Zarife Kuloğlu

Early-onset inflammatory bowel disease and common variable immunodeficiency–like disease caused by IL-21 deficiency

BACKGROUND Alterations of immune homeostasis in the gut can result in development of inflammatory bowel disease (IBD). Recently, Mendelian forms of IBD have been discovered, as exemplified by deficiency of IL-10 or its receptor subunits. In addition, other types of primary immunodeficiency disorders might be associated with intestinal inflammation as one of their leading clinical presentations. OBJECTIVE We investigated a large consanguineous family with 3 children who presented with early-onset IBD within the first year of life, leading to death in infancy in 2 of them. METHODS Homozygosity mapping combined with exome sequencing was performed to identify the molecular cause of the disorder. Functional experiments were performed to assess the effect of IL-21 on the immune system. RESULTS A homozygous mutation in IL21 was discovered that showed perfect segregation with the disease. Deficiency of IL-21 resulted in reduced numbers of circulating CD19(+) B cells, including IgM(+) naive and class-switched IgG memory B cells, with a concomitant increase in transitional B-cell numbers. In vitro assays demonstrated that mutant IL-21(Leu49Pro) did not induce signal transducer and activator of transcription 3 phosphorylation and immunoglobulin class-switch recombination. CONCLUSION Our study uncovers IL-21 deficiency as a novel cause of early-onset IBD in human subjects accompanied by defects in B-cell development similar to those found in patients with common variable immunodeficiency. IBD might mask an underlying primary immunodeficiency, as illustrated here with IL-21 deficiency.

Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype.

Background:Inflammatory bowel diseases (IBDs) denote a heterogeneous group of disorders associated with an imbalance of gut microbiome and the immune system. Importance of the immune system in the gut is endorsed by the presence of IBD-like symptoms in several primary immunodeficiencies. A fraction of early-onset IBDs presenting with more severe disease course and incomplete response to conventional treatment is assumed to be inherited in a Mendelian fashion, as exemplified by the recent discovery of interleukin (IL)-10 (receptor) deficiency. Methods:We analyzed a patient born to consanguineous parents suffering from severe intestinal manifestations since 6 months of age and later diagnosed as IBD. Eventually, she developed autoimmune manifestations including thyroiditis and type I diabetes at the age of 6 and 9 years, respectively. Combined single-nucleotide polymorphism array-based homozygosity mapping and exome sequencing was performed to identify the underlying genetic defect. Protein structural predictions were calculated using I-TASSER. Immunoblot was performed to assess protein expression. Flow cytometric analysis was applied to investigate B-cell subpopulations. Results:We identified a homozygous missense mutation (p.Ile2824Pro) in lipopolysaccharide-responsive and beige-like anchor (LRBA) affecting the C-terminal WD40 domain of the protein. In contrast to previously published LRBA-deficient patients, the mutant protein was expressed at similar levels to healthy controls. Immunophenotyping of the index patient revealed normal B-cell subpopulations except increased CD21low B cells. Conclusions:We describe a patient with a novel missense mutation in LRBA who presented with IBD-like symptoms at early age, illustrating that LRBA deficiency should be considered in the differential diagnosis for IBD(-like) disease even in the absence of overt immunodeficiency.

Celiac disease: presentation of 109 children.

Purpose The clinical features of patients with celiac disease (CD) are variable. In the present study, clinical and laboratory features of 109 patients with CD were retrospectively evaluated. Materials and Methods In all cases, diagnosis of CD was made by European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) criteria and clinical and laboratory findings, including hematological and biochemical analyses, immunoglobulin levels, autoantibodies [antinucler antibody (ANA), antidouble stranded DNA (dsDNA), antimitochondrial antibody (AMA), anti-smooth muscle antibody (ASMA), liver kidney antibody (LKM-1), anti thyroid peroxidase (TPO), anti thyroglobulin (Tg)], bone mineral density (BMD), and electroencephalogram were evaluated. The type of CD was recorded. Results Of 109 patients with CD, 66 (60.6%) were classical type, 41 (37.6%) were atypical type and 2 (1.8%) were silent type. The mean age was 8.81 ± 4.63 years and the most common symptom was diarrhea (53.2%) followed by failure to thrive, short stature, and abdominal pain. Paleness (40.4%), underweight (34.8%), and short stature (31.2%) were the most common findings. Iron deficinecy anemia (81.6%), zinc deficiency (64.1%), prolonged prothrombin time (35.8%), and elevated transaminase levels (24.7%) were the most common laboratory findings. Eight percent of patients had at least 1 autoantibody, and 28 of 52 patients had low BMD. Four of 38 patients had abnormalty in electroencephalograms. The prevalance of selective immunoglobulin (Ig) A deficiency was 9.1%. Histocompatibility antigen HLA-DQ and/or DQ8 genotypes were found in 91% of patients. Abdominal distention, iron deficiency, prolonged prothrombine time, hypoalbuminemia, and elevated transaminase levels were more significantly frequent in the classical type than atypical type (p < 0.005). Conclusion Although classical CD was seen in most patients in the present study, clinical variability of the condition should be kept in mind.

