title: Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome.
abstract: OBJECTIVE
  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that predominantly affects women. Despite isolated reports of patients with coexisting Klinefelter's syndrome (47,XXY) and SLE, no association of Klinefelter's syndrome with SLE or any other autoimmune disease has been established. The present study was undertaken to investigate the prevalence of Klinefelter's syndrome in a large population of patients with SLE.
  
  
  METHODS
  Sex chromosome genotyping was performed in 981 SLE patients, of whom 213 were men. A first group of 844 SLE patients from 378 multiplex families and a second group of 137 men with nonfamilial SLE were evaluated. In selected cases, chromosomes were enumerated by fluorescence in situ hybridization (FISH) and karyotyping in transformed B cell lines.
  
  
  RESULTS
  Of 213 men with SLE, 5 had Klinefelter's syndrome (1 in 43). Four of them were heterozygous at X markers, and Klinefelter's syndrome was confirmed by FISH and karyotyping in the fifth. An overall rate of 47,XXY of 235 per 10,000 male SLE patients was found (95% confidence interval 77-539), a dramatic increase over the known prevalence of Klinefelter's syndrome in an unselected population (17 per 10,000 live male births). Asking men with SLE about fertility was highly sensitive (100%) for Klinefelter's syndrome. All 768 women with SLE were heterozygous at X.
  
  
  CONCLUSIONS
  The frequency of Klinefelter's syndrome (47,XXY), often subclinical, is increased in men with SLE by approximately 14-fold compared with its prevalence in men without SLE. Diagnostic vigilance for 47,XXY in male patients with SLE is warranted. These data are the first to show an association of Klinefelter's syndrome with an autoimmune disease found predominantly in women. The risk of SLE in men with Klinefelter's syndrome is predicted to be similar to the risk in normal women with 46,XX and approximately 14-fold higher than in men with 46,XY, consistent with the notion that SLE susceptibility is partly explained by an X chromosome gene-dose effect.
authors.affiliation: Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, and Oklahoma City VAMC, Oklahoma City, OK 73104, USA. hal-scofield@omrf.ouhsc.edu <hal-scofield@omrf.ouhsc.edu>
authors.forename: R Hal
authors.initials: RH
authors.lastname: Scofield
authors.forename: Gail R
authors.initials: GR
authors.lastname: Bruner
authors.forename: Bahram
authors.initials: B
authors.lastname: Namjou
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.forename: Graciela S
authors.initials: GS
authors.lastname: Alarcón
authors.forename: Luis M
authors.initials: LM
authors.lastname: Vilá
authors.forename: Jeff
authors.initials: J
authors.lastname: Reid
authors.forename: Bryan
authors.initials: B
authors.lastname: Harris
authors.forename: Shibo
authors.initials: S
authors.lastname: Li
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
mesh_terms: D016022:Case-Control Studies; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007621:Karyotyping; D007713:Klinefelter Syndrome / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D010375:Pedigree; D015995:Prevalence