No abstract

No abstract

ABSTRACT. X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency is a developmental and immunologic disorder caused by mutations in nuclear factor-B essential modulator (NEMO), which is essential for nuclear factor-B activation. Early in life, affected boys present a typical appearance, with hypotrichosis or atrichosis, hypohidrosis or anhidrosis, and hypodontia or anodontia with conical incisors. They are also susceptible to various microorganisms, mostly pyogenic bacteria and mycobacteria. Here we report 2 unrelated boys, aged 6 and 11 years, who have novel mutations in NEMO and present conical incisors and hypodontia as their sole and long-unrecognized developmental anomaly. One child had isolated recurrent pneumococcal disease, whereas the other had multiple infections. Our ABBREVIATIONS. XL-EDA-ID, X-linked anhidrotic ectodermal dysplasia with immunodeficiency; NF-B, nuclear factor-B; NEMO, nuclear factor-B essential modulator; TNF, tumor necrosis factor; IL, interleukin; Ig, immunoglobulin; Hib, Haemophilus influenzae type b. X -linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is a rare congenital disease, characterized by abnormal development of ectoderm-derived skin appendages and susceptibility to infectious diseases. [1][2][3][4][5][6][7][8][9][10][11][12] Most affected individuals are male. In early childhood, they generally present multiple overt developmental anomalies, such as hypohidrosis or anhidrosis resulting in intolerance to heat, hypotrichosis or atrichosis, and hypodontia or anodontia with conical incisors, resulting in a typical facial appearance. A small number of patients also present with osteopetrosis and lymphedema. More than half of the known patients died from severe infections, generally caused by pyogenic bacteria and poorly pathogenic mycobacteria. Paradoxically, the only anomaly that is found consistently during routine immunologic tests is an impaired antibody response to polysaccharide antigens. Various hypomorphic mutations have been found in nuclear factor-B (NF-B) essential modulator (NEMO), which encodes a critical component of the NF-B signaling pathway. The EDA phenotype results from impaired NF-B activation by the single ectodysplasin receptor. In contrast, immunodeficiency results from impaired NF-B activation by multiple immune receptors, such as members of the Toll-like receptor, interleukin (IL)-1 receptor, and tumor necrosis factor (TNF) receptor superfamilies and T/B-cell receptors. We report 2 unrelated boys who bear mutations in NEMO. Both experienced severe infectious diseases. Abnormal teeth were their sole developmental anomaly. CASE REPORTSPatient 1 is a 6.5-year-old white boy who was born to unrelated French parents. He had been hospitalized previously for 3 episodes of Streptococcus pneumoniae arthritis, affecting a knee at the age of 2 years, an ankle at 5 years, and a hip at 5.5 years. At 3 years, the patient was hospitalized for Haemophilus influenzae lobar pneumonia. No other unusually severe infections were ...

BackgroundAsthma and wheezing disorders in childhood and adulthood are clinically heterogeneous regarding disease presentation, natural course, and response to treatment. Deciphering common disease mechanisms in distinct subgroups requires harmonized molecular (endo-) phenotyping of both children and adult patients with asthma in a prospective, longitudinal setting.MethodsThe ALL Age Asthma Cohort (ALLIANCE) of the German Center for Lung Research (DZL) is a prospective, multi-center, observational cohort study with seven recruiting sites across Germany. Data are derived from four sources: (a) patient history from medical records, (b) standardized questionnaires and structured interviews, (c) telephone interviews, and (d) objective measurements. Objective measurements include amongst others lung function and quantitative assessment of airway inflammation and exhaled breath, peripheral blood, skin, nasal, pharyngeal, and nasopharyngeal swabs, nasal secretions, primary nasal epithelial cells, and induced sputum. In cases, objective measurements and biomaterial collection are performed regularly, while control subjects are only examined once at baseline.DiscussionThe standardized and detailed collection of epidemiological and physiological data, and the molecular deep phenotyping of a comprehensive range of biomaterials in a considerable number of study participants across all ages are the outstanding characteristics of this multi-center cohort. Despite extensive biomaterial sampling, and a recruitment strategy that also includes pre-school children as young as 6 months, attrition is low. In children 83.9%, and in adults 90.5% attended the 12-month follow-up. The earliest time-point to include cases, however, is disease manifestation. Therefore, unraveling mechanisms that drive disease onset is limited, as this question can only be answered in a population-based birth cohort. Nonetheless, ALLIANCE offers a unique, integrative and inter-disciplinary framework with a comprehensive molecular approach in a prospective and identical fashion across ages in order to identify biomarkers and predictors for distinct childhood wheeze and asthma trajectories as well as their further course during adulthood. Ultimately, this approach aims to translate its most significant findings into clinical practice, and to improve asthma transition from adolescence to adulthood.Trial registrationNCT02496468 for pediatric arm, NCT02419274 for adult arm.

The metagenome development of the human respiratory tract was investigated by shotgun metagenome metagenomic sequencing of cough swabs from healthy children and children with cystic fibrosis (CF) between 3 weeks and 6 years of age. A healthy microbial community signature was associated with increased absolute abundances in terms of bacterial–human cell ratios of core and rare species across all age groups, with a higher diversity of rare species and a tightly interconnected species co-occurrence network, in which individual members were found in close proximity to each other and negative correlations were absent. Even without typical CF pathogens, the CF infant co-occurrence network was found to be less stable and prone to fragmentation due to fewer connections between species, a higher number of bridging species and the presence of negative species correlations. Detection of low-abundant DNA of the CF hallmark pathogen Pseudomonas aeruginosa was neither disease- nor age-associated in our cohort. Healthy and CF children come into contact with P. aeruginosa on a regular basis and from early on.