Phosphomannomutase 2 (PMM2) variants leading to hyperinsulinism-polycystic kidney disease are associated with early-onset inflammatory bowel disease and gastric antral foveolar hyperplasia

Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology

Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years

OBJECTIVES: Inflammatory bowel disease presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of two years and establish phenotypic features associated with underlying monogenicity. METHODS: Phenotype data of 62 children with disease-onset before the age of two years presenting over the last 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. RESULTS: 62 patients (55% male) were identified. The median disease-onset was three months of age [IQR: 1 to 11]. Conventional IBD classification only applied to 15 patients with Crohn's disease-like (24%) and three with ulcerative colitis-like (5%) phenotype. Forty-four patients (71%) were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition (40%), extensive immunosuppression (31%), hematopoietic stem-cell transplantation (29%) and abdominal surgery (19%). In 31% of patients underlying monogenic diseases were established (EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A). Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease-onset before the 6(th) month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. CONCLUSION: IBD in children with disease-onset before the age of two years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant and can be indistinguishable from monogenic diseases with IBD-like phenotype

Quantitative assessment of terminal ileum motility on MR enterography in Crohn disease: a feasibility study in children

Objectives: Investigate the relationship between quantified terminal ileal (TI) motility and histopathological activity grading, Crohn Disease MRI Index (CDMI) and faecal calprotectin. / Methods: Retrospective review of children with Crohn disease or unclassified inflammatory bowel disease, who underwent MR enterography. Dynamic imaging for 25 patients (median age 12, range 5 to 16) was analysed with a validated motility algorithm. The TI motility score was derived. The primary reference standard was TI Endoscopic biopsy Assessment of Inflammatory Activity (eAIS) within 40 days of the MR enterography. Secondary reference standards: (1) the Crohn Disease MRI Index (CDMI) and (2) faecal calprotectin levels. / Results: MR enterography median motility score was 0.17 a.u. (IQR 0.12 to 0.25; range 0.05 to 0.55), and median CDMI was 3 (IQR 0 to 5.5). Forty-three percent of patients had active disease (eAIS > 0) with a median eAIS score of 0 (IQR 0 to 2; range 0 to 5). The correlation between eAIS and motility was r = − 0.58 (p = 0.004, N = 23). Between CDMI and motility, r = − 0.42 (p = 0.037, N = 25). Motility score was lower in active disease (median 0.12 vs 0.21, p = 0.020) while CDMI was higher (median 5 vs 1, p = 0.04). In a subset of 12 patients with faecal calprotectin within 3 months of MR enterography, correlation with motility was r = − 0.27 (p = 0.4). / Conclusions: Quantified terminal ileum motility decreases with increasing histopathological abnormality in children with Crohn disease, reproducing findings in adults. TI motility showed a negative correlation with an MRI activity score but not with faecal calprotectin levels

Joint BSPGHAN and coeliac UK guidelines for the diagnosis and management of coeliac disease in children

The revised BSPGHAN guidelines for the diagnosis and management of coeliac disease represent an important shift in diagnostic strategy, aimed at simplifying and shortening the diagnostic process in selected cases. Guidance is given concerning the indications for testing for coeliac disease, which is still significantly underdiagnosed in the UK. While screening data suggest a likely incidence of 1 in 100 persons, only 10%–20% of this figure is currently being diagnosed.The BSPGHAN guidelines follow the new ESPGHAN guidelines in overall diagnostic strategy, while providing more didactic stratagems, which should be of assistance for paediatricians in specialties other than gastroenterology

Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children

The revised BSPGHAN guidelines for the diagnosis and management of coeliac disease represent an important shift in diagnostic strategy, aimed at simplifying and shortening the diagnostic process in selected cases. Guidance is given concerning the indications for testing for coeliac disease, which is still significantly underdiagnosed in the UK. While screening data suggest a likely incidence of 1 in 100 persons, only 10%–20% of this figure is currently being diagnosed.The BSPGHAN guidelines follow the new ESPGHAN guidelines in overall diagnostic strategy, while providing more didactic stratagems, which should be of assistance for paediatricians in specialties other than gastroenterology

Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of two years.

Inflammatory bowel disease presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of two years and establish phenotypic features associated with underlying monogenicity.Phenotype data of 62 children with disease-onset before the age of two years presenting over the last 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing.62 patients (55% male) were identified. The median disease-onset was three months of age [IQR: 1 to 11]. Conventional IBD classification only applied to 15 patients with Crohn's disease-like (24%) and three with ulcerative colitis-like (5%) phenotype. Forty-four patients (71%) were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition (40%), extensive immunosuppression (31%), hematopoietic stem-cell transplantation (29%) and abdominal surgery (19%). In 31% of patients underlying monogenic diseases were established (EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A). Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease-onset before the 6(th) month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities.IBD in children with disease-onset before the age of two years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant and can be indistinguishable from monogenic diseases with IBD-like phenotype

A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease

International audienceBackground: Adalimumab is efficacious therapy for adults with Crohn's disease (CD). Aim: To summarise the United Kingdom and Republic of Ireland paediatric adalimumab experience. Methods: British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) members with Inflammatory Bowel Disease (IBD) patients <18 years old commencing adalimumab with at least 4 weeks follow up. Patient demographics and details of treatment were then collected. Response and remission was assessed using the Paediatric Crohn's Disease Activity Index (PCDAI) /Physicians Global Assessment (PGA). Results: 72 patients (70 CD, 1 Ulcerative Colitis (UC), 1 IBD Unclassified (IBDU)) from 19 paediatric-centres received adalimumab at a median age of 14.8 (IQR 3.1, range 6.1-17.8) years; 66/70 CD (94%) had previously received infliximab. A dose of 80mg then 40mg was used for induction in 41(59%) and 40mg fortnightly for maintenance in 61 (90%). Remission rates were 24%, 58% and 41% at 1, 6 and 12 months respectively. Overall 43 (61%) went into remission at some point, with 24 (35%) requiring escalation of therapy. Remission rates were higher in those on concomitant immunosuppression cf. those not on immunosuppression [34/46 (74%) vs. 9/24 (37%) respectively (Χ28.8, p=0.003)]. There were 15 adverse events (21%) including 4 (6%) serious adverse events with 2 sepsis related deaths in patients who were also on immunosuppression and home parenteral nutrition (3% mortality rate). Conclusions: Adalimumab is useful in treatment refractory paediatric patients with a remission rate of 61%. This treatment benefit should be balanced against side effects, including in this study a 3% mortality rate