• IL-10R beta deficiency
• anakinra
• early-onset inflammatory bowel disease
• immune dysregulation
• interleukin-10

• Humans
• Interleukin 1 Receptor Antagonist Protein/therapeutic use
• Male
• Infant
• Interleukin-10 Receptor beta Subunit/genetics
• Interleukin-10 Receptor beta Subunit/deficiency
• Hematopoietic Stem Cell Transplantation
• Treatment Outcome
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/diagnosis

• Inflammatory bowel disease (IBD)
• Primary immunodeficiency (PID)
• Severe and protracted diarrhea (SD)

• CMRPG3M0351 the Chang-Gung Medical Research Progress
• CIRPG3M0081 the Chang-Gung Medical Research Progress
• CMRPG 4B0051-53 the Chang-Gung Medical Research Progress
• MOST 110-2314-B-182A-033- the National Science Council
• 111-2314-B-182A-110- the National Science Council
• NMRPG3L0241and NMRPG3M0321 the National Science Council
• TFRD the Taiwan Foundation for Rare Disorders
• PMRPG3M0061 the Taiwan Foundation for Rare Disorders

• infantile onset
• inflammatory bowel disease
• long-term outcome
• remission
• surgery

• Flow cytometry
• Inborn error of immunity
• Inflammatory bowel disease
• Monogenic
• Primary immunodeficiency

• Age of Onset
• Child
• Genetic Testing
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/genetics
• Intestines

• R01 DK127044 NIDDK NIH HHS
• R01 DK111843 NIDDK NIH HHS

• Age of Onset
• Child
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/genetics
• Phenotype

• Very early onset inflammatory bowel disease
• disease course
• whole exome sequencing

Interleukin 10 receptor alpha subunit (IL10RA) dysfunction is the main cause of very early-onset inflammatory bowel disease (VEO-IBD) in East Asians.

To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.

From May 2016 to September 2020, four young patients with clinically diagnosed VEO-IBD were recruited. Before hospitalization, using targeted gene panel sequencing and trio-whole-exome sequencing (WES), three patients were found to harbor a IL10RA mutation (c.301C>T, p.R101W in one patient; c.537G>A, p.T179T in two patients), but WES results of the fourth patient were not conclusive. We performed whole-genome sequencing (WGS) on patients A and B and reanalyzed the data from patients C and D. Peripheral blood mononuclear cells (PBMCs) from patient D were isolated and stimulated with lipopolysaccharide (LPS), interleukin 10 (IL-10), and LPS + IL-10. Serum IL-10 levels in four patients and tumor necrosis factor-α (TNF-α) in the cell supernatant were determined by enzyme-linked immunosorbent assay. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.

The four children in our study consisted of two males and two females. The age at disease onset ranged from 18 d to 9 mo. After hospitalization, a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data. Patient D was homozygous for the 333 bp deletion. All four patients had elevated serum IL-10 levels. In vitro, IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-α production induced by LPS. Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS + IL-10 in both healthy subjects and in patient D.

WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD, whereas the WES results were inconclusive.

• Interleukin 10 receptor alpha subunit mutation
• Very early-onset inflammatory bowel disease
• Whole-genome sequencing
• Immunodeficiency
• Crohn’s disease
• Whole-exon sequencing

• Base Pairing
• Female
• Humans
• Inflammatory Bowel Diseases/genetics
• Interleukin-10 Receptor alpha Subunit/genetics
• Interleukin-10 Receptor beta Subunit/genetics
• Leukocytes, Mononuclear
• Male

Wiskott–Aldrich syndrome (WAS) is an uncommon X-linked combined-immunodeficiency disorder characterized by a triad of thrombocytopenia, eczema, and immunodeficiency. Patients with WAS are also predisposed to autoimmunity and malignancy. Autoimmune manifestations have been reported in 26%–72% of patients with WAS. Autoimmunity is an independent predictor of poor prognosis and predisposes to malignancy. Development of autoimmunity is also an early pointer of the need for hematopoietic stem–cell transplantation. In this manuscript, we have collated the published data and present a narrative review on autoimmune manifestations in WAS. A summary of currently proposed immunopathogenic mechanisms and genetic variants associated with development of autoimmunity in WAS is also included.

• bleeding
• genetics
• hematopoietic stem–cell transplant
• malignancy
• thrombocytopenia
• vasculitis

• Inflammatory bowel disease
• Pediatric Crohn’s disease
• Pediatric ulcerative colitis

• Autoimmune enteropathy
• Enteropathies
• Very-early-onset inflammatory bowel disease

• Perianal abscesses
• infant
• inflammatory bowel disease

• monogenic etiologies
• primary immune deficiency
• very early onset inflammatory bowel disease

• disease course
• growth failure
• very early onset-inflammatory bowel disease

• Adolescent
• Child
• Child, Preschool
• Female
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/epidemiology
• Inflammatory Bowel Diseases/pathology
• Male
• Phenotype
• Philadelphia/epidemiology
• Retrospective Studies
• Severity of Illness Index
• Treatment Failure

• K23 DK100461 NIDDK NIH HHS
• K23 DK119585 NIDDK NIH HHS
• R01 DK111843 NIDDK NIH HHS
• R01 DK127044 NIDDK NIH HHS
• National Institutes of Health
• Broad Research
• Keystone Team Science

• Adolescent
• Adult
• Child
• Colitis
• Gastroenterology
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/therapy
• Nutritional Status
• Phenotype
• United States

• K23 DK100461 NIDDK NIH HHS
• R01 DK111843 NIDDK NIH HHS

Inflammatory bowel disease (IBD) is more common in adults than in children. Onset of IBD before 17 years of age is referred as pediatric onset IBD and is further categorized as very early onset IBD (VEO-IBD) for children who are diagnosed before 6 years of age, infantile IBD who had the disease before 2 years of age and neonatal onset IBD for children less than 28 days of life. Children presenting with early onset disease may have a monogenic basis. Knowledge and awareness of the clinical manifestations facilitates early evaluation and diagnosis. Next generation sequencing is helpful in making the genetic diagnosis. Treatment of childhood IBD is difficult; targeted therapies and hematopoietic stem cell transplantation form the mainstay. In this review we aim to summarize the genetic defects associated with IBD phenotype. We describe genetic location and functions of various genetic defect associated with VEO-IBD with their key clinical manifestations. We also provide clinical clues to suspect these conditions and approaches to the diagnosis of these disorders and suitable treatment options.

• IPEX
• Il-10 signalling defect
• Next generation sequencing
• Targeted therapy
• Very early onset inflammatory bowel disease

• Enterostomy
• Immunodeficiency
• Inflammatory bowel disease
• Surgical indication
• Surgical treatment

• Child, Preschool
• Enterostomy/adverse effects
• Enterostomy/methods
• Female
• Hematopoietic Stem Cell Transplantation
• Humans
• Infant
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/pathology
• Inflammatory Bowel Diseases/surgery
• Intestinal Obstruction/surgery
• Male
• Mutation
• Postoperative Complications
• Primary Immunodeficiency Diseases/genetics
• Primary Immunodeficiency Diseases/pathology
• Primary Immunodeficiency Diseases/surgery
• Reoperation
• Retrospective Studies
• Surgical Wound Dehiscence/etiology
• Surgical Wound Infection/etiology

Inflammatory bowel disease (IBD) with very early onset manifestations (younger than six years of age) is an essential pediatric gastrointestinal disease that encompasses a group of diverse and rare genetic defects. It may be associated with chronicity, premalignant nature, and high morbidity and mortality during childhood. Because of overlapping phenotypes, the definitive diagnosis based on conventional strategies is frequently a challenge. However, many patients with different molecular pathologies are treated with the same therapeutic strategy. In this context, it is essential to define a more reliable method to provide an opportunity for a rapid and accurate diagnosis. Here we report a novel homozygous exonic variant in a patient with an IBD-like lesion in the colon during the infancy period. A 7 months old boy who was born of a consanguineous marriage developed gastrointestinal disorders early in life. After complete diagnostic workups, this case underwent conventional therapy of IBD for five months; but clinical remission was not achieved. We identified a novel homozygous mutation (c.684C>T p(=)) in exon 7 of IL-12RB1 gene that in silico studies indicated its significance in the splicing process. At the 14^th month of age, this case died. Our finding reveals the importance of genetic screening as an early diagnostic tool in the identification of the underlying causes of IBD with very early onset manifestations, particularly infantile (< 2 years of age) IBD. This strategy makes an opportunity in prompt diagnosis and targeted therapy.

• Early onset inflammatory bowel disease
• IL-12RB1 deficiency
• genetic
• pediatric

• Paediatric inflammatory bowel disease
• diagnostic pathology
• immunodeficiency

• Adolescent
• Age of Onset
• Biopsy
• Child
• Child, Preschool
• Colonoscopy
• Female
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/pathology
• Intestines/pathology
• Male
• Retrospective Studies

• K23 DK100461 NIDDK NIH HHS

• immunodeficiency
• very early-onset inflammatory bowel disease
• whole-exome sequencing

• Early-onset and late-onset IBD
• Elderly IBD
• Pediatric IBD
• Pediatric-adult transition of IBD care

• Candidate Gene Approach
• Complex Trait
• Inflammatory Bowel Disease
• Mendelian Disorder

• Apical periodontitis
• biologic medications
• inflammatory bowel diseases

To screen primary immunodeficiency, Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD) among children with inflammatory bowel disease (IBD).

This was a single-center retrospective study. Eighteen children with IBD were investigated. We analyzed their expression of Wiskott-Aldrich syndrome protein (WASP) in lymphocytes and superoxide generation in phagocytes using flow cytometry. When the expression of WASP or superoxide generation was low or absent, we performed genetic analysis to determine the cause of this.

Eighteen patients were classified as having ulcerative colitis (n = 10), Crohn’s disease (n = 5), or IBD-unclassified (n = 3). In total, three patients revealed low expression of WASP associated with a WAS gene c.1378 C>T p.Pro460Ser mutation, which has previously been reported as a pathogenic mutation in WAS and X-linked thrombocytopenia. However, with respect to the major symptoms of WAS, none of these three patients showed either thrombocytopenia or increased susceptibility to infection, but one patient showed generalized eczema. No CGD patients were discovered in this study.

Despite the lack of typical clinical manifestations of WAS, low expression of WASP could be associated with the pathogenesis of a subtype of IBD patients.

• Inflammatory bowel disease
• Wiskott-Aldrich syndrome
• Primary immunodeficiency
• Children
• Screening

• Age of Onset
• Child
• Child, Preschool
• Female
• Flow Cytometry
• Humans
• Infant
• Inflammatory Bowel Diseases/blood
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/immunology
• Lymphocytes/metabolism
• Male
• Mutation
• Phagocytes/metabolism
• Retrospective Studies
• Superoxides/metabolism
• Wiskott-Aldrich Syndrome/blood
• Wiskott-Aldrich Syndrome/genetics
• Wiskott-Aldrich Syndrome Protein/genetics

• very early-onset ibd (veo-ibd)
• whole exome sequencing
• immunodeficiency

The gastrointestinal tract contains the largest lymphoid organ to react with pathogenic microorganisms and suppress excess inflammation. Patients with primary immunodeficiency diseases (PIDs) can suffer from refractory diarrhea. In this study, we present two siblings who began to suffer from refractory diarrhea with a poor response to aggressive antibiotic and immunosuppressive treatment after surgical release of neonatal intestinal obstruction. Their lymphocyte proliferation was low, but superoxide production and IL-10 signaling were normal. Candidate genetic approach targeted to genes involved in PIDs with inflammatory bowel disease (IBD)-like manifestation was unrevealing. Whole-genome sequencing revealed novel heterozygous mutations Glu75Lys and nucleotide 520–521 CT deletion in the tetratricopeptide repeat domain 7A (TTC7A) gene. A Medline search identified 49 patients with TTC7A mutations, of whom 20 survived. Their phenotypes included both multiple intestinal atresia (MIA) and combined T and/or B immunodeficiency (CID) in 16, both IBD and CID in 14, isolated MIA in 8, MIA, IBD, and CID complex in 8, and isolated IBD in 3. Of these 98 mutant alleles over-through the coding region clustering on exon 2 (40 alleles), exon 7 (12 alleles), and exon 20 (10 alleles), 2 common hotspot mutations were c.211 G>A (p.E71K in exon 2) in 26 alleles and AAGT deletion in exon 7 (+3) in 10 alleles. Kaplan–Meier analysis showed that those with biallelic missense mutations (p = 0.0168), unaffected tetratricopeptide repeat domains (p = 0.0311), and developing autoimmune disorders (p = 0.001) had a relatively better prognosis. Hematopoietic stem cell transplantation (HSCT) restored immunity and seemed to decrease the frequency of infections; however, refractory diarrhea persisted. Clinical improvement was reported upon intestinal and liver transplantation in a child with CID and MIA of unknown genetic etiology. In conclusion, patients with TTC7A mutations presenting with the very early onset of refractory diarrhea had limit improvement by HSCT or/and tailored immunosuppressive therapy in the absence of suitable intestine donors. We suggest that MIA–CID–IBD disorder caused by TTC7A mutations should also be included in the PID classification of “immunodeficiencies affecting cellular and humoral immunity” to allow for prompt recognition and optimal treatment.

• combined T and B immunodeficiency
• inflammatory bowel disease
• multiple intestinal atresia
• refractory diarrhea
• tetratricopeptide repeat domain 7A

• Children
• Enteropathy
• Histopathology
• Inflammatory bowel disease

Diarrhoea lasting longer than 14 days and failing to respond to conventional management is defined as severe and protracted diarrhoea (SD). In this study, we investigated the prevalence, pathogens and prognosis of SD in primary immunodeficiency diseases (PIDs). Among 246 patients with predominantly paediatric-onset PIDs from 2003–2015, 21 [Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG2 (one each)] and five [CVID (four), SCID (one)] without identified mutations had SD before prophylactic treatment. Detectable pathogens included pseudomonas, salmonella (six each), E. coli, cytomegalovirus, coxsackie virus and cryptosporidium (one each), all of whom improved after a mean 17 days of antibiotics and/or IVIG treatment. Seven (7/26; 27.0%) patients died [respiratory failure (four), lymphoma, sepsis and intracranial haemorrhage (one each)]. The patients with WAS, CGD and CD40L and SD had a higher mortality rate than those without. Another five males with mutant XIAP, STAT1, FOXP3 (one each) and STAT3 (two) had undetectable-pathogenic refractory diarrhoea (RD) that persisted >21 days despite aggressive antibiotic/steroid treatment and directly resulted in mortality. For the patients with RD without anti-inflammatory optimization, those with mutant XIAP and FOXP3 died of Crohn’s-like colitis and electrolyte exhaustion in awaiting transplantation, while transplantation cured the STAT1 patient.

Eosinophilic colitis (EC) is a common cause of haematochezia in infants and young children. The exact pathomechanism is not understood, and the diagnosis is challenging. The role of microRNAs as key class of regulators of mRNA expression and translation in patients with EC has not been explored. Therefore, the aim of the present study was to explore the miRNA profile in EC with respect to eosinophilic inflammation. Patients enrolled in the study (n = 10) had persistent rectal bleeding, and did not respond to elimination dietary treatment. High-throughput microRNA sequencing was carried out on colonic biopsy specimens of children with EC (EC: n = 4) and controls (C: n = 4) as a preliminary screening of the miRNA profile. Based on the next-generation sequencing (NGS) results and literature data, a potentially relevant panel of miRNAs were selected for further measurements by real-time reverse transcription (RT)-PCR (EC: n = 14, C: n = 10). Validation by RT-PCR resulted in significantly altered expression of miR-21, -31, -99b, -125a, -146a, -184, -221, -223, and -559 compared to controls (p ≤ 0.05). Elevation in miR-21, -99b, -146a, -221, and -223 showed statistically significant correlation to the extent of tissue eosinophilia. Based on our results, we conclude that the dysregulated miRNAs have a potential role in the regulation of apoptosis by targeting Protein kinase B/Mechanistic target of rapamycin (AKT/mTOR)-related pathways in inflammation by modulating Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related signalling and eosinophil cell recruitment and activation, mainly by regulating the expression of the chemoattractant eotaxin and the adhesion molecule CD44. Our results could serve as a basis for further extended research exploring the pathomechanism of EC.

• eosinophilic colitis
• haematochezia
• microRNA

• Epithelial barrier defects
• IL-10 defects
• IPEX
• Inflammasome
• Neutrophil defects
• T cell or B cell defects
• Very early onset IBD (VEO-IBD)

• Inflammatory bowel disease
• genetics
• immunodeficiency
• infantile-onset
• next-generation sequencing
• paediatrics
• phenotype

• Calprotectin
• Chronic granulomatous disease
• Colitis
• Inflammatory bowel disease

• Adolescent
• Asymptomatic Diseases
• Biomarkers/analysis
• Biomarkers/metabolism
• Child
• Child, Preschool
• Colitis/complications
• Colitis/diagnosis
• Colitis/immunology
• Feces/chemistry
• Female
• Granulomatous Disease, Chronic/complications
• Granulomatous Disease, Chronic/diagnosis
• Granulomatous Disease, Chronic/immunology
• Humans
• Intestinal Mucosa/immunology
• Leukocyte L1 Antigen Complex/analysis
• Leukocyte L1 Antigen Complex/metabolism
• Male
• Neutrophils/immunology
• Prognosis

• Inflammatory bowel diseases
• microbiota
• virome

Most children with Inflammatory Bowel Disease (IBD) are diagnosed between 11 and 16 years of age, commonly presenting with features of typical IBD. Children with onset of gut inflammation under 5 years of age often have a different underlying pathophysiology, one that is genetically and phenotypically distinct from other children with IBD. We therefore set out to assess whether children diagnosed after the age of 5 years, but before the age of 11, have a different clinical presentation and outcome when compared to those presenting later.

Retrospective cohort study conducted at two European Paediatric Gastroenterology Units. Two cohorts of children with IBD (total number = 160) were compared: 80 children diagnosed between 5 and 10 years (Group A), versus 80 children diagnosed between 11 and 16 (Group B). Statistical analysis included multiple logistic regression.

Group A presented with a greater disease activity (p = 0.05 for Crohn’s disease (CD), p = 0.03 for Ulcerative Colitis (UC); Odds Ratio 1.09, 95 % Confidence Interval: 1.02–1.1), and disease extent (L2 location more frequent amongst Group A children with CD (p = 0.05)). No significant differences were observed between age groups in terms of gastro-intestinal and extra-intestinal signs and symptoms at disease presentation, nor was there a difference in the number of hospitalisations due to relapsing IBD during follow-up. However, children in Group A were treated earlier with immunosuppressants and had more frequent endoscopic assessments.

While clinicians feel children between 5 and 10 years of age have a more severe disease course than adolescents, our analysis also suggests a greater disease burden in this age group. Nevertheless, randomized trials to document longer-term clinical outcomes are urgently needed, in order to address the question whether a younger age at disease onset should prompt per se a more “aggressive” treatment. We speculate that non-clinical factors (e.g. genetics, epigenetics) may have more potential to predict longer term outcome than simple clinical measures such as age at diagnosis.

The online version of this article (doi:10.1186/s12876-016-0455-y) contains supplementary material, which is available to authorized users.

• Age
• Children
• Inflammatory Bowel Disease (IBD)
• Location
• Outcomes
• Presentation
• Severity

• Crohn’s disease
• Diffusion-weighted MRI
• MR enterography
• Pediatric radiology
• Perianal fistula

Aggressive course and resistance to treatments usually characterize very early onset inflammatory bowel disease (VEO-IBD). Some VEO-IBD cases are due to monogenic immune defects and can benefit from hematopoietic stem cell transplantation (HSCT).

We describe a Caucasian male baby who presented in the first months of life macrophage activation syndrome, followed by intractable colitis, recurrent episodes of fever and mild splenomegaly. After several immunological, genetic and clinical investigations, subsequently a therapeutic attempt with colectomy, analysis of VEO-IBD-associated genes, revealed a causative mutation in XIAP. The genetic diagnosis of a primary immune deficiency allowed curing the boy with hematopoietic stem cell transplantation.

Our report, together with novel findings from recent literature, should contribute to increase awareness of monogenic immune defects as a cause of VEO-IBD. Comprehensive genetic analysis can allow a prompt diagnosis, resulting in the choice of effective treatments and sparing useless and damaging procedures.

Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn’s disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6^th year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

• Inflammatory bowel disease
• Primary immunodeficiency disease
• Early onset
• Next generation sequencing
• Genome wide association studies

• Adaptive Immunity/genetics
• Age of Onset
• Animals
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/immunology
• Colitis, Ulcerative/therapy
• Crohn Disease/diagnosis
• Crohn Disease/genetics
• Crohn Disease/immunology
• Crohn Disease/therapy
• Genetic Loci
• Genetic Markers
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• High-Throughput Nucleotide Sequencing
• Humans
• Immunity, Cellular/genetics
• Immunity, Innate/genetics
• Phenotype
• Precision Medicine
• Predictive Value of Tests
• Prognosis
• Risk Factors

• CVID
• Common Variable Immune Deficiency
• IBD
• Inherited Defects
• Innate and Adaptive Immunity

• Autophagy
• Crohn's Disease
• Epigenetics
• Ulcerative Colitis