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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The presentation of celiac disease in 220 Turkish children.

The aim of this study was to investigate the presentation pattern of newly diagnosed celiac disease (CD) in Turkish children in the last eight years. Two hundred twenty patients with newly diagnosed CD were included. The medical records of all the patients between January 2000 and October 2008 were reviewed. The clinical spectrum was divided into three categories according to the main symptoms that led to the diagnosis: gastrointestinal presentation, non-gastrointestinal presentation, and silent cases. The mean age of the patients was 7.2 +/- 4.3 years at diagnosis. According to the presenting signs, the patients were defined as gastrointestinal presentation (129 patients, 58.6%), non-gastrointestinal presentation (76 patients, 34.6%) and silent cases (15 patients, 6.8%). This study showed that the number/percentage of CD cases who presented with non-gastrointestinal symptoms/conditions, so-called "non-gastrointestinal presentation", have been increasing in the last eight years.

Autoimmune hemolytic anemia and giant cell hepatitis: Report of three infants.

Giant cell hepatitis associated with direct Coombs' test-positive hemolytic anemia is a rare condition of childhood and the pathogenesis remains unclear. An autoimmune activation and loss of self-tolerance in these patients may be the underlying pathology related to the response of some of the patients to immunosuppressive treatment. Herein, we report the clinical presentation and course of three consecutive patients with this rare condition. We conclude that serum ferritin at diagnosis may be used for prediction of the outcome.

[Different clinical form of tuberculosis in childhood: three cases]. / Cocukluk çaginda tüberkülozun farkli klinik formlari: Uç olgu.

Childhood tuberculosis (Tbc) is an important cause of morbidity and mortality and the highest case burden, an estimated 95% of all Tbc cases is found in developing countries. Although childhood Tbc contributes to only 3-6% of the total caseload in industrialized countries, it makes up a large proportion (15-20%) of all Tbc cases in developing countries. The diagnosis of tuberculosis in children is quite difficult and seldom confirmed and is based mainly on clinical signs, symptoms, history of contact with adult and special investigations. Tbc in children, which is paucibacillary in nature, is usually smear-negative. Bacteriological confirmation by culture of Mycobacterium tuberculosis the gold standard of diagnosis, but rarely exceeds 30-40%. In this writing, we report three different cases those are diagnosed as a Tbc and treated.

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.

Nasal carriage of Staphylococcus aureus in children with allergic rhinitis and the effect of intranasal fluticasone propionate treatment on carriage status.

OBJECTIVE: The aim of this study is to determine the rate of nasal carriage of Staphylococcus aureus (NCSA) in children with allergic rhinitis (AR) and to determine the effect of intranasal fluticasone propionate spray on the NCSA. PATIENTS AND METHODS: Nasal swabs were taken from the children admitted to general pediatrics and pediatric pulmonology clinics. Patients were divided into two groups according to the presence or absence of AR. Diagnosis of AR was based on the patient's symptoms. Nasal swabs were taken from AR patients before and after the treatment with intranasal fluticasone propionate, and from the control group at the beginning and after 2 months. RESULTS: Whole NCSA rate was 17.9%; it was 21.4% for AR patients and 15.9% for control group, respectively (p>0.05). Treatment with intranasal fluticasone propionate spray did not influence NCSA in AR patients. CONCLUSION: It seemed that NCSA was not increased in children with AR and treatment with intranasal fluticasone propionate spray did not change NCSA in AR patients. It is obvious that better understanding of the factors affecting the acquisition and loss of NCSA might increase our knowledge about the relationship between NCSA, allergic airway diseases and their treatments.

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.

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.