A Successful HSCT in a Girl with Novel LRBA Mutation with Refractory Celiac Disease

To the Editor The gastrointestinal tract is the largest lymphoid organ in the body. One of the major functions of the gastrointestinal tract is maintaining of the balance between active immunity, tolerance and immunosuppression. Dysregulation of this physiologic process can lead to diseases such as food allergy, celiac disease (CD) or inflammatory bowel disease [1]. Therefore, gastrointestinal symptoms such as chronic diarrhea and malabsorption might be indicative of primary immunodeficiency diseases [1]. A 10-year-old girl referred to our clinic with a six-year history of chronic watery diarrhea and unresponsiveness to a gluten free diet. She had been evaluated and treated previously for chronic diarrhea, intermittent fever, recurrent pneumonia, candida esophagitis, pancytopenia, hypoalbuminemia, hypolipidemia, vitamin B12 and folic acid deficiencies. She was diagnosed with CD, based on serologic and histopathological findings. She was placed on a strict gluten free diet for a year, but diarrhea did not improve. She has two healthy brothers. Her parents were consanguineous. On physical examination, she was cachectic; with height for age below 3 % (height SDS −5.18) and weight for age below 3 % (weight SDS −5.27). Bone age and height age of the patient were 6 years, 10 months and 5 years, 3 months, respectively. She had protuberant abdomen and clubbing. Liver and spleenwere palpable at 1 cm and 4 cm below the costal margins. Laboratory tests revealed mildly increased liver transaminases. Hemoglobin was 8.32 g/dl; MCV, 85 fL; RDW, 23.4 %; white blood cell, 5570/mm; platelet, 230,000/mm; reticulocyte count, 1 % and ferritin, 2.8 ng/ml. Coombs test was negative. Sedimentation rate was 18 mm/h, C-reactive protein, 1.78 mg/dl. Stool examinations were normal. 25-hydroxi vitamin D level was 25.7 ng/ml. Insulin like growth factor 1 (IGF-1) was 3.5 ng/mL (Normal, 108–648 ng/mL) and insulin like growth factor binding protein (IGFBP-3), 580 ng/mL (Normal, 2690–7200 ng/mL). Stimulated IGF-1 and IGFBP-3 were 2.85 ng/mL and 720 ng/mL, respectively, both markedly reduced. Basal and stimulated growth hormone levels were compatible with growth hormone insensitivity (12.9 ng/mL and 9.79 ng/mL, respectively). Anti-tissue transglutaminase IgA was positive with a titer of 200 IU/ml. Thyroid auto-antibodies, anti-saccharomyces cerevicea antibody and pANCA were negative. Bone mineral density showed severe osteoporosis (Z score, −5). Chest X-ray showed reticular density in the parenchyma of the lung. High-resolution chest tomography showed bilateral tubular bronchiectasis. Smear staining for acid resistant bacteria and tuberculosis PCR, and culture were negative. Upper gastrointestinal endoscopic examination revealed scalloping in the duodenal mucosa. Colonoscopy showed nonspecific Buket Dalgic and Aydan Ikinciogullari contributed equally to this work.

A rapid lateral flow stool antigen immunoassay and 14C-urea breath test for the diagnosis and eradication of Helicobacter pylori infection in children

Our aim was to evaluate diagnostic accuracy of rapid immunochromatographic stool antigen test (Rapid HpSA; LINEAR Chemical, Barcelona, Spain) and a practical low-dose (14)C urea breath test (UBT) (Heliprobetrade mark) test before and after eradication therapy. One hundred nine children with abdominal symptoms (age range, 5-17 years; mean, 12.1) underwent endoscopy, (14)C-UBT, and Rapid HpSA. Patients were defined as Hp infected when histology was positive for Hp. Forty children (36.6%) were Hp infected. The sensitivity of Rapid HpSA and (14)C-UBT was 65% and 92.5% (P = 0.0003), respectively; the specificity of Rapid HpSA and (14)C-UBT was 92.3% and 85.5% (P = 0.180), respectively. After eradication therapy endoscopy, (14)C-UBT and Rapid HpSA were repeated. The eradication rate was 70.5%. After eradication, the sensitivity of Rapid HpSA and (14)C-UBT was 60% and 100%, respectively; the specificity of Rapid HpSA and (14)C-UBT was 100%. (14)C-UBT was more reliable than the Rapid HpSA test for the diagnosis and for confirming eradication of Hp infection.

