title: Clinical manifestations of highly prevalent corticosteroid-binding globulin mutations in a village in southern Italy.
abstract: BACKGROUND
  Corticosteroid-binding globulin (CBG) is the binding protein for cortisol. Rare kindreds with CBG mutations reducing CBG levels or altering binding affinity have been described, along with clinical manifestations encompassing fatigue, chronic pain, and hypotension. The largest kindred, exhibiting two mutations (null and Lyon) were Australian immigrants from Italy.
  
  
  OBJECTIVE
  Our objective was to determine the prevalence of the null/Lyon mutations in the village where the original null/Lyon family emigrated and compare subjects with and without CBG mutations, without previous knowledge of their mutation status.
  
  
  METHODS
  We conducted a survey field study that included 495 adult residents.
  
  
  RESULTS
  We assessed clinical history, CBG mutation analysis, plasma CBG, salivary cortisol, body mass index, waist circumference, blood pressure, and the Krupp fatigue scale.
  
  
  RESULTS
  Eighteen of 495 participants (3.6%, seven males and 11 females) had one of two function-altering CBG mutations. All were heterozygous for the null (n = 6) or Lyon mutations (n = 12). Of 12 Lyon participants (four males and eight females), eight (two males and six females) had chronic widespread pain and five osteoarthritis with associated pain (one male and four females). Of six null participants (three males and three females), three (one male and two females) had chronic pain and four osteoarthritis with associated pain (two males and two females).
  
  
  CONCLUSIONS
  A high combined prevalence (3.6%) of these two CBG mutations was detected. The presence of either mutation conferred a propensity to chronic pain. In other communities, individuals with the same genetic background complain more of fatigue than pain, suggesting an environmental effect on the phenotype. These findings, combined with animal CBG gene knockout and human CBG single-nucleotide polymorphism haplotype studies, suggest that CBG influences the endocrine and neurobehavioral response to stress, including the development of pain/fatigue syndromes.
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA. cizzag@intra.niddk.nih.gov
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cizza
authors.forename: Livia
authors.initials: L
authors.lastname: Bernardi
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Smirne
authors.forename: Raffaele
authors.initials: R
authors.lastname: Maletta
authors.forename: Carmine
authors.initials: C
authors.lastname: Tomaino
authors.forename: Angela
authors.initials: A
authors.lastname: Costanzo
authors.forename: Maura
authors.initials: M
authors.lastname: Gallo
authors.forename: John G
authors.initials: JG
authors.lastname: Lewis
authors.forename: Silvana
authors.initials: S
authors.lastname: Geracitano
authors.forename: Maria Beatrice
authors.initials: MB
authors.lastname: Grasso
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Potenza
authors.forename: Cosimo
authors.initials: C
authors.lastname: Monteleone
authors.forename: Giacomino
authors.initials: G
authors.lastname: Brancati
authors.forename: Jui T
authors.initials: JT
authors.lastname: Ho
authors.forename: David J
authors.initials: DJ
authors.lastname: Torpy
authors.forename: Amalia C
authors.initials: AC
authors.lastname: Bruni
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D002908:Chronic Disease; D004247:DNA / Q000235:genetics; D004641:Emigration and Immigration; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007558:Italy / Q000453:epidemiology / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D018763:Muscle Fatigue / Q000235:genetics; D009154:Mutation; D010146:Pain / Q000453:epidemiology / Q000235:genetics; D010375:Pedigree; D011788:Quality of Life; D012463:Saliva / Q000378:metabolism; D014156:Transcortin / Q000235:genetics*; D055815:Young Adult
chemical_list: D000324:Adrenocorticotropic Hormone; D004247:DNA; D014156:Transcortin; D006854:Hydrocortisone