X-Linked Lymphoproliferative Syndrome and Common Variable Immunodeficiency May Not Be Differentiated by SH2D1A and XIAP/BIRC4 Genes Sequence Analysis

The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency characterized by recurrent episodes of hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and/or lymphomas. Recently, X-linked inhibitor of apoptosis (XIAP/BIRC4) gene defects, in families with XLP but without SH2D1A gene defects, has been defined. The distinction from primary immunodeficiencies with a defined genetic cause is mandatory. A six-year-old male patient was admitted with the complaints of persistent general lymphadenopathy, for two years had fever, bilateral cervical multiple microlymphadenopathy, hepatic/splenic enlargement with laboratory findings as decreased serum immunoglobulins, negative EBV VCA IgM (viral capsid antigen) and anti-EBV EA (antibody to early D antigen), positive EBV VCA IgG (viral capsid antigen) and EBV EBNA (antibody to nuclear antigen). SH2D1A gene analysis was negative. XIAP/BIRC4 sequencing revealed two novel single nucleotide variants (exon 7, 1978G > A, and 1996T > A) in the 3′UTR of the gene in both patient and mother which were not disease causing. XIAP protein expression was found to be normal. The clinical and laboratory resemblance, no gene mutations, and normal XIAP protein expression led us to think that there may be another responsible gene for XLP. The patient will to be followed up as CVID until he presents new diagnostic signs or until the identification of a new gene

Granulomatous pyoderma preceding chronic recurrent multifocal osteomyelitis triggered by vaccinations in a two-year-old boy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Chronic recurrent multifocal osteomyelitis is a rare, systemic, aseptic, inflammatory disorder that involves different sites. Pathogenesis of chronic recurrent multifocal osteomyelitis is currently unknown.</p> <p>Case presentation</p> <p>A two-year-old Caucasian boy, diagnosed with chronic recurrent multifocal osteomyelitis with granulomatous pyoderma following routine vaccinations is presented for the first time in the literature.</p> <p>Conclusion</p> <p>We conclude that antigen exposures might have provoked this inflammatory condition for our case. Skin and/or bone lesions following vaccinations should raise suspicion of an inflammatory response such as chronic recurrent multifocal osteomyelitis only after thorough evaluation for chronic infection, autoimmune, immunodeficiency or vasculitic diseases.</p

Comparison of the efficacy of once- and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever - a randomized controlled noninferiority trial

Background: In this study, we examined the efficacy and safety of a once-daily dosage schema of colchicine compared with a twice-daily dosage schema in pediatric patients with familial Mediterranean fever (FMF). Methods: In this 24-week, multicenter, randomized controlled noninferiority trial, pediatric patients newly diagnosed with FMF carrying a homozygous or compound heterozygous mutation and not receiving any treatment were included. Patients were randomly assigned using a block randomization method to receive treatment with a once- or twice-daily dosage. Clinical and laboratory characteristics and medication side effects were recorded and compared between groups. The study was carried out in compliance with Good Clinical Practice and the Consolidated Standards for Reporting of Trials (CONSORT) statement. Results: A total of 92 patients were selected, and 79 patients completed the study. There were 42 patients in the once-daily dosage group and 37 in the twice-daily dosage group. The results indicated that the once-daily dosage was not inferior to the twice-daily dosage regarding decrease in attack frequency and duration as well as improvement in clinical findings and Mor severity scores. Alterations in laboratory findings indicating inflammation, such as erythrocyte sedimentation rate, C-reactive protein, and serum amyloid A, were similar in both groups. The rates of drug side effects were similar between the once- and twice-daily dosage groups, implying comparable safety of colchicine, with the exception of diarrhea, which was slightly higher in the once-daily dosage group. Conclusions: Using colchicine with either a once- or twice-daily dosage provides similar clinical and laboratory improvements. Considering both efficacy and safety, colchicine can be prescribed with a once-daily dosage. Trial Registration ID: ClinicalTrials.gov identifier NCT02602028. Registered 5 November 2015

Mutations affecting the actin regulator WD repeat–containing protein 1 lead to aberrant lymphoid immunity

Background: The actin-interacting protein WD repeat–containing protein 1 (WDR1) promotes cofilin-dependent actin filament turnover. Biallelic WDR1 mutations have been identified recently in an immunodeficiency/autoinflammatory syndrome with aberrant morphology and function of myeloid cells. Objective: Given the pleiotropic expression of WDR1, here we investigated to what extent it might control the lymphoid arm of the immune system in human subjects. Methods: Histologic and detailed immunologic analyses were performed to elucidate the role of WDR1 in the development and function of B and T lymphocytes. Results: Here we identified novel homozygous and compound heterozygous WDR1 missense mutations in 6 patients belonging to 3 kindreds who presented with respiratory tract infections, skin ulceration, and stomatitis. In addition to defective adhesion and motility of neutrophils and monocytes, WDR1 deficiency was associated with aberrant T-cell activation and B-cell development. T lymphocytes appeared to develop normally in the patients, except for the follicular helper T-cell subset. However, peripheral T cells from the patients accumulated atypical actin structures at the immunologic synapse and displayed reduced calcium flux and mildly impaired proliferation on T-cell receptor stimulation. WDR1 deficiency was associated with even more severe abnormalities of the B-cell compartment, including peripheral B-cell lymphopenia, paucity of B-cell progenitors in the bone marrow, lack of switched memory B cells, reduced clonal diversity, abnormal B-cell spreading, and increased apoptosis on B-cell receptor/Toll-like receptor stimulation. Conclusion: Our study identifies a novel role for WDR1 in adaptive immunity, highlighting WDR1 as a central regulator of actin turnover during formation of the B-cell and T-cell immunologic synapses

The outcome of patients with unclassified hypogammaglobulinemia in early childhood

WOS: 000270662700013PubMed ID: 19196447Symptomatic hypogammaglobulinemia in childhood may be the initial finding of primary immunodeficiency (PID) or may be due to delay in maturation of immunoglobulin synthesis. The aim of this study was to review the clinical and laboratory records of patients with unclassified hypogammaglobulinemia and to evaluate whether these children experience changes in serum immunoglobulin concentrations during long-term followup and have an exact diagnosis in natural course of disease. We reviewed the data of 412 patients who were diagnosed as PID with symptomatic hypogammaglobulinemia. Thirty-seven patients with hypogammaglobulinemia [19 males (51.4%) and 18 females (48.6%), with a followup of 34.1 +/- 22.0 months] who were not classified according to European Society for Immunodeficiencies diagnostic criteria were included in this study. The mean age at the beginning of the symptoms was 21.4 +/- 20.6 months and the mean age at admission was 51.5 +/- 25.8 months. The commonest clinical presentations were recurrent upper (94.6%) and/or lower (40.5%) respiratory infections, urinary infection (27%) and gastroenteritis (10.8%). Percentage of consanguinity was 8%. Of the initial 37 patients, 18 (48.6%) spontaneously corrected their immunoglobulin abnormalities during followup. Clinical symptoms of these patients were also improved. IgG, IgA and IgM levels reached to normal levels at ages 62.5 +/- 21.8, 72.0 +/- 11.2, 55.2 +/- 7.8 months, respectively. In remaining 19 patients with undefined/unclassified hypogammaglobulinemia, three partial IgA deficiency, seven IgG subclass deficiency, two selective IgM deficiency and two common variable immunodeficiency (CVID) were diagnosed by long-term monitoring of immunoglobulin levels. Five (13.5%) of the 37 unclassified patients could not be exactly diagnosed while two of them might have a T-cell defect and three of them still had low IgG and IgA levels but adequate antibody responses against vaccine antigens. In conclusion, it is important to monitor symptomatic patients with hypogammaglobulinemia periodically. Some children may spontaneously correct their immunoglobulin abnormalities not in the first 30 months of age, but during the first decade of life and some of them may have a severe PID like CVID

Long-term effectiveness and safety of canakinumab in pediatric familial Mediterranean fever patients

Background: Little is known about the long-term efficacy and safety of canakinumab in paediatric FMF patients. Aim: To present the single centre experience of colchicine-resistant paediatric-onset FMF patients who were treated with canakinumab by off-label use since 2012. Methods: The hospital files of 15 children who used canakinumab were retrospectively evaluated. Clinical and laboratory data of each visit were recorded. Drug-related adverse events were recorded. Complete remission was described as no attacks and normal acute phase reactants; partial remission was defined as decrease in severity and rate of attacks and/or elevated acute phase reactants with anti-IL-1 treatment. Results: The average duration of canakinumab use was 23.9 months (min:12, max:58 months). Twelve patients were M694V homozygotes. Eleven patients achieved complete remission after the first dose at 2 months and 12 patients at 6 months. Canakinumab interval was shortened in 2 patients from 150 mg/8 weeks to 150 mg/4 weeks. Except one, 14 patients achieved complete remission by 12 months. Two patients had mild urinary tract infections. One patient had bronchopneumonia requiring hospitalization. Two patients had teeth abscess. There were no serious adverse events such as opportunistic infections, malignancies, or deaths. Besides, no significant laboratory abnormalities occurred in complete blood count parameters, liver and kidney function tests. Conclusion: To the best of our knowledge, this is the longest outcome study about canakinumab use in paediatric FMF patients. This study suggested that canakinumab is safe and effective in children with FMF in the long term

Evaluation of the international severity score for FMF (ISSF) scores in Turkish children diagnosed with FMF: a single-center experience

Aims The aim of this study is to evaluate our patients with the newly developed international severity score for FMF (ISSF) and make comparisons with the literature

Common variable immunodeficiency: familial inheritance and autoimmune manifestations in two siblings

WOS: 000276572900015PubMed ID: 20402074Edeer-Karaca N, Gulez N, Aksu G, Kutukculer N. Common variable immunodeficiency: familial inheritance and autoimmune manifestations in two siblings. Turk J Pediatr 2010; 52: 89-93. Common variable immunodeficiency (CVID) is an immunodeficiency syndrome characterized by generalized defective antibody production and recurrent sinopulmonary bacterial infections. Autoimmune disease is common in CVID, occurring in approximately 20% of patients, with a slight female predominance. Familial inheritance of CVID is very rare, and we here report two siblings with CVID presenting remarkable autoimmune manifestations such as relapsing polychondritis, juvenile idiopathic arthritis and chronic inflammatory bowel disease. Autoimmune and inflammatory complications showed minimal improvement under regular intravenous immunoglobulin replacement therapy, prophylactic antibiotics and immunosuppressives in these patients