Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients.

Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34+ cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment.

Genetic, Immunological, and Clinical Features of 32 Patients with Autosomal Recessive STAT1 Deficiency.

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections. We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette-Guérin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly.

Factors that predict disease severity in atopic dermatitis: The role of serum basal tryptase.

BACKGROUND: Increased numbers of mast cells that contain tryptase are found in lesional atopic dermatitis (AD) skin. The association of serum basal tryptase (sBT) with anaphylactic reactions and mast cell diseases has recently been shown in children with venom and food allergy. OBJECTIVE: We aimed to identify the risk factors that predict the severity of AD and the association of sBT levels with AD and disease severity. METHOD: AD diagnosis was made according to Hanifin and Rajka criteria. Disease severity was scored by the objective scoring atopic dermatitis (SCORAD) index. The sBT levels were measured. Skin-prick testing, total immunoglobulin E, eosinophil percentages and counts, and a questionnaire concerning the history of atopic diseases and the risk factors of AD were applied. RESULTS: The children, ages 0.5 to 3.0 years, with AD (n = 85) were analyzed in two groups according to the presence (AD+/atopy+ [n = 55]) or absence (AD+/atopy- [n = 30]) of skin-prick test positivity. The comparisons were made with an age- and sex-matched control group (n = 82). The median (interquartile range) sBT in the AD+/atopy+, AD+/atopy-, and control groups were 5.01 ng/mL (2.75-6.79 ng/mL), 3.02 ng/mL (1.67-4.44 ng/mL), and 2.63 ng/mL (1.31-4.49 ng/mL), respectively (p = 0.003). The median (interquartile range) sBT levels were higher in patients with moderate-severe objective SCORAD index scores compared with the those with mild disease (3.85 ng/mL [2.04-5.91 ng/mL] versus 2.80 ng/mL [1.83-3.48 ng/mL]; p = 0.038). Multivariate logistic regression analysis showed that an sBT level of ≥3.9 ng/mL (odds ratio 8.77 [95% confidence interval, 1.87-41.18]; p = 0.006) was independently associated with an increased risk of moderate-severe AD (objective SCORAD index). CONCLUSION: To our knowledge, this was the first study that indicated that sBT levels may be important in the AD disease process and associated with the disease severity and atopy.

The association of forced expiratory volume in one second and forced expiratory flow at 50% of the vital capacity, peak expiratory flow parameters, and blood eosinophil counts in exercise-induced bronchospasm in children with mild asthma.

BACKGROUND: Exercise-induced bronchoconstriction (EIB), which describes acute airway narrowing that occurs as a result of exercise, is associated with eosinophilic airway inflammation, bronchial hyperresponsiveness. The forced expiratory volume in one second (FEV1) is the most commonly used spirometric test in the diagnosis of EIB in exercise challenge in asthma. Other parameters such as forced expiratory flow at 50% of the vital capacity (FEF50%) and peak expiratory flow (PEF) are used less often in the diagnosis of EIB. OBJECTIVE: The purpose of this study is to evaluate the association of FEV1 and FEF50%, PEF parameters, blood eosinophil counts in EIB in children with mild asthma. METHODS: Sixty-seven children (male: 39, female: 28) with mild asthma were included in this study. Pulmonary functions were assessed before and at 1, 5, 10, 15, and 20 minutes after exercise. The values of spirometric FEV1, FEF50%, PEF, and blood eosinophil counts were evaluated in EIB in children with mild asthma. RESULTS: There was a positive correlation between FEV1 with FEF50% and PEF values (p<0.05; FEF50%, r=0.68; PEF, r=0.65). Also, a positive correlation was found between blood eosinophil counts and the values of spirometric FEV1, FEF50%, and PEF (p<0.05; FEV1, r=0.54; FEF50%, r=0.42; PEF, r=0.26). In addition to these correlations, in the exercise negative group for FEV1, the FEF50% and PEF values decreased more than the cutoff values in 3, and 2 patients, respectively. CONCLUSION: According to the presented study, eosinophil may play a major role in the severity of EIB in mild asthma. FEF50% and PEF values can decrease in response to exercise without changes in FEV1 in mild asthmatic patients.

An evaluation of serum paraoxonase together with arylesterase activities and oxidative stress in children with intractable epilepsy: a cross-sectional study.

Epilepsy is the most common chronic neurological illness in childhood and adolescence. The aim of this study was to investigate paraoxonase and arylesterase activities along with oxidative status parameters in children with intractable epilepsy. The study comprised 42 subjects with intractable epilepsy and a control group of 35 healthy subjects. Serum paraoxonase and arylesterase activities, and lipid hydroperoxide levels were determined. All paraoxonase and arylesterase activities were significantly lower in the intractable epilepsy subjects than in the controls (P<0.001), whereas lipid hydroperoxide levels were significantly higher (P<0.05). In conclusion, paraoxonase and arylesterase activities were decreased and the lipid hydroperoxide level was increased in patients with intractable epilepsy. These results showed that intractable epilepsy subjects may be more prone to the development of atherosclerosis.

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.

BACKGROUND: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

Chronic granulomatous disease with markedly elevated IgE levels mimicking hyperimmunoglobulin E syndrome.

Patients with hyperimmunoglobulin E syndrome (HIES) and chronic granulomatous disease (CGD) have prominently increased immunoglobulin (Ig) E levels. We present a 9-year-old boy with medical history revealing recurrent pneumonia, suppurative lymphadenitis, diarrhea, and otitis. The patient was hospitalized with severe pneumonia. The examination showed tachypnea, crackles at the right and left base of the lung, freckles on his face, red-hair, gingivitis, a high arched palate, and retained primary dentition. Serum IgE level was markedly increased. Nevertheless, patient did not have STAT3 or DOCK8 mutation, characteristic of HIES. Neutrophil function test with dihydrorhodamine (DHR) showed X linked-CGD pattern and molecular analysis of DNAshowed a splice site mutation (c.338-1G > A) in CYBB gene. Herein, we present a case of CGD with selective IgA deficiency. Laboratory findings and elevated IgE mimic the features seen in HIES. Thus, CGD must be considered as a differential diagnosis in patients with elevated Ig E.

Anaphylaxis Provoked by Bovine Gelatin Caused by Ingestion of Jelly Candy and Using Hair Gel.

Gelatin, a product obtained by the partial hydrolysis of collagen, is widely used in foods and pharmaceuticals. In the past, most commercially available vaccines, both live and inactivated, contained gelatin as a stabilizer, and allergic reactions to gelatin contained in measles, mumps, and rubella vaccine were reported. However, gelatin-allergy to foods was thought to be rare. It was unknown what factors predisposed recipients to vaccine-related gelatin allergy. There can be a genetic predisposition to gelatin allergy. We report a patient who experienced anaphylactic reaction on ingestion of jelly candy containing bovine gelatin and using hair gel.

Autoimmune diseases detected in children with primary immunodeficiency diseases: results from a reference centre at middle anatolia.

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of disorders that genetically affect distinct components of the immune system; thus, predispose individuals to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (ADs), which developed during the course of PID in children, were discussed.Twenty-five patients were included in this study. Symptoms related to ADs, such as autoimmune thyroiditis, type 1 diabetes mellitus, coeliac disease, juvenile idiopathic arthritis, dermatomyositis, autoimmune haemolytic anaemia, leukocytoclastic vasculitis, Henoch-Schonlein purpura, hypoparathyroidism, alopecia areata, Addison's disease, vitiligo and systemic lupus erythematosus were detected in these patients, who have been followed with diagnosis of PID including common variable immunodeficiency, selective and partial IgA deficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, hyperimmunoglobulin E syndrome, chronic mucocutaneous candidiasis, Griscelli syndrome, and partial C4 deficiency.Immunodeficiency and autoimmune phenomenon may concomitantly present in an individual, although they seem to be incompatible ends in the spectrum of the clinical immune response. Patients with primary immune deficiency should be closely monitored for development of autoimmune diseases.

Hashimoto thyroiditis associated with ataxia telangiectasia.

Ataxia telangiectasia is a rare genetic disease characterized by neurological manifestations, infections, and cancers. In addition to these cardinal features, different autoimmune diseases can be seen in patients with ataxia telangiectasia. Although there were reports of positive autoimmune thyroid antibodies associated with ataxia telangiectasia, to our knowledge, we report the first cases of nodular Hashimoto thyroiditis in two patients with ataxia telangiectasia in the English medical literature. These cases illustrate that despite the rarity of nodular Hashimoto thyroiditis associated with ataxia telangiectasia, physicians should be aware of this possibility. Furthermore, thyroid examination of patient with ataxia telangiectasia is recommended for early diagnosis.