Introduction
According to the latest classification of inborn errors of immunity, updated in 2024, 559 disease entities belonging to inborn errors of immunity have been recognized. Inborn errors of immunity (formerly primary immunodeficiencies – PIDs) are a heterogeneous group of diseases affecting multiple organs with diverse clinical presentations, including recurrent infections, increased cancer risk, autoimmune and autoinflammatory diseases, allergies, and bone marrow failure disorders [1]. The Jeffrey Modell Foundation (JMF) has created two lists of 10 symptoms that may indicate the presence of congenital immunodeficiency, which are presented in Tables I and II [2, 3].
Table I
Ten warning symptoms that may indicate the presence of congenital immunodeficiency in children. Adapted from the Jeffrey Modell Foundation [2, 3]
Table II
Ten warning symptoms that may indicate congenital immunodeficiency in adults. Adapted from the Jeffrey Modell Foundation [2, 3]
Studies show that the above list of symptoms, especially in children and young adults, has low sensitivity and specificity and is of little importance in screening for inborn errors of immunity (IEI) [4–6]. It is mentioned that up to one third of patients suffering from IEI do not meet the above ten symptoms distinguished by the Jeffrey Modell Foundation [2, 3, 5]. In a study conducted by Dąbrowska et al., four additional symptoms – severe eczema, oncologic and hematologic disorders, allergies, and autoimmunity – were proposed as potentially useful indicators of severe IEI [2].
Epidemiology of IEI in children and adults
IEI comprise a diverse spectrum of 559 disorders, with over 50% of cases occurring in adults over 25 years of age [1, 7–9]. Their incidence is estimated at 1 : 1200, likely higher due to diagnostic delays [9]. Gastrointestinal manifestations are the second most frequent organ involvement after respiratory disease, affecting 5–50% of patients, most often as chronic diarrhea, intestinal inflammation, or hepatosplenomegaly. In certain deficiencies, prevalence reaches 20–60% in common variable immunodeficiency (CVID), about 35% in X-linked agammaglobulinemia (XLA), and up to 80% in chronic granulomatous disease (CGD), while monogenic IEI is detected in 3–12% of children with early-onset inflammatory bowel disease [10, 11].
Classification of IEI
According to the classification of inborn errors of immunity, updated in 2024, they are divided into ten main groups. The ten main groups are listed in Table III [1].
Table III
Ten main groups of inborn errors of immunity (IEI) [1]
Symptoms
IEIs and gastrointestinal diseases are understudied, despite their potential interconnectedness. IEIs may cause gastrointestinal diseases, and these diseases can negatively impact quality of life. Inborn errors of immunity with gastrointestinal symptoms are presented in Table IV.
Table IV
Gastrointestinal manifestations in inborn errors of immunity (IEIs) based on works by International Union of Immunological Societies Experts Committee [1, 13]
[i] ADAM17 – a disintegrin and metalloproteinase 17, ALPI – alkaline phosphatase intestinal, ALPS – autoimmune lymphoproliferative syndrome, ALPS-FAS – autoimmune lymphoproliferative syndrome – first apoptosis signal receptor, ALPS-FASLG – autoimmune lymphoproliferative syndrome – first apoptosis signal receptor ligand, APDS – activated phosphoinositide 3-kinase δ syndrome, APECED – autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, CARD11 – caspase recruitment domain-containing protein 11, CD – cluster of differentiation, CDC42 – cell division cycle 42, CGD – chronic granulomatous disease, CHARGE – coloboma, heart defects, atresia choanae, retardation of growth/development, genital and ear abnormalities, CHH – cartilage-hair hypoplasia, CMC – chronic mucocutaneous candidiasis , CRACR2A – calcium release-activated calcium channel regulator 2A, CRMCC – cerebrospinal microangiopathy with calcifications and cysts, CVID – common variable immunodeficiency, CyN – cyclic neutropenia, DEF6 – differentially expressed in FDCP 6, DGS – DiGeorge syndrome or 22q11.2 deletion syndrome, DOCK11 – dedicator of cytokinesis 11, ELF4 – E74 like ETS transcription factor 4, FA – Fanconi anemia, FADD – Fas-associated protein with death domain, FDCP – factor-dependent continuous proliferation, FLT3L – Fms-like tyrosine kinase 3 ligand, FMF – familial Mediterranean fever, Fms – feline McDonough sarcoma, FNIP1 – folliculin-interacting protein 1, GINS4 – Go-Ichi-Ni-San complex subunit 4, GOF – gain-of-function, HAE – hereditary angioedema, HIES – hyper-IgE syndrome, HIGM – hyper IgM syndrome, ICOS – inducible T-cell co-stimulator, IL-21R – interleukin 21 receptor, IPEX – immune dysregulation polyendocrinopathy enteropathy X-linked, IRF4 – interferon regulatory factor, IRHOM – inactive rhomboid protein, ITCH – itchy E3 ubiquitin protein ligase, ITPR3 – inositol 1,4,5-trisphosphate receptor type 3, JAK – Janus kinase, KARS1 – lysyl-tRNA synthetase 1, LOF – loss of function, LRBA – lipopolysaccharide-responsive and beige-like anchor protein, LYN – Lyn tyrosine kinase, MBL – mannose-binding lectin, MHC – major histocompatibility complex, MIRAGE – myelodysplasia, infection, restricted growth, adrenal hypoplasia, genital phenotypes, enteropathy, MSMD – Mendelian susceptibility to mycobacterial disease, NBEAL2 – neurobeachin-like 2, NCK – non-catalytic region of tyrosine kinase adaptor protein, NCKAP1L – NCK-associated protein 1 like, NFAT5 – nuclear factor of activated T cells 5, ORAS – OTULIN-related autoinflammatory syndrome, OTU – ovarian tumor domain, OTULIN – OTU deubiquitinase with linear linkage specificity, PIK3CG – phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, PLS – Papillon–Lefèvre syndrome, PMS2 – postmeiotic segregation increased 2, PRAID – proteasome-related autoinflammatory disease, PRIM1 – DNA primase polypeptide 1, Ras – Rat sarcoma, RH – Ras homology, RHOG – Ras homolog family member G, RIPK1 – receptor-interacting serine/threonine-protein kinase 1, S703I – refers to a point mutation in a protein where the amino acid serine (S) at position 703 is replaced by isoleucine (I), SCID – Severe combined immunodeficiency, SCN – severe congenital neutropenia, SDS – Shwachman–Diamond syndrome, SH2B3 – SH2B adaptor protein 3, SHANK – SH3 and multiple ankyrin repeat domains protein, SHARPIN – SHANK-associated RH domain-interacting protein, SIgAD – selective immunoglobulin A deficiency, SOCS1 – suppressor of cytokine signaling 1, STAT – signal transducer and activator of transcription, SYK – spleen tyrosine kinase, TCRα – T-cell receptor alpha, TET2 – ten-eleven translocation 2, TGFβ1 – transforming growth factor-β1, THI – transient hypogammaglobulinemia of infancy, TLR – Toll-like receptor, TRAPS – TNF receptor-associated periodic syndrome, TRIM22 – tripartite motif containing 22, UNC93B1 – Unc-93 homolog B1, VODI – VPS45 deficiency with osteopetrosis, neutropenia, and immunodeficiency, VPS45 – vacuolar protein sorting 45, WAS – Wiskott-Aldrich syndrome, XIAP – X-linked inhibitor of apoptosis protein, XIAP – X-linked inhibitor of apoptosis deficiency, XLA – X-linked agammaglobulinemia or Bruton’s agammaglobulinemia, XLP1 – X-linked lymphoproliferative syndrome or Duncan disease, ZNFX1 – zinc finger NFX1-type containing 1.
Diagnosis
Diagnosing inborn errors of immunity in patients with gastrointestinal symptoms requires a structured approach that begins with basic screening tests, including complete blood count, serum immunoglobulin concentration, complement, and vaccine responses. Due to the limited availability of immunoglobulin testing, assessment of total protein and serum protein electrophoresis is recommended, allowing exclusion of secondary protein loss and estimation of immunoglobulin concentration within the gamma fraction [2, 12–14]. Endoscopy with biopsy is essential, as characteristic findings such as paucity of plasma cells, lymphoid hyperplasia, granulomas, or unexplained eosinophilia should raise suspicion of IEI [15, 16]. In cases with abnormal results, extended immunophenotyping, immunological assays, and targeted gene screening are recommended in collaboration with a clinical immunologist [10, 11, 14, 17, 18]. Early referral is crucial, as timely diagnosis allows initiation of targeted therapies. Gastroenterologists should remain alert to “warning signs” such as recurrent infections, chronic diarrhea with weight loss, poor growth, need for intravenous antibiotics, or family history of IEI, which may indicate an underlying disorder. Symptoms mentioned in Tables I and II could be useful screening tools [2, 3, 10, 11, 15, 19].
Treatment options
The treatment of inborn errors of immunity is based on a comprehensive approach, including personal hygiene, isolation during infections, prompt treatment of contagious diseases, nutritional monitoring, avoiding crowded places, appropriate physical activity, and stress reduction strategies [20]. It is recommended that patients receive vitamin D [21]. It is very important to administer additional vaccinations, not only to the patient, but also to people in the immediate environment (cocoon vaccinations). Live vaccines are usually not generally recommended in patients with severe humoral immunity disorders (XLA, CVID), although each case should be considered individually. Patients undergoing replacement therapy with human immunoglobulins are also not vaccinated. An exception is the annual vaccination against influenza. However, there are no contraindications to their use in mild antibody deficiencies, i.e. in selective IgA deficiency, IgG subclass deficiency, or specific antibody deficiency. Inactivated vaccines, such as vaccination against influenza virus, are recommended, as are protein and polysaccharide vaccines (against S. pneumoniae, H. influenzae, meningococci and tetanus). Despite antibody production disorders, there is evidence of the benefits of protective vaccinations due to the often preserved cellular immunity [21]. Some patients may need immunoglobulin therapy, particularly for IgG deficiency, specific antibody deficiencies, or, in some cases, acute autoimmune conditions. The initiation of treatment is guided primarily by the patient’s clinical presentation rather than the IgG reduction [22].
Long-term prophylactic antibiotics are commonly used in primary immunodeficiency management, especially in fall and winter, after tooth extractions, and during tissue-disrupting procedures. Infections may require prolonged antibiotic treatment [23]. Patients may require antifungal and antiviral prophylaxis. Hematopoietic stem cell transplantation is a treatment option for some PIDs, while certain groups also benefit from gene therapy and enzyme replacement therapy [20].
In most cases, immunoglobulin and antibiotic therapies do not reverse or prevent gastrointestinal disease progression in patients with PIDs, requiring additional treatments. Managing immunodeficient patients with gastrointestinal disease can be complex, often needing immunomodulatory treatment in severe cases [20, 23].
Conclusions
Gastrointestinal manifestations of IEI pose a diagnostic and therapeutic challenge due to their heterogeneity. Early diagnosis is crucial to prevent complications and improve quality of life. Understanding epidemiology, classification, symptoms, diagnostics, and treatment strategies enhances disease management. Advances in genetic testing and personalized medicine will further refine diagnosis and therapy, highlighting the need for research and interdisciplinary collaboration.
