NOD2 Polymorphisms May Direct a Crohn Disease Phenotype in Patients With Very Early-Onset Inflammatory Bowel Disease.

NOD2/CARD15 was the first susceptibility gene recognized for adult-onset Crohn's (or Crohn) disease (CD). Recessive inheritance of NOD2 polymorphisms has been implicated as a mechanistic driver of pediatric-onset CD. In patients with very early-onset inflammatory bowel disease (VEO-IBD), however, the clinical relevance of NOD2 polymorphisms has not been fully established. Ten VEO-IBD patients with NOD2 polymorphisms ( NOD2 +) were compared to 16 VEO-IBD patients without genetic variants in NOD2 or any other VEO-IBD susceptibility genes ( NOD2 -). The majority of NOD2 + patients exhibited a CD-like phenotype (90%), linear growth impairment (90%), and arthropathy (60%), all of which were significantly more common than in the NOD2 - group ( P = 0.037, P = 0.004, P = 0.026, respectively). We propose that the presence of NOD2 polymorphisms in patients with VEO-IBD might confer a CD-like phenotype, linear growth impairment, and arthropathy. These findings should be validated in larger cohorts and may guide precision medicine for patients with VEO-IBD in the future.

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350.

Untargeted metabolomic profiling in a patient with glycogen storage disease Ib receiving empagliflozin treatment.

Glycogen storage disease type Ib (GSD-Ib) is a rare inborn error of glycogen metabolism uniquely associated with neutropenia and neutrophil dysfunction, causing severe infections, inflammatory bowel disease (IBD), and impaired wound healing. Recently, kidney sodium-glucose co-transporter-2 (SGLT2) inhibitors such as empagliflozin known to reduce plasma levels of 1,5-anhydroglucitol (1,5-AG) and its toxic derivatives in neutrophils, have been described as a new treatment option in case reports of patients with GSD-Ib from Europe and Asia. We report our experience with an 11-year-old girl with GSD-Ib presenting with short fasting hypoglycemia, neutropenia with neutrophil dysfunction, recurrent infections, suboptimal growth, iron-deficiency anemia, and IBD. Treatment with daily empagliflozin improved neutrophil counts and function with a significant reduction in G-CSF needs. Significant improvement in IBD has led to weight gain with improved nutritional markers and improved fasting tolerance. Reduction of maximum empagliflozin dose was needed due to arthralgia. No other significant side effects of empagliflozin were observed. This report uniquely highlights the novel use of untargeted metabolomics profiling for monitoring plasma levels of 1,5-AG to assess empagliflozin dose responsiveness and guide dietary management and G-CSF therapy. Clinical improvement correlated to rapid normalization of 1,5-AG levels in plasma sustained after dose reduction. In conclusion, empagliflozin appeared to be a safe treatment option for GSD-Ib-associated neutropenia and neutrophil dysfunction. Global untargeted metabolomics is an efficient method to assess biochemical responsiveness to treatment.

Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels.

BACKGROUND: Chronic transfusions are effective in preventing stroke and other complications of sickle cell disease. The aim of this study was to determine whether serum ferritin levels correlated with liver iron content in sickle cell patients on chronic transfusion. PROCEDURE: Forty-four liver biopsy specimens from 38 patients with homozygous sickle cell anemia (HbSS) and one patient with sickle thalassemia receiving chronic transfusions were studied. Five patients underwent a second liver biopsy for follow up. Three ferritin measurements were used to calculate a mean for each patient. The association between serum ferritin levels and liver iron quantitation was measured using the Spearman rank correlation, and sensitivity and specificity were determined for selected threshold values of serum ferritin. RESULTS: Serum ferritin levels ranged from 515 to 6076 ng/ml, liver iron concentration ranged from 1.8 to 67.97 mg/g dry weight. The amount of iron per gram liver dry weight was moderately correlated with serum ferritin values (r = 0.46). The correlation of duration of transfusion with serum ferritin (r = 0.40) and with liver iron content (r = 0.41) also indicated moderate correlation. Liver biopsy results led to changes in the management after 29/44 (66%) of the biopsies. Serum ferritin >/=2500 ng/ml predicted high liver iron content (>/=7 mg/g), with a sensitivity of 62.5% and a specificity of 77.8%. CONCLUSION: We found a poor correlation between serum ferritin levels and liver iron content (LIC). Despite being on chelation therapy, many patients on chronic transfusion had high levels of liver iron. Measurement of LIC is highly recommended in these patients.

Disseminated tuberculosis in 2 children with inflammatory bowel disease receiving infliximab.

Patients with inflammatory bowel disease are predisposed to opportunistic infections. We report 2 cases of disseminated tuberculosis in adolescents receiving a TNF antagonist, infliximab. Both had negative baseline tuberculin skin tests. Multimodal testing using tuberculin skin tests and interferon gamma release assays at the time of inflammatory bowel disease diagnosis and annually may increase the sensitivity of LTBI testing in these high risk children.