Ahmet Ozen

Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K

Lucas et al. identify humans with a gain-of-function mutation in PIK3R1, encoding the p85α subunit of PI3K. The splice site mutation causes in-frame skipping of exon 11, resulting in altered p85α association with p110δ that stabilizes the catalytic subunit but fails to properly inhibit catalytic activity. The patients have immunodeficiency and lymphoproliferation with skewing of CD8+ T cells toward terminally differentiated and senescent effector cells that have shortened telomeres.

Natural history and symptomatology of Helicobacter pylori in childhood and factors determining the epidemiology of infection

Background: High seroprevalence rates for Helicobacter pylori have been reported in developing countries, yet few studies exist determining the pattern of change in the epidemiology of H. pylori infection in children. The knowledge of acquisition and loss rates of H. pylori and the relevance to the sociodemographic properties and the symptomatology of infection may provide clues for lifestyle changes that might protect children from infection, and also, it may provide rationale for eradication, screening, and protection policies. Our aim was to conduct a prospective study to elucidate the outcome, rate of acquisition, and loss of H. pylori infection in a population of healthy children. Methods: This study is based on follow-up of 327 healthy Turkish children aged 3 to 12 years. The follow-up was conducted 6 years after the baseline examination. Helicobacter pylori status was determined by 13C-urea breath test. Children were investigated for sociodemographic variables and several symptoms. Results: Data from 136 (41%) of 327 children were available. The prevalence of infection increased from 52.9% to 56.6%, mainly increasing in children younger than 10 years. The incidence of H. pylori infection among previously uninfected children was 14%, and the loss rate of infection among previously infected children was 5.5% during the follow-up. Socioeconomic status, household density, and antibiotic use during last 6 months were inversely related to H. pylori prevalence. Children infected with H. pylori were complaining more often of headache but not of abdominal pain or dyspepsia. Conclusions: In this study, the acquisition rate of H. pylori infection was 2.5-fold higher than the loss of infection, and the acquisition mostly occurred before 10 years of age. Data regarding acquisition and loss of H. pylori infection are critical for understanding the epidemiology of infection and development of preventive and treatment strategies.

Serum IGF-I and IGFBP-3 levels of Turkish children during childhood and adolescence: establishment of reference ranges with emphasis on puberty.

Aims/Methods: We established age- and sex-related reference ranges for serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels in 807 healthy Turkish children (428 boys, 379 girls), and constructed a model for calculation of standard deviation scores of IGF-I and IGFBP-3 according to age, sex and pubertal stage. Results: Serum IGF-I and IGFBP-3 concentrations tended to be higher in girls compared to boys of the same ages, but the differences were statistically significant only in pubertal ages (9–14 years) for IGF-I and only in prepubertal ages for IGFBP-3 (6–8 years) (p < 0.05). Peak IGF-I concentrations were observed earlier in girls than boys (14 vs. 15 years, Tanner stage IV vs. V) starting to decline thereafter. IGFBP-3 levels peaked at age 13 and at Tanner stage IV in both sexes with a subsequent fall. Serum levels of IGF-I and IGFBP-3 increased steadily with age in the prepubertal stage followed by a rapid increase in IGF-I in the early pubertal stages. A relatively steeper increase in IGF-I but not in IGFBP-3 levels was observed at age 10–11 years in girls and at 12–13 years in boys which preceded the reported age of pubertal growth spurt. At late pubertal stages, both IGF-I and IGFBP-3 either did not change or decreased by increasing age. Interrelationships between growth factors and anthropometric measurements have been described, and the physiologic consequences of these have been discussed in detail. Conclusions: Differences in the pattern of IGF-I and IGFBP-3 in the present paper and those reported in other studies emphasize the importance of locally established reference ranges. Establishment of this reference data and a standard deviation score prediction model based on age, sex and puberty will enhance the diagnostic power and utility of IGF-I and IGFBP-3 in evaluating growth disorders in our population.

