IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Haemophilus influenzae type b colonization in children in a hospital-based day care center

We sought to assess the effect of day care center (DCC) attendance and parental health care work environment on the prevalence of Haemophilus influenzae type b (Hib) pharyngeal colonization in children in Turkey. Children of health care workers were evaluated by nasopharyngeal culture specimens obtained prior to enrollment at a hospital-based DCC at Cerrahpasa Medical Faculty (CMF-DCC) and then again after 3 months of attendance. A larger cohort from this same DCC was evaluated after 6 months of attendance and compared to a group of children of non-health care workers enrolled in Bahcelievler-DCC. As is standard of care in Turkey, none of these children had received the Hib vaccine. Fifty children of health care workers were evaluated prior to their enrollment and then again after 3 months at CMF-DCC. The incidence of Hib carrier state at enrollment was 4% and increased to 22% after 3 months at the DCC. To assess the affect of parental health care employment on Hib carriage rates, 103 children from CMF-DCC and 40 children of non-medical families at Bahcelievler-DCC were evaluated. Hib carrier state was identified in 40.7 and 47.5% after more than 6 months of attendance at CMF-DCC and Bahcelievler-DCC, respectively. No significant difference was observed between carriage rates of children coming from medical and non-medical families and the average carriage rate was 42.6% when duration of day-care attendance exceeded 6 months. Our results demonstrate that Hib carriage rates are affected by the duration of DCC attendance. Parents' employment in a health care facility does not affect carriage rates

Impaired Th17 differentiation is a common attribute of genetically distinct forms of the hyper IgE syndrome in a cohort of Turkish children

28th Congress of the European-Academy-of-Allergy-and-Clinical-Immunology -- JUN 06-10, 2009 -- Warsaw, POLANDWOS: 000266171500956…European Acad Allergy & Clin Immuno

Defects along the TH17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome

PubMedID: 19577286Background: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired TH17 differentiation. Objective: To elucidate mechanisms underlying different forms of HIES. Methods: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-? was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. TH17 and TH1 cell differentiation was assessed by measuring the production of IL-17 and IFN-?, respectively. Results: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired TH17 responses, but whereas STAT3 mutations abrogated early steps in TH17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. Conclusion: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired TH17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome. © 2009 American Academy of Allergy, Asthma & Immunology

Clinical and genetic heterogeneity of hyper IgE syndrome in a Turkish cohort

13th European-Soc-for-Immunodeficiencies/10th Int-Patient-Org-for-Primary-Immunodeficiencies/8th Int-Nursing-Group-for-Immunodeficiencies Meeting -- OCT 16-19, 2008 -- Hertogenbosch, NETHERLANDSWOS: 000262727500122…European Soc Immunodeficiencies, Int Patient Org Primary Immunodeficiencies, Int Nursing Grp Immunodeficiencie