Saliha Esenboga

Combined immunodeficiency with CD4 lymphopenia and sclerosing cholangitis caused by a novel loss-of-function mutation affecting IL21R

Combined immunodeficiencies (CIDs) comprise a heterogeneous group of monogenic disorders manifesting with lymphocyte defects, recurrent infections and dysregulated immune response. Recently, we and others have described clinical and molecular features of the combined immunodeficiency syndromes

An infant with ZAP-70 deficiency with disseminated mycobacterial disease

To the Editor: Combined immunodeficiency (CID) is a genetic disorder characterized by defects in the development of T and B lymphocytes. A variety of mechanisms affecting antigen presentation, cytokine signaling, recombination events, T cell receptor signal transduction or other basic cellular processes play role in the pathogenesis of CID. Regardless of the underlying genetic defect, patients with CID classically present with recurrent and severe infections such as oral candidiasis, CMV pneumonia or chronic diarrhea resulting in failure to thrive in the early years of life [1]. Zeta chain associated protein kinase 70 (ZAP-70), a cytoplasmic tyrosine kinase involved in T-cell receptor(TCR) signalling, play a critical role in T cell differentiation and function. Its deficiency which is caused by autosomal recessive mutations in ZAP-70 gene, can lead to a rare form of CID. CD8 Tcell lymphopenia and presence of anergic CD4+ Tcells unresponsive to mitogens are usually the hallmark findings of ZAP-70 deficiency, however the clinical presentation can be variable, Similar to other forms of CID, hematopoietic stem cell transplantation is usually considered as a definite therapy for ZAP-70 deficiency. Here, we present a case of male patient with ZAP-70 deficiency and bronchial hyperreactivity who presented with disseminated mycobacterial infection. Invagination developed due to enlarged intraabdominal lymph nodes led to the diagnosis of mycobacterial infection. A thirteen-month old boy presented to our emergency department with three week history of fever and more recent onset of vomiting and abdominal distention. He was born at term with a normal birth weight to non-consanguineous parents originating from the same territory of a city in Turkey. The family reported history of recurrent wheezing episodes and hospitalizations starting around 8 months of age. His physical examination revealedweight of 9100 g (3rd 10th percentiles), height of 74 cm (10th 25th percentiles), head circumference of 43 cm (10th 25th percentiles), distended abdomen and hepatomegaly (liver palpable 2 cm below the costal margin). Abdominal ultrasound showed multiple conglomerated mesenteric lymphadenopathies (the largest 30 mm in diameter), minimal dilatation of intestinal loops with invagination of a short segment in the left upper quadrant. Initial differential diagnosis was broad and included infections, malignancy and hemophagocytosis. The laboratory analysis and a normal bone marrow aspiration smear ruled out hemophagocytic lymphohistiocytosis (HLH). A ppd. test was performedand it was found to be anergic despite BCG vaccination at 2 months of age as a part of the vaccination schedule in Turkey. It was found out from the medical records that he had no local complications after BCG vaccination. Smears of gastric lavage collected in 3 consecutive days were negative for acid-fast bacilli. Thorax and abdominal computed tomography showed mediastinal, hilar, axillary and extensive intraabdominal (mesenteric and paraaortic) lymphadenopathy,with lymph node diameter as large 13 mm in the abdomen and 25 mm in the thorax (Fig. 1). The patient underwent abdominal surgery for invagination which was thought to be due to enlarged intraabdominal lymph nodes. Excisional mesenteric lymph node biopsy was positive with Ziehl-Neelsen dye and tissue PCR revealedM. tuberculosis complex. The patient was started * Saliha Esenboga salihaeren@yahoo.com

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.

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.

Hypomorphic RAG1 defect in a child presented with pulmonary hemorrhage and digital necrosis

• In the patients with atypical presentations of vasculitis, suspicion of monogenic disorders may avoid delays in diagnosis and treatment.

Selective loss of function variants in IL6ST cause Hyper-IgE Syndrome with distinct impairments of T cell phenotype and function

Hyper-IgE syndromes comprise a group of inborn errors of immunity. STAT3-deficient hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections and eczema, and characteristic skeletal anomalies. A loss-of-function biallelic mutation in IL6ST encoding the GP130 receptor subunit (p.N404Y) has very recently been identified in a singleton patient (herein referred to as PN404Y) as a novel etiology of hyper-IgE syndrome. Here, we studied a patient with hyper-IgE syndrome caused by a novel homozygous mutation in IL6ST (p.P498L; patient herein referred to as PP498L) leading to abrogated GP130 signaling after stimulation with IL-6 and IL-27 in peripheral blood mononuclear cells as well as IL-6 and IL-11 in fibroblasts. Extending the initial identification of selective GP130 deficiency, we aimed to dissect the effects of aberrant cytokine signaling on T-helper cell differentiation in both patients. Our results reveal the importance of IL-6 signaling for the development of CCR6-expressing memory CD4+ T cells (including T-helper 17-enriched subsets) and non-conventional CD8+T cells which were reduced in both patients. Downstream functional analysis of the GP130 mutants (p.N404Y and p.P498L) have shown differences in response to IL-27, with the p.P498L mutation having a more severe effect that is reflected by reduced T-helper 1 cells in this patient (PP498L) only. Collectively, our data suggest that characteristic features of GP130-deficient hyper-IgE syndrome phenotype are IL-6 and IL-11 dominated, and indicate selective roles of aberrant IL-6 and IL-27 signaling on the differentiation of T-cell subsets.

Two siblings with PRKDC defect who presented with cutaneous granulomas and review of the literature

V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.

Subcutaneous venom immunotherapy in children: Efficacy and safety

BACKGROUND Venom immunotherapy (VIT) is safe in children, although adverse effects can occur. OBJECTIVE To document adverse effects and to determine re-sting reactions and the efficacy of VIT in childhood. METHODS We retrospectively analyzed data from children who had taken VIT from 2002 through 2015. These patients were queried by telephone to determine reactions after re-stings during or after VIT. RESULTS In total 107 children with a systemic reaction after Hymenoptera sting and with proved immunoglobulin E-mediated sensitization were enrolled. Participants had a median age of 10.0 years (7.2-12.4 years) at the beginning of immunotherapy. Fifty-two participants had allergic reactions during VIT; 40 of these reactions were local (37.4%), 5 were large local (4.7%), and 7 were systemic (6.5%). Of the 52 patients with adverse reactions, most reactions were local (n = 40, 89%) and were observed mainly in dose-increase periods (n = 25, 60%; P < .001). Although local reactions were more frequently seen with Vespula treatment (P = .047), systemic reactions were common with Apis treatment (P = .031). Sixty-eight patients (63.5%) were queried for re-sting, 33 (48.5%) had a re-sting and 24 (72.7%) of these 33 patients developed allergic reactions. The reactions were local (n = 19), large local (n = 1), and systemic (n = 4). Risk analysis for local and systemic reactions during VIT showed pre-existing asthma as an independent risk factor (odds ratio 4.1, 95% confidence interval 1.3-12.7, P = .016). CONCLUSION In children, VIT appears to be safe and protective against severe reactions after re-sting. However, pre-existing asthma was identified as a risk factor for systemic and large local reactions during VIT in children.

Characteristics of drug-induced anaphylaxis in children and adolescents

BACKGROUND Although data on anaphylaxis in the general population exist for different allergens, there is still lack of detailed etiologic data on drug-induced anaphylaxis (DIA), particularly in children. OBJECTIVE To define the etiology of DIA, to determine the accuracy of drug-related anaphylaxis histories, along with the severity and culprit drug associations among individuals <18 years old. METHODS Patients with a history of drug hypersensitivity reaction (DHR) referred to our center between January 2012 and February 2016 were included. After the collection of European Network for Drug Allergy questionnaire results, initial skin tests and/or provocation tests were performed for the offending drug. RESULTS Among 561 children and adolescents referred due to a suspected DHR, 113 (19%) (median age [interquartile range], 9.6 years [5.4-13.8 years]; 55% boys) had anaphylaxis in their history. At the end of diagnostic evaluation of the patients, 84 (74% of the patients with a history of DIA) were actually hypersensitive to the offending drug. Major drugs that resulted in DIA were antibiotics (33%), nonsteroidal anti-inflammatory drugs (25%), and chemotherapeutics (19%). The majority of patients reported grade 2 (moderate) (45%) and grade 3 (severe) (33%) anaphylactic reactions. A history of systemic illness (41.7 versus 7.1%; p = 0.001), concomitant intake of other drugs regularly (36.9 versus 10.3%; p = 0.007), and the use of chemotherapeutics as the culprit drug (19 versus 0%; p = 0.011) were more frequent, whereas the use of antibiotics was less frequent (34.5 versus 75.9%; p < 0.001) among patients with actual DIA compared to drug tolerant patients. CONCLUSION Three-fourths of the children and adolescents referred due to a suspected history of DIA were found to actually be drug hypersensitive. Prediagnosed systemic illness and different types of drugs would have an impact on the risk of DIA; however, atopic disease or a family history of drug hypersensitivity did not have an impact on actual DIA.