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.

Turkish Translation, Validation, and Reliability Analysis of Pediatric Eosinophilic Esophagitis Symptom Severity Module Version 2.0.

The Paediatric Eosinophilic Esophagitis Symptom Severity Modules Version 2.0 (T-PEESv2.0) was developed in English as a valid, reliable questionnaire for follow up. This work aimed to develop a Turkish version of T-PEESv2.0 via translation and cultural adaptation and then to test its validation and reliability. Methods: The PEESv2.0 was translated into Turkish by standardized procedural steps completed in cooperation with the Mapi Research Trust. The final version of the questionnaire was submitted to eosinophilic oesophagitis patients or their parents at 2 times point separated by 1 week. An age-matched control group was used to test the discriminant validity. Construct validity was tested using the Wilcoxon test, and internal consistency was tested using Cronbach's alpha. Test-retest reliability was measured with Cohen's kappa and intraclass correlation coefficient. Results: One hundred twenty-eight participants (70 patients, 58 parents) were enrolled. Fifty-eight (39.1%) of them completed T-PEESv2.0-parent by proxy and 70 (54.7%) were T-PEESv2.0. The Cronbach's alpha coefficient and intraclass correlation coefficient for test-retest reliability were >0.70 for both questionnaires and for all domain (frequency and severity) and total scores. For discriminant validity analysis, subscale (frequency and domain) and total scores of the patient group were compared with those of the control group. The subscale and total scores were significantly different between the groups (P < 0.05). Conclusion: T-PEESv2.0 appeared to be valid and reliable, ready to be introduced as a clinical and research tool for the assessment of patients with eosinophilic oesophagitis.

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.

The HLA groups and their relationship with clinical features in Turkish children and adolescents with celiac disease.

BACKGROUND: We aimed to investigate the relationship between human leukocyte antigens (HLA)-groups and clinical features, and degree of intestinal injury in children with celiac disease (CD). METHODS: Study group included 73 (50 females, 68.5%) children with CD. Demographic and clinical features, accompanying autoimmune diseases, family history for CD and degree of damage in small intestinal mucosa (according to Marsh classification) at the time of diagnosis were determined. Twenty-two siblings of celiac patients without CD (15 females, 65.2%) consisted control group 1, and 66 (40 females, 60.6%) people from the normal population consisted control group 2. RESULTS: The allele frequencies of HLA B8, B50, C6, C7, DR3, DR7, DQ2, and DR3 homozygosity were higher in the patient group. HLA DQ2 positivity was 89% in the patient group, 73.9 and 45.5% in control groups 1 and 2, respectively (p < 0.0001). HLA A30, C14, DR11, DQ3 frequency were lower in patients compared to both control groups. HLA-DR15 alleles in patient and control group 1 was significantly lower compared to the general population (p < 0.05). Thirty (41.1%) patients had typical, 43 (58.9%) patients had atypical presentation. Thirteen (17.8%) patients had other autoimmune diseases. There was no association between coexisting autoimmune diseases and the HLA antigens. Fifteen patients (20.5%) had a positive family history for CD; patients with HLA A69, B41 and C12 alleles had a higher positive family history (p < 0.05). Intestinal mucosal damage was as follows: 5 patients (6.8%) had Marsh 2, 25 (34.3%) Marsh 3a, 28 (38.4%) Marsh 3b, 15 (20.5%) Marsh 3c. Patients with HLA-DR15 alleles had more frequent Marsh 3a lesions (p < 0.05). CONCLUSIONS: B8, B50, C6, C7, DR3, DR7, DR3/DR3, DQ2 alleles were risk factors for CD in the Turkish population. HLA C14, DR11, DR15, and DQ3 alleles were found to have a protective role in the same population.

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.

Transarterial and Transhepatic Endovascular Intervention to Alleviate Portal Hypertension Secondary to Arterioportal Fistula in a Trisomy 21 Infant.

Individuals with trisomy 21 have an 80% risk reduction of vascular anomalies compared with general population. However, an association of trisomy 21 and portal vascular and arteriovenous anomalies has been defined in the literature. The primary hemodynamic abnormality in portal hypertension is increased resistance to portal blood flow. In various case reports in adults and pediatric age group patients, transarterial coil embolization of hepatoportal fistula was described. One of the authors of this article has previously reported successful treatment of congenital arterioportal fistula (APF) with percutaneous transhepatic liquid embolization in a patient who previously had transarterial coil embolization. To date, eight patients with trisomy 21 (Down syndrome) and congenital portosystemic shunts were reported of which four were treated with embolization. Here, we describe a 3-month-old infant with trisomy 21 and intrahepatic APF associated with extrahepatic portal hypertension and massive ascites. In the current report, a rare case of a patient with a diagnosis of trisomy 21 is discussed who was attempted to be treated with transarterial coil embolization and percutaneous transhepatic liquid embolization of the congenital APF in a single session.

Effects of Gluten-Free Diet on Quality of Life and Depression in Children With Celiac Disease.

OBJECTIVES: The aim of this study was to investigate the level of depression and quality of life in children with celiac disease (CD). In addition, it aimed to examine the relations of depression level and life quality with adherence to a gluten-free diet (GFD). METHODS: Twenty-five children with CD and 25 healthy controls were included. The Depression Scale for Children and the General Purpose Health-Related Quality of Life Scale for Children were performed on patients before and after receiving recommendations to follow a GFD. RESULTS: No significant differences were found in the depression scores between the patients and the control subjects (P > 0.05). In contrast, total scores and scores of the emotional well-being subscale of the measure of Quality of Life Scale for Children were significantly lower in patients with CD compared with the control group (P < 0.05). No significant improvements were observed in depression or life quality scores of the total subsample of celiac patients, all of whom received a recommendation to follow a GFD (P > 0.05). Significant decrease was observed in the depression scores, however, of celiac patients who were able to actually adhere to the GFD compared with nonadherent patients. CONCLUSIONS: CD negatively affected quality of life in children. Adherence to GFD was associated with reduction in depression symptoms. Improving the adherence of celiac patients to a GFD may have a favorable effect on their depression symptoms.

Empiric treatment of children with gastroesophageal reflux-like symptoms: Effect of proton pump inhibitors.

Gastroesophageal reflux disease is an important cause of morbidity in childhood. Although various diagnostic methods are available, short course of empiric treatment with a proton pump inhibitor is widely used in adults as a diagnostic test. Data about empiric treatment is scarce in children. The aim of this study is to evaluate the effectiveness of empiric treatment of reflux-like symptoms in children. Pediatric gastroenterology outpatient files were searched and patients with a diagnosis of gastroesophageal reflux were found. Patient complaints, history and the treatments provided were recorded. Treatment naive patients older than 2 years of age with symptoms suggestive of gastroesophageal reflux were selected and included if they were given empiric treatment with a proton pump inhibitor. Empiric treatment was found to be effective in 78% of patients. Treatment response tended to be better in children older than 5 years of age. Of the 22 non-responders 9 underwent endoscopy and pathological findings were discovered in 7 of them. Treatment of children with gastroesophageal reflux symptoms with a proton pump inhibitor might significantly decrease the need for extensive evaluations. However it is important to investigate non-responders to empiric therapy, as it seems there might be high probability of pathological findings.

Is compliance with gluten-free diet sufficient? Diet composition of celiac patients.

This study was planned to investigate the amount and content of foods consumed by child patients with celiac disease on a long-term gluten-free diet. Children aged 3-18 years who were diagnosed with celiac disease according to ESPGHAN criteria and were compliant to the gluten-free diet for at least one year were included. Age and gender matched healthy children were included as the control group. Food consumption records including the amount and content of the foods consumed for a total of three days were obtained. Once the records had been completed on the food consumption form, quantity analysis was again performed by the same dietician. Energy and other nutritional elements taken in through foodstuffs consumed by the patient and control groups were calculated using the Nutrition Data System for Research Package; these results were shown as mean ± standard deviation (x ±SD) and the values compared. The study consisted of 28 patients with a mean age of 10.3 ± 4.6 and 25 healthy controls with a mean age of 9.5 ± 3.4. Average age at diagnosis in the patient group was 6.7 ± 4.3 and mean duration of gluten-free diet was 4.0 ± 3.3 years. Children with celiac disease on a gluten-free diet had significantly lower daily energy intake levels compared to the healthy controls (p<0.05). The proportional fat consumption was significantly higher in the patient group compared to the controls (p<0.05). Moreover, proportional carbohydrate and protein, vitamin E and vitamin B1, and microelements such as magnesium, phosphorus and zinc consumptions were significantly lower in celiac group with respect to v-control group. Solely determining compliance to the gluten free diet might be inadequate in the follow-up of children with celiac disease, adequacy of the nutritional content in terms of macro and micronutrients of celiac disease patients is also important.

Prevalence of irritable bowel syndrome in adolescents in Turkey: effects of gender, lifestyle and psychological factors.

Scarce data exist concerning the prevalence of irritable bowel syndrome in adolescence. Changes in lifestyle, presence of stressors and psychological vulnerability during this stage of life place adolescents in the risk group for irritable bowel syndrome. The aim of this study is to determine the prevalence of irritable bowel syndrome in adolescents who are about to begin their university studies and to identify lifestyle and psychological factors related to irritable bowel syndrome. All students newly enrolled at Abant Izzet Baysal University during the 2005-2006 academic year were recruited. Questionnaires including the Rome II questionnaire, the Beck Depression Inventory and the State-Trait Anxiety Inventory were sent to the addresses of the eligible students before matriculation to the university. A total of 2217 students completed the questionnaires, of which 2038 (91.9%) were regarded as valid. Irritable bowel syndrome prevalence was 10.8% and was significantly higher in females than in males (14.0% vs. 7.1%, p<0.001). In logistic regression analyses, gender (OR=2.48, 95% CI=1.68-3.66) and depression (OR=1.08, 95% CI=1.04-1.12) were significantly linked to irritable bowel syndrome. The prevalence of irritable bowel syndrome in this adolescent population is similar to that reported in other studies. The association of irritable bowel syndrome with depression should guide preventive and therapeutic efforts for this specific age group.

Ornidazole-based sequential therapy is not effective in Helicobacter pylori eradication in children.

BACKGROUND/AIMS: Sequential therapy is one of the recent answers given to the problem of increasing antibiotic resistance and decreasing eradication rates of Helicobacter pylori infection. The aim of this study is to compare the ornidazole-based sequentialtherapy with the standard triple therapy in Helicobacter pylori eradication. MATERIALS AND METHODS: Children aged 4-18 years diagnosed with Helicobacter pylori infection based on histology and at least one of 13 C urea breath test and rapid urease test positivity were included in the study. Children were randomized to standard triple therapy with amoxicillin, clarithromycin, and lansoprazole for 14 days and sequential therapy with amoxicillin and lansoprazole for the first 5 days and clarithromycin, ornidazole and lansoprazole for another 5 days in 2:3 randomization. At the end of the treatment, families were contacted by phone, and side effects of and the compliance to the treatment were noted. Patients were requested to do 13 C urea breath test 6-8 weeks after the treatment. RESULTS: Sixty-one children were included for the final analysis. Per-protocol eradication rates were 48.6% for sequential therapy group and 54.2% for standard triple therapy group. Intention to treat eradication rates were 40.9% and 46.0%, respectively. There were no differences between eradication rates in the two study groups. Side effect rates were also similar between the two groups. CONCLUSIONS: Ornidazole-based sequential therapy did not show any superiority compared to the standard triple treatment in children with Helicobacter pylori infection.

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.

Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype-phenotype correlation in childhood.

PURPOSE: Lansoprazole, a cytochrome P450 2C19 (CYP2C19) substrate, has been widely used in children to manage acid-related diseases. CYP2C19 exhibits marked genetic polymorphisms, and distribution of these polymorphisms varies among different ethnic groups. There is limited data regarding the use of probe drugs for determining CYP2C19 activity in children. The aim of this study was to evaluate lansoprazole as an in vivo phenotyping probe for assessing CYP2C19 activity in children. METHODS: The CYP2C19*2, *3, and *17 variants were determined in 244 children. Three hours after a single oral dose of lansoprazole (n = 94) or omeprazole (n = 19), plasma lansoprazole and 5-hydroxy lansoprazole or omeprazole and 5-hydroxy omeprazole concentrations were analyzed by high-performance liquid chromatography. RESULTS: The CYP2C19*17 was the most frequent variant allele (24.4%). The group of patients with CYP2C19*17*17 genotype had a 70% lower (p < 0.05) mean lansoprazole plasma concentration compared with the CYP2C19*1*1 genotype group, whereas the CYP2C19*2*2 group had 6.9-fold higher (p < 0.01) mean lansoprazole plasma concentration. Lansoprazole metabolic ratios (lansoprazole/5-hydroxy-lansoprazole) were found to be significantly lower in the *17*17 [mean ± standard deviation (SD); 2.8 ± 2.1] group and higher in the *2*2 group (63.5 ± 12.2) compared with that of the *1*1 genotype group (6.1 ± 4.5). CONCLUSION: According to our results from a Turkish pediatric population, lansoprazole is a suitable probe drug for phenotyping CYP2C19. The CYP2C19*2 and *17 variants should be taken into consideration in predicting the clinical outcome of therapy with lansoprazole in the pediatric population.

Obesity in adolescents with celiac disease: two adolescents and two different presentations.

Celiac disease (CD) usually presents with diarrhea and growth retardation in childhood. Obesity is one of the paradoxical conditions in children with CD. We present two adolescents with CD and obesity. One of these patients was diagnosed as CD with malnutrition. His body weight had returned to normal after a gluten-free diet, and after stopping the diet, he had become obese. The second patient was an obese adolescent presenting with dyspeptic symptoms who was diagnosed as CD. Although rare, pediatricians should remember that obesity might be seen in CD before or after the diagnosis.

Three cases of a rare disease, congenital chloride diarrhea, summons up the variation in the clinical course and significance of early diagnosis and adequate treatment in the prevention of intellectual disability.

Congenital chloride diarrhea (CLD) (OMIM #214700) is a rare, autosomal recessive disease that is characterized by increased chloride loss in stool. As a result of electrolyte loss, surviving patients might have some complications, one of them being mental retardation. Here, we present three new Turkish patients with new mutations in the SLC26A3 gene. Although the clinical picture of the patients might be similar, consequences of the disease and complications might differ greatly among patients. Pediatricians should be aware of CLD as a potentially fatal or disabling disease if untreated. History of polyhydramnios, watery diarrhea, failure to thrive, poor growth, soiling, metabolic alkalosis and hypokalemia/hypochloremia should be an alarming set of findings for the diagnosis. Salt substitution therapy started early in life prevents early complications, allows normal growth and development, and favors good long-term prognosis.

Responsiveness of children with celiac disease to different hepatitis B vaccination protocols.

BACKGROUND/AIMS: We aimed to compare the response rates to hepatitis B virus vaccination in the first year of life, using two different immunization protocols, in children with celiac disease. METHODS: Study Group 1 included patients with celiac disease who received 10 µg of hepatitis B vaccine intramuscularly at birth (0), 2 and 9-12 months of life. Group 2 included those who received hepatitis B vaccine at 0, 1 and 6 months of life. Healthy children were divided into two control groups according to the above schedules. RESULTS: The total study group included 64 patients and 49 healthy controls. Celiac patients were found to have lower response rates with respect to controls (78.1% vs. 95.9%, respectively). The difference in response rates in the two patient groups was not statistically significant. CONCLUSIONS: The response rates of celiac patients to the two different hepatitis B vaccination schedules showed no statistically significant difference.

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.

Outcome of enzyme replacement therapy in Turkish patients with Gaucher disease: does late intervention affect the response?

We aimed to evaluate the outcome of enzyme replacement therapy (ERT) in Turkish Gaucher patients since it first became available in our country. Eleven patients with type I and one patient with type III Gaucher disease (GD) received therapy as 30-60 U/kg and 120 U/kg every two weeks, respectively, for at least six months, starting a mean period of 4.2 years after the diagnosis. Assessment of response included serial measurements of hematological and biochemical parameters and liver and spleen volumes. Symptoms and signs of bone disease, growth and severity scores were also evaluated. ERT in Turkish patients led to marked improvement in hematological parameters and organomegaly in the majority of them. Patients with growth failure demonstrated catch-up growth. Progression of bone disease was not observed except in two patients who experienced a delay of 15 and 8.6 years, respectively, between the diagnosis and the start of ERT.