title: Adult-onset presentations of genetic immunodeficiencies: genes can throw slow curves.
abstract: OBJECTIVE
  The molecular and genetic mechanisms behind adult presentations of primary immunodeficiency diseases are examined, with particular emphasis on cases where this was heralded by severe, recurrent, or opportunistic infection.
  
  
  RESULTS
  A detailed analysis over the last two decades of the relationship between genotype and clinical phenotype for a number of genetic immunodeficiencies has revealed multiple mechanisms that can account for the delayed presentation of genetic disorders that typically present in childhood, including hypomorphic gene mutations and X-linked gene mutations with age-related skewing in random X-chromosome inactivation. Adult-onset presentations of chronic granulomatous disease, X-linked agammaglobulinemia, IL-12/Th1/IFN-gamma and IL-23/Th17/IL-17 pathway defects, and X-linked lymphoproliferative disorder are used to illustrate these mechanisms. Finally, certain genetic types of common variable immunodeficiency are used to illustrate that inherited null mutations can take decades to manifest immunologically.
  
  
  CONCLUSIONS
  Both genetic mechanisms and environmental factors can account for adult-onset infectious and noninfectious complications as manifestations of disorders that are typically present in childhood. This emphasizes the potential complexity in the relationship between genotype and phenotype with natural human mutations.
authors.affiliation: Division of Immunology and Allergy, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA.
authors.forename: Katharine S
authors.initials: KS
authors.lastname: Nelson
authors.forename: David B
authors.initials: DB
authors.lastname: Lewis
mesh_terms: D000328:Adult; D017668:Age of Onset; D030342:Genetic Diseases, Inborn / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000453:epidemiology / Q000235:genetics