Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency.

BACKGROUND: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations. METHODS: The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cTFH ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape. RESULTS: Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4+ T cells, Treg, and cTFH cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years). CONCLUSION: This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.

Familial Mediterranean Fever Mutation Analysis in Pediatric Patients With Inflammatory Bowel Disease: A Multicenter Study.

BACKGROUND: The aim of the study was to evaluate familial Mediterranean fever (FMF) mutation analysis in pediatric patients with inflammatory bowel disease (IBD). The relation between MEFV mutations and chronic inflammatory diseases has been reported previously. METHODS: Children with IBD (334 ulcerative colitis (UC), 224 Crohn's disease (CD), 39 indeterminate colitis (IC)) were tested for FMF mutations in this multicenter study. The distribution of mutations according to disease type, histopathological findings, and disease activity indexes was determined. RESULTS: A total of 597 children (mean age: 10.8 ± 4.6 years, M/F: 1.05) with IBD were included in the study. In this study, 41.9% of the patients had FMF mutations. E148Q was the most common mutation in UC and CD, and M694V in IC (30.5%, 34.5%, 47.1%, respectively). There was a significant difference in terms of endoscopic and histopathological findings according to mutation types (homozygous/ heterozygous) in patients with UC (P < .05). There was a statistically significant difference between colonoscopy findings in patients with or without mutations (P = .031, P = .045, respectively). The patients with UC who had mutations had lower Pediatric Ulcerative Colitis Activity Index (PUCAI) scores than the patients without mutations (P = .007). CONCLUSION: Although FMF mutations are unrelated to CD patients, but observed in UC patients with low PUCAI scores, it was established that mutations do not have a high impact on inflammatory response and clinical outcome of the disease.

Graft-versus-host disease in a child with neuroblastoma after autologous stem cell transplantation.

In the pediatric population, hematopoietic stem cell transplantation (HSCT) is used to treat a wide variety of diseases, both malignant and nonmalignant. For many of these diseases, HSCT is a well-established treatment. Acute graft-versus-host disease (GVHD) continues to be a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Graft versus host disease is a common complication of allo-SCT which is induced by donor T cell recognition of recipient alloantigens. The occurrence of autologous GVHD suggests that inappropriate recognition of host self-antigens may occur. GVHD in patients who received autologous HSCT is extremely rare compared to patients who received allogeneic HSCT. We present the case of a 4-year-old girl with metastatic neuroblastoma who spontaneously developed autologous GVHD after autologous HSCT.

Fecal calprotectin concentration is increased in children with celiac disease: relation with histopathological findings.

BACKGROUND/AIMS: The aim of this study was to compare the fecal calprotectin concentration in children with newly diagnosed celiac disease, children with celiac disease strictly adhering to a gluten-free diet and healthy controls. We also tried to correlate the fecal calprotectin concentration with the clinical presentation, degree of neutrophilic infiltration and the severity of histopathological injury (Marsh grade) in the small bowel mucosa. MATERIAL AND METHODS: The study included three groups: children with untreated celiac disease, children with treated celiac disease, and healthy controls. Moreover, we obtained a second fecal sample from nine newly diagnosed children when their endomysial antibody became negative after gluten-free diet. RESULTS: Fecal calprotectin concentrations were significantly higher in newly diagnosed celiac patients (n=31) compared to patients on gluten-free diet (n=33) and healthy controls (n=34) (117.2 µg/g (3.2-306) vs. 3.7 µg/g (0.5-58.2) and 9.6 µg/g (1-70), respectively, p<0.001). Patients presenting with gastrointestinal symptoms had higher fecal calprotectin concentration compared to the patients presenting with nongastrointestinal symptoms [142.8 (12.2-306) vs. 79.7 (3.2-243.2) respectively, p=0.04]. Nine newly diagnosed patients gave a second fecal sample after starting gluten-free diet when endomysial antibody became negative. Their fecal calprotectin concentration had decreased from 113.7 µg/g (8.7-295.2) to 4.2 µg/g (0.5-20.7) (p<0.01). CONCLUSIONS: Increased fecal calprotectin concentration can be used as a non-invasive marker that might aid in the diagnosis of celiac disease, especially in patients with gastrointestinal presentation. Fecal calprotectin concentration returns to normal on a strict gluten-free diet. Fecal calprotectin may be used as a marker of diet adherence and improvement in gastrointestinal inflammation in children with celiac disease. Additionally, it may be used for the differentiation of celiac disease from functional disorders of the gastrointestinal system.

Internal iliac vein thrombosis in pediatric Crohn's disease.

Thromboembolic events are one of the important extraintestinal manifestations of inflammatory bowel diseases that are associated with considerable morbidity and mortality. Iliac vein thrombosis is rarely reported in inflammatory bowel diseases. A 9.5 year-old girl was presented with joint pain, nausea, vomiting and weight loss. She was diagnosed with Crohn's disease and right internal iliac vein thrombosis. With the implementation of immunosuppressive and anticoagulant therapies clinical picture has improved and thrombosis has resolved. Timely diagnosis and early treatment of extraintestinal complications of inflammatory bowel diseases might be lifesaving.

Double heterotopic pancreas and Meckel's diverticulum in a child: do they have a common origin?

Heterotopic pancreatic tissue consists of normally differentiated pancreatic tissue without a real anatomic and vascular connection to the pancreas, whereas Meckel's diverticulum is one of the most important cause of lower gastrointestinal bleeding in children. Although heterotopic pancreatic tissue is related to various gastrointestinal diseases/malformations in both humans and animals, it is rarely associated with Meckel's diverticulum. Herein, we report a five-year old boy who presented with melena and hematochezia, which were discovered to be the result of Meckel's diverticulum. He also had multiple heterotopic pancreatic tissues in various parts of the gastrointestinal tract. The reason for this association is not known, but might involve some abnormalities of signaling molecules expressed in the development of the gastrointestinal tract and associated organs. In clinical practice, it is important to remember that Meckel's diverticulum and heterotopic pancreatic tissue might occur together or accompany various other gastrointestinal anomalies.

Concurrent septic arthritis and urinary tract infection in a patient with nephrocalcinosis and vesicoureteral reflux.

An eight-month-old boy who presented with a 15-day history of vomiting was revealed to be suffering from urinary tract infection and nephrocalcinosis caused by vitamin D intoxication. During the treatment of vitamin D intoxication (alendronate, 5 mg/day), he developed urinary tract infection and septic arthritis of the left hip joint. Escherchia coli was isolated from his blood, urine, and joint fluid culture. He was operated, joint drainage was performed and appropriate intravenous antibiotic treatment was given for four weeks. After discharge, a voiding cystoureterogram revealed grade 4 vesicoureteral reflux in the right ureter. Combination of complex urinary anomalies associated with stagnation of urine flow and altered urinary dynamics, and metabolic urinary anomalies, such as hypercalciuria/nephrocalcinosis, may facilitate the occurrence of rare systemic complications of urinary tract infection.

A case of tuberous sclerosis presenting with dysrhythmia in the first day of life.

Cardiac rhabdomyoma (CR) is the most common primary cardiac tumor in childhood. Although CRs are asymptomatic in many cases, they may cause arrhythmia, heart failure and fetal hydrops. Babies with arrhythmia in the neonatal period must be investigated for structural heart disease including CR. Cardiac rhabdomyoma may either present as an isolated tumor or may be related with tuberous sclerosis. Arrhythmia due to CR may be the initial sign of tuberous sclerosis. We report a case of tuberous sclerosis presenting with ventricular premature beats and second-degree atrioventricular block in the first day of life who was found to have multiple CR during echocardiographic examination.

Gastric histopathology, iron status and iron deficiency anemia in children with Helicobacter pylori infection.

OBJECTIVES: Helicobacter pylori has been established as a major cause of gastritis and peptic ulcer disease in adults and children. H. pylori infection may also have a role in the development of some extra-gastrointestinal diseases, including iron deficiency anemia. The aim of this study is to investigate H. pylori-related changes in gastric physiology and histology and the relationship of these changes to iron deficiency anemia in children. METHODS: Fifty-two patients with gastrointestinal complaints were studied. Hematologic parameters, 3-day vitamin C and iron consumption, serum gastrin levels, and gastric juice ascorbic acid levels were compared in patients with and without H. pylori infection. Dietary intake of vitamin C and iron, serum gastrin, gastric juice ascorbic acid content, and gastric histology were compared in patients with H. pylori infection and anemia and in patients with H pylori infection and no anemia. The CagA status of the H. pylori organisms was evaluated. RESULTS: Twenty-eight of 52 patients had H. pylori. Thirty-one patients had iron deficiency anemia. H. pylori infection was associated with low serum iron levels. H. pylori gastritis was associated with a decrease in the gastric juice ascorbic acid level. Infection with CagA-positive strains was associated with a greater decrease in gastric juice ascorbic acid than infection with CagA-negative strains. However, the gastric juice ascorbic acid levels of patients with H. pylori and anemia were not different from those of non-anemic patients with H. pylori. Among patients with H. pylori infection, pangastritis was twice as common in those with anemia than in those without anemia. CONCLUSIONS: H. pylori infection was associated with a decrease in gastric juice ascorbic acid concentration, and this effect was more pronounced in patients with the CagA-positive strain. Pangastritis was more common in patients whose H. pylori.infection was accompanied by anemia.