Deniz Cagdas

IL-12Rβ1 deficiency: mutation update and description of the IL12RB1 variation database

IL‐12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL‐12Rβ1 is a receptor chain of both the IL‐12 and the IL‐23 receptor and deficiency of IL‐12Rβ1 thus abolishes both IL‐12 and IL‐23 signaling. IL‐12Rβ1 deficiency is caused by bi‐allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL‐12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL‐12Rβ1 protein. In addition to disease‐causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL‐12Rβ1 and molecular genetics of human IL12RB1.

RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics

RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.

Identification of ITK deficiency as a novel genetic cause of idiopathic CD4+ T-cell lymphopenia.

To the editor: Idiopathic CD4 lymphopenia represents a heterogeneous group of combined primary immunodeficiencies with markedly reduced CD4+ T-cell counts. Although several genetic etiologies including MHC class II deficiency[1][1] or mutations in RAG1 ,[2][2] MST1 ,[3][3] or LCK [4][4] have been

Glucocorticoid-induced Diabetic Ketoacidosis in Acute Rheumatic Fever

Glucocorticoids are used as anti-inflammatory agents and are associated with many side effects including hyperglycemia, hypertension, pancreatitis, peptic ulcer, and so on. Hyperglycemia is a common side effect, but ketoacidosis is observed rarely. We present a girl who developed diabetic ketoacidosis after the administration of methylprednisolone during the treatment of acute rheumatic fever. She did not have diabetes and was not obese. She developed ketoacidosis after glucocorticoid therapy. Glucocorticoid-induced insulin resistance, lipolysis, and ketogenesis were likely to have precipitated ketoacidosis. During the treatment of ketoacidosis, the insulin need of the patient was gradually decreased by reducing glucocorticoid dose. In addition to the gradual reduction in glucocorticoid dose, salicylate therapy could be considered the treatment for insulin resistance. In this patient, screening for blood gases and urine was diagnostic in the diagnosis of ketoacidosis. The risk of ketoacidosis as well as hyperglycemia should be considered in the course of glucocorticoid therapy.

Two SCID cases with Cernunnos-XLF deficiency successfully treated by hematopoietic stem cell transplantation

Çağdaş D, Özgür TT, Asal GT, Revy P, De Villartay J‐P, van der Burg M, Sanal Ö, Tezcan İ. Two SCID cases with Cernunnos‐XLF deficiency successfully treated by hematopoietic stem cell transplantation.

Familial Mediterranean fever and mesangial proliferative glomerulonephritis: report of a case and review of the literature

In familial Mediterranean fever (FMF), a genetically inherited disease characterized by fever and serositis, renal involvement is mainly AA amyloidosis. We report a patient with FMF who developed mesangial proliferative glomerulonephritis; presumably in response to colchicine treatment, the activity of the disease decreased and renal function tests and urinary findings normalized. This report emphasizes the concurrent existence of mesangial proliferative glomerulonephritis with FMF in the absence of renal amyloidosis. Due to increased inflammatory response observed in FMF, immunologic glomerular injury, a common cause of glomerulonephritis, may occur more frequently in patients with FMF.

Diagnosis of Interstitial Lung Disease Caused by Possible Hypersensitivity Pneumonitis in a Child: Think CGD

Interstitial lung disease (ILD) is a rare and heterogeneous group of disorder affecting the lung parenchyma and has a detrimental effect on gas exchange. Chronic granulomatous disease (CGD), when it affects primarily lungs, may cause ILD. We report a 16-year-old patient with CGD caused by homozygous deletion of NCF1 who atypically presented with ILD. The patient had many pigeons and was a pigeon breeder. Exacerbated clinical symptoms were linked to hypersensitivity pneumonitis (HP), and the patient was suggested to keep away from pigeons. In addition to allergen avoidance and prophylactic antibacterial therapy, treatment with corticosteroids and hydroxychloroquine was started for mainly obstructive and persistant symptoms of ILD. CGD is known to cause a hyperinflammatory state and the patients present with excessive granuloma formation and HP. Control of inflammation either by avoidance of allergen exposure and by anti-inflammatory drugs is necessary for the relief of symptoms.

Detection of parasites in children with chronic diarrhea

The aim of this study was to investigate the frequency of intestinal parasites in patients with chronic diarrhea and clarify the importance of these parasitic pathogens in such cases. A total of 60 pediatric patients with chronic diarrhea between June 2012 and October 2014 were enrolled in the study. Out of 60 stool samples, five were positive for Giardia lamblia, two, Dientamoeba fragilis, and one, Blastocystis hominis. One stool sample was positive for Entamoeba hartmanni and B. hominis, another one was positive for G. lamblia and B. hominis, another, G. lamblia and E. hartmanni and one sample was positive for Enterobius vermicularis, D. fragilis and B. hominis together. Parasitic infection, which decreases quality of life and increases susceptibility to other infections, should not be neglected, particularly in patients with chronic diarrhea. Accurate diagnosis decreases morbidity and mortality in patients with parasite infection.

Clinical and genetic features of the patients with X-Linked agammaglobulinemia from Turkey: Single-centre experience

X‐linked agammaglobulinemia is a primary immunodeficiency disorder resulting from BTK gene mutations. There are many studies in the literature suggesting contradictory ideas about phenotype‐genotype correlation. The aim of this study was to identify the mutations and clinical findings of patients with XLA in Turkey, to determine long‐term complications related to the disease and to analyse the phenotype‐genotype correlation. Thirty‐two patients with XLA diagnosed between 1985 and 2016 in Pediatric Immunology Department of Hacettepe University Ihsan Dogramaci Childrens Hospital were investigated. A clinical survey including clinical features of the patients was completed, and thirty‐two patients from 26 different families were included in the study. Getting early diagnosis and regular assessment with imaging techniques seem to be the most important issues for improving the health status of the patients with XLA. Early molecular analysis gives chance for definitive diagnosis and genetic counselling, but not for predicting the clinical severity and prognosis.

ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome

IntroductionAdenosine deaminase (ADA) deficiency is an autosomal recessive primary immunodeficiency. It results in the intracellular accumulation of toxic metabolites which have effects particularly on lymphocytes and the brain. The aim of this study was to evaluate the outcome of 13 ADA-deficient patients. We planned to evaluate their clinical and laboratory findings before and after enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (aHSCT), and hematopoietic stem cell gene therapy (HSCGT).MethodsMeasurement of ADA enzyme activity and metabolites and sequencing of the ADA gene were performed in most of the patients with ADA deficiency. One of the patients with late-onset ADA deficiency was diagnosed by the help of primary immunodeficiency panel screening.ResultsTen out of 13 patients were diagnosed as SCID, while 3 out of 13 were diagnosed as delayed-/late-onset ADA deficiency. Late-onset ADA deficiency patients had clinical and laboratory findings of combined immunodeficiency (CID). Eight patients with ADA-SCID were found to have higher levels of ADA metabolite (dAXP%) (62.1% (34.6–71.9)) than 3 patients with delayed-/late-onset ADA deficiency (6.9% (2.1–8.9). All but one patient with SCID had T-B-NK− phenotype, one had T-B-NK+ phenotype. Genetic defect was documented in 11 patients. Four out of 11 patients had compound heterozygous defects. Three out of 4 patients with compound heterozygous defects had delayed-onset/late-onset ADA deficiency. Seven out of 11 patients with SCID had homozygous defects. Five out of 7 had the same homozygous indel frameshift mutation (c.955-959delGAAGA) showing a founder effect. There were two novel splice site defects: one (IVS10+2T>C) was heterozygous in a patient with late-onset ADA deficiency, and the other was homozygous (IVS2delT+2) in a SCID patient. Other defects were missense defects. Nine out of 13 patients were put on pegylated ADA ERT. Four out of six patients were transplanted without using a conditioning regimen. HSCGT was performed to one of the patients.ConclusionThe genetic diagnosis of SCID is utmost important. There is a chance to give ERT before the definitive therapy if the patient with SCID/CID has ADA deficiency. Although ERT was insufficient to restore a normal immune function in ADA-SCID patients, it was useful to improve and stabilize the clinical status before curative therapy (aHSCT/HSCGT). Enzyme replacement therapy was successful in patients with late-/delayed-onset ADA deficiency who presented with the features of combined immunodeficiency. Gastrointestinal polyposis in a patient with late-onset ADA deficiency may be an association or a coincidental finding. Intermittent neurodevelopmental evaluation especially for hearing impairment should be performed in most of the ADA-deficient patients. This may alleviate the speech delay and cognitive abnormalities which may be observed in the follow-up.