Infantile Inflammatory Bowel Disease Research Articles

Infantile inflammatory bowel disease in three Syrian infants: a case series

BackgroundInflammatory bowel diseases, consisting of Crohn’s disease and ulcerative colitis, are chronic bowel relapsing inflammatory disorders. Inflammatory bowel diseases begin rarely in infants. Approximately 25% of patients with inflammatory bowel diseases present before the age of 20 years. Very early-onset inflammatory bowel disease occurs before the age of 6 years; infantile inflammatory bowel diseases occurs before the age of 2 years, and is extremely rare in infants under 1 year of age.Case presentationHerein, we report a case series of 7-month-, 11-month-, and 12-month-old Syrian infants that presented with diarrhea, hematochezia, and pale appearance and were finally diagnosed with infantile inflammatory bowel disease and treated.ConclusionsEarly diagnosis and ruling out infantile inflammatory bowel diseases despite its rarity are recommended. Over and above that, new drugs such as vedolizumab, golimumab, and less invasive treatment methods should also be taken into consideration for better response and adequate remission with improved quality of life.

UNIQUE MONOCYTE EXPRESSION SIGNATURE IN A STXBP2 MUTATION CAUSING INFANTILE ONSET VEO-IBD AND HLH

Abstract Mutations in syntaxin-binding-protein-2 (STXBP2) can result in NK cell dysfunction leading to a hyperinflammatory state including familial HLH and infantile onset inflammatory bowel disease (IBD). While the function of STXBP2 in NK cells and cytotoxic T cells has been well described, it is highly expressed in monocytes with unclear relevance. We report the case of an infant who presented with severe infantile onset diarrhea with an identified pathogenic mutation in STXBP2. We sought to utilize scRNA-Seq to study the impact of STXBP2 deficiency on monocyte transcription, with the goal of generating insight into the pathogenesis of disease. METHODS: Trio whole exome sequencing was performed. PBMCs were collected from the described patient (case), and two control groups: 3 patients with VEO-IBD, and 3 age matched healthy controls. Single cell RNA-Seq was performed using the 10x platform and data analysis was done using Seurat in R. RESULTS: A male infant presented at 1 week of age with diarrhea and metabolic acidosis. Endoscopic evaluation at 4 weeks of age showed histologic findings of colitis and marked epithelial cell changes, including cell rounding. WES identified a homozygous pathogenic mutation in STXBP2. Due to significant risk of HLH, he underwent evaluation for stem cell transplant. However, in the interim he developed severe HLH requiring ICU level care. He recovered following aggressive treatment and underwent HSCT at 4 months of age and retransplant for graft failure at 11 months of age. He is currently in endoscopic remission off therapy. We analyzed PBMCs from the case patient using single cell RNA-Seq, as compared to patients with VEO-IBD and age-matched controls. STXBP2 expression was most enriched in monocyte populations and reduced in the case patient compared to controls. 231 and 187 genes were differentially expressed in the case monocytes as compared to both controls. The case patient had a paucity of non-classical monocytes. Within the classical monocytes, differentially expressed genes showed enrichment of host defense, cytokine processes, and apoptotic processes. Within the intermediate monocytes, differentially expressed genes showed enrichment of chemotaxis pathways, antigen presentation and T cell activation processes. CONCLUSIONS: Mutations in STXBP2 are a life-threatening cause of fHLH and infantile onset IBD. We report a case of infantile onset IBD due to a homozygous mutation in STXBP2 with resolution of disease post HSCT. Transcriptional analysis of PBMCs from this patient reveals a paucity of non-classical monocytes in the peripheral blood, and differential regulation of genes implicated in host defenses, antigen presentation, chemotaxis and apoptosis. These results may suggest the role of monocyte function in pathogenesis of STXBP2 and in other forms of IBD.

Intractable diarrhea in infancy and molecular analysis: We are beyond the tip of the iceberg

BackgroundIntractable diarrhea (ID) could be defined as a syndrome of severe chronic diarrhea associated with malnutrition not easily resolved by conventional management. AimsTo provide an overview on etiology and management of ID patients in Italy in the last 12 years. MethodsThe members of Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) enrolled all ID patients seen between January 1, 2011 and December 31, 2022. Results69 children were enrolled (49 M, 20 F; median age at ID onset 9.5 days) from 7 tertiary care pediatric centers. Overall 62 patients had genetic diseases; 3 had infantile Inflammatory Bowel Disease and 1 autoimmune enteropathy in absence of genetic mutations; 2 undefined ID. Defects of intestinal immune-related homeostasis caused ID in 29 patients (42 %). ConclusionID is a rare but challenging problem, although the potential for diagnosis has improved over time. In particular, molecular analysis allowed to identity genetic defects in 90 % of patients and to detect new genetic mutations responsible for ID. Due to both the challenging diagnosis and the treatment for many of these diseases, the close relationship between immune system and digestive tract should require a close collaboration between pediatric immunologists and gastroenterologists, to optimize epidemiologic surveillance and management of ID.

S27 A Rare Presentation of Cerebral Venous Thrombosis as a Complication of Infantile Inflammatory Bowel Disease in a 17-Month-Old Infant

S27 A Rare Presentation of Cerebral Venous Thrombosis as a Complication of Infantile Inflammatory Bowel Disease in a 17-Month-Old Infant

An Eleven Months Old Infant with Very Early Onset Inflammatory Bowel Diseases (IBD): A Rare Case Report

Inflammatory bowel disease (IBD) in pediatric cases has been seen rapidly increasing in number over the last decade. Now a days four types of pediatric IBD has been identified: less than ten years of age - early onset IBD, less than six years of age - very early onset IBD, less than two years of age- infantile IBD and less than twenty eight days of age - neonatal onset IBD. Young children presented with more aggressive clinical features and severity is more than the older children and adults. Early onset disease presenting in children may have a monogenic basis. Infantile IBD or neonatal IBD having the high rates to affect the first-degree relatives and there is very high chance to develop resistance against immunosuppressive treatment. Very early onset IBD (VEO-IBD) most commonly presenting per rectal bleeding with or without mucous stools, isolated colonic disease, perianal involvement, skin lesions, whereas early onset IBD (EO-IBD) commonly presented with abdominal pain and weight loss. A thorough history, physical examination, biochemical markers, endoscopic evaluation with macroscop and microscopic findings are the only way to reach the diagnosis. The treatment of VEO-IBD is the same as that given to the adolescents and adults with IBD (eg, anti-inflammatory agents, immunomodulators, biologics, antibiotics, and surgical approaches). Here, we report a rare case of very early onset IBD of a 11 months old male infant, who presented with the complaints of blood and mucus mixed loose watery stool for 10 days, having similar episodes for last five months. He was mildly pale, and had thrombocytosis with raised C reactive protein (CRP), features of colitis in stool routine microscopic test. The diagnosis was confirmed by colonoscopy and histopathology study, which showed features of Crohn’s colitis. He was treated by anti-inflammatory drugs (steroid and mesalazine) with a significant improvement in a short time. Bangladesh Med J. 2021 May; 50(2) : 45-49

Histopathological Features of Monogenic Inflammatory Bowel Disease: Subanalysis of Systematic Review

Histopathological Features of Monogenic Inflammatory Bowel Disease: Subanalysis of Systematic Review

Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR)

ABSTRACT We describe a cohort of 25 Iranian patients with infantile inflammatory bowel disease (IBD), 14 (56%) of whom had monogenic defects. After proper screening, patients were referred for whole exome sequencing (WES). Four patients had missense mutations in the IL10 RA, and one had a large deletion in the IL10 RB. Four patients had mutations in genes implicated in host:microbiome homeostasis, including TTC7A deficiency, and two patients with novel mutations in the TTC37 and NOX1. We found a novel homozygous mutation in the SRP54 in a deceased patient and the heterozygous variant in his sibling with a milder phenotype. Three patients had combined immunodeficiency: one with ZAP-70 deficiency (T+B+NK−), and two with atypical SCID due to mutations in RAG1 and LIG4. One patient had a G6PC3 mutation without neutropenia. Eleven of the 14 patients with monogenic defects were results of consanguinity and only 4 of them were alive to this date.

Clinical and genotypic characteristics of infantile inflammatory bowel disease

Objective: To analyze the clinical and genotypic characteristics of infantile inflammatory bowel disease (IBD). Methods: The age of onset, family history, clinical manifestations, and treatment effect were retrospectively analyzed in 39 infants (male 23 cases, female 16 cases) with IBD who were admitted to the Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from January 2007 to December 2017. Next generation sequencing (NGS) based on target gene panel was used for gene analysis in 17 patients. Results: The median age of onset was 0.5 (0.5, 1.0) month. The most common clinical symptoms included diarrhea (39, 100%), malnutrition (38, 97%), hematochezia (34, 87%), fever (25, 64%), and perianal diseases (24, 61%). Four children had associated family history. Among the 17 patients whose gene was analyzed, 10 were found to have the pathogenic gene variation, within whom 7 had interleukin-10 receptor α subunit (IL-10RA) mutation, 2 had CYBB heterozygous mutation, 1 had interleukin-10 receptor β subunit (IL-10RB) mutation. The therapeutic medicine included mesalazine, steroids, and thalidomide. Eighteen children (46%) reached clinical remission (10 cases) or partial remission (8 cases). Conclusions: The incidence of single gene mutation in infants with IBD is high, with IL-10RA mutation as the most common. Refractory diarrhea and malnutrition may indicate infantile IBD.

Tu1708 – Early Childhood Inflammatory Bowel Disease is Distinct from Infantile and Pediatric Inflammatory Bowel Disease

Tu1708 – Early Childhood Inflammatory Bowel Disease is Distinct from Infantile and Pediatric Inflammatory Bowel Disease

Current concepts in pediatric inflammatory bowel disease; IL10/IL10R colitis as a model disease.

Inflammatory bowel disease (IBD) is a heterogeneous group of disorders composed mainly of ulcerative colitis (UC) and Crohn's disease (CD) and undetermined IBD. The peak incidence of occurrence is mainly beyond the pediatric age group. Recent knowledge about genetic factors had been strongly linked to pediatric IBD (PIBD). Recent advances in genomic technologies have prompted the identification of genetic defects underlying rare, very early-onset IBD (VEO-IBD) as a disease subgroup noted especially in populations with higher consanguinity rates. A better understanding of key players in the complex homeostasis of the immune system in the gut and illustrating the relationships between intestinal microbiome, systemic immune dysregulation and primary immunodeficiency have received growing recognition over the years. In this article, we provide a review of the key players of the immunity of the gut, compare between adult and pediatric IBD as an interesting module to investigate the relationship between monogenic and multifactorial/polygenic diseases, list genetic mutations confirmed to be linked to VEO IBD and summarize the scientific work that led to the discovery of one of the monogenic mutations related to infantile colitis, namely IL10 and IL10 receptor defects.

Very early onset inflammatory bowel disease: Investigation of the IL-10 signaling pathway in Iranian children

Background & aimComparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as an important cause of infantile (Very Early Onset) IBD to find any possible variants. MethodWith the next generation sequencing technique we screened IL-10, IL-10RA and IL10RB genes of 15 children affected by very early onset-GI (gastrointestinal) disorders. Additionally, we analyzed them based on Thermo Fisher immune deficiency panel for genes either having a known role in IBD pathogenesis or cause the disorders with overlapping manifestations. We performed multiple functional analyses only for the cases showing variants in IL-10- related genes. ResultIn 3 out of 15 patients we identified variants including a homozygous and heterozygote mutations in IL-10RA and a novel homozygous mutation in IL-12RB1. Our functional studies reveal that in contrast to the IL-10RA heterozygote mutation that does not have deleterious effects, the homozygous mutation abrogates the IL-10 signaling pathway. ConclusionOur study suggests we need to modify the classical diagnostic approach from functional assays followed by candidate- gene or genes sequencing to the firstly parallel genomic screening followed by functional studies.

Single center retrospective study of 184 children with inflammatory bowel disease seen from 2000-2014

Objective: To investigate the clinical data of children with inflammatory bowel disease (IBD) retrospectively, including Crohn's disease (CD) and ulcerative colitis (UC) and identify the clinical characteristics and trends of change. Method: Clinical data of hospitalized patients diagnosed as IBD in Beijing Children's Hospital from January 2000 to December 2014 were collected and retrospectively analyzed. Patients were divided into six groups based on type of disease and year of admission: Group A1(CD, 2000-2004) included 12 patients, Group B1(CD, 2005-2009) included 11, Group C1(CD, 2010-2014) included 51; Group A2(UC, 2000-2004) included 17, Group B2(UC, 2005-2009) included 25, Group C2(UC, 2010-2014) included 68. Result: A total of 184 IBD patients were included in the study, 74 had CD and 110 had UC. The hospitalization constituent ratio of CD increased from 0.6/10 000 in Year 2000 to 2.9/10 000 in Year 2014. The hospitalization constituent ratio of UC increased from 0.5/10 000 in Year 2001 to 3.9/10 000 in Year 2014. The hospitalization constituent ratios of CD and UC both increased gradually(P<0.05). Up to 61.4%(113/184) of IBD patients belong to early onset IBD, furthermore the very early onset IBD and infantile IBD accounted for 41.8%(77/184) and 26.6%(49/184) respectively. For CD, ileocolonic type(47.3%, 35/74) and non-structuring, non-penetrating type (67.6%, 50/74) were more common. Perianal disease occured in 31.1%(23/74) of CD patients; 81.1%(60/74) of CD patients had moderate/severe activity. For UC, pancolitis type(59.1%, 65/110) was more common. There were no significant changes for location of pathological change, disease behavior, activity degree of CD, extent of UC lesion and incidence of surgery, intestinal perforation and hemorrhage of gastrointestinal tract for IBD in the past 15 years(P>0.05). Severe UC(S3) was more common in Group A2(64.7%, 11/17), but moderate UC(S2) was more common in Group C2(48.5%, 33/68), the difference was statistically significant (P=0.001 7). Conclusion: During the past 15 years, the hospitalization constituent ratio for IBD in our hospital showed a growing trend. The ratio of infantile IBD and very early onset IBD was high. For CD, perianal disease was commonly seen and most patients had moderate/severe activity. The surgery rate and incidence of intestinal obstruction and perforation were higher in the CD patients than UC patients. For UC, the lesions were more extensively combined with higher disease activity.

Treatment of Infantile Inflammatory Bowel Disease and Autoimmunity by Allogeneic Stem Cell Transplantation in LPS-Responsive Beige-Like Anchor Deficiency.

Inflammatory bowel disease (IBD) in young children can be a clinical manifestation of various primary immunodeficiency syndromes. Poor clinical outcome is associated with poor quality of life and high morbidity from the complications of prolonged immunosuppressive treatment and malabsorption. In 2012, mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified as the cause of an autoimmunity and immunodeficiency syndrome. Since then, several LRBA-deficient patients have been reported with a broad spectrum of clinical manifestations without reliable predictive prognostic markers. Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been performed in a few severely affected patients with complete or partial response. Herein, we present a detailed course of the disease and the transplantation procedure used in a LRBA-deficient patient suffering primarily from infantile IBD with immune enteropathy since the age of 6 weeks, and progressive autoimmunity with major complications following long-term immunosuppressive treatment. At 12 years of age, alloHSCT using bone marrow of a fully matched sibling donor—a healthy heterozygous LRBA mutant carrier—was performed after conditioning with a reduced-intensity regimen. During the 6-year follow-up, we observed a complete remission of enteropathy, autoimmunity, and skin vitiligo, with complete donor chimerism. The genetic diagnosis of LRBA deficiency was made post-alloHSCT by detection of two compound heterozygous mutations, using targeted sequencing of DNA samples extracted from peripheral blood before the transplantation.

Clinical Pattern of Early-Onset Inflammatory Bowel Disease in Saudi Arabia: A Multicenter National Study.

The objectives of this multicenter national study were to compare the clinical phenotype of early-onset inflammatory bowel disease (IBD) (EO-IBD) with IBD in older children and to examine whether there is any variability in consanguinity rate and familial aggregation in EO-IBD compared with later onset IBD. A retrospective analysis was performed on children aged 0 to 14 years with IBD in 17 centers located in geographically distinct regions in Saudi Arabia, from 2003 to 2012. Data of patients with EO-IBD (0 to <6 yrs) were compared with those with later onset IBD (6-14 yrs). Moreover, we evaluated differences in clinical pattern of infantile or toddler onset IBD subgroup (0-3 yr) as compared with those presenting in older children. Of 352 IBD patients identified during the 10-year study period, 76 children (21.6%) younger than 6 years were diagnosed with IBD. Among the Crohn's disease (CD) group, infantile or toddler onset CD subgroup showed a more frequent isolated colonic involvement (L2) than later-onset group (57% versus 20%; P = 0.002). Positive family history was significantly more common in the infantile or toddler onset ulcerative colitis subgroup (29.4% versus 4.2% in later onset ulcerative colitis; P < 0.0001). The consanguinity rate was significantly higher in the infantile or toddler onset CD subgroup as compared with later onset CD group (57.1% versus 25.3%; P = 0.04). In conclusion, EO-IBD exhibits a unique clinical phenotype with a strikingly higher familial aggregation in early-onset ulcerative colitis. Our data suggest a significant genetic impact on the onset of CD in the very young children.

Hematopoietic stem cell transplantation completely reversed colitis but not arthritis in IL-10Rα deficiency

Mutations in IL-10R1, IL-10R2, and IL-10 have been identified in infants with severe colitis. The only possible hope for cure in these conditions is a hematopoietic stem cell transplantation (HSCT). We report here on a patient with IL-10R1 deficiency who suffered severe colitis and arthritis. She received a HSCT from a matched unrelated donor and her post-transplant course was uneventful. She has fully engrafted and her immune reconstitution was complete and robust. Although signs of colitis were completely resolved, arthritis was not reversed by HSCT. She continues to have joint swelling in the knees and inflammatory changes in the wrists. In conclusion, HSCT seems to have reversed colitis, but was insufficient to improve arthritis and possibly other autoimmune manifestations. Statement of novelty: This report describes a successful HSCT in severe infantile colitis caused by mutations in IL-10R1. Yet, the arthritis remains active, suggesting that conditions such as severe rheumatic disorders in childhood may not be reversed by replacement of the hematopoietic system.

Infantile Colitis as a Novel Presentation of Familial Mediterranean Fever Responding to Colchicine Therapy

Infantile Colitis as a Novel Presentation of Familial Mediterranean Fever Responding to Colchicine Therapy

Is Infantile Inflammatory Bowel Disease Curable with Hematopoietic Stem Cell Transplantation?

교신저자: 고재성, 110-744, 서울시 종로구 대학로 101, 서울대학교 어린이병원 소아청소년과 Correspondence to: Jae Sung Ko, Department of Pediatrics, Seoul National University Children’s Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea. Tel: +82-2-2072-2197, Fax: +82-2-743-3455, E-mail: kojs@snu.ac.kr Financial support: None. Conflict of interest: None. 요약: 염증성 장질환은 유전적 소인을 가진 사람에서 환경 인자에 의해 만성적인 장의 염증이 발생하는 다유전자(multigenic) 질환으로 알려져 있다. Genome-wide association study (GWAS)를 통해 크론병과 궤양성 대장염과 연관된 유 전자다형태(genetic polymorphism)가 100개 이상 발견되었 다. 반면에 영아기에 발병하는 염증성 장질환에서 단일유전자 (monogenic) 질환이 밝혀졌는데, interleukin-10 receptor (IL-10R)와 interleukin-10 (IL-10) 유전자의 돌연변이가 보고 되었다. 이 연구에서는 조기(5세 이전)에 발병한 66명의 염증 성 장질환 환자를 대상으로 IL-10R1, IL-10R2, IL-10 유전자 를 염기서열분석하고 말초혈액을 이용하여 기능분석을 시행 하여 동종조혈모세포이식의 치료효과를 평가하였다. 16명의 환자에서 IL-10 관련유전자의 돌연변이가 확인되었는데, 5명 은 IL-10R1, 8명은 IL-10R2, 3명은 IL-10 유전자의 돌연변이 를 가지고 있었다. 이 중에서 9개의 돌연변이는 이전에 보고 되지 않은 것이었다. 돌연변이가 발견된 환자들은 생후 3개월 이내에 중증의 진행성 대장염으로 발병하였고 성장부진, 반복 적인 발열과 감염, 농양, 항문주위 치루, 모낭염이 동반되었으 며 장관영양, 면역억제제, 장루, 장절제 등 여러 가지 치료에 반응하지 않았다. IL-10R 돌연변이 환자에서 채취한 말초혈 액단핵세포는 IL-10으로 자극하더라도 signal transducer and activator of transcription 3 (STAT3)의 인산화가 유도 되지 않아 IL-10이 매개하는 신호전달에 장애가 발생하였다. 또한 IL-10과 lipopolysaccharide (LPS)로 동시에 자극했을 때 IL-10에 의존적인 음 되먹임(negative feedback) 조절이 되지 않아서 tumor necrosis factor (TNF)-α의 분비가 억제 되지 않았다. 면역억제 치료와 수술에 반응하지 않는 IL10-R 결핍 환자 5명을 대상으로 동종조혈모세포이식을 시행하였 다. 이식 2년 후 4명에서 완전한 임상관해가 지속되었고 1명 에서는 대장염이 호전되었으나 치루가 치유되지 않았다. 이식 받은 환자의 말초혈액단핵세포 기능분석에서 STAT3의 인산화 가 이루어졌고, IL-10과 LPS 동시 자극에 TNF-α의 분비가 억제되었다. 이것은 조혈모세포이식 후에 IL-10R가 매개하는 신호전달이 회복된 것을 의미한다. 결론으로 영아기에 발병하 고 항문주위 병변이 있는 염증성 장질환 환자는 IL-10, IL-10R 유전자검사를 시행해야 하고, 동종조혈모세포이식이 IL-10R 결핍 환자에서 지속적 관해를 유도할 수 있다.

Covering the Cover

Covering the Cover

Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease: Implications for Diagnosis and Therapy

Homozygous loss of function mutations in interleukin-10 (IL10) and interleukin-10 receptors (IL10R) cause severe infantile (very early onset) inflammatory bowel disease (IBD). Allogeneic hematopoietic stem cell transplantation (HSCT) was reported to induce sustained remission in 1 patient with IL-10R deficiency. We investigated heterogeneity among patients with very early onset IBD, its mechanisms, and the use of allogeneic HSCT to treat this disorder. We analyzed 66 patients with early onset IBD (younger than 5 years of age) for mutations in the genes encoding IL-10, IL-10R1, and IL-10R2. IL-10R deficiency was confirmed by functional assays on patients' peripheral blood mononuclear cells (immunoblot and enzyme-linked immunosorbent assay analyses). We assessed the therapeutic effects of standardized allogeneic HSCT. Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency: 3 patients had mutations in IL-10, 5 had mutations in IL-10R1, and 8 had mutations in IL-10R2. Refractory colitis became manifest in all patients within the first 3 months of life and was associated with perianal disease (16 of 16 patients). Extraintestinal symptoms included folliculitis (11 of 16) and arthritis (4 of 16). Allogeneic HSCT was performed in 5 patients and induced sustained clinical remission with a median follow-up time of 2 years. In vitro experiments confirmed reconstitution of IL-10R-mediated signaling in all patients who received the transplant. We identified loss of function mutations in IL-10 and IL-10R in patients with very early onset IBD. These findings indicate that infantile IBD patients with perianal disease should be screened for IL-10 and IL-10R deficiency and that allogeneic HSCT can induce remission in those with IL-10R deficiency.

Infantile Colitis as a Novel Presentation of Familial Mediterranean Fever Responding to Colchicine Therapy

Infantile Colitis as a Novel Presentation of Familial Mediterranean Fever Responding to Colchicine Therapy