RESUMO
We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease-associated genes by a next-generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor-like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold-induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor-like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1-related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.
Assuntos
Anormalidades Múltiplas/genética , Acalasia Esofágica/genética , Deformidades Congênitas da Mão/genética , Hiperidrose/genética , Receptores de Citocinas/genética , Trismo/congênito , Anormalidades Múltiplas/fisiopatologia , Morte Súbita , Acalasia Esofágica/fisiopatologia , Fácies , Predisposição Genética para Doença , Deformidades Congênitas da Mão/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Hiperidrose/fisiopatologia , Mutação , Linhagem , Trismo/genética , Trismo/fisiopatologiaRESUMO
BACKGROUND: Bioaerosol pollution of workplace and home environments mainly affects airways and mucous membranes. The effect of environmental outdoor residential bioaerosol pollution, for example, livestock holdings, farming, and waste disposal plants, is unclear. AIMS: To investigate the perceived health of residents living in areas with measurable outdoor bioaerosol pollution (for example, spores of Aspergillus fumigatus and actinomycetes), and effects of accompanying odours. METHODS: In a cross sectional study, double blinded to ongoing microbial measurements, doctors collected 356 questionnaires from residents near a large scale composting site, and from unexposed controls in 1997. Self reported prevalence of health complaints during the past year, doctors' diagnoses, as well as residential odour annoyance were assessed. Microbiological pollution was measured simultaneously in residential outdoor air. RESULTS: Concentrations of >10(5) colony forming units of thermophilic actinomycetes, moulds, and total bacteria/m(3) air were measured 200 m from the site, dropping to near background concentrations within 300 m. Positive adjusted associations were observed for residency within 150-200 m from the site versus unexposed controls for self reported health complaints: "waking up due to coughing", odds ratio (OR) 6.59 (95% confidence interval (CI) 2.57 to 17.73); "coughing on rising or during the day", OR 3.18 (95% CI 1.24 to 8.36); "bronchitis", OR 3.59 (95% CI 1.40 to 9.4); and "excessive tiredness", OR 4.27 (95% CI 1.56 to 12.15). Reports of irritative airway complaints were associated with residency in the highest bioaerosol exposure, 150-200 m (versus residency >400-500 m) from the site, and period of residency more than five years, but not residential odour annoyance. Lifetime prevalence of self reported diseases did not differ with exposure. CONCLUSIONS: Bioaerosol pollution of residential outdoor air can occur in concentrations found in occupational environments. For the first time residents exposed to bioaerosol pollution were shown to report irritative respiratory complaints similar to mucous membrane irritation independently of perceived odours.