warts in adulthood, or extensive and recurrent warts, suggest immunodeficiency, in particular HIV infection or GATA2 deficiency, in which warts may be the first sign and the full blood count often shows monocytopenia, fluctuating neutropenia, macrocytosis with usually moderate anaemia and moderate thrombocytopenia.
• Poxviruses. Molluscum contagiosum arising in adulthood, or florid and chronic in a child, suggests immunodeficiency (HIV or IEI); certain cutaneous fungal infections mimic molluscum.
• BCG. Fever and deterioration in general condition a few weeks after vaccination, particularly with an inflamed and painful draining lymphadenopathy (regional BCGitis), warrant specialist advice because of the possibility of a T-cell defect, SCID, an IL-12/IFN-γ pathway defect or chronic granulomatous disease; isolated local BCGitis that heals without treatment does not necessarily require it. A severe reaction to another live attenuated vaccine and atypical tuberculosis in adults are also reasons for investigation. In France, BCG is no longer mandatory and is recommended for children under 5 years from populations in which tuberculosis is endemic or before travel to an endemic area.
• Environmental mycobacteria. Extrapulmonary or disseminated forms should prompt a search for a T-cell defect, an IL-12/IFN-γ pathway defect, chronic granulomatous disease or GATA2 deficiency, and for secondary causes (HIV, chronic lymphoid haematological malignancies, some myelodysplasias).
• Giardiasis. Chronic or recurrent Giardia infection should prompt a search for a humoral deficiency (CVID, other hypogammaglobulinaemias, complete IgA deficiency).
• Meningitis. Severe herpetic meningoencephalitis warrants a search for genetic predisposition, particularly with a family history; in the absence of an anatomical osteomeningeal breach, meningitis due to an encapsulated bacterium should prompt a search for antibody deficiency, complement deficiency or asplenia: S. pneumoniae or H. influenzae point to humoral deficiency, impaired polysaccharide response, asplenia or complement; Neisseria meningitidis points to complement or asplenia and, more rarely, humoral deficiency.
• Delayed umbilical cord separation. Up to 15 days to 1 month this is not necessarily pathological; with omphalitis and repeated or severe skin or gastrointestinal infections, a leucocyte adhesion defect should be excluded, which a simple full blood count suggests (leucocytosis above 30,000/mm³, mainly neutrophilic, during infections); the disease usually becomes apparent before 1 year of age and can be cured by HSCT.

3.3. Immune dysregulation, lymphoproliferation and malignancy

Autoimmunity and malignancy complicate many IEI and frequently arise from the same defect predisposing to infection; autoimmune cytopenias, inflammatory arthropathies and vasculitides are examples, and malignancies are predominantly haematological [18]. In CVID, according to data summarised in the 2015 parameter, approximately 20% of patients have autoimmune disease, mainly cytopenias (11–12%); up to one-third have lymphoproliferation (splenomegaly, intestinal lymphoid hyperplasia, lymphadenopathy); 8–22% have granulomatous infiltration; B-cell lymphoma prevalence is 1.8–8.2%, with non-Hodgkin lymphoma relative risk estimated at 30 to 400 times the general population; gastric cancer relative risk is approximately 10-fold, with prevalence 0.8–1.7% [18]. These percentages derive from referred-patient series and should not be interpreted as individual lifetime risks.

The French PNDS, drawing on the CEREDIH national registry, reports autoimmune or inflammatory manifestations in approximately 25–30% of patients with IEI, throughout life and in virtually all groups, a risk of inflammatory disease (intestinal or articular) approximately 10 times that of the general population, and an unfavourable prognostic value of these manifestations; it gives autoimmune cytopenias in 25% of patients with CVID, a figure higher than the 11–12% summarised in the 2015 American practice parameter, a difference reflecting distinct cohorts and definitions [5, 18]. Practical measures follow from this: any autoimmune cytopenia in a child (immune thrombocytopenic purpura, autoimmune haemolytic anaemia, more rarely autoimmune neutropenia) warrants measurement of IgG, IgA and IgM and, if IgG is normal with repeated bronchial or ear, nose and throat infections, of IgG subclasses; a first episode of immune thrombocytopenic purpura or Evans syndrome at an atypical age warrants specialist advice; and hypomorphic forms of SCID may present in the first years of life with autoimmune cytopenias [5]. Diagnosing an IEI in a patient with autoimmune disease allows monitoring, assessment of the appropriateness of immunosuppression and the addition of antimicrobial prophylaxis when required [5]. Organ-specific autoimmunity (vitiligo, pernicious anaemia, thyroiditis) also warrants measurement of IgG, IgA and IgM; in isolated IgA deficiency, the late onset of IgG deficiency, which manifests as ear, nose and throat and pulmonary infections, should be monitored clinically, and the great majority of patients with IgA deficiency and infections have IgG2/IgG4 deficiency with an impaired vaccine response [5].

Regarding cancer, the PNDS estimates a risk 10 to 20 times that of the population without IEI for some IEI, citing the example of ataxia-telangiectasia (haematological malignancies, particularly EBV-induced B-cell lymphomas), and notes an increased incidence of gastrointestinal cancers (colon and stomach) in many IEI with hypogammaglobulinaemia, which warrants endoscopic surveillance; in DNA repair defects, genotoxic chemotherapy and radiotherapy should be adapted to the mechanism and imaging with ionising radiation kept to a minimum [5].

In monogenic IEI with a CVID phenotype, dysregulation frequently dominates the presentation. GeneGuidance curation of APDS1 reports herpesvirus susceptibility in up to 49% of patients, autoimmune cytopenias in 19–30%, enteropathy in up to half, growth delay in approximately half, and lymphoma in approximately 12.8%, mainly diffuse large B-cell lymphoma [16]. In CTLA-4 haploinsufficiency, an international cohort of 133 carriers from 54 families documented incomplete penetrance and lymphocytic organ infiltration [19]. NFKB1 LOF variants were the most frequent monogenic CVID cause in Europeans (4% of 390 cases), and a worldwide cohort of 157 carriers of 56 variants included asymptomatic carriers [20, 21]. In NFKB2 deficiency, corticotroph deficiency occurred in 44% of 50 pooled patients, justifying pituitary–adrenal axis assessment even in relatives identified through cascade testing [16, 22]. A STAT3 GOF cohort of 191 patients from 33 countries documented early-onset lymphoproliferation and autoimmunity [23], while the STAT1 GOF cohort of 274 patients showed a broad phenotype beyond chronic mucocutaneous candidiasis [24].

3.4. Systemic manifestations

Respiratory system. Recurrent respiratory infections are the most frequent IEI manifestation, and bronchiectasis and other infiltrative and inflammatory lung diseases determine morbidity, mortality and quality of life [18]. In CVID, bronchiectasis occurs in 10–20%, chronic non-infectious lung disease in approximately 30% (associated with lower survival), an asthma-like presentation in 10–15% and granulomatous–lymphocytic interstitial lung disease (GLILD) in approximately 10%, frequently with splenomegaly and diffuse lymphadenopathy [18]. Chronic lung disease, especially bronchiectasis, persists in antibody deficiencies when diagnosis is late, immunoglobulin replacement insufficient or intercurrent infections inadequately treated promptly [13].

Gastrointestinal system and liver. Approximately 20–25% of CVID patients have gastrointestinal complications (chronic gastritis with or without pernicious anaemia, nodular lymphoid hyperplasia, villous atrophy, inflammatory bowel disease, enteropathy), approximately 40% have abnormal liver tests, and nodular regenerative hyperplasia is the commonest chronic liver disease, frequently with non-jaundiced portal hypertension [18]. Sclerosing cholangitis is a particular risk in CD40L deficiency [13]. Very-early-onset inflammatory bowel disease, especially before age 6 years, warrants consideration of an IEI [1].

Skin and mucosae. Skin examination should assess eczema, erythroderma and viral skin infections such as warts [13]. Erythroderma suggests Omenn syndrome; atypical eczema with small-platelet thrombocytopenia suggests Wiskott–Aldrich syndrome; disseminated warts prompt T- and NK-cell evaluation [1, 13].

Lymphoid system. Absent tonsils and palpable lymph nodes characterise agammaglobulinaemia and distinguish it from other antibody deficiencies [1]; in SCID, tonsils and the thymic shadow on chest radiography are usually absent [13]. Lymphadenopathy and hepatosplenomegaly suggest dysregulation (CVID with lymphoproliferation, APDS, CTLA-4, ALPS) or malignancy [1, 18].

Skeleton and growth. Immuno-osseous dysplasias combine severe short stature, skeletal abnormalities and T-cell lymphopenia [18]. In cartilage–hair hypoplasia (RMRP, AR), short-limbed short stature is present in 100%, in-vitro T-cell function is impaired in 88%, anaemia occurs in 79%, lymphopenia in 62% and neutropenia in 27%; Hirschsprung disease occurs in approximately 10%, severe prolonged varicella signals underlying immunodeficiency but affects no more than approximately one-third, and non-Hodgkin lymphoma and basal cell carcinoma are increased [25]. In Schimke immuno-osseous dysplasia (SMARCAL1, AR), short-trunk short stature is associated with focal segmental glomerulosclerosis progressing to renal insufficiency within 2 to 12 years, cellular immunodeficiency, lymphopenia, hypothyroidism in 50% and cerebral infarcts due to progressive arteriosclerotic stenoses [26]. ADA1 deficiency features skeletal dysplasia (scapular spur and costochondral widening), sensorineural hearing loss, developmental delay and liver failure [15].

Nervous system. PNP deficiency is associated with ataxia, intellectual disability and spasticity from late in the second year of life, and approximately one-third of patients have autoimmune diseases [15]. Ataxia-telangiectasia, Nijmegen syndrome (microcephaly), Cockayne syndrome and other DNA repair disorders combine immunodeficiency with neurological signs [14]. In ataxia-telangiectasia, immunodeficiency occurs in 80%, typically with sinusitis and bronchitis or pneumonia, and cancer, mainly lymphoma and leukaemia, in 10–30%, including 15% of patients under 16 years of age [14].

Endocrine system. Autoimmune polyendocrinopathy (APECED, AIRE), IPEX syndrome (FOXP3) with severe enteropathy and early-onset type 1 diabetes, and central adrenal insufficiency in NFKB2 deficiency illustrate endocrine involvement in IEI [13, 22].

Haematology. Autoimmune cytopenias, small-platelet thrombocytopenia (Wiskott–Aldrich), neutropenia (CD40L deficiency, reticular dysgenesis) and anaemia (cartilage–hair hypoplasia) are diagnostic clues; bone marrow failure has its own classification table [1, 2, 15, 25].

4. Clinical Recognition and Warning Signs

4.1. When to suspect an IEI

The 2025 parameter recommends investigating IEI in patients with recurrent, severe or rare infections, autoinflammation, autoimmunity, severe atopy, atypical malignancy, bone marrow failure or combinations of these conditions (strong recommendation, high certainty) [1]. Suspicion should increase with infections that have severe outcomes, recur or involve opportunistic pathogens; early-onset, severe, multiple or refractory autoimmunity; chronic inflammatory processes, granulomas or prolonged postinfectious inflammation; very-early-onset inflammatory bowel disease; and chronic or refractory severe atopy [1].

History should include a three-generation pedigree extended on the maternal side, with specific questions on immunodeficiency, unexplained or infection-related infant deaths, malignancy and haematological diseases; infection chronology, pathogens, predominant type (bacterial, viral, opportunistic or fungal), and vaccination history, including BCG [13]. Family IEI manifestations and the absence of infections in siblings of a frequently ill child suggest increased susceptibility; maternal IgG protection may delay severe infection onset [18]. In one large cohort, only 1.5% of patients were diagnosed through family history, while another series reported positive family history in 26% at initial presentation [1]. Consanguinity suggests recessive inheritance [1].

The French PNDS adds simple rules for primary care: in adults, a single unexplained pneumonia should raise the possibility of IEI, as should repeated, severe or unexplained infections; in children, a severe infection with a community pathogen (sepsis without a focus, meningitis) or with an opportunistic or usually non-pathogenic organism (recurrent or invasive aspergillosis or candidiasis, pneumocystosis) and severe or unusually repeated viral infections (herpes zoster, varicella, herpes simplex, measles) are warning signs; the number of antibiotic courses per year, or the “child health record sign” of a record overloaded with supplementary pages, helps to confirm the reality of recurrent infections; and faltering or a fall-off in the growth curve, with or without chronic diarrhoea, may be the presenting feature [5]. The same document directs the patient to a competence or reference centre when initial tests show an IEI, when they are normal despite suggestive clinical signs (to complete the hospital evaluation) and in cases of diagnostic doubt [5].

Physical examination should document growth (weight, height and head circumference), skin, lymph nodes, tonsils and hepatosplenomegaly [13], alongside syndromic dysmorphism (e.g. DiGeorge syndrome), infection signs (warts, bronchiectasis), autoimmunity signs (alopecia, vitiligo), lymphoproliferation and severe atopy [1].

4.2. Warning signs: Jeffrey Modell Foundation and French PNDS

The Jeffrey Modell Foundation proposes that two or more warning signs prompt discussion with a physician about possible primary immunodeficiency [27]. The signs differ between children and adults:

The French PNDS proposes its own list of manifestations that should raise suspicion of IEI, without a minimum count rule, with infection thresholds different from those of the Jeffrey Modell Foundation and with the explicit inclusion of non-infectious manifestations [5]:

The comparison shows lower PNDS thresholds for adults (more than two episodes of pneumonia, otitis or sinusitis per year in total, instead of one pneumonia per year for more than one year) and for invasive infection (a single episode suffices), and the inclusion of autoimmunity, granulomas, lymphoproliferation, severe atopy and unusual neoplasia, which the Jeffrey Modell Foundation's ten signs do not cover [5, 27]. The PNDS presents no performance data for its list, which results from expert consensus.

4.3. Performance and limitations of warning signs

Warning signs were developed as an awareness tool and have limited validation. In a retrospective study of 563 children referred to two northern England centres (430 with defined primary immunodeficiency and 133 without a specific diagnosis), 96% of diagnosed children were referred by hospital clinicians; the strongest identifiers were family history, intravenous antibiotics for sepsis in neutrophil defects and failure to thrive in T-cell defects; these three signs correctly identified 96% of children with neutrophil and complement defects and 89% with T-cell defects, while family history was the only sign identifying children with B-cell defects [28]. The authors concluded that signs should target hospital paediatricians and families with an immunodeficiency history; a subsequent review emphasised that they do not address autoimmune, autoinflammatory or malignant presentations [29]. In a US electronic-record cohort of 152 million patients, the proportion of IEI patients with two or more signs was 0.33, compared with 0.031 in controls; the strongest signs were deep infections, fungal infections, failure to thrive and pneumonias [4]. These data demonstrate that absence of signs does not exclude IEI: two-thirds of US cohort patients lacked two recorded signs [4].

4.4. Warning situations requiring urgent action

Suspected SCID is a clinical emergency: infants with recurrent, persistent or severe bacterial, viral or fungal infections, or with failure to thrive, require immediate evaluation, and abnormal newborn screening by T-cell receptor excision circle (TREC) quantification requires urgent confirmation by a full blood count with differential and flow cytometry of lymphocyte subsets, including naïve T cells [1, 18]. Until immunodeficiency is excluded, newborns from families with IL-12/IFN-γ/STAT1 pathway, NEMO or IκBα defects should not receive BCG [1].

The French PNDS defines three therapeutic emergencies [5]:

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles: integrated, staged assessment

The 2025 parameter recommends an integrated approach with three components (clinical, immunological and genetic) and recommends that evaluation include a search for secondary causes of immunodeficiency (both strong recommendations, moderate certainty) [1]. Secondary immunodeficiencies are, collectively, more prevalent than IEI, especially in adults, and include anatomical causes (nasal polyposis, septal deviation, adenoidal hypertrophy, cerebrospinal fluid fistula), epithelial barrier defects (primary ciliary dyskinesia, cystic fibrosis), malnutrition, infections affecting immune cells (HIV, measles, EBV), immunosuppressive medicines (corticosteroids, ciclosporin, rituximab), lymphatic malformations and the extremes of age, including prematurity [1]. Antiepileptic medicines may alter immune cells unpredictably, and immunoglobulin loss through the intestine, respiratory tract or lymphatics (hydrops, protein-losing enteropathy, intestinal lymphangiectasia, lymphovenous malformations, chylothorax) also causes immunodeficiency [1]. Anticytokine autoantibodies produce IEI phenocopies, for example anti-GM-CSF antibodies (cryptococcal meningitis and pulmonary alveolar proteinosis) and anti-IFN-γ antibodies (disseminated mycobacterial, Salmonella, Cryptococcus, Histoplasma, Penicillium and varicella-zoster virus infections) [1, 18]. The French PNDS adds diabetes, chronic alcoholism, nephrotic syndrome and exudative enteropathy to the list of secondary causes to consider in adults, and proposes simple tests to exclude them (HIV serology, dipstick testing for proteinuria) [5].

The French PNDS organises investigation in two stages [5]. In the first, available in outpatient care and reimbursed, a full blood count with absolute differential leucocyte count interpreted for age, measurement of IgG, IgA and IgM with paediatric or adult reference values and tetanus serology are requested (other vaccine serologies are not reimbursed outside hospital); with a personal or family history of meningococcal meningitis, complement studies (C3, C4, CH50 and AP50) are added. The full blood count looks for neutropenia (below 500/mm³ it may, in isolation, explain infections; if chronic and without antineutrophil antibodies, it warrants bone marrow aspiration and genetic testing for congenital neutropenia), lymphopenia, anaemia or thrombocytopenia suggesting an autoimmune complication, thrombocytopenia with small platelets (Wiskott–Aldrich) and Howell–Jolly bodies (asplenia). Imaging complements the initial evaluation: chest radiography in children (thymic shadow before 1 year, pneumonia, bronchial syndrome), chest CT (thymoma, bronchiectasis, nodules, mediastinal lymphadenopathy), sinus CT for repeated sinusitis and abdominal ultrasound or CT (deep lymphadenopathy, granulomas, splenomegaly or asplenia; functional asplenia is defined by the combination of Howell–Jolly bodies and a splenic vascularisation defect on Doppler). The second stage, guided by the type of IEI suspected, is triggered by at least one of four abnormalities (confirmed isolated lymphopenia, hypogammaglobulinaemia measured after 3 months of age, low or absent serologies after documented infection, isolated vaccine antibody deficiency confirmed 4 to 6 weeks after revaccination) and consists, as a minimum, of T, B and NK lymphocyte phenotyping by flow cytometry; neutrophil oxidative burst tests (for bacterial infections with normal total IgG and IgE, or typical infections such as aspergillosis) and complement measurement (for invasive infection with an encapsulated bacterium) are requested by the competence or reference centre [5].

Screening tests are relatively inexpensive, rapid and reasonably sensitive and specific; abnormal results indicate a need for more specialised tests [18]. The Jeffrey Modell Foundation proposes four stages summarising this approach [27]:

The 2025 parameter changes the sequence relative to this classic scheme: because IEI may present atypically or incompletely, it recommends considering genetic testing from the start of investigation [1]. The IUIS phenotypic classification organises reasoning into a decision tree whose first question concerns the predominant manifestation: infection, autoinflammation, lymphoproliferation, autoimmunity or a non-immune syndrome [9]. For infections, the branch divides into a broad or narrow pathogen spectrum; in a broad spectrum with opportunistic infections, T-cell lymphopenia or absent TREC lead to SCID, while their absence leads to CID, or syndromic CID if a non-immune syndrome coexists; with non-opportunistic infections, the next question concerns antibody or neutrophil defects; with a narrow spectrum, viral, bacterial (including complement deficiency investigation), fungal, parasitic and mycobacterial infections direct attention to innate immunity or complement tables [9]. The authors warn that phenotypes expand, hypomorphic or neomorphic variants may present atypically, penetrance and expressivity are incomplete, and the correct diagnosis is not always reached on the first traversal of the tree [9]. The tree corresponds to figure 1 of that publication, which was consulted and is available at PMC12829316, figure 1.

5.2. Evaluation of antibody deficiencies

The first level consists of serum IgG, IgA and IgM quantification interpreted against age- and laboratory-specific reference intervals [1]. Low IgG is defined as a value more than 2 standard deviations below the age-specific mean on two measurements more than 3 weeks apart; when IgG is very low initially (below 100–300 mg/dL, depending on age), one measurement may suffice to expedite investigation and treatment [1]. With hypogammaglobulinaemia, the IUIS phenotypic classification first recommends excluding secondary causes (medicines, myeloma, chronic lymphocytic leukaemia, lymphoma, urinary, gastrointestinal or skin loss) and enumerating CD19+ B lymphocytes by cytometry: absent B cells with reduced levels of all Ig classes suggest agammaglobulinaemia; B cells above 1% suggest the CVID phenotype, subdivided into infections alone, autoimmunity, lymphoproliferation or other features [9]. The same article's figure 8, which was consulted, summarises this algorithm (PMC12829316, figure 8).

The French PNDS adds age-related interpretation rules [5]. IgG reflects maternal IgG transferred in the last trimester and should not be measured before 3 months of age (elsewhere, the same document considers it uninterpretable before 4 months); transient hypogammaglobulinaemia of infancy may occur between 3 and 15 months. In adults, measurement of IgG, IgA and IgM is always combined with serum protein electrophoresis with immunofixation, so as not to miss a monoclonal peak, and hypogammaglobulinaemia found on electrophoresis leads to isotype-specific measurement; in children, electrophoresis has no diagnostic value and only quantitative measurement of the three classes establishes hypogammaglobulinaemia. IgG subclasses are not interpretable before 18–24 months, are not a first-line test and are indicated for recurrent infections with normal total IgG. The indicative age-related ranges used by the PNDS (Picard, 2013) are as follows, in g/L:

These ranges are for guidance; interpretation should use the reference values of the laboratory performing the measurement [1, 5].

Enumeration of CD3+, CD4+ and CD8+ T cells, CD19+ B cells and CD16/56+CD3− NK cells is necessary to distinguish CID from agammaglobulinaemia [1]. B-cell subset evaluation, particularly class-switched memory B cells (CD27+IgD−IgM−), is recommended in antibody deficiencies: values below 2% of CD19+ B cells are associated with absent protective vaccine responses, including to COVID-19 mRNA vaccines, and high autoimmunity and mortality risk; expansion of early transitional B cells or CD21low B cells is associated with autoimmune and inflammatory organ disease [1]. T-cell subset evaluation may reveal defects leading to CVID reclassification, particularly “Tregopathies” such as CTLA-4 deficiency [1].

Normal IgG does not exclude humoral dysfunction, and assessing protein and polysaccharide antigen responses is essential [1, 18]. Responses to protein vaccines (tetanus and diphtheria toxoids) and polysaccharides are measured before and 3 to 4 weeks after boosting; a normal protein response is at least a 4-fold rise [18]. For antipneumococcal antibodies, guidance cited in the 2025 parameter uses 1.3 µg/mL after polysaccharide vaccine and 0.35 µg/mL after conjugate vaccine as protective thresholds against invasive infection, measured before, 4 weeks and 6 months after vaccination in the same laboratory because results vary between laboratories [1]. Widespread 20-valent conjugate vaccination limits 23-valent polysaccharide vaccine use as a diagnostic challenge because only four serotypes (2, 9N, 17F and 20) are present in the 23-valent but absent from the 20-valent vaccine; polysaccharide typhoid vaccine has been proposed as an alternative, with limited sensitivity and specificity studies [1]. IgG isohaemagglutinins provide an additional indicator of polysaccharide immunity [18], and hepatitis B vaccination is not recommended for routine vaccine response assessment because of lower immunogenicity [1].

The French PNDS frames the same evaluation in primary care terms [5]. Post-vaccination or post-infection serologies are not interpretable before 6 months of age, because of maternal IgG, and depend on the type of immunisation and the time elapsed: if more than 2 years have passed since the last dose, a low titre is not considered pathological, a booster is given (tetanus alone or combined, Haemophilus or pneumococcus) and serology is repeated at least 4 to 6 weeks later, being pathological only if it remains low. Antipeptide antibodies, produced after natural infection, protein vaccine (tetanus toxoid) or conjugate vaccine, are distinguished from antipolysaccharide antibodies, produced after infection with an encapsulated bacterium or unconjugated polysaccharide vaccine, which cannot be assessed before 2 years of age. The “global” antipneumococcal tests available in routine practice are of very limited value because of heterogeneity between serotypes; only serotype-specific response is recommended, with restricted access and indications. In practice, tetanus, Haemophilus and pneumococcal serologies suffice to assess the specific humoral response. The PNDS interval of 4 to 6 weeks between booster and serology differs from the 3 to 4 weeks of the 2015 parameter and the 4 weeks of the 2025 parameter for antipneumococcal antibodies [1, 5, 18].

5.3. Diagnostic criteria for predominantly antibody deficiencies

The divergence between American and European CVID criteria has practical consequences. ESID includes switched memory B cells as an alternative to vaccine response and requires exclusion of profound T-cell deficiency, defined by two of three criteria (CD4/µL below 300 at ages 2–6 years, 250 at ages 6–12 years and 200 above age 12 years; naïve CD4 below 25%, 20% or 10% in the same age groups; or absent T-cell proliferation) [7]. Mandatory application of these criteria in the ESID registry led to reclassification of 8% of adults and 27% of children previously diagnosed with CVID (176 of 1704) into 22 other immunodeficiencies [7]. Similarly, ESID CID criteria require a clinical manifestation (severe infection requiring hospitalisation, immune dysregulation, malignancy or an affected relative), two of four T-cell criteria (reduced CD3, CD4 or CD8; reduced naïve T cells; increased γδ T cells; reduced proliferation to mitogens or TCR stimulation), and exclusion of HIV and defined CID-associated syndromes [7].

5.4. Evaluation of cellular immunity and CID

For suspected CID, the 2025 parameter recommends a full blood count with differential (lymphopenia: e.g. absolute count below 1000/µL in adults or 2500/µL in infants), Ig quantification with specific antibodies, T/B/NK phenotyping with percentages and absolute counts, naïve and memory T-cell and recent thymic emigrant phenotyping (CD45RA+CD31+), B-cell phenotyping, quantification of Tregs (CD4+CD127lowFOXP3+CD25high, approximately 5–10% of CD4+ cells), follicular helper T cells and activated, exhausted or senescent T cells, and T-cell proliferation assays using mitogens (phytohaemagglutinin, concanavalin A, pokeweed), anti-CD3 with IL-2 or anti-CD28, and antigens (tetanus toxoid, Candida) [1]. A discrepancy between CD3+ and the sum of CD4+ and CD8+ should prompt investigation of double-negative αβ (ALPS) or γδ T cells (infections and CID such as ataxia-telangiectasia); an altered CD4:CD8 ratio suggests MHC class I or ZAP70 deficiency (low CD8) or MHC class II deficiency (low CD4) [1]. In severe lymphopenia, cytometric proliferation methods using DNA dyes are more specific than tritiated thymidine incorporation [1].

The French PNDS gives guidance for incidentally discovered lymphopenia [5]. In older children, adolescents and adults, it defines lymphopenia as below 1000/mm³; in adults, the causes to consider first are secondary: HIV, haematological diseases, immunosuppressants (corticosteroids, ciclosporin, azathioprine, cyclophosphamide, rituximab, chemotherapy), exudative enteropathy, zinc deficiency, sarcoidosis, external radiotherapy, organ transplantation and some autoimmune diseases. Lymphopenia should be confirmed and monitored, with a personal and family history taken, and the indication for lymphocyte phenotyping and anti-infective prophylaxis is decided case by case with the specialist, because management is not codified; in adults, moderate (0.7–1 × 10⁹/L) and isolated lymphopenia, without clinical manifestations or other full blood count abnormalities and with negative HIV serology, is not necessarily pathological and requires no further investigation. In children, lymphopenia is interpreted against age-specific values: it may be repeated later (viral infection) or investigated immediately if there are signs of a cellular or humoral deficiency; any child under 1 year with fewer than 3000 lymphocytes/mm³, or with warning signs (severe or opportunistic viral infections), should have the full blood count repeated and, if lymphopenia persists, undergo immunophenotyping to exclude SCID; exposure to immunosuppressants during pregnancy may cause transient lymphopenia in the infant. The indicative age-related values used by the PNDS (Picard, 2013), in 10⁹/L, are:

The PNDS threshold of 3000/mm³ below 1 year of age differs from the example of 2500/µL in infants given in the 2025 parameter, both presented as guidance values rather than diagnostic criteria [1, 5].

For DNA repair defects, the Oxford Desk Reference describes elevated alpha-fetoprotein in ataxia-telangiectasia, Ig subclasses (frequent IgA and IgG2 deficiency), radiosensitivity assays (up to a 10-fold increase in chromosomal breaks after irradiation), translocations involving chromosomes 7 and 14 in T cells, and confirmation through ATM or nibrin western blot in lymphoblastoid cell lines (approximately 6 weeks); in Nijmegen syndrome, a common 5 bp deletion is homozygous or compound heterozygous in most patients [14].

5.5. Inborn errors of metabolism with immunodeficiency

Absent or very low erythrocyte ADA activity (<1% of normal) confirms ADA1 deficiency; in late-onset forms, newborn TREC may be above the threshold, preventing detection by screening, whereas detection of adenosine and 2′-deoxyadenosine would be positive [15]. ADA alleles are classified by residual activity: group I alleles (deletions and nonsense variants, <0.05% activity) cause SCID, group II alleles late-onset immunodeficiency, group III alleles late or partial phenotypes, and group IV alleles partial deficiency in individuals identified by newborn screening or in healthy relatives of patients [31]. In PNP deficiency, low plasma uric acid is not always a reliable marker, enzyme activity is measured in erythrocyte lysates, blood spots or leucocytes, confirmation is molecular, and late onset of immunodeficiency may allow normal TREC/KREC screening, with mass spectrometry of metabolites (guanosine, inosine, deoxyguanosine and deoxyinosine) in dried blood being a more accurate neonatal method [15]. ADA2 deficiency has normal adenosine and deoxyadenosine and is suggested by low or absent plasma ADA2 activity, with molecular confirmation [15]. Transcobalamin 2 deficiency, hereditary folate malabsorption and MTHFD1 deficiency can mimic SCID and should enter the differential diagnosis [1, 18].

5.6. Genetic testing: platform selection

Table adapted from table 3A of the 2025 parameter; “variable” reflects the note that sensitivity depends on protocol design [1].

The corresponding recommendations are: single-gene sequencing when an affected relative has a known defect or the gene is poorly analysed by massively parallel sequencing; a targeted IEI panel or exome as the first step otherwise, because diagnostic yields are similar and selection depends on availability, turnaround time, depth, CNV detection and cost; genome (conditional suggestion) with non-immunological features or strong suspicion of a non-coding defect; CNV testing when deletion or duplication is suspected; ACMG variant classification; family testing to resolve pathogenicity (strong) and estimate risk in unaffected relatives (conditional); and investigation of multiple diagnoses when a monogenic diagnosis does not explain the presentation [1]. Given overlapping phenotypes, the IUIS phenotypic classification recommends broad panels or exome rather than restricted panels, except for a few diseases such as XLA with a rationale for targeted testing [9]. The Italian IPINet consensus recommends offering genetic testing to selected patients with warning signs and emphasises phenotyping and functional testing in completing diagnosis (content limited to the consulted abstract) [32].

Technical details affecting interpretation include mean depth of approximately 500 reads or more in panels, approximately 100 in exome and 20–30 in genome sequencing; exome-based “virtual” panels lose the depth advantage and non-coding regions included in true panels; genome sequencing does not detect low-frequency mosaicism because of limited depth; Sanger sequencing lacks sensitivity below 15–20% mosaicism, whereas deep massively parallel sequencing can detect allele frequencies below 1% [1]. Chromosomal microarray detects CNV from approximately 400 kb and is preferable to FISH for microdeletions such as 22q11.2; massively parallel sequencing is less sensitive than microarray for 1–2-exon deletions, and none of these methods reliably detects balanced rearrangements, some repeat expansions or low-level mosaicism [1]. Genes with pseudogenes (IKBKG, NCF1, ATAD3A, C4A, CFB, IRAK1, SBDS, USP18) pose difficulties for massively parallel sequencing, while targeted sequencing can distinguish gene and pseudogene [1]. Pathogenic non-coding variants have been described in genes such as LRBA, DOCK8 and ARPC1B, and the parameter's table 3C lists more than 80 IEI genes with described non-coding variants [1]. In AR disease with a single pathogenic variant, CNV testing helps exclude or confirm a second-allele variant [1]. Exome or genome is preferable in children whose parents have a high likelihood of consanguinity and when malformations or neurological impairment are present, because genes for syndromes not classified as IEI (e.g. CREBBP in Rubinstein–Taybi syndrome) are absent from panels [1].

In France, according to the PNDS, the indication for genetic testing rests on individual and family criteria, taking into account the frequency of AR inheritance (with an increased risk in the children of consanguineous couples) and the existence of X-linked and AD forms; the next-generation sequencing gene panel is the first-line technique and is performed in reference laboratories, including the Centre d'Étude des Déficits Immunitaires (CEDI, Hôpital Necker, Paris) [5]. The search for a new gene starts from clinical and immunological characterisation, discussed between the centres and the CEDI or at national multidisciplinary team meetings; in a severe infection without a variant in a known gene, studies of genetic predisposition to severe infections may be proposed; genetic diagnosis should be accompanied by a geneticist; and genetic, clinical and therapeutic data are recorded, with the consent of the patient or legal representative, in the CEREDIH national database and the ESID European registry [5].

5.7. Diagnostic yield and interpretation

In a review of next-generation sequencing studies in primary immunodeficiency cohorts, the mean yield was 29% (range 10–79%) and 38% for exome (15–70%), with the variation explained mainly by the clinical characteristics of the cohorts and by the methods [33]. Approximately 30% of CVID cases have an identifiable genetic aetiology [1]. In a Turkish cohort of 1407 patients followed from 2010 to 2020, with parental consanguinity in 32.1%, testing was performed in 417 selected patients, with a yield of 66.8% for panels and 68.4% for exome; turnaround time fell from 28.1 months in 2010 to 2.3 months in 2020, and the results changed the diagnosis or treatment in 20.6% [34]. These figures reflect clinical selection and the frequency of consanguinity and cannot be extrapolated to unselected adult cohorts. The rate of multiple molecular diagnoses in IEI was 9–11% of diagnosed patients, higher than the approximately 5% in genetic diseases in general [1]. In the French CEREDIH registry, 48% of registered patients had no identified genetic abnormality (data cited in the 2023 PNDS); the document does not separate untested patients from patients with a negative test, so this value does not measure the yield of genetic testing [5].

The 2025 parameter distinguishes variant classification from clinical interpretation: the five-class ACMG classification (benign, likely benign, uncertain significance, likely pathogenic, pathogenic) acts as a likelihood ratio that should be combined with clinician-estimated pretest probability [1]. ACMG criteria favour loss-of-function mechanisms (nonsense, frameshift, canonical splicing sites, exon deletions) and are less suited to GOF mechanisms; few gene-specific specifications exist for IEI [1]. Parameter examples include a boy with agammaglobulinaemia and absent B cells, in whom a BTK VUS retains high post-test probability; a girl with SCID, in whom a single pathogenic JAK3 variant suggests a second undetected variant; and a healthy adult with an incidental likely pathogenic COPA variant, which has little relevance, acknowledging that the carrier may be presymptomatic [1]. These clinical reasoning principles do not permit reclassifying a VUS as pathogenic based on therapeutic response or partial segregation; segregation depends on penetrance, which is not necessarily complete, and parental testing (trio analysis) defines the origin and cis/trans phase of candidate variants [1].

Genetic reports should identify the gene, versioned reference transcript, HGVS nomenclature, zygosity, ACMG/AMP classification and test limitations. For example, the recurrent APDS1 variant is described as NM_005026.5(PIK3CD):c.3061G>A, p.(Glu1021Lys), NC_000001.11:g.9726972G>A on GRCh38; VariantValidator confirmed NM_005026.5 as the MANE Select transcript and validated its genomic correspondence [35], and ClinVar classifies it as pathogenic with expert panel review (VCV000088675.78, evaluated 19 December 2025) [36]. TNFRSF13B variant genetics illustrates interpretative limitations: heterozygous variants occur in approximately 1% of the healthy population and are insufficient to cause antibody deficiency [2, 17].

A negative result does not exclude an IEI with a convincing phenotype: coverage may omit non-coding regions, small CNV, pseudogenes or low-level mosaicism, and the responsible gene may remain undescribed [1, 2]. The parameter recommends allowing clinicians experienced in IEI to request genetic testing, with pre- and post-test genetic counselling addressing defect nature, inheritance, penetrance and reproductive implications, alongside informed consent and information protection [1]. Through its molecular testing working group, ERN RITA maintains a European list of specialised functional testing laboratories and states that most countries should offer naïve and memory T- and B-cell immunophenotyping including Treg, a neutrophil panel, MHC I and DR, proliferation assays (PHA, CD3 and memory antigens), vaccine responses, Ig and functional complement, and NBT/DHR [10].

6. Differential Diagnosis

The differential for recurrent infections begins with conditions increasing susceptibility without IEI: allergic inflammation predisposing to otitis and sinusitis; adenoidal hypertrophy; cystic fibrosis, ciliary dyskinesia and pulmonary anatomical abnormalities; and lifestyle factors such as older siblings, nursery attendance and tobacco smoke exposure [18]. Secondary immunodeficiency due to immunosuppressive therapy, malnutrition, infiltrative or malignant disease, infections such as HIV, protein loss, surgery and age extremes should be excluded [1, 18]. Immunodeficiency may also be acquired in critically ill children with overwhelming infection; discussion with an immunologist helps determine whether it is part of the underlying disease or an acquired effect [13].

Distinguishing CVID from monogenic IEI with a similar phenotype warrants attention because it changes treatment: APDS, CTLA-4 and LRBA deficiencies, X-linked lymphoproliferative disease, attenuated-phenotype XLA, class-switch defects and myelodysplasia with hypogammaglobulinaemia may present as CVID [1, 18]. Some BTK variants produce milder phenotypes, with sufficient Ig to suggest CVID or SAD, but with CD19+ B cells always low [18]. Hyper-IgM syndromes with a T-cell defect (CD40L, NEMO) are distinguished from AID and UNG defects by T-cell proliferation and opportunistic infections, a distinction that is not always reliable and requires molecular definition because prognosis and therapy differ [1, 18]. In ataxia-telangiectasia, the pattern of low IgG, IgA and IgE with normal or raised IgM brings hyper-IgM into the differential diagnosis [1].

7. Treatment and Risk Management Strategies

7.1. General principles

After diagnosis, preventive and replacement measures should start promptly because delayed reconstitution may cause permanent organ injury (bronchiectasis, bronchiolitis obliterans) or death from infection [18]. The 2025 parameter suggests clinical immunologist consultation and multidisciplinary care, with regular assessments every 4 to 12 months according to diagnosis [1]. The following table summarises general therapeutic recommendations from the 2025 parameter, with recommendation strength and evidence certainty [1].

7.2. Immunoglobulin replacement: indications

Human polyclonal IgG replacement provides passive immunity and prevents serious bacterial infections (pneumonia, sepsis, meningitis, visceral abscesses, osteomyelitis/septic arthritis) in IEI with humoral deficiency [1]. It is indicated as essential ongoing therapy; only selected cases, such as childhood SAD or transient hypogammaglobulinaemia, permit temporary interruption to assess resolution, and this strategy should not be repeated if the assessment demonstrates persistent deficiency [1]. It may remain necessary after HSCT if B-cell function is not restored [18].

The British BSI/UKPIN consensus, developed through a modified Delphi method with 73 recommendations, indicates replacement in confirmed CVID with recurrent infections or significant autoimmune or inflammatory disease (e.g. GLILD), XLA or AR agammaglobulinaemia, SCID, hyper-IgM syndromes and Good syndrome with low IgG and infections [8]. Otherwise, it proposes decisions based on IgG and vaccine response thresholds: with IgG ≥4 g/L, preserved responses and low infection burden, replacement is not routinely indicated; with IgG ≥4 g/L and poor responses (including SAD), only after 6 months of antibiotic prophylaxis and optimisation (e.g. chest physiotherapy) without control, or with bronchiectasis; with IgG <4 g/L and poor responses, consider replacement unless infection burden is low; with IgG <2 g/L and increased infection burden, initiation may precede an antibiotic prophylaxis trial [8]. The authors acknowledge that 2 and 4 g/L thresholds are arbitrary and not evidence-based [8]. For SAD, the 2015 parameter proposed decisions based on immunological and clinical severity and, in stabilised patients, discontinuation after 1 to 2 years for 4 to 6 months for reassessment [18]. In selective IgA deficiency, replacement is controversial and reserved for patients whose infections impair quality of life despite antibiotic prophylaxis [18].

The French PNDS sets a formal indication in agammaglobulinaemias and when IgG is below 3 g/L; in other hypogammaglobulinaemias, including CVID, and in humoral deficiencies, the decision weighs the number of infections, IgG, clinical impact and vaccine protection, after discussing with a competence or reference centre the absence of an alternative, such as antibiotic prophylaxis; in secondary immunodeficiencies, the indication requires specialist advice and discussion at a multidisciplinary team meeting [5]. The French threshold of 3 g/L lies between the two thresholds of the British consensus (2 and 4 g/L) [5, 8]. The PNDS points out that immunoglobulins are blood-derived medicines, obtained from plasma collected in France or abroad (Europe and the USA), pooled from several hundred donors after quarantine and viral inactivation, fractionated and purified so that only IgG is administered (IgA and IgM in minimal quantities), and that supply tensions led the French medicines agency (ANSM) to keep IEI as a priority indication [5].

7.3. Doses, targets and divergences between sources

The divergence between the European label target (≥6 g/L, i.e. 600 mg/dL) and American and British guideline targets (>800 mg/dL or ≥8 g/L) reflects their different roles: the SmPC sets a regulatory minimum common to all replacement indications, while guidelines incorporate biological trough and pneumonia data [1, 8, 40]. “Biological trough” captures individual variation: in a study cited by the 2025 parameter, at doses of 200 to 1200 mg/kg/month, patients with XLA required troughs of 800 to 1300 mg/dL to remain infection-free, and those with CVID required 500 to 1700 mg/dL [1]. IgG is measured at trough (before infusion) for IV treatment and at steady state for SC treatment, every 6 months to annually in stable patients, and monthly with intercurrent infections, pregnancy, protein loss, immunosuppression, weight changes or adherence concerns [1]. With SC administration, peak occurs 3 to 5 days after infusion and steady state after 4 to 6 months; some American manufacturers recommend multiplying the IV dose by 1.35 to 1.53 when converting to SC [1].

The French PNDS describes the practical organisation [5]. The IV route usually requires a day hospital, with infusions of 2 to 4 hours every 3 to 4 weeks depending on the patient, the type of IEI and pulmonary or gastrointestinal complications, and may move to the home if medical conditions are met; the first infusions and their initial frequency are adjusted to baseline IgG to reach a protective trough quickly. The SC route is mainly by home self-administration, with infusions of at most 50 mL, 2 to 4 times a month depending on weight and type of IEI, or monthly after injection of hyaluronidase, which allows 300 to 400 mL per site. In adults, long-term venous access should be avoided whenever possible, because of the infectious risk, by seeking an alternative to the IV route; the route and brand may change over time according to preference and tolerance, and each administration should be traceable. The PNDS position on the “summer break” diverges from the American recommendation of continuous replacement and from the caveat that interruption is justified only once, to reassess potentially transient diagnoses [1, 5].

7.4. Products: US and EU labels

All American immunoglobulin labels have boxed warnings for thrombosis and, for IV products, acute renal dysfunction and failure, more frequent with sucrose-containing products; Privigen contains no sucrose [42, 44, 45]. The 2025 parameter warns that Ig products are not interchangeable generics and product changes should involve the prescriber, although an analysis of 802 shortage-related switches in 2017–2018 recorded only 12 reactions, none requiring hospitalisation [1]. The American “primary humoral immunodeficiency” indication is class-defined and includes, without being limited to, congenital agammaglobulinaemia, CVID, XLA, Wiskott–Aldrich syndrome and SCID [42]; use in a specific unlisted IEI (e.g. APDS) falls within this class indication and is not off-label when humoral deficiency is demonstrated.

7.5. Immunoglobulin adverse effects and management

Infusion reactions (fever, chills, malaise, headache, myalgia, low back pain, flushing, nausea, blood pressure changes, tachycardia, volume overload and local reactions with SC administration) occur in 5–15% of IV infusions, are generally mild and rate- or dose-dependent, and are more frequent with active inflammation; slowing or stopping infusion for 15 to 30 minutes reverses many reactions [1]. An Immune Deficiency Foundation survey found that 34% of reactions occurred during the first infusion of a product, and new reactions become less likely after three treatments with the same product [1]. Following a reaction, premedication one hour beforehand (ibuprofen or paracetamol and an H1 antihistamine and/or hydrocortisone) and hydration may be used, cautiously in renal or cardiac insufficiency and diabetes [1]. Rare severe effects include kidney injury, thrombosis, aseptic meningitis, haemolysis (more frequent with blood groups A and AB and high doses), arrhythmia and transfusion-related acute lung injury; thrombosis risk factors include cardiovascular disease, diabetes, dehydration, age over 65 years, sepsis, paraproteinaemia, hyperviscosity, hypercholesterolaemia and hypertension [1]. SC administration has fewer systemic effects [1]. Central venous catheters exclusively for IVIg are not recommended, and SC administration is the alternative with difficult venous access [1].

Regarding IgA deficiency, most patients with low IgA, with or without IgG anti-IgA antibodies, receive IVIg without difficulty; with significant systemic symptoms, SC administration or an IgA-depleted product should be considered [1]. The labels contraindicate the products in patients with IgA deficiency, anti-IgA antibodies and a history of hypersensitivity [42, 44]. The French PNDS is aligned with this caution: preparations very low in IgA (Gammagard®, Takeda, in the PNDS designation) are scarce and more expensive, are not justified as first line in IgA deficiency and are reserved for patients with acquired anti-IgA antibodies responsible for severe clinical intolerance, assessed case by case, because intolerance reactions (chills, fever, hypotension, headache, fatigue, influenza-like illness) are very frequent with all preparations, even without anti-IgA antibodies, and tend to disappear after a few weeks of treatment [5]. To control them, the PNDS proposes reducing the infusion rate, ensuring good hydration and premedicating with paracetamol and/or an antihistamine started before the infusion and continued for 24 hours, which extends the premedication given one hour before the infusion described in the American parameter [1, 5].

7.6. Anti-infective prophylaxis

Prophylaxis targets the defect. The table integrates 2025 parameter regimens, with aciclovir corrections from the 28 September 2026 corrigendum [1, 6].

The 2015 parameter provided alternative respiratory prophylaxis regimens (e.g. amoxicillin 10–20 mg/kg once or twice daily in children and 500–1000 mg in adults; TMP-SMX 5 mg/kg TMP in children and 160 mg in adults; azithromycin 10 mg/kg weekly or 5 mg/kg on alternate days in children and 500 mg weekly or 250 mg on alternate days in adults; clarithromycin 7.5 mg/kg or 500 mg; doxycycline above age 8 years), noting that no prospective antibiotic prophylaxis studies existed in IEI outside chronic granulomatous disease [18]. This gap was partly addressed by an Italian randomised double-blind trial in 89 patients with primary antibody deficiency and chronic lung disease receiving Ig: azithromycin 250 mg three times weekly for 2 years reduced respiratory exacerbations from 5.2 to 3.6 per patient-year (P = 0.02), with an exacerbation hazard ratio of 0.5 and fewer additional antibiotic courses (2.3 vs 3.6 per patient-year), and safety comparable to placebo; 25% of H. influenzae and S. pneumoniae isolates were macrolide-insensitive in both arms [50]. Before starting azithromycin, non-tuberculous pulmonary mycobacterial disease should be excluded; bronchiectasis makes azithromycin the preferred prophylaxis because of antimicrobial and anti-inflammatory actions [1]. In SAD, transient hypogammaglobulinaemia and other hypogammaglobulinaemias, antibiotic prophylaxis is the first-line alternative to Ig [1].

For ear, nose and throat and pulmonary infections due to encapsulated bacteria with moderate hypogammaglobulinaemia, the French PNDS proposes co-trimoxazole (Bactrim® in the French designation; sulfamethoxazole + trimethoprim) 25 mg/kg/day, with a maximum of 800 mg/day, as a single daily dose and long term, possibly combined with immunoglobulin 0.4 g/kg every 3 weeks for at least 9 months a year (October to June) [5]. The dose and maximum refer to the sulfamethoxazole component (the double-strength tablet contains 800 mg of sulfamethoxazole and 160 mg of trimethoprim), that is, approximately 5 mg/kg/day of trimethoprim with a maximum of 160 mg, values close to those of the 2015 parameter (5 mg/kg of trimethoprim in children and 160 mg in adults) [18]. The decision is individual, with the reference immunologist, according to the recurrence of infections and the severity of the humoral deficiency, if necessary after a multidisciplinary team meeting, and co-trimoxazole requires laboratory monitoring of tolerance (neutropenia, hepatic cytolysis) 1 month after initiation and then at least annually [5]. Azithromycin is the alternative, as second-line antibiotic in co-trimoxazole intolerance (without prophylactic effect against Pneumocystis) or as first line with bronchial anti-inflammatory intent in some pulmonary diseases of isolated humoral deficiencies, particularly bronchiectasis with chronic productive cough, at a dose of 250 mg three times a week (or on alternate days) in adults, after an electrocardiogram excluding long QT, with reassessment at 3 months; the PNDS reports good tolerance for up to 2 years and relies on experience in cystic fibrosis for long-term safety [5]. Penicillin remains first-line antibiotic prophylaxis in splenectomised patients [5]. The differences from the American parameter concern the regimen and the choice of drug: the PNDS uses daily co-trimoxazole as antibacterial prophylaxis for humoral deficiencies, whereas the 2025 parameter reserves co-trimoxazole 2–3 times a week for the prevention of pneumocystosis in SCID and athymia and prefers azithromycin, with amoxicillin or co-trimoxazole as alternatives, for respiratory prophylaxis of antibody deficiencies on Ig; for azithromycin, the fixed adult dose in the PNDS (250 mg three times a week) coincides with that of the Italian randomised trial, whereas the 2025 parameter gives 5 mg/kg/day (maximum 250 mg/day) or 500 mg three days a week [1, 5, 50]. For co-trimoxazole prophylaxis, the reference dose is that of the PNDS and of the 2015 parameter, which are concordant [5, 18].

Specific precautions: TMP-SMX may cause neonatal hyperbilirubinaemia; antimicrobials used in IEI (TMP-SMX, azoles, tetracyclines, fluoroquinolones) require pregnancy risk discussion; voriconazole and doxycycline (and TMP-SMX to a lesser extent) cause photosensitivity, while prolonged voriconazole is associated with skin cancer; azithromycin, fluoroquinolones and some azoles prolong QTc [1]. Following at-risk varicella exposure, susceptible patients may receive specific varicella immunoglobulin or, alternatively, Ig 400 mg/kg within the following 10 days (if not receiving Ig), or aciclovir/valaciclovir for 7 days starting on the 7th–10th day [1]. Following measles exposure, the European SmPC specifies 0.4 g/kg within the following 6 days or an additional dose in IVIg recipients; if maintenance is below 0.53 g/kg every 3–4 weeks, increase it once to 0.53 g/kg before anticipated exposure [40].

7.7. Blood products, environment and surgery

In CID or athymia, only irradiated, CMV-negative and leucocyte-depleted blood products should be used to prevent transfusion-associated graft-versus-host disease and CMV infection [1]. Exposure education includes massive mould inhalation, endemic fungi, untreated fresh water and Cryptosporidium sources; safe water and hygiene reduce giardiasis and bacterial intestinal infections in antibody deficiencies [1]. Surgical procedures intended to reduce infection susceptibility (tympanostomy tubes, tonsillectomy, endoscopic sinus surgery) lack demonstrated efficacy in IEI [18]. Isolated antibody deficiencies do not usually require antibiotic prophylaxis for invasive dental treatment, unlike neutropenias and STAT3 HIES [1].

For patients with neutrophil dysfunction, such as chronic granulomatous disease, and with central neutropenia, the French PNDS details domestic antifungal precautions [5]: do not carry out heavy building work in the patient's presence (stripping wallpaper, drilling or altering walls) and clean all surfaces several times with a damp cloth before the patient returns, avoiding passing through building sites or wearing a mask when unavoidable; avoid attics, cellars, barns, stables and places with compost, hay or straw; do not inhale pepper, tea, freeze-dried soups or the inside of flowers (eating cooked foods and spending time in gardens are allowed); do not use chalk erasers; wear long trousers on woodland walks and do not climb trees, to avoid wounds from wood; do not handle soil, or be present during ploughing, hay handling, lawn mowing or handling of manure and compost. Daily cleaning of the home is not necessary; keeping it clean is sufficient [5].

Travel is possible to most destinations, but, depending on the IEI, the PNDS advises avoiding stays in rural areas, contact with domestic or wild animals, food of uncertain quality or poorly preserved, non-bottled water, pre-peeled fruit and the rainy season (vector proliferation) [5]. Travel is prepared in advance with the specialist team: required or contraindicated vaccines (in particular live vaccines), malaria prophylaxis according to the country's general recommendations, with attention to interactions with IEI medication, logistics of immunoglobulin replacement and insurance conditions for care and repatriation; it is pointed out that several IEI reduce vaccine response and, therefore, protection [5].

7.8. Vaccination

Patients with isolated T-cell lymphopenia and preserved cellular and humoral function (including 22q11.2 deletion syndrome, CHARGE and non-SCID T-cell lymphopenia on newborn screening) may receive live vaccines; guidance cited in the parameter proposes CD4 above 400/µL, CD8 above 200/µL, naïve CD4 above 20% and protective tetanus titres [1]. HPV vaccination is recommended from ages 9 to 45 years in all IEI, including Ig recipients, in three doses, because Ig preparations contain insufficient antibodies and clearance depends on CD4 [1]. Patients no longer requiring Ig should receive catch-up live viral vaccines at least 6 to 8 months after the last infusion [1]; the 2015 parameter advised delaying MMR and varicella for 8 months after a replacement dose (300–800 mg/kg) and 11 months after 2 g/kg [18]. Inactivated vaccines may follow usual schedules, particularly those not covered by polyclonal IgG, such as influenza [18].

The French PNDS refers to the recommendations of the Haut Conseil de la Santé Publique on vaccination of immunocompromised people and to documents from CEREDIH and the IRIS association, and adds practical points [5]. Live attenuated vaccines are formally contraindicated in profound cellular deficiencies (and under certain immunosuppressants), and BCG is contraindicated in innate immunity disorders; each indication should be discussed with the patient's IEI reference physician. Some countries do not accept exemption from yellow fever vaccination; the PNDS advises against issuing contraindication certificates to patients with IEI, because natural flavivirus infection is also dangerous for them, and recommends assessing with the reference physician the need for a stay in an endemic area according to the depth of the cellular deficiency. The absence of antibodies after vaccination may contribute to the diagnosis. When a profession or training requires mandatory vaccination (for example, hepatitis B) in a patient on immunoglobulin, a serology showing protective antibodies conferred by replacement may be presented and/or the vaccine administered, which at least serves as proof of vaccination. Influenza and COVID-19 vaccination is recommended for the patient and household contacts (“cocooning” strategy), without specific contraindications beyond those of the general population. Patients with humoral deficiencies should be up to date with routine vaccination against diphtheria, tetanus, poliomyelitis and pertussis, and with meningococcal (quadrivalent and serogroup B), pneumococcal and Haemophilus vaccines [5]. The PNDS mentions the contraindication of live vaccines only in cellular deficiencies and does not expressly address isolated humoral deficiencies, whereas the American parameter also contraindicates them in antibody deficiencies and highlights, on Ig, the vaccines whose protection Ig does not provide (influenza, COVID-19, HPV, recombinant zoster) [1, 5].

7.9. Immune reconstitution

Overall 5-year survival after allogeneic HSCT in IEI is approximately 80%, varying with the disease, HLA compatibility, conditioning, cell source, age and comorbidities [1]. HSCT or gene therapy is recommended in typical and atypical SCID; cultured thymus tissue implantation in congenital athymia; HSCT should be considered in CID with a severe cellular defect or refractory complications, in primary haemophagocytic lymphohistiocytoses and in XLP1, and suggested in severe or refractory dysregulation disorders, and should be performed in experienced centres with lifelong follow-up [1]. For SCID, the Oxford Desk Reference reports survival above 90% with an HLA-identical sibling and 60–80% with a matched unrelated donor, phenotypically identical relative or haploidentical parent [13]. In ADA1 deficiency, the consensus cited in Saudubray reports survival above 80% with unconditioned HSCT from an HLA-matched sibling, with enzyme replacement therapy before transplantation and autologous gene therapy as an alternative in the absence of a matched donor [15]; Strimvelis® gene therapy has been authorised in the EU since 26/05/2016 for ADA-SCID without an HLA-matched family donor [43]. Minimal-intensity conditioning is used in radiosensitive diseases [1]. In France, HSCT for IEI is reserved for expert centres defined by CEREDIH, and the 2023 PNDS presents gene therapy by transfer of a functional gene as an option for children who cannot receive a rapid and safe HSCT, still limited to very few patients and diseases [5].

7.10. Precision medicine

The 2025 parameter recommends targeted therapies based on the molecular defect or a suggestive phenotype (conditional to strong; low to high certainty) [1]. The table distinguishes medicines with approved IEI indications from off-label uses.

Adverse effects determine monitoring: JAK inhibitors are associated with viral infections, cytopenias, elevated liver enzymes and triglycerides, requiring blood counts, liver profiles and viral PCR [1]; leniolisib may cause fetal harm (check pregnancy status before initiation), and commonest effects (>10%) were headache, sinusitis and atopic dermatitis from age 12 years and abdominal pain, cough and respiratory infection at ages 4–11 years; neutrophil counts of 500–1500/µL occurred in 33% of patients ≥12 years and 63% aged 4–11 years, with none below 500/µL [52]; mavorixafor is contraindicated with medicines highly dependent on CYP2D6, prolongs QTc and has embryofetal toxicity, and commonest effects were thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting and dizziness [59]; abatacept should not be combined with live vaccines or TNF inhibitors [1]. In CTLA-4 haploinsufficiency, splenectomy for cytopenias produced sustained responses in only 4 of 16 patients, and HSCT cured 13 of 18 (72%) [54]; in STAT1 GOF, HSCT in 15 patients had overall survival of 40% [16].

7.11. Regulatory table for targeted medicines

Authorisation does not guarantee marketing, reimbursement or access in each country; INFARMED or ANVISA/CONITEC data for these medicines were not consulted.

7.12. Pivotal trials and interpretation limits

These studies do not permit indirect drug comparisons. Targeted inhibitor trials included approximately 30 patients each, with surrogate endpoints (lymph node, naïve B cells, time above a neutrophil threshold) and durations of 12–52 weeks; infection reduction in the mavorixafor trial was a secondary endpoint with nominal P. Immunoglobulin trials are single-arm studies in previously treated patients and demonstrate maintenance of a low serious infection rate rather than superiority between products. Abatacept, JAK inhibitor and sirolimus evidence derives from cohorts and a single-arm trial, without a published randomised trial [1, 16, 54].

7.13. Developments in the past 6–12 months (April–October 2026)

According to ClinicalTrials.gov, phase 3 leniolisib trials are ongoing in children aged 4–11 years (NCT05438407, 15 participants, primary completion expected November 2026) and 1–6 years (NCT05693129, 16 participants, expected July 2028), alongside phase 2 trials in patients with IEI and immune dysregulation (NCT06549114; extension NCT06990529) [63]. No IUIS classification update after 2024 was identified in the search, which does not establish that one is not being prepared.

7.14. Divergences between the French PNDS and other guidelines

The French PNDS, with text dated December 2022, predates the 2025 American parameter and is aimed mainly at the attending physician [1, 5, 8]. For doses, the guideline is the reference; labels serve for comparison.

8. Reproductive Options and Family Counselling

Counselling should address the specific diagnosis, and molecular diagnosis underpins information about carrier status and prenatal diagnosis [13]. The 2015 parameter recommended defining carrier status in all potentially affected relatives in severe IEI and considering X-linked disease even in females after other possibilities are excluded, because extremely skewed X inactivation may produce the phenotype in carriers of chronic granulomatous disease, Wiskott–Aldrich, XLA and CD40L deficiency [18]. The 2025 parameter adds that carriers in some X-linked diseases may have health problems even without skewed X inactivation [1].

XLA illustrates counselling figures for X-linked diseases: half of newly diagnosed boys lack a family history; in these sporadic cases, 80–85% of mothers are carriers and 15–20% of variants are de novo, usually arising in the maternal grandfather; maternal grandmothers are carriers in fewer than 20% of isolated cases, so carrier risk for a woman whose sister has a son with XLA, without other family history, is below 10%; more than 90% of affected boys have a detectable BTK variant, and even if the mother is not a carrier, a small recurrence possibility (<5%) remains through germline mosaicism [13]. In AR DNA repair diseases, future pregnancy risk is 1 in 4; in ataxia-telangiectasia, with carrier frequency approximately 1 in 200, a healthy sibling's risk of an affected child is 2/3 × 1/200 × 1/4 = 1/1200, and an uncle's or aunt's risk 1/1600, unless consanguinity applies [14]. In AD diseases with incomplete penetrance (CTLA-4, STAT1 GOF, NFKB1), testing unaffected relatives enables surveillance, but variant presence does not predict disease with certainty [1, 21].

Testing unaffected minors should consider whether results have an immediate health impact or can await adulthood; in biallelic and X-linked diseases, carrier testing serves family planning [1]. Prenatal diagnosis through chorionic villus sampling is possible when the proband's variant is identified; in ADA and PNP deficiency, prenatal diagnosis may use villus enzyme analysis and carrier status may be established biochemically; when the molecular defect underlying SCID is unknown but the phenotype is unequivocal, fetal blood lymphocyte subset analysis may be offered in the second trimester [13]. The Oxford Desk Reference recommends considering collection and storage of newborn siblings' cord blood in severe immunodeficiencies potentially requiring HSCT (as a stem cell source for the affected sibling if the newborn is unaffected, or for future gene therapy if affected) and, without prenatal diagnosis, sending cord blood for immunophenotyping, coordinated with obstetrics and the laboratory [13]. In DNA repair defects, prenatal diagnosis is usually possible at 11 weeks through chorionic villus sampling in liaison with a specialised laboratory [14].

Heterozygous ATM carriers have an approximately 3.6-fold higher risk of breast cancer, and the Oxford Desk Reference advises avoiding regular mammography, preferring clinical assessment from age 50 years, and minimising diagnostic radiographs [14]; this guidance should be weighed against current guidelines. Pregnancy in a patient with antibody deficiency requires more frequent (monthly) IgG monitoring [1] and may favour the SC route [1]; IgG crosses the placenta increasingly after 30 weeks, and the Privigen label states that there are no human data on fetal risk [42]. Leniolisib and mavorixafor have documented embryofetal toxicity in animals and require effective contraception [52, 59].

The French PNDS recommends that plans for pregnancy be discussed in advance with the reference immunologist and the centre's geneticist, which allows transmission to be addressed and, depending on the IEI and if the genetic cause is identified, a joint decision (immunologist, obstetrician, attending physician and geneticist) on prenatal diagnosis, newborn screening or later evaluation of the child born to a parent with IEI [5]. Pregnancy, delivery, anaesthesia and breastfeeding generally follow the arrangements of the general population; the infectious risk matters mainly if there is associated neutropenia and the haemorrhagic risk if there is thrombocytopenia, and the teratogenic risk of the mother's long-term treatments is discussed in terms of the benefit/risk balance [5]. Immunoglobulin replacement should not be interrupted during pregnancy and the dose often has to be increased, which agrees with the monthly IgG monitoring proposed in the American parameter [1, 5]. An IEI diagnosis may cause psychological distress and depression in patients and parents, and the neonatal period adds the risk of postpartum depression, so screening for depression in close relatives may be considered [1].

9. Special Considerations: Population Diversity and Epidemiology

The true incidence of IEI is unknown because it has not been studied prospectively [18]. The 2015 parameter summarised registry and survey data suggesting symptomatic IEI incidence of 1 in 10,000 to 1 in 2000 live births and general population prevalence of 1 in 10,000 to 1 in 12,000, with US SCID incidence approximately 1:58,000 live births, much higher frequencies in some consanguineous communities and a male:female ratio of approximately 5:1 in children, approaching 1:1 in adults [18]. The more recent US estimate, based on standardised electronic health records for 152 million patients, was 6 per 10,000 (0.056%), corresponding to 150,000 to 200,000 affected people [4]; this depends on diagnostic coding and does not constitute genetically confirmed prevalence. The Jeffrey Modell Foundation publicises a frequency of 1 in 500 people affected by a known primary immunodeficiency [27], an awareness figure including common conditions such as selective IgA deficiency.

Antibody deficiencies account for approximately half of IEI; combined defects, phagocyte defects and other syndromes each account for 10–20%, while dysregulation, innate immunity, autoinflammatory and complement disorders each account for less than 1%, according to registries summarised in 2015 [18]. CVID affects approximately 1:30,000 people, with particularly high prevalence described in northern Europe [1]; GeneGuidance, drawing on Orphanet data for “CVID and related diseases” (ORPHA:696851), records 2.5 per 100,000 [16]. Selective IgA deficiency affects approximately 1:500 white individuals and is less frequent in Asians (1:3000 to 1:18,000) [1], while chronic granulomatous disease affects approximately 1:200,000 live births [18]. These frequencies apply to individual conditions and should not be transferred to single genes: for example, NFKB1 LOF variants explained 4% of 390 European CVID cases [20], and estimated APDS prevalence is approximately 1 per million (0.1/100,000) for APDS1 and APDS2 together [16].

The ESID registry, a central European platform established in 2004, contained information on more than 25,000 patients in 2019, with CVID the largest group [7]. Consanguinity increases the proportion of AR diseases and the yield of genetic testing: in the Turkish cohort of 1407 patients, 32.1% had consanguineous parents and 71.4% of the identified variants showed AR inheritance, with a predominance of antibody deficiencies (67.8%) and combined immunodeficiencies (12.2%) [34]. In Brazil, a systematic review of national studies using next-generation sequencing identified 10 studies (6 case reports and 4 series) involving 419 patients, of whom 82 (19.6%) received an IEI diagnosis, mainly SCID, chronic granulomatous disease and XLA; the studies came from the Southeast, Northeast and South regions, with no data from the North or Central-West, and the authors cite an IEI prevalence in Latin America of approximately 1 in 10,000 [65]. In France, the 2023 PNDS, based on the CEREDIH national registry, estimates approximately 400 new cases per year (approximately 1 in 2000 births) and a prevalence of 9.44 per 100,000 inhabitants (data as of 14 December 2021); 80% of patients followed are aged between 6 and 25 years, there is a male predominance, attributed to X-linked forms, and diagnostic delay is frequent because of the heterogeneity of presentations [5]. This registry prevalence, approximately 1 in 10,600, is lower than the American estimate from electronic records (6 per 10,000), but the two values result from different methods (a registry of patients followed in centres in one case; coding of diagnoses in electronic records in the other) and are not directly comparable [4, 5]. The PNDS counts at least 600 IEI, more than 480 of them with a known genetic cause at the time, figures already exceeded by the 2024 classification [2, 5]. The same document estimates selective IgA deficiency at approximately 1 in 600 Caucasians (elsewhere, 1 in 500 to 700 in the general population), with a much lower frequency in Asians and in Africans or African Americans [5]. No epidemiological data from Portugal were found in the consulted sources; this absence does not demonstrate that published studies do not exist. Some DNA repair diseases have population-specific frequencies: Bloom syndrome is more frequent in Ashkenazi Jews, and FANCC is the most frequent Fanconi anaemia gene in this population [14].

Networks and organisations. In Europe, ERN RITA brings together reference centres for rare immunological diseases, with primary immunodeficiency, autoinflammatory, autoimmune and paediatric rheumatology streams, its own registry, a molecular testing group and a clinical guidelines group [10]. The European Society for Immunodeficiencies (ESID), the International Patient Organisation for Primary Immunodeficiencies (IPOPI), the Immune Deficiency Foundation, the Jeffrey Modell Foundation and the United States Immunodeficiency Network (USIDNET) are among the clinician and patient resources listed in the 2015 parameter [18]; in the UK, the Oxford Desk Reference lists PID UK, the CGD Society and the AT Society [13]. In France, according to the PNDS, the Reference Centre for Hereditary Immune Deficiencies (CEREDIH), coordinated at Hôpital Necker-Enfants Malades with constituent centres in Angers, at Hôpital Saint-Louis (Paris) and in Marseille, operates as a national network of paediatric and adult clinicians and biologists supported by all university hospital centres of metropolitan and overseas France, under the aegis of the immuno-haematological rare disease health network (MaRIH); it organises monthly multidisciplinary team meetings by videoconference (including the national North and South meetings) for cases of difficult diagnosis or treatment and maintains the national registry, linked to the ESID European registry [5]. The care pathway may include the long-term condition scheme (ALD 2, “immune deficiencies”) [5]. The national patient association IRIS (Immuno-déficience primitive, Recherche, Information, Soutien), founded in 1998, recognised as being of public utility and a founding member of CEREDIH, supports patients and families with medical and social information and regional volunteers; the PNDS also lists the Society of Paediatric Haemato-Immunology (SHIP) and the French National Society of Internal Medicine as resources [5]. Specific Portuguese or Brazilian organisations were not verified in the consulted sources.

10. Illustrative Clinical Case

Ahmad Shawaludin and colleagues (Malaysia, 2025) published this case to illustrate diagnostic pitfalls in an IEI with a combined immunodeficiency phenotype [66]. A boy, the fifth of seven healthy siblings, born at 37 weeks to non-consanguineous parents without an immunodeficiency family history, had repeated admissions from age 9 months for respiratory infections requiring antibiotics and oxygen, 3 to 4 ear infections per year, recurrent rhinosinusitis, slowly resolving herpes zoster with a keloid, and eczema; growth delay, lymphadenopathy and hepatosplenomegaly subsequently developed, without dysmorphism or developmental delay [66].

Assessed in immunology clinic at age 2 years and 5 months, he had lymphopenia (1.0 × 10⁹/L) and thrombocytopenia (86 × 10⁹/L) without blasts, elevated IgM (2.92 g/L; reference 0.31–1.79) with IgA and IgG within or near reference values (IgG 7.56, reference 7.7–15.1, units as reported by the authors), B cells 283/µL (reference 1800–3000) and T cells 907/µL (reference 1200–2600), and an inadequate response to 23-valent pneumococcal polysaccharide vaccine and tetanus toxoid (less than a 4-fold increase) [66]. Serial laboratory values appear in the article's Table 1 and Table 2 and the article contains no figures. Combined immunodeficiency was suspected and, because of thrombocytopenia and hepatosplenomegaly, Langerhans cell histiocytosis was considered, but the parents declined bone marrow aspiration, genetic testing and Ig; prophylactic azithromycin 5 mg/kg three times weekly was started, with partial control (2 to 3 mild episodes annually without admission) [66].

After interrupted follow-up between 2020 and 2023 and a change of centre, cytopenias, B- and T-cell lymphopenia, lymphadenopathy and hepatosplenomegaly persisted; exome sequencing funded by the parents' employer (mean coverage 156.95×) identified the heterozygous NM_005026.5:c.3061G>A, p.(Glu1021Lys) variant in PIK3CD, classified as pathogenic, confirming APDS1 [66]. Notation, genomic correspondence (NC_000001.11:g.9726972G>A) and transcript MANE Select status were confirmed in VariantValidator, and ClinVar classifies the variant as pathogenic with expert panel review [35, 36]. IVIg 0.4 g/kg every 4 weeks was initiated without reactions, achieving a trough of 8 g/L, fewer infections, no admissions and improved school attendance; chest CT showed no bronchiectasis, audiometry was normal and the blood film showed no lymphoma; the parents were counselled about immunosuppressants and targeted treatment but remained undecided because of financial and access concerns, and relatives were not tested because of resource constraints [66].

The case illustrates several points of this article: elevated IgM with low B cells and poor vaccine responses should prompt testing of the PI3Kδ pathway rather than CD40L alone; antibiotic prophylaxis alone partially controls infections but not lymphoproliferation; delayed molecular diagnosis prevented access to targeted therapies; and a monthly 0.4 g/kg dose with an 8 g/L trough aligns with American and British guidelines [1, 8, 66]. Management reflects the report and does not replace recommendations: at publication, leniolisib was US-approved only from age 12 years; since 11 September 2026, the American label includes children from age 4 years weighing at least 27 kg, while the EU indication requires age 12 years and 45 kg [52, 53].

11. Prognosis and Long-Term Follow-up

The natural history of IEI is highly variable, and severity may vary within a family [13]. In primary antibody deficiencies, the long-term prognosis should be good if diagnosis is not delayed and Ig replacement and monitoring are adequate; infants with SCID rarely survive beyond age 2 years without corrective treatment; and, in many other diseases, the prognosis is less favourable and HSCT, other forms of transplantation or gene therapy are increasingly recommended [13]. Long-term complications result from infectious injury (particularly bronchiectasis) or immune dysregulation: enteroviral meningoencephalitis in XLA and CVID has become less frequent with higher Ig doses; autoimmunity and granulomatous disease are common in CVID; liver disease, particularly sclerosing cholangitis, is a risk in CD40L deficiency; and lymphoproliferative disease and malignancy are risks in many diseases, particularly chromosomal fragility disorders [13]. In CVID, chronic non-infectious lung disease is associated with reduced survival [18]. In the French CEREDIH national registry, overall mortality, adults and children combined, was 19% in December 2021; at the same time, the PNDS emphasises the clear improvement in life expectancy of paediatric patients with optimised care [5]. This proportion of deaths among registered patients is neither a period mortality rate nor applicable to each entity.

Radiosensitive diseases require avoidance of therapeutic ionising radiation and caution with diagnostic radiographs [14, 18]. In APDS, the case report proposes surveillance for bronchiectasis and lymphoma with specialist review every 6 to 12 months, in the absence of formal guidelines [66], and the GeneGuidance curation summarises the surveillance described in GeneReviews (annual assessment of EBV, CMV and HSV, Ig and subsets, lung function tests, chest CT or MRI every 3–5 years and liver ultrasonography every 2–3 years) [16]. Paediatric-to-adult transition is the subject of recommendations listed by ERN RITA [10]; in France, the CEREDIH network includes paediatric and adult clinicians, and the PNDS emphasises that the paediatric and adult specificities of diagnosis and treatment should be respected throughout the care pathway [5]. Education of the patient and family about inheritance, manifestations, signs of infection and when to seek help, and access to patient organisations, form part of treatment [1, 18].

12. Summary and Final Considerations

Inborn errors of immunity are germline monogenic diseases whose 2024 classification encompasses 508 genes and 559 conditions, organised into ten tables, with somatic and autoantibody phenocopies classified separately [2]. The same gene may cause opposite diseases depending on mechanism (LOF, GOF, neomorphic), penetrance may be incomplete and mosaicism is increasingly recognised, so genetic interpretation requires knowledge of mechanism and phenotype [1, 2].

Recognition rests on recurrent, severe or unusual-pathogen infections, but also early or multiple autoimmunity, lymphoproliferation, severe atopy, atypical malignancy and bone marrow failure [1]. The ten warning signs are useful for awareness but perform imperfectly: family history, intravenous antibiotic use and failure to thrive have the greatest value, and many patients do not meet two signs [4, 28].

Investigation is staged: blood counts and serum Ig, protein and polysaccharide vaccine responses, T-, B- and NK-cell subsets including switched memory B cells, functional assays and specific tests, always excluding secondary causes; genetic testing enters early, favouring broad panels or exome, with genome and CNV in selected situations and recognition of each platform's limitations [1, 9]. CVID criteria differ between the American parameter and ESID definitions, which require exclusion of profound T-cell deficiency and permit memory B-cell criteria [1, 7].

Immunoglobulin replacement is the cornerstone of humoral deficiencies, starting at 400–600 mg/kg/month and adjusted to the biological trough, with targets above 800 mg/dL or 8 g/L in the American and British guidelines, above the 6 g/L minimum of the European labels [1, 8, 40]. Antimicrobial prophylaxis should be targeted to the defect, with the aciclovir doses corrected in 2026 [6]. The 2023 French PNDS adds the primary care perspective: warning signs with their own thresholds and non-infectious manifestations, age-specific reference values for immunoglobulins and lymphocytes, a formal Ig indication with IgG below 3 g/L, daily co-trimoxazole prophylaxis or azithromycin three times a week, three emergencies (SCID, macrophage activation syndrome and Wiskott–Aldrich) and the CEREDIH network organisation [5]. Live vaccines are contraindicated in severe defects, and targeted therapies (leniolisib, mavorixafor, abatacept, JAK inhibitors) require molecular diagnosis and a distinction between approved indication and off-label use, with US–EU differences in the authorised age and weight for leniolisib [1, 52, 53].

13. References

1. 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.
2. Poli MC, Aksentijevich I, Bousfiha AA, Cunningham-Rundles C, Hambleton S, Klein C, et al. Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. J Hum Immun. 2025;1(1):e20250003. doi:10.70962/jhi.20250003. PMID:41608114. PMCID:PMC12829761.
3. Orphanet. ORPHA:101997 (Primary immunodeficiency) and ORPHA:179006 (Primary immunodeficiency due to a defect in adaptive immunity), classification level “Group of disorders” [Internet]. Orphacode API; version dated 2 Jul 2026. [https://api.orphacode.org](https://api.orphacode.org). Accessed on 6 Oct 2026.
4. Rider NL, Truxton A, Ohrt T, Margolin-Katz I, Horan M, Shin H, et al. Validating inborn error of immunity prevalence and risk with nationally representative electronic health record data. J Allergy Clin Immunol. 2024;153(6):1704-10. doi:10.1016/j.jaci.2024.01.011. PMID:38278184.
5. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Les déficits immunitaires héréditaires (adultes et enfants). Coordination: Centre de référence des déficits immunitaires héréditaires (CEREDIH) and filière MaRIH; text dated December 2022. Saint-Denis La Plaine: HAS; 4 May 2023. [https://www.has-sante.fr/jcms/p_3431471](https://www.has-sante.fr/jcms/p_3431471)
6. Orange JS, Chinen J, Horner CC, et al. Corrigendum to «2025 Inborn errors of immunity practice parameter». Ann Allergy Asthma Immunol. 2026;137(5):690–692 (published online on 28 Sep 2026). doi:10.1016/j.anai.2026.08.003. PMID:42808930.
7. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract. 2019;7(6):1763-70. doi:10.1016/j.jaip.2019.02.004. PMID:30776527.
8. 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.
9. Bousfiha AA, Jeddane L, Moundir A, Poli MC, Aksentijevich I, Cunningham-Rundles C, et al. The 2024 update of IUIS phenotypic classification of human inborn errors of immunity. J Hum Immun. 2025;1(1):e20250002. doi:10.70962/jhi.20250002. PMID:41608113. PMCID:PMC12829316.
10. European Reference Network on Rare Immunological Disorders (ERN RITA). Institutional website, Published guidelines and Molecular Testing working group [Internet]. [https://ern-rita.org/](https://ern-rita.org/). Accessed on 6 Oct 2026.
11. Smith CIE, Berglöf A. X-Linked Agammaglobulinemia. In: GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 5 Apr 2001; updated on 27 Jun 2024. NBK1453.
12. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722-8. PMID:14929630.
13. 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.
14. Firth HV, Hurst JA. DNA repair disorders. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 398–401.
15. Marie S, Dewulf JP, Nassogne MC. Disorders of Purine and Pyrimidine Metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 32, section 32.3 (Diseases with Predominant Immunologic or Hematological Symptoms). doi:10.1007/978-3-662-63123-2_32.
16. GeneGuidance. Gene-specific curation of PIK3CD, CTLA4, NFKB1, NFKB2, TNFRSF13B, IKZF1, STAT1, STAT3, LRBA, CD40LG, ICOS and CXCR4 (version of 26 Sep 2026), with the cited primary references (GeneReviews NBK611655; Leiding 2018, PMID:28601685; Orphanet ORPHA:696851). User database; accessed on 6 Oct 2026.
17. Abolhassani H, Caballero-Oteyza A, Yang M, Proietti M, Delavari S, Maffucci P, et al. Re-evaluation of the contribution of TNFRSF13B variants to antibody deficiency. J Hum Immun. 2025;1(4):e20250016. doi:10.70962/jhi.20250016. PMID:40959164.
18. 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.
19. Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142(6):1932-46. doi:10.1016/j.jaci.2018.02.055. PMID:29729943.
20. Tuijnenburg P, Lango Allen H, Burns SO, Greene D, Jansen MH, Staples E, et al. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. J Allergy Clin Immunol. 2018;142(4):1285-96. doi:10.1016/j.jaci.2018.01.039. PMID:29477724.
21. Lorenzini T, Fliegauf M, Klammer N, Frede N, Proietti M, Bulashevska A, et al. Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. J Allergy Clin Immunol. 2020;146(4):901-11. doi:10.1016/j.jaci.2019.11.051. PMID:32278790.
22. Klemann C, Camacho-Ordonez N, Yang L, Eskandarian Z, Rojas-Restrepo JL, Frede N, et al. Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2. Front Immunol. 2019;10:297. doi:10.3389/fimmu.2019.00297. PMID:30941118.
23. Leiding JW, Vogel TP, Santarlas VGJ, Mhaskar R, Smith MR, Carisey A, et al. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome. J Allergy Clin Immunol. 2023;151(4):1081-95. doi:10.1016/j.jaci.2022.09.002. PMID:36228738.
24. Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127(25):3154-64. doi:10.1182/blood-2015-11-679902. PMID:27114460.
25. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Cartilage-Hair Hypoplasia (MIM 250250, 607095). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 37–40.
26. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Schimke Immunoosseous Dysplasia (MIM 242900). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 218–21.
27. Jeffrey Modell Foundation. 10 Warning Signs of Primary Immunodeficiency; 10 Warning Signs of Primary Immunodeficiency for Adults; 4 Stages of Testing for Primary Immunodeficiency [Internet]. © 2026. [https://www.info4pi.org/information-booth/10-warning-signs/](https://www.info4pi.org/information-booth/10-warning-signs/). Accessed on 6 Oct 2026.
28. Subbarayan A, Colarusso G, Hughes SM, Gennery AR, Slatter M, Cant AJ, et al. Clinical features that identify children with primary immunodeficiency diseases. Pediatrics. 2011;127(5):810-6. doi:10.1542/peds.2010-3680. PMID:21482601.
29. Arkwright PD, Gennery AR. Ten warning signs of primary immunodeficiency: a new paradigm is needed for the 21st century. Ann N Y Acad Sci. 2011;1238:7-14. doi:10.1111/j.1749-6632.2011.06206.x. PMID:22129048.
30. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome); p. 386–91.
31. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Adenosine deaminase deficiency. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 521–527.
32. Giardino G, Di Matteo G, Giliani S, Ferrari S, Lougaris V, Badolato R, et al. Consensus of the Italian Primary Immunodeficiency Network on the use and interpretation of genetic testing for diagnosing inborn errors of immunity. J Allergy Clin Immunol. 2025;155(4):1149-60. doi:10.1016/j.jaci.2024.11.030. PMID:39622296.
33. Vorsteveld EE, Hoischen A, van der Made CI. Next-Generation Sequencing in the Field of Primary Immunodeficiencies: Current Yield, Challenges, and Future Perspectives. Clin Rev Allergy Immunol. 2021;61(2):212-25. doi:10.1007/s12016-021-08838-5. PMID:33666867.
34. Kaymaz D, Haskologlu ZS, Celik DB, Bal SK, Islamoglu C, Baskin AK, et al. Diagnostic yield and clinical impact of genetic testing in inborn errors of immunity: lessons from a large Turkish cohort. Eur J Pediatr. 2026;185(3):138. doi:10.1007/s00431-026-06810-z. PMID:41714534.
35. VariantValidator (version 4.0.1; database vvdb_2025_3). Validation of NM_005026.5:c.3061G>A on GRCh38 with MANE Select annotation [Internet]. [https://variantvalidator.org](https://variantvalidator.org). Accessed on 6 Oct 2026.
36. ClinVar. NM_005026.5(PIK3CD):c.3061G>A (p.Glu1021Lys). VCV000088675.78; germline classification: Pathogenic, reviewed by expert panel (19 Dec 2025) [Internet]. [https://www.ncbi.nlm.nih.gov/clinvar/variation/88675/](https://www.ncbi.nlm.nih.gov/clinvar/variation/88675/). Accessed on 6 Oct 2026.
37. Saudubray JM, García-Cazorla Á. Clinical Approach to Inborn Errors of Metabolism in Paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, sections 1.6.5 (Table 1.38) and 1.6.7 (Immunology). doi:10.1007/978-3-662-63123-2_1.
38. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Vici syndrome; p. 864–5.
39. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Multiple carboxylase deficiency/biotinidase deficiency. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 52–61.
40. 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 on 6 Oct 2026.
41. 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 on 6 Oct 2026.
42. 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).
43. European Medicines Agency. Medicines data [Internet]: entries for Privigen, Kiovig, Hizentra, HyQvia, Deqsiga, Joenja, Xolremdi and Strimvelis. [https://www.ema.europa.eu/en/about-us/about-website/download-website-data](https://www.ema.europa.eu/en/about-us/about-website/download-website-data). Accessed on 6 Oct 2026.
44. Takeda. GAMMAGARD LIQUID (immune globulin infusion [human]) 10%. Prescribing information. DailyMed setid 9d42adca-0dd7-4df7-864d-5a7feee52130, version 22, effective 10 Dec 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).
45. CSL Behring. HIZENTRA (immune globulin subcutaneous [human], 20% liquid). Prescribing information. DailyMed setid 7b58f5ff-0316-49a3-b585-1f6003ddb953, version 26, effective 20 Apr 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).
46. Takeda. HYQVIA (immune globulin infusion 10% [human] with recombinant human hyaluronidase). Prescribing information. DailyMed setid 7ca2c26f-4be2-48cd-be5b-486e350654ba, version 23, effective 18 Jun 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).
47. 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 on 6 Oct 2026.
48. Takeda. CUVITRU (immune globulin subcutaneous [human]) 20%. Prescribing information. DailyMed setid 9aad7ec9-6097-4805-8f1b-898bec35f218, version 19, effective 25 Nov 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).
49. Kedrion. QIVIGY (immune globulin intravenous, human-kthm) 10%. Prescribing information. DailyMed setid 6f1933e0-240f-48f4-b246-8a30e63a4160, effective 2 Feb 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).
50. Milito C, Pulvirenti F, Cinetto F, Lougaris V, Soresina A, Pecoraro A, et al. Double-blind, placebo-controlled, randomized trial on low-dose azithromycin prophylaxis in patients with primary antibody deficiencies. J Allergy Clin Immunol. 2019;144(2):584-93.e7. doi:10.1016/j.jaci.2019.01.051. PMID:30910492.
51. Rao VK, Webster S, Šedivá A, Plebani A, Schuetz C, Shcherbina A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971-83. doi:10.1182/blood.2022018546. PMID:36399712.
52. Pharming Healthcare. JOENJA (leniolisib) tablets. Prescribing information. DailyMed setid eefbcef8-2130-4654-8f29-b58077e08212, version 8, effective 30 Sep 2026 [Internet]. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eefbcef8-2130-4654-8f29-b58077e08212](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eefbcef8-2130-4654-8f29-b58077e08212).
53. European Medicines Agency. Joenja (leniolisib): summary of product characteristics, sections 4.1–4.2 [Internet]. EMEA/H/C/005927. [https://www.ema.europa.eu/en/medicines/human/EPAR/joenja](https://www.ema.europa.eu/en/medicines/human/EPAR/joenja). Accessed on 6 Oct 2026.
54. Egg D, Rump IC, Mitsuiki N, Rojas-Restrepo J, Maccari ME, Schwab C, et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2022;149(2):736-46. doi:10.1016/j.jaci.2021.04.039. PMID:34111452.
55. Kiykim A, Ogulur I, Dursun E, Charbonnier LM, Nain E, Cekic S, et al. Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency. J Allergy Clin Immunol Pract. 2019;7(8):2790-2800.e15. doi:10.1016/j.jaip.2019.06.011. PMID:31238161.
56. Taghizade N, Babayeva R, Kara A, Karakus IS, Catak MC, Bulutoglu A, et al. Therapeutic modalities and clinical outcomes in a large cohort with LRBA deficiency and CTLA4 insufficiency. J Allergy Clin Immunol. 2023;152(6):1634-45. doi:10.1016/j.jaci.2023.08.004. PMID:37595759.
57. Krausz M, Uhlmann A, Rump IC, Ihorst G, Goldacker S, Sogkas G, et al. The ABACHAI clinical trial protocol: Safety and efficacy of abatacept (s.c.) in patients with CTLA-4 insufficiency or LRBA deficiency: A non controlled phase 2 clinical trial. Contemp Clin Trials Commun. 2022;30:101008. doi:10.1016/j.conctc.2022.101008. PMID:36262801.
58. Badolato R, Alsina L, Azar A, Bertrand Y, Bolyard AA, Dale D, et al. A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome. Blood. 2024;144(1):35-45. doi:10.1182/blood.2023022658. PMID:38643510.
59. X4 Pharmaceuticals. XOLREMDI (mavorixafor) capsules. Prescribing information. DailyMed setid 7f3a5ee3-ca73-4876-85a0-ed1e108a2237, version 7, effective 12 Nov 2024 [Internet]. [https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7f3a5ee3-ca73-4876-85a0-ed1e108a2237](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7f3a5ee3-ca73-4876-85a0-ed1e108a2237).
60. European Medicines Agency. Xolremdi (mavorixafor): summary of product characteristics, sections 4.1–4.2 [Internet]. EMEA/H/C/006496. [https://www.ema.europa.eu/en/medicines/human/EPAR/xolremdi](https://www.ema.europa.eu/en/medicines/human/EPAR/xolremdi). Accessed on 6 Oct 2026.
61. U.S. Food and Drug Administration. Drugs@FDA: NDA 217759 (Joenja; ORIG-1 approved 24 Mar 2023; efficacy SUPPL-6 approved 11 Sep 2026) and NDA 218709 (Xolremdi; ORIG-1 approved 26 Apr 2024) [Internet]. [https://www.accessdata.fda.gov/scripts/cder/daf/](https://www.accessdata.fda.gov/scripts/cder/daf/). Accessed on 6 Oct 2026.
62. Chinen J, Horner CC, Orange JS. Practice parameter for inborn errors of immunity: What is new in the 2025 update. J Allergy Clin Immunol. 2026;158(2):368-73. doi:10.1016/j.jaci.2026.05.014. PMID:42208906.
63. ClinicalTrials.gov. Leniolisib studies NCT05438407, NCT05693129, NCT06897358, NCT06549114 and NCT06990529 [Internet]. [https://clinicaltrials.gov](https://clinicaltrials.gov). Accessed on 6 Oct 2026.
64. Bintalib HM, van de Ven AAJM, Rojas-Reyes MX, Davidsen JR, Hanitsch LG, Cinetto F, et al. Clinical practice guideline for the diagnosis of granulomatous-lymphocytic interstitial lung disease in patients with common variable immunodeficiency disorders: an ERS Clinical Research Collaboration. Eur Respir J. 2026;68(3):2502224. doi:10.1183/13993003.02224-2025. PMID:42350065.
65. 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.
66. Ahmad Shawaludin MQ, Zainudeen ZT, Taib F, Husin A, Ali A, Abd Hamid IJ. A rare case report of activated PI3K delta syndrome (APDS): diagnostic pitfalls. BMC Pediatr. 2025;25(1):898. doi:10.1186/s12887-025-06286-0. PMID:41184801. PMCID:PMC12581585.