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Cystic fibrosis liver disease (CFLD) is a common complication of cystic fibrosis (CF), typically emerging within the first two decades of life. It significantly impacts both short- and long-term prognosis, being the third leading cause of mortality in this population. We present the case of a child with a rare CF mutation who was diagnosed with CFLD, portal hypertension, esophageal varices, and early-onset CF-related diabetes at the age of 6. This case provides valuable insights into the early onset and progression of CF liver disease, highlighting the importance of timely diagnosis and management.

Store-operated Ca2+ entry (SOCE) represents a predominant Ca2+ influx pathway in non-excitable cells. SOCE is required for immune cell activation and is mediated by the plasma membrane (PM) channel ORAI1 and the endoplasmic reticulum (ER) Ca2+ sensor STIM1. Mutations in the Orai1 or STIM1 genes abolish SOCE leading to combined immunodeficiency (CID), muscular hypotonia, and anhidrotic ectodermal dysplasia. Here, we identify a novel autosomal recessive mutation in ORAI1 in a child with CID. The patient is homozygous for p.C126R mutation in the second transmembrane domain (TM2) of ORAI1, a region with no previous loss-of-function mutations. SOCE is suppressed in the patient’s lymphocytes, which is associated with impaired T cell proliferation and cytokine production. Functional analyses demonstrate that the p.C126R mutation does not alter protein expression but disrupts ORAI1 trafficking. Orai1-C126R does not insert properly into the bilayer resulting in ER retention. Insertion of an Arg on the opposite face of TM2 (L135R) also results in defective folding and trafficking. We conclude that positive side chains within ORAI1 TM2 are not tolerated and result in misfolding, defective bilayer insertion, and channel trafficking thus abolishing SOCE and resulting in CID.

Introduction: Familial Mediterranean fever (FMF) and Crohn’s disease (CD) are chronic autoinflammatory disorders that share similar clinical and biological features. Both disorders are characterized by chronic and relapsing symptoms. In some cases, FMF can coexist with CD, which makes diagnosis and treatment challenging.Case Presentation: A 9-year-old Egyptian child was diagnosed with CD at the age of 5, based on clinical symptoms and endoscopic histopathologic findings. Initially, the patient responded well to biological therapy (anti-TNFα), showing improvements in symptoms along with declines in inflammatory markers and fecal calprotectin levels. At the age of 7, the child began experiencing frequent episodes of fever accompanied by pleuritic chest pain. Right-sided pleural effusion was identified on repeated chest X-rays. The patient was diagnosed with recurrent acute bacterial pneumonia due to immune suppression and was managed with multiple courses of oral antibiotics. During the last presentation, in one of these episodes, further investigation was pursued due to a lack of response to antibiotics, indicated by persistently elevated inflammatory markers (CRP, ESR) and nonresolving mild right-sided pleural effusion. FMF was suspected based on the patient’s clinical presentation and chest imaging. A detailed family history revealed a positive FMF diagnosis in a first-degree cousin. Genetic testing was performed, which revealed two heterozygous pathogenic mutations that support the FMF diagnosis. Treatment with colchicine prevented further episodes. The patient continued to receive follow-up care from the GI team for CD and was maintained on adalimumab.Conclusions: FMF should be considered for children with CD who exhibit pulmonary symptoms that do not respond to CD treatment.

Celiac disease (CeD) is a common small bowel enteropathy characterized by an altered adaptive immune system and increased mucosal antigen presenting cells. This study aims to establish if quantification of corneal Langerhans cells (LCs) using corneal confocal microscopy (CCM) could act as a surrogate marker for antigen presenting cell status and hence disease activity in children with CeD. Twenty children with stable CeD and 20 age-matched controls underwent CCM and quantification of central corneal total, mature and immature LC density. There was no difference in age (11.78 ± 1.7 vs. 12.83 ± 1.91; P  = 0.077) or height (1.38 ± 0.14 vs. 1.44 ± 0.13; P  = 0.125). BMI (18.81 ± 3.90 vs. 22.26 ± 5.47; P  = 0.031) and 25 OHD levels (43.50 ± 13.36 vs. 59.77 ± 22.45; P  = 0.014) were significantly lower in children with CeD compared to controls. The total (33.33(16.67–59.37) vs. 51.56(30.21–85.42); P  = 0.343), immature (33.33(16.67–52.08) vs. 44.79(29.17–82.29); P  = 0.752) and mature (1.56(0–5) vs. 1.56(1.04–8.33); P  = 0.752) LC density did not differ between the CeD and control groups. However, immature (r = 0.535, P  = 0.015), mature (r = 0.464, P  = 0.039), and total (r = 0.548, P  = 0.012) LC density correlated with age. Immature (r = 0.602, P  = 0.038) and total (r = 0.637, P  = 0.026) LC density also correlated with tissue transglutaminase antibody (Anti-TtG) levels assessed in 12/20 subjects with CeD. There was no difference in corneal LC density between children with CeD and controls. However, the correlation between corneal LC density and anti-TtG levels suggests a relationship with disease activity in CeD and requires further study.

The aim of this study was to utilise corneal confocal microscopy to quantify corneal nerve morphology and establish the presence of sub-clinical small fibre damage and peripheral neuropathy in children with celiac disease. This is a cross-sectional cohort study of twenty children with celiac disease and 20 healthy controls who underwent clinical and laboratory assessments and corneal confocal microscopy. Corneal nerve fiber density (no.mm.sup.2 ), corneal nerve branch density (no.mm.sup.2 ), corneal nerve fiber length (mm.mm.sup.2 ), corneal nerve fiber tortuosity and inferior whorl length (mm.mm.sup.2) were quantified manually. Corneal nerve fiber density (34.7±8.6 vs. 32.9±8.6; P = 0.5), corneal nerve branch density (47.2±24.5 vs. 47.3±20.0; P = 0.1) and corneal nerve fiber length (20.0±5.1 vs. 19.5±4.5; P = 0.8) did not differ between children with celiac disease and healthy controls. Corneal nerve fiber tortuosity (11.4±1.9 vs 13.5±3.0; P = 0.01) was significantly lower and inferior whorl length (20.0±5.5 vs 23.0±3.8; P = 0.06) showed a non-significant reduction in children with celiac disease compared to healthy controls. Inferior whorl length correlated significantly with corneal nerve fiber density (P = 0.005), corneal nerve branch density (P = 0.04), and corneal nerve fiber length (P = 0.002). Corneal confocal microscopy demonstrates minimal evidence of neuropathy in children with celiac disease.