Hemorrhagic shock and encephalopathy syndrome: neurologic features.

Hemorrhagic shock and encephalopathy syndrome (HSES) is a severe disease that affects previously healthy infants of less than 1 year of age and is associated with significant mortality and neurologic morbidity. It is characterized by sudden onset of shock, convulsions and coma, bleeding due to severe coagulopathy, fever, diarrhea, metabolic acidosis, and hepatorenal dysfunction. Central nervous system involvement with recurrent seizures and brain edema is the most common cause of high mortality and neurological morbidity. In this report, we describe four patients of HSES and review the initial and follow-up neurological features, electroencephalography findings, and the results of neuroradiological examinations of this catastrophic illness.

Congenital absence of portal vein associated with nodular regenerative hyperplasia of the liver and pulmonary hypertension

We present a 15-year-old girl with congenital absence of the portal vein, pulmonary arterial hypertension and multiple liver lesions proven to be nodular regenerative hyperplasia with biopsy. Ultrasonography, computed tomography, and magnetic resonance imaging findings of the liver lesions and Type I portosystemic shunt are presented.

OBSTRUCTIVE JAUNDICE: An Unusual Initial Manifestation of Intra-Abdominal Non-Hodgkin Lymphoma in a Child

Obstructive jaundice is an unusual manifestation of non-Hodgkin lymphomas in children. Although surgical drainage is one of the initial treatment choices in some cases, usually lymphomatous masses rapidly response to chemotherapy and jaundice decreases due to regression of the mass, without any surgical procedure. The authors report the case of a 16-year-old girl who presented with biliary obstruction due to a neoplasm involving the duodenum. Histological examination of the specimen, which was taken from the mass by endoscopic biopsy, revealed Burkitt lymphoma infiltrating the duodenum. Chemotherapy including cyclophosphamide was started immediately. In a few days, jaundice decreased rapidly by the shrinkage of the mass. Neither surgery nor percutaneous drainage were needed. In conclusion, biliary tract obstruction due to non-Hodgkin lymphoma can be effectively treated with chemotherapy alone without any surgical procedure.

Hypertrophic osteoarthropathy in a child with biliary atresia.

Hypertrophic osteoarthropathy is a syndrome characterized by clubbing of the digits of the hand/foot, periosteal reaction and arthralgia or arthritis which is usually secondary to cyanotic congenital heart disease and chronic pulmonary infections. This syndrome rarely occurs in association with chronic liver disease in childhood. Here, we report on a child with biliary atresia who developed arthralgia and arthritis during follow‐up and which was diagnosed as hepatic hypertrophic osteoarthropathy. It is emphasized that hypertrophic osteoarthropathy should be considered in the differential diagnosis of arthralgia and arthritis in children with long‐standing chronic liver diseases, especially if finger clubbing is also present.

Liver Histology of Children With Chronic Hepatitis Treated With Interferon-α Alone or in Combination With Lamivudine

Aim: To evaluate histological changes with interferon monotherapy or interferon plus lamivudine combination therapy in children with hepatitis B e antigen (HBeAg)–positive chronic hepatitis B. Patients and Methods: 31 children aged 2–13 years were randomly treated with interferon (IFN) (group 1, n = 16) or IFN plus simultaneously started lamivudine (group 2, n = 15). IFN-α2a was given 9 MU/m2 3 times per week for 6 months in each group; lamivudine was given 4 mg · kg−1 · day−1 for 24 months. Liver biopsy specimens were evaluated according to the Knodell score before therapy and after 24 months of therapy. Histological response was defined as a decrease in the histological activity index (HAI) score by at least 2 points. Efficacy of therapy was evaluated at 24 months of therapy in all children. Results: Alanine aminotransferase normalization, HbeAg, and hepatitis B virus DNA clearance were not different. Complete response and histological response were 37.5%/62.5% and 40%/46.7% in groups 1 and 2, respectively (P = NS). At baseline and at 24 months of therapy, total HAI and components of HAI were not different in the 2 groups. In comparison with baseline, a significant decrease in scores of periportal ± bridging necrosis was observed in group 1 (P = 0.01); periportal ± bridging necrosis, intralobular degeneration, focal necrosis, and necroinflammation scores significantly decreased in group 2 (P = 0.04 and P = 0.02) at 24 months of therapy. Conclusions: The addition of lamivudine to IFN-α did not increase the effectiveness of the treatment in terms of complete and histological responses. Both therapies seemed to be effective in the regression of periportal ± bridging necrosis. In addition, combination therapy was also effective in the regression of intralobular degeneration, focal necrosis, and necroinflammatory activity index.