Introduction
The clinical complexity of inborn errors of immunity (IEI) is reflected, among others, in the diversity of gastrointestinal symptoms. Based on the 2024 IUIS classification, the second part of this review is dedicated to disease entities associated with specific and often diagnostically challenging gastroenterological manifestations. The aim of this review is to thoroughly discuss the underlying pathophysiological mechanisms, diagnostic tools, and modern treatment methods, thereby contributing to the improvement of diagnostic and therapeutic processes in everyday clinical practice [1, 2]. This article constitutes a continuation of Part 2A and therefore follows the previously established organizational framework.
Congenital defects in the number or function of phagocytes
Severe congenital neutropaenia (SCN)
Severe congenital neutropaenias are rare disorders (1–3 cases per million) causing chronic neutropaenia (ANC < 0.5 × 109/l) and recurrent infections from early life. Diagnosis involves clinical symptoms, neutrophil count, bone marrow examination, and genetic tests. Gastrointestinal issues include diarrhoea, infections, poor weight gain, abscesses, and inflammatory bowel disease. Treatment includes daily G-CSF or stem cell transplantation, with a risk of progression to myelodysplasia or leukaemia [3, 4].
Chronic granulomatous disease (CGD)
Chronic granulomatous disease (CGD) results from NADPH oxidase defects due to mutations in six genes, impairing the phagocyte oxidative burst and ROS production, leading to uncontrolled infections [5, 6]. Gastrointestinal symptoms, common early in life, are abdominal pain, diarrhoea, fever, rectal bleeding, granulomas, and inflammatory bowel disease (IBD). Treatment involves interferon-g (IFN-g), with HSCT as an option, although it may cause complications like abscesses and granulomas requiring surgery [5, 7, 8].
Defects in intrinsic and innate immunity
Mendelian susceptibility to mycobacterial disease (MSMD)
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder causing heightened vulnerability to infections by low-virulence mycobacteria, including BCG vaccine strains and environmental mycobacteria. It is caused by genetic mutations, such as in the IFNGR1 and IFNGR2 genes. MSMD typically manifests in childhood and increases susceptibility to salmonellosis, candidiasis, and tuberculosis. Treatment involves antitubercular medications (rifampin, isoniazid, pyrazinamide, ethambutol) combined with other antibiotics like ciprofloxacin, clarithromycin, or antiviral drugs [9, 10].
Interferon-g and interleukin-12 receptor defect
IFN-g, mainly produced by T and NK cells, enhances immune effector function. Mutations in IFNGR1 or IFNGR2 causing IFN-g unresponsiveness lead to severe, often fatal mycobacterial infections from infancy, affecting multiple organs. Aggressive antibiotics may help, but the prognosis is poor; bone marrow transplantation is often effective [11]. Gastrointestinal symptoms include enteropathy, abdominal distension, and Crohn’s disease [11, 12].
Predisposition to severe viral infection
Severe viral infection predisposition occurs due to genetic mutations, immunosuppression, or aging. Defective type I IFNs can impair viral control. Viral infections may cause GI issues like hepatitis and liver failure (IL18BP mutation) or norovirus diarrhoea (FUT2 mutation) [13].
Predisposition to invasive fungal diseases
Predisposition to invasive fungal diseases increases susceptibility to serious fungal infections, like systemic candidiasis, which can affect the bloodstream, CNS, liver, spleen, heart, and kidneys. Conditions like CGD, LAD-1, complete MPO deficiency, and CARD9 deficiency increase this risk. CARD9 deficiency, inherited recessively, may also cause colitis. Treatment includes polyenes, 5-flucytosine, azoles, and echinocandins [14].
Predisposition to mucocutaneous candidiasis
Mucocutaneous candidiasis (CMC) causes recurrent Candida infections, often with autoimmune thyroiditis and other conditions like enterocolitis and lupus. It is linked to IL-17RA, IL-17F, MAPK8, and STAT1-GOF mutations. Oesophageal candidiasis can lead to dysphagia. Treatment includes antifungals like triazoles, nystatin, and fluconazole [15, 16].
TLR signalling pathway deficiency with bacterial susceptibility
Toll-like receptor (TLR) deficiencies, including mutations in IRAK-4 and MyD88, increase susceptibility to infections. MyD88 deficiency, caused by IκBα mutation, can lead to colitis and recurrent diarrhoea due to weakened immune responses [17].
Autoinflammatory disorders
Familial Mediterranean fever (FMF)
Familial Mediterranean fever (FMF), caused by MEFV gene mutations, leads to recurrent peritonitis, pleuritis, arthritis, rash, and fever. Prevalence ranges from 1 in 500 to 1 in 1000 in endemic regions. Diagnosis is based on history, inflammatory markers, and genetics. Treatment includes colchicine to prevent amyloidosis, with IL-1 inhibitors as alternatives [18].
TNF receptor-associated periodic syndrome (TRAPS)
Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder caused by TNFRSF1A mutations, leading to chronic inflammation. It presents with recurrent fever, abdominal pain, arthralgia, myalgia, rash, and gastrointestinal issues like diarrhoea and splenomegaly. AA amyloidosis is a severe complication. Diagnosis is based on clinical signs and genetic testing. Treatment includes TNF-a, IL-6, and IL-1 inhibitors [19].
Deficiency of complement components
Hereditary angioedema (HAE)
Hereditary angioedema (HAE) is a rare autosomal dominant disorder (1 : 50,000) caused by SERPING1 mutations, leading to C1 esterase inhibitor deficiency and recurrent swelling due to increased vascular permeability. Symptoms include swelling, abdominal pain, fatigue, and flu-like signs, typically emerging in the early twenties. Diagnosis involves C1-INH levels, bradykinin, C4, and D-dimer tests. Treatment includes C1-esterase inhibitors (Haegarda) and plasma kallikrein inhibitors (Takhzyro) to reduce attack severity and frequency [20].
Bone marrow failure syndromes
Fanconi anaemia (FA)
Fanconi anaemia (FA) is a rare genetic disorder (1–9 cases per million) affecting multiple organs, with congenital deformities, bone marrow failure, and increased cancer risk, including leukaemia and gastrointestinal cancers. Gastrointestinal anomalies occur in 7% of patients and may include atresia, malrotation, and strictures. Symptoms like nausea, abdominal pain, diarrhoea, and reflux require management with proton pump inhibitors, avoiding H2 antagonists due to bone marrow suppression [21–23].
Diagnosis involves chromosome fragility testing, flow cytometry, and genetic sequencing. Treatment includes androgens, granulocyte colony-stimulating factors, transfusions, and broad-spectrum antibiotics. Haematopoietic stem cell transplantation (HCT) is the definitive treatment, with 5-year survival rates of 85% (familial donor) and 80% (unrelated donor). FA has 22 genetic types, mostly autosomal recessive, except X-linked type B. Without HCT, life expectancy is around 20 years [22–24].
MIRAGE syndrome
MIRAGE syndrome is a genetic disorder caused by SAMD9 mutations, presenting from birth with myelodysplasia, infections, growth retardation, adrenal hypoplasia, genital defects, and enteropathy. Gastrointestinal symptoms include chronic diarrhoea, colonic dilatation, reflux, dysphagia, and aspiration pneumonia [25, 26]. Diagnosis involves prenatal ultrasound and genetic sequencing. Treatment focuses on infection prevention, adrenal hormone replacement, surgical corrections, tube feeding, and early psychomotor intervention [26].
Dyskeratosis congenita (DKC; DC)
Dyskeratosis congenita (DKC), or Zinsser-Engman-Cole syndrome, is a genetic disorder affecting multiple organs, with 30% of cases linked to the X chromosome. It has a prevalence of 1–9 cases per million. Gastrointestinal and liver symptoms affect 7.3% of patients and may include oesophageal dysfunction, gastric ulcers, liver fibrosis, and anal leukoplakia [1, 27].
Treatment focuses on supporting bone marrow function with androgens, colony-stimulating factors, and erythropoietin, along with haematopoietic stem cell transplantation. Surgical interventions may be needed for gastrointestinal issues. The prognosis is poor, with a 15% cancer rate and death primarily from bone marrow failure, aplastic anaemia, cancer, or lung disease [27, 28].
Coats Plus syndrome
Coats plus syndrome (CRMCC) is a rare autosomal recessive genetic disorder with an incidence of < 1/1,000,000, beginning in childhood. It affects multiple organs, including the digestive system, eyes, bones, and central nervous system. Symptoms include cognitive decline, ataxia, spasticity, seizures, and visual impairment due to retinal exudates and telangiectasias. Gastrointestinal symptoms include recurrent bleeding caused by vascular ectasia and portal hypertension. Treatment focuses on preventing gastrointestinal bleeding, with octreotide used to manage bleeding from angiodysplasia. Endoscopic and surgical interventions may be insufficient due to the multifocal nature of lesions [29, 30].
Phenocopies of inborn errors of immunity
Chronic mucocutaneous candidiasis (CMC)
Chronic cutaneous mucosal candidiasis (CMC) is a group of diseases that typically begins in early childhood, characterised by chronic or recurrent Candida infections, particularly C. albicans. There is a risk of oesophageal squamous cell carcinoma in some patients [15, 16]. Treatment includes long-term antifungals (fluconazole, voriconazole, posaconazole, IV amphotericin B, echinocandins, or terbinafine), antibiotic prophylaxis (co-trimoxazole, macrolides), polyvalent immunoglobulins, immunotherapy, and immunosuppressive therapy.
Conclusion
This study reinforces the critical role of gastrointestinal symptoms as indicators of inborn errors of immunity (IEIs), particularly in disease entities associated with diagnostically challenging gastroenterological manifestations. The review provides valuable insights to support clinicians in the diagnostic and therapeutic process, emphasising the importance of a comprehensive and multidisciplinary approach. Furthermore, it highlights the need for continued investigation into the mechanisms linking immune dysregulation with gastrointestinal pathology, which will be essential for the development of more effective and targeted therapeutic strategies, ultimately improving patient care.
