Introduction
Gastrointestinal symptoms are an important component of the clinical picture in many inborn errors of immunity (IEI), highlighting the link between immune dysfunction and the gastrointestinal tract. This review aims to support clinicians by synthesising current scientific evidence on pathophysiology, diagnostic methods, and treatment strategies, thereby improving diagnostic accuracy and the effectiveness of therapeutic interventions [1, 2].
Complex immunodeficiencies
Severe combined immune deficiency (SCID)
SCID is a severe immune deficiency, inherited autosomal or X-linked recessively (50%). Symptoms appear in the first months, although T-cell dysfunction begins in foetal life [3]. It is characterised by a lack of functional T and B cells, with diagnostic criteria including < 300 CD3 T cells/mm3 and maternal T-cell presence. SCID leads to recurrent infections, malignancies, and gastrointestinal issues like dysmotility, malabsorption, and feeding challenges. Early haematopoietic stem cell transplantation or gene therapy significantly improves survival [4].
Hyper-immunoglobulin M syndrome (HIGM)
Hyper-IgM syndrome is an immunodeficiency with low IgG, IgA, and IgE but normal/elevated IgM [5]. It predisposes patients to sino-pulmonary and opportunistic infections, neutropaenia, autoimmune diseases, and cancers (liver, pancreas, biliary tract). Inherited mostly autosomal recessively, it also presents with GI symptoms, including recurrent infections, enteropathy, and chronic diarrhoea from Histoplasma capsulatum and Cryptosporidium parvum. Severe cases involve hepatitis, cirrhosis, cholestasis, and potential liver failure requiring transplantation. Measuring immunoglobulin levels and testing for genetic mutations in CD40LG, AICDA, CD40, UNG, and PIK3CD are essential for diagnosing HIGM. Treatment includes immunoglobulin replacement, antimicrobials, and sometimes stem cell transplantation [5, 6].
Combined immunodeficiencies with associated or syndromic features
Wiskott-Aldrich Syndrome (WAS)
Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency (1–10/million males) caused by WAS gene mutations. It features microthrombocytopaenia, eczema, recurrent infections, autoimmunity, and malignancies, with severe cases having an estimated 15-year life expectancy. Patients present with bleeding diathesis (purpura, haematemesis, melena, epistaxis, haematuria) and, in 5–10% of cases, severe early-onset IBD with rectal masses, ulcers, diarrhoea, malabsorption, and abdominal pain [7, 8].
DiGeorge syndrome (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcaemia resulting from 22q11 deletion = CATCH 22)
Chromosome 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) affects ~1 : 4000 births, causing mild to moderate immune deficiency and frequent cardiac anomalies [9]. Other features include renal and eye anomalies, hypoparathyroidism, skeletal defects, and developmental delay. GI issues, though less common, include malrotation, Hirschsprung disease, imperforate anus, oesophageal atresia, reflux, and feeding difficulties in infancy. Managing constipation involves fibre, hydration, exercise, and a bowel routine [9, 10].
Predominantly antibody deficiencies
X-linked agammaglobulinaemia (XLA)
X-linked agammaglobulinaemia (XLA), caused by a mutation in Bruton’s tyrosine kinase, resulting in B cell development arrest and an increased risk of infections such as pneumonia, diarrhoea, and meningitis. Diarrhoea is commonly caused by pathogens like Giardia lamblia and Salmonella spp. Treatment involves lifelong immunoglobulin replacement, but no guidelines for prophylactic antibiotics exist [11, 12].
Common variable immunodeficiency (CVID)
Common variable immunodeficiency (CVID) is a heterogeneous immunodeficiency (1 in 10,000–50,000 newborns) characterised by hypogammaglobulinaemia and poor antibody response. It leads to recurrent infections, mainly in the respiratory and GI tracts (Enteroviruses, Salmonella, C. jejuni, Giardia lamblia). Non-infectious enteropathy (IBD, celiac disease) affects 20–60% of patients. Treatment includes globulin infusions, although IVIG is ineffective for enteropathy, while steroids help reduce inflammation and restore mucosal structure [11, 13, 14].
Selective immunoglobulin A deficiency (SIgAD)
Selective immunoglobulin A deficiency is the most common primary antibody deficiency, with a prevalence of 1 : 223 to 1 : 1000. Since most children and adults with IgA deficiency remain healthy and show no apparent symptoms, determining the actual impact of IgA deficiency is challenging. Because secretory IgA helps protect mucosal surfaces, those with IgA deficiency may be more prone to lung infections, allergies, autoimmune diseases, and gastrointestinal issues like infections, celiac disease, or inflammatory bowel disease [15]. Recommended treatment of gastrointestinal diseases does not vary from regular recommendations [16].
Transient hypogammaglobulinaemia of infancy (THI)
Transient hypogammaglobulinaemia of infancy (THI) is characterised by a temporary drop in IgG levels in infants aged 5 to 24 months, typically returning to normal by 2–6 years. Diagnosis is made when IgG levels are more than two standard deviations below the mean for their age. Symptoms include severe pneumonia, fungal or Staphylococcus infections, gastrointestinal issues like gastroenteritis and diarrhoea, and bloodstream infections. Treatment involves antibiotics, with IVIG recommended for severe infections [17, 18].
Diseases of immune dysregulation
Autoimmune polyendocrine syndrome; autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy (APS-1; APECED)
Autoimmune polyendocrine syndromes cause dysfunction in multiple endocrine glands due to immune tolerance loss. APS-1 presents with chronic candidiasis, adrenal insufficiency, and hypoparathyroidism. Treatment includes hormone replacement: glucocorticoids for adrenal insufficiency, L-thyroxine for hypothyroidism, and calcium with vitamin D to balance calcium while preventing stones [19, 20].
Immune dysregulation with colitis
Interleukin 10 (IL-10) and interleukin 10 receptor (IL-10R) deficiency
IL-10, produced by regulatory T-cells and macrophages, regulates inflammation and tissue repair. IL10/IL10R defects, inherited monogenically, cause a hyper-inflammatory state, mainly in the intestines, leading to early-onset IBD. Treatment includes allogeneic stem cell transplantation and monoclonal antibodies like anakinra and adalimumab [21].
NFAT5 (nuclear factor of activated T cells 5) haploinsufficiency
Nuclear factor of activated T cells 5, also known as tonicity enhancer binding protein (TonEBP), is a DNA-binding protein activated in response to osmotic stress, which is responsible for cell cycle progression and inflammation. In vivo, NFAT5 directly binds to the TNFα promoter, which suggests a critical role in mediating inflammation and regulating immune responses. AIE is a rare disease that might cause intractable diarrhoea, histologic changes in the intestinal mucosa, and the presence of autoantibodies against gut enterocytes or goblet cells [22].
TGFB1 (transforming growth factor beta 1) deficiency
The TGF-b1 gene encodes a key regulator of embryogenesis, tissue homeostasis, and immune balance. Overactivity can lead to cancer, fibrosis, or diaphyseal dysplasia, while reduced activity is linked to early tumourigenesis, vascular dysplasia, developmental defects, severe IBS, and atherosclerosis. It is essential for intestinal immune homeostasis and CNS function [23].
RIPK1 (receptor interacting serine/threonine kinase 1)
Receptor interacting serine/threonine kinase 1 is one of the key signalling molecules controlling inflammation and cell death, thereby playing an essential role in maintaining human immune homeostasis [24]. In most cases, RIPK1 dysfunction is caused by homozygous mutations [24]. However, RIPK1 is key in controlling skin and intestinal inflammation, autoimmunity, and tissue fibrosis [25]. Li et al. studied 8 patients with biallelic RIPK1 mutations and inflammatory bowel disease. The patients displayed gastroenterological symptoms, including chronic mucous and bloody diarrhoea, oral aphthous lesions, colitis signs, and IBD-like conditions [24].
ELF4 (E74-like ETS transcription factor 4)
ELF4 deficiency (DEX) is a newly identified X-linked condition within inborn errors of immunity (IEIs), classified as a disease of immune dysregulation. DEX results from hemizygous loss-of-function mutations in the ELF 4 gene on the X chromosome (Xq26.1), primarily affecting paediatric males [26]. ELF4 manifests as recurrent and prolonged ulcerations in the digestive tract, abdominal pain, diarrhoea, decreased appetite, inflammatory bowel disease-like symptoms, and fever of unknown origin [27]. Treatment includes the use of glucocorticosteroids and biologics [26].
Autoimmune lymphoproliferative syndrome (ALPS)
Autoimmune lymphoproliferative syndrome is an inherited disorder caused by mutations in the FAS signalling pathway, leading to defects in FAS-mediated apoptosis. This results in the expansion of autoreactive double-negative T-cells, causing cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and an increased risk of lymphoma. Symptoms typically develop by 11.5 months and include non-malignant lymphadenopathy and splenomegaly. Splenomegaly can be severe, sometimes requiring chest bracing. Cytopaenias are often linked to serum IgG level changes [28, 29].
X-linked lymphoproliferative syndrome (XLP; Duncan disease)
The main clinical features of X-linked lymphoproliferative disease are haemophagocytic lymphohistiocytosis (HLH), dysgammaglobulinaemia, and lymphoma, but other described manifestations include aplastic anaemia, vasculitis, chronic gastritis, and skin lesions. HLH is the most common and lethal presentation, tending to occur early in childhood and associated with significant mortality, with a proportion of patients succumbing before haematopoietic stem cell transplant (HSCT) [28]. Treatment of XLP1 focuses on managing specific clinical symptoms and providing supportive care. For EBV-driven diseases, such as HLH, rituximab (a monoclonal anti-CD20 antibody) is used to deplete B cells harbouring the virus. While antiviral agents are generally ineffective against EBV, acyclovir may be used in certain cases [28, 29].
Conclusions
This study emphasises the importance of recognising gastrointestinal symptoms as early clues to underlying IEIs. The findings provide clinicians with a structured framework to enhance diagnostic accuracy and optimise treatment strategies. In particular, the work underlines the necessity for multidisciplinary collaboration to ensure effective patient management. Future research should continue to explore the intricate relationship between immune dysfunction and gastrointestinal manifestations in these disorders, paving the way for more targeted therapies and improved patient outcomes.