Vitamin D as an adjunct to subcutaneous allergen immunotherapy in asthmatic children sensitized to house dust mite

We aimed to investigate the efficacy, safety, and T regulatory cell response of vitamin D as an adjunct to allergen‐specific immunotherapy (IT).

Upper segment/lower segment ratio and armspan–height difference in healthy Turkish children

Aim: The determination of body proportions is an important part of the clinical evaluation of children with short stature. The upper segment/lower segment ratio (US/LS ratio) and armspan–height difference is commonly used for this purpose. However, reference data are scarce in this respect, and available standards do not include standard deviations for the measurements. We aimed to establish the normal values for upper segment/lower segment ratio and armspan–height difference in Turkish children. Methods: In the present study, height, upper and lower segment, and armspan were measured in 1302 healthy children (3–18 y). The age‐related mean and standard deviation curves of the US/LS ratio and armspan–height difference were constructed for each sex. Results: The mean values of the US/LS ratio in boys were decreased from 1.108 at 3 y to 0.984 at 10 y. The nadir of the US/LS ratio (0.922) was reached at age 15 y. In girls, the mean value of the US/LS ratio gradually decreased to less than 1 at 9 y of age (1 y earlier than in boys). The nadir of the US/LS ratio (0.946) was reached at age 13 y in girls (2 y earlier than in boys). Armspan was shorter than height as expected in younger ages, but became slightly longer at around age 12 in girls and boys. Unlike boys, the armspan–height difference did not change much after puberty in girls.

Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1

PurposeLoss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID).MethodsClinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17+ T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer.ResultsPatient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2xa0months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4xa0months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154Cu2009>u2009T; p.T385M; P2. c.971Gu2009>u2009T; p.C324F). Circulating CD4+ T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-β and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib.ConclusionSTAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis

Background Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. Methods We studied 11 patients with abdominal pain and diarrhea caused by early‐onset protein‐losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole‐exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients’ cells, which we confirmed by means of exogenous induction of expression of CD55. Results We identified homozygous loss‐of‐function mutations in the gene encoding CD55 (decay‐accelerating factor), which lead to loss of protein expression. Patients’ T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement‐inhibitory therapeutic antibody reversed abnormal complement activation. Conclusions CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein‐losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss‐of‐function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

Potentially Beneficial Effect of Hydroxychloroquine in a Patient with a Novel Mutation in Protein Kinase Cδ Deficiency

Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine.

Clinical heterogeneity of immunodysregulation, polyendocrinopathy, enteropathy, X-linked: pulmonary involvement as a non-classical disease manifestation.

PurposeIPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) is a rare X-linked recessive life-threatening disorder characterized by autoimmunity and early death. Pulmonary complication related with IPEX has not been elucidated exactly. Here, we report 4 IPEX patients, 3 of which died from severe pulmonary disease.MethodsClinical data and laboratory findings including autoantibodies, immunoglobulin levels as well as number of T, B and NK cells were evaluated. FOXP3 expression and T reg activity were analyzed. The FOXP3 gene was sequenced and RNA analysis was performed.ResultsPatient I (PI) presented with nephrotic syndrome at 3xa0years of age and then developed autoimmune hepatitis without eczema, enteropathy or high IgE and died at 9xa0years of age due to acute respiratory distress syndrome (ARDS). Two cousins of PI had the same hypomorphic splice site mutation leading to a deletion of 27 amino acids, but normal FOXP3 protein expression and normal suppressive capacity of T reg in a proliferation inhibition assay. However, they exhibited typical symptoms such as eczema, diabetes and enteropathy with eosinophilia at early age (PII, PIII) and were transplanted in infancy. One of them had severe respiratory distress right after birth (PIII). Patient IV from another family presented with chronic diarrhea without autoimmune manifestations and died due to ARDS.ConclusionLung disease related to IPEX syndrome has not been reported before and this entity could be a critical factor in disease outcome.

Patients with Primary Immunodeficiencies Are a Reservoir of Poliovirus and a Risk to Polio Eradication

Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4u2009days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2u2009months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6u2009months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame.