ARTHRITIS & RHEUMATISMVol. 58, No. 8, August 2008, pp 2511–2517DOI 10.1002/art.23701© 2008, American College of Rheumatology

Klinefelter’s Syndrome (47,XXY) inMale Systemic Lupus Erythematosus Patients

Support for the Notion of a Gene-Dose Effect From the X Chromosome

R. Hal Scofield,1 Gail R. Bruner,2 Bahram Namjou,2 Robert P. Kimberly,3

Rosalind Ramsey-Goldman,4 Michelle Petri,5 John D. Reveille,6 Graciela S. Alarcon,3

Luis M. Vila,7 Jeff Reid,2 Bryan Harris,2 Shibo Li,8 Jennifer A. Kelly,2 and John B. Harley1

Objective. Systemic lupus erythematosus (SLE) isa systemic autoimmune disease that predominantlyaffects women. Despite isolated reports of patients withcoexisting Klinefelter’s syndrome (47,XXY) and SLE, noassociation of Klinefelter’s syndrome with SLE or anyother autoimmune disease has been established. Thepresent study was undertaken to investigate the preva-lence of Klinefelter’s syndrome in a large population ofpatients with SLE.

Methods. Sex chromosome genotyping was per-formed in 981 SLE patients, of whom 213 were men. Afirst group of 844 SLE patients from 378 multiplexfamilies and a second group of 137 men with nonfamilialSLE were evaluated. In selected cases, chromosomeswere enumerated by fluorescence in situ hybridization(FISH) and karyotyping in transformed B cell lines.

Results. Of 213 men with SLE, 5 had Klinefelter’ssyndrome (1 in 43). Four of them were heterozygous atX markers, and Klinefelter’s syndrome was confirmedby FISH and karyotyping in the fifth. An overall rate of47,XXY of 235 per 10,000 male SLE patients was found(95% confidence interval 77–539), a dramatic increaseover the known prevalence of Klinefelter’s syndrome inan unselected population (17 per 10,000 live malebirths). Asking men with SLE about fertility was highlysensitive (100%) for Klinefelter’s syndrome. All 768women with SLE were heterozygous at X.

Conclusion. The frequency of Klinefelter’s syn-drome (47,XXY), often subclinical, is increased in menwith SLE by �14-fold compared with its prevalence inmen without SLE. Diagnostic vigilance for 47,XXY inmale patients with SLE is warranted. These data are thefirst to show an association of Klinefelter’s syndromewith an autoimmune disease found predominantly inwomen. The risk of SLE in men with Klinefelter’ssyndrome is predicted to be similar to the risk in normalwomen with 46,XX and �14-fold higher than in menwith 46,XY, consistent with the notion that SLE suscep-tibility is partly explained by an X chromosome gene-dose effect.

Systemic lupus erythematosus (SLE) is uncom-mon in men, being 10-fold more prevalent in women, a

Supported by the NIH (grants AI-24717, AI-31584, AI-54117,AI-053747, AI-062629, AR-12253, AR-24260, AR-43727, AR-48940,AR-049084, AR-049743, AR-053734, DE-015223, RR-015577, RR-019369, and RR-020143), the Alliance for Lupus Research, and the USDepartment of Veterans Affairs, as well as by the General ClinicalResearch Centers at Johns Hopkins University (NIH grant M01-RR-00052), Northwestern University Feinberg School of Medicine (NIHgrant M01-RR-00048), and the University of Oklahoma Health Sci-ences Center (NIH grant M01-RR-014467). Oklahoma Medical Re-search Foundation was constructed with support from the NIHNational Center for Research Resources (Research Facilities Im-provement Program grant C06-RR-14570-01). Dr. Harley is a MaryKirkland Scholar.

1R. Hal Scofield, MD, John B. Harley, MD, PhD: OklahomaMedical Research Foundation, University of Oklahoma Health Sci-ences Center, and Oklahoma City VAMC, Oklahoma City; 2Gail R.Bruner, RN, BSN, Bahram Namjou, MD, Jeff Reid, BS, Bryan Harris,BS, Jennifer A. Kelly, MPH: Oklahoma Medical Research Founda-tion, Oklahoma City; 3Robert P. Kimberly, MD, Graciela S. Alarcon,MD, MPH: University of Alabama at Birmingham; 4Rosalind Ramsey-Goldman, MD, DrPH: Northwestern University, Chicago, Illinois;5Michelle Petri, MD, MPH: Johns Hopkins University School ofMedicine, Baltimore, Maryland; 6John D. Reveille, MD: University ofTexas–Houston Health Science Center, Houston; 7Luis M. Vila, MD:University of Puerto Rico, San Juan, Puerto Rico; 8Shibo Li, MD:University of Oklahoma Health Sciences Center, Oklahoma City.

Address correspondence and reprint requests to R. HalScofield, MD, Oklahoma Medical Research Foundation, 825 NE 13thStreet, Oklahoma City, OK 73104. E-mail: hal-scofield@omrf.ouhsc.edu.

Submitted for publication November 14, 2007; accepted inrevised form April 18, 2008.

2511

difference usually attributed to sex hormones (for re-view, see ref. 1). Since 1969, there have been publishedreports of SLE in 30 men with Klinefelter’s syndrome(2–6), with 2 others having anti–U1 RNP and “mixedconnective tissue disease” (7,8). Klinefelter’s syndrome,resulting from a 47,XXY karyotype, is present in 17 of10,000 live male births (95% confidence interval [95%CI] 14–20 per 10,000 as calculated from published data][9–11]). Klinefelter’s syndrome is characterized by ab-normal sexual development at puberty due to sex hor-mone metabolic differences, with small testes, gynecoidbody habitus, absent secondary sexual characteristics,gynecomastia, impotence, and sterility. In many menwith 47,XXY, the condition remains undiagnosed untilwell after puberty.

In a study of 22 men with SLE, no instance ofKlinefelter’s syndrome was found (12), and in a study of500 patients with Klinefelter’s syndrome, none had ordeveloped SLE after a decade of observation (13). Theseefforts failed to support the notion of an associationbetween Klinefelter’s syndrome and SLE, but the sam-ple sizes were small for studies of uncommon diseases.

In our SLE genetic studies, �90% of the patientsare women, as would be anticipated (14). In the presentinvestigation, we studied patients with familial SLE andnonfamilial SLE to determine whether the prevalence ofKlinefelter’s syndrome is increased in men with SLE.

PATIENTS AND METHODS

Patient ascertainment and clinical data collection.After providing written informed consent, patients who metthe American College of Rheumatology classification criteriafor SLE (15,16) and their families (14) were enrolled. Partic-ipants who were members of multiplex lupus families (n �1,258: 76 men with SLE, 768 women with SLE, and 414 menwithout SLE) were part of the lupus genetics studies conductedat Oklahoma Medical Research Foundation. Ninety-eight ofthe 137 male nonfamilial SLE cases were part of the PROFILE(The Genetic Profile Predicting the Phenotype) cohort (17),and the remaining 39 male nonfamilial SLE cases came fromsimplex families from the lupus genetics studies based inOklahoma (Table 1). Data collection included a questionnaire,an interview, and medical record review. At the time of studyenrollment 1 male SLE patient had known Klinefelter’s syn-drome, which had been diagnosed at age �17 years, coincidentwith the onset of SLE. Androgen therapy led to apparentimprovement, with no evidence of an SLE recurrence in thesubsequent 15 years (Scofield RH, Bruner GR, Harley JB:unpublished observations).

Genotyping and karyotyping. Each SLE patient in themultiplex lupus group was genotyped with a panel of up to 16microsatellite nucleotide repeats on the X chromosome, with 2from the pseudoautosomal regions. Each male in the study wasalso typed for 2 Y chromosome markers, YS390 and YS389.

Chromosomes from lymphoblastoid cell lines from 3 patientswere analyzed by trypsin-Giemsa banding (18) and fluores-cence in situ hybridization (FISH) analysis with X and Ycentromere–specific DNA probes (Vysis, Downers Grove, IL).

The confirmatory cohort of 137 male patients withnonfamilial SLE was typed with 7 X and 2 Y chromosomemarkers. In both sets of microsatellite typing experiments,markers that spanned the length of the X chromosome werechosen. The male SLE patient with previously diagnosedKlinefelter’s syndrome, from the latter cohort, was typed at256 single nucleotide polymorphisms (SNPs) from the non-pseudoautosomal regions of the X chromosome, using the 10KGeneChip array (Affymetrix, Santa Clara, CA).

Statistical analysis. Bayes theorem (P[B/A] � (P[A/B]� P[B])/P[A]) was used to estimate the frequency of SLE inKlinefelter’s syndrome (where A � the frequency ofKlinefelter’s syndrome, B � the frequency of SLE in men, andP[B/A] indicates the probability of SLE within the group withKlinefelter’s syndrome). Binomial 95% CIs were calculatedwith the raw data and then converted to numbers per 10,000,for ease of presentation.

RESULTS

In 378 families with 2 or more SLE patients (844patients total), there were 76 men with SLE. Seventy-four of these men with SLE were monozygous at each ofthe X chromosome microsatellites tested (Table 1). Onemale SLE patient was heterozygous at 14 and the otherat 12 of the 16 X chromosome markers. Both had alleleassignments identical to those in their mothers (Figure1). The 2 Y chromosome markers, and hence also the Ychromosomes, were present in both of the phenotypicmales with heterozygous X chromosomes. A diagnosis ofKlinefelter’s syndrome or 47,XXY had not been previ-ously considered for either of these men. Cytogenetic

Table 1. Sex chromosome findings in the study subjects*

Genotype (or karyotype)†

46,XY 47,XXY 46,XX 45,XO

Group 1 (familial SLE[Oklahoma])

SLE men 74 2† 0 0SLE women 0 0 768 0Non-SLE men 414 0 0 0

Group 2 (nonfamilial SLE)SLE men (Oklahoma) 38 1†‡ 0 0SLE men (PROFILE) 96 2 0 0

Total SLE men (groups 1 and 2) 208 5 0 0

* PROFILE � The Genetic Profile Predicting the Phenotype.† In 3 of the men with systemic lupus erythematosus (SLE), 47,XXYwas established by fluorescence in situ hybridization and karyotyping.All other sex chromosome designations were deduced from genotyp-ing.‡ Patient (see Figure 2) was found to have 47,XXY with a duplicatedX chromosome.

2512 SCOFIELD ET AL

and FISH analyses confirmed that both patients had theKlinefelter’s syndrome karyotype, 47,XXY. Genotypingstudies in 414 men without SLE in these families showedno evidence of �1 X chromosome. All 768 women withSLE studied from the 378 families were heterozygous atmultiple X chromosome microsatellite markers, provid-ing no evidence of Turner’s syndrome coexisting withSLE in this population.

Thus, 2 of the 76 men with SLE in multiplexfamilies had Klinefelter’s syndrome, yielding a preva-lence of 263 per 10,000 men with SLE (95% CI 32–918),which is �15 times higher than the rate of Klinefelter’ssyndrome in the general population and is well above theexpected population rate of Klinefelter’s syndrome of 17per 10,000 (9–11). Thus, Klinefelter’s syndrome oc-curred more frequently than expected in these men withSLE (P � 0.007 by Fisher’s exact test).

In an effort to test and replicate our findings, wetyped an independent group of 137 men with nonfamilialSLE. Of these, 135 were homozygous at the X and Ymarkers. However, in 1 of them, Klinefelter’s syndrome

had been diagnosed several years previously. Karyotypeand FISH analysis of a lymphoblastoid cell line from thispatient revealed 47,XXY (Figure 2), consistent withmeiosis II non-disjunction resulting in a duplication of amaternal X chromosome, which is present in �18% ofKlinefelter’s syndrome patients (19). Ascertainment forstudy enrollment had been based on the patient’s SLE,with the presence or absence of Klinefelter’s syndromehaving no consequence upon the decision to enroll himin the study. The other 2 men were homozygous at the Ymarkers and heterozygous at multiple X chromosomemarkers (Table 1). One had 2 alleles at 6 of 7 and theother had 2 alleles at 7 of 7 X chromosome microsatel-lite markers. Thus, the association of Klinefelter’s syn-drome and SLE was confirmed in 3 of 137 patients inthis group (217 per 10,000 [95% CI 45–622]); the knownrate of Klinefelter’s syndrome, 17 per 10,000 live malebirths (9–11), is excluded from the confidence interval.

Given the estimates of the prevalence rates ofKlinefelter’s syndrome in the original and replicationgroups, a combined rate of 5 of 213 was obtained (235

Figure 1. Pedigree of a male systemic lupus erythematosus (SLE) patient (arrow) who was found to beheterozygous at an X chromosome marker. The marker shown (GATA144D04) is located at 44.7 Mb on the Xchromosome. The SLE patient was also heterozygous at 13 of another 15 X chromosome markers (data notshown). He had alleles at this marker identical to those in his mother, and thus inherited both maternal Xchromosomes. His father was not typed, but the father’s identical twin brother was homozygous with an alleledistinct from those in the patient and the patient’s mother. Circles � females; squares � males; solid symbols �affected subjects; open symbols � unaffected subjects; symbols with diagonal lines � deceased subjects (notgenotyped [NG]).

KLINEFELTER’S SYNDROME AND SLE 2513

men with 47,XXY for every 10,000 men with SLE[95% CI 77–539]), a �13-fold higher prevalence ofKlinefelter’s syndrome than is found in the general malepopulation (9–11) (P � 0.001 by Fisher’s exact test).

The prevalence of SLE is between 1 in 485 forAfrican American women and 1 in 2,762 for EuropeanAmerican women (20,21). Of the SLE patients in thepresent study, 26.8% were African American and 55.9%European American. With this ethnic distribution, anSLE prevalence of 1 per 1,324 women would be pre-dicted. Data on ethnic differences in SLE prevalencerates among males are not reliable because of the smallsamples studied (22,23). Since lupus is 10 times morecommon in women than in men, we predicted anestimated prevalence of �1 in 13,240 for the SLE malesstudied. The rate of Klinefelter’s syndrome among menwith SLE (5 in 213) has been presented above, and theincidence of Klinefelter’s syndrome in the general pop-ulation is 17 in 10,000 (9–11). Therefore, since measuresof the other 3 variables were available, using Bayestheorem we estimated the rate of SLE amongKlinefelter’s syndrome patients to be 1 in 960 (Figure 3).This number approximates the rate of SLE in womenand is much (nearly 14-fold) higher than the rate of SLEin normal men with 46,XY (22,23).

Upon study entry, the 135 men with SLE enrolledin this study through the Oklahoma genetics studieswere asked “Are you infertile?” All 3 men subsequentlyfound to have Klinefelter’s syndrome, along with 6 other

men, answered this question with a response other than“no.” Two stated “yes” and the third answered he “didnot know.” Thus, this simple clinical question was 100%sensitive and 33% specific for identification ofKlinefelter’s syndrome in men with SLE (P � 0.00021comparing men with Klinefelter’s syndrome with theother men with SLE, by Fisher’s exact test).

DISCUSSION

Klinefelter’s syndrome and SLE, two very differ-ent conditions, occur with similar prevalence rates in thepopulation. Herein we have shown that these diseasesoccur together more often than would be expected bychance alone (Figure 3).

There are reasons to suspect that Klinefelter’ssyndrome and SLE might be associated. First, numerouscase reports document the coexistence of the two dis-eases (1–8,12,13,24). Second, sex hormone similaritiesbetween men with Klinefelter’s syndrome and womenare associated with SLE (1,4,25,26). The argument isbolstered by data from some animal models of SLE,demonstrating increased disease susceptibility with es-trogen and disease protection with androgens (for re-view, see ref. 1). Third, Klinefelter’s syndrome is alsoassociated with several sex-related conditions. For exam-ple, men with Klinefelter’s syndrome die of breastcancer at a similar rate as women (27). Approximately 2

Figure 2. The 47,XXY chromosomal karyotype of a male systemiclupus erythematosus patient. The diagnosis of Klinefelter’s syndromein this patient was made clinically when he was �17 years old. He wasshown to be homozygous at all polymorphic X chromosome markerstested, and therefore must have Klinefelter’s syndrome as a result of ameiosis II non-disjunction in his mother.

Figure 3. Prevalence of 47,XXY in males with systemic lupus ery-thematosus (SLE). We found that 1 in 43 men with SLE hadKlinefelter’s syndrome. The known rate of Klinefelter’s syndrome inthe general population is 17 in 10,000. Using Bayes theorem, weestimated that 1 of every 960 men with Klinefelter’s syndrome willhave SLE. This number of SLE men and Klinefelter’s men would befound in a sample of �565,000 men ([960 � 10,000]/17) with theproportional racial composition of the present study population.

2514 SCOFIELD ET AL

in 50 men with breast cancer have Klinefelter’s syn-drome (28), a rate similar to that found among men withSLE in the present study. There may be an increase inrheumatoid factor levels in the serum of patients withKlinefelter’s syndrome (29). Testosterone treatment re-verses immune activation abnormalities in Klinefelter’ssyndrome (30), and has also led to improvement of SLEas described in individual case reports (5,31) and ob-served in one of our patients (Scofield RH, Bruner GR,Harley JB: unpublished observations). These observa-tions may be related to the beneficial effect of the mildandrogen dehydroepiandrosterone (prasterone) on mildSLE in women (32).

Investigation of X chromosome polymorphismsdoes not enable detection of 47,XXY caused by dupli-cation of the X chromosome and produced by a mater-nal meiosis II non-disjunction, which we discovered in 1patient upon followup of his clinical presentation. Anysubclinical 47,XXY caused by this mechanism would nothave been detected by X chromosome polymorphismscreening, as was applied to some of our study subjects.The actual population prevalence of 47,XXY in ourmale SLE sample may thus be higher than the 5 in 213we detected. However, the best estimate suggests thatonly 18% of patients with Klinefelter’s syndrome havethis mechanism of supernumerary X chromosomes (19).Therefore, there is a small but finite possibility of anadditional man with undiscovered Klinefelter’s syn-drome among the male SLE patients studied by geno-typing of the X chromosome only. Of course, typing of Xchromosome markers is not the usual clinical modalityfor diagnosis for Klinefelter’s syndrome, but karyotypeand FISH, the usual clinical tests, require testing of cells,which were not available in some subjects.

In other work, we have typed several hundred Xchromosome SNPs. We found heterozygosity for 40–60% of these markers in the men identified by micro-satellite marker as having 47,XXY in the present study(Scofield RH, Harley JB: unpublished observations).This rate of heterozygosity is similar to that found innormal women. Thus, we are confident that the tech-niques used in this study have accurately identified menwith Klinefelter’s syndrome, as well as men with 46,XY.

Klinefelter’s syndrome is a genetic abnormality inwhich androgen and estrogen levels are abnormal fromat least the beginning of puberty (33). It may specificallypredispose men to development of SLE, compared withother more common forms of hypogonadism, such asprimary testicular failure. However, 5 of 35 men withSLE were found to have hypergonadotropic hypogonad-ism in one study, although the etiology of the hypogo-

nadism was not otherwise delineated (34). Anothershowed a high rate of hypogonadism in men withrheumatic diseases (only 2 of whom had SLE). Ofinterest, of 13 men with rheumatic disease and untreatedhypogonadism, 5 had Klinefelter’s syndrome, 2 hadKallmann’s syndrome, and 2 had idiopathic cryp-torchism; thus, 9 of 13 had a congenital form of hypo-gonadism (6). There are case reports of Klinefelter’ssyndrome occurring in conjunction with other female-predominant autoimmune diseases (35,36). However,the present data are the first to conclusively demonstratean association of Klinefelter’s syndrome with a female-predominant autoimmune disease.

We estimate that 1 SLE patient will be foundamong every 960 males with Klinefelter’s syndrome.This is much closer to the 1 SLE patient in 1,324 womenbased on the ethnic distribution in our population thanit is to the estimated prevalence of 1 in �14,000 for theSLE males. Thus, males with 47,XXY have a risk oflupus comparable with that in females with 46,XX, andnot the �10-fold lower risk in males with 46,XY. Thisresult is consistent with the notion of a gene-dose effectfor lupus risk originating from the X chromosome,where XX (whether 46,XX or 47,XXY) confers a 10-fold higher risk than 46,XY.

Perhaps, future studies of large numbers ofwomen with SLE will be conducted to estimate therelative risk of SLE associated with 45,XO (Turner’ssyndrome). If the gene-dose hypothesis is correct, thenthe rate of SLE among individuals with 45,XO should besimilar to the rate in males with 46,XY. Our sample of768 women with SLE is too small to determine whetherthis is the case. Turner’s syndrome is �4-fold lessprevalent than Klinefelter’s syndrome (4 per 10,000)(11,12). Even so, SLE in Turner’s syndrome patients isvirtually unreported (37,38). In contrast, autoimmunethyroid disease has an increased prevalence amongpatients with Turner’s syndrome, especially in patientswith an Xq isochromosome (39). These differencessuggest that SLE and autoimmune thyroid disease, bothof which are female-dominated autoimmune diseases,have distinct X chromosome–dependent susceptibilities.In particular, our data imply that X chromosome mono-somy, either congenital or acquired, may not be a riskfactor for SLE, as has been suggested for primary biliarycirrhosis (40) or autoimmune thyroid disease (41).

The 46,XX and 47,XXY karyotypic risks for SLEappear to be similar. Consequently, some feature orfeatures of Klinefelter’s syndrome must be sufficient toconfer the full risk of SLE in females, and, applyingparsimony, it can be surmised that the many differences

KLINEFELTER’S SYNDROME AND SLE 2515

between normal females with 46,XX and males with47,XXY are not sufficient to alter the risk for SLE. Thedecreased estrogen levels in individuals with 47,XXYcompared with those with 46,XX, for example, do notalter the SLE risk. Thus, our data support the notionthat differences in estrogen levels alone do not explainthe much lower incidence and prevalence of SLE in menwith 46,XY compared with women with 46,XX. Somemight construe the lack of an association of oral contra-ceptive use with disease exacerbation in established SLE(42) as being consistent with this interpretation.

The increased androgen levels in individuals with47,XXY compared with those with 46,XX do not protectagainst SLE. The other implication from the 47,XXYprevalence in males with SLE is that the Y chromosomedoes not appear to influence the overall risk of SLE inmen. The increased prevalence of 47,XXY in the SLEpopulation supports the idea that the difference betweenthe prevalence of SLE in men with 46,XY and womenwith 46,XX is dominated by the X chromosome dose.

Based on the present findings, clinicians treatingmales with SLE should be aware that such patients havea greater likelihood of having 47,XXY. Increased aware-ness of Klinefelter’s syndrome may improve diagnosticrecognition. In the present study population, 3 of 3 maleSLE patients with Klinefelter’s syndrome answered thefertility question in a way that increased suspicion ofinfertility. There were only 6 such responses from othermen. This question, which was asked and answeredbefore this study was initiated, may be the most generallydiscriminating initial question to ask men with SLEwhen screening to identify 47,XXY. Certainly, in anymale SLE patient whose fertility is questionable, anevaluation for the physical, and perhaps laboratory,features of Klinefelter’s syndrome is warranted.

The finding of an increased prevalence ofKlinefelter’s syndrome in males with SLE has implica-tions for understanding the genetics of SLE, by suggest-ing a gene-dose effect at the X chromosome. In addition,diagnosing the presence of 47,XXY among male SLEpatients provides them access to potentially importantmedical management.

ACKNOWLEDGMENTS

The authors are grateful for the help and cooperationof the SLE patients and their families and the referral of casesfrom support groups and physicians. The statistical advice ofDr. Barbara Neas, technical assistance of Michele Calvo,Parvathi Viswanathan, David Hutchings, Carisa Cooney, andCarrie Thornton, and critical reading of the manuscript by Dr.Michael Lockshin are all appreciated.

AUTHOR CONTRIBUTIONS

Dr. Scofield had full access to all of the data in the study andtakes responsibility for the integrity of the data and the accuracy of thedata analysis.Study design. Scofield, Bruner, Kimberly, Li, Harley.Acquisition of data. Scofield, Bruner, Namjou, Kimberly, Ramsey-Goldman, Petri, Reveille, Alarcon, Vila, Reid, Harris, Li, Harley.Analysis and interpretation of data. Scofield, Bruner, Kimberly,Ramsey-Goldman, Li, Kelly, Harley.Manuscript preparation. Scofield, Bruner, Namjou, Kimberly,Ramsey-Goldman, Reveille, Li, Kelly, Harley.Statistical analysis. Scofield, Kelly, Harley.

REFERENCES

1. Lahita RG. Sex hormones and systemic lupus erythematosus.Rheum Dis Clin North Am 2000;26:951–68.

2. Ortiz-Neu C, LeRoy EC. The coincidence of Klinefelter’s syn-drome and systemic lupus erythematosus. Arthritis Rheum 1969;12:241–6.

3. Gilliland WR, Stashower ME. Klinefelter’s syndrome and systemiclupus erythematosus. Clin Exp Rheumatol 2000;18:107–9.

4. Lahita RG, Bradlow HL. Klinefelter’s syndrome: hormone metab-olism in hypogonadal males with systemic lupus erythematosus.J Rheumatol 1987;14:154–7.

5. Bizzarro A, Valentini G, Di Martino G, DaPonte A, De Bellis A,Iacono G. Influence of testosterone therapy on clinical andimmunologic features of autoimmune diseases associated withKlinefelter’s syndrome. J Clin Endocrinol Metab 1987;64:32–6.

6. Jimenez-Balderas FJ, Tapia-Serrano R, Fonseca ME, Arellano J,Beltran A, Yanez P, et al. High frequency of association ofrheumatic/autoimmune diseases and untreated male hypogonad-ism with severe testicular dysfunction. Arthritis Res 2001;3:362–7.

7. Takeuchi Y, Murata Y, Sintani J, Masukawa H, Nakamura R, OiH, et al. Klinefelter’s syndrome accompanied by mixed connectivetissue disease and diabetes mellitus. Intern Med 1999;38:875–81.

8. Ishihara K, Yoshimura M, Nakao H, Kanakura Y, Kanayama Y,Matsuzawa Y. T cell abnormalities in mixed connective tissuedisease complicated with Klinefelter’s syndrome. Intern Med1994;33:714–7.

9. Brown WM. Sex chromosome aneuploidy in man and its fre-quency, with special reference to mental subnormality and crimi-nal behavior. Int Rev Exp Pathol 1969;7:31–97.

10. Neilen J, Wohlert M. Chromosome abnormalities found among34,910 newborn children: results from a 13-year incidence studyfrom Arhus, Denmark. Hum Genet 1991;87:81–3.

11. Hamerton JL, Canning N, Ray M, Smith S. A cytogenetic survey of14,069 newborn infants. Clin Genet 1975;8:223–43.

12. Dubois EL, Kaplan BJ. SLE and Klinefelter’s syndrome [letter].Lancet 1976;1:93.

13. Price WH, MacLean N, Littlewood AP. SLE and Klinefelter’ssyndrome [letter]. Lancet 1976;1:807.

14. Moser KL, Neas BR, Salmon JE, Yu H, Gray-McGuire C, AsundiN, et al. Genome scan of human systemic lupus erythematosus:evidence for linkage on chromosome 1q in African-Americanpedigrees. Proc Natl Acad Sci U S A 1998;95:14869–74.

15. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, RothfieldNF, et al. The 1982 revised criteria for the classification of systemiclupus erythematosus. Arthritis Rheum 1982;25:1271–7.

16. Hochberg MC, for the Diagnostic and Therapeutic Criteria Com-mittee of the American College of Rheumatology. Updating theAmerican College of Rheumatology revised criteria for the clas-sification of systemic lupus erythematosus [letter]. ArthritisRheum 1997;40:1725.

17. Alarcon GS, McGwin G Jr, Petri M, Reveille JD, Ramsey-Goldman R, Kimberly RP, PROFILE Study Group. Baseline

2516 SCOFIELD ET AL

characteristics of a multiethnic lupus cohort: PROFILE [publishederratum appears in Lupus 2002;11:402]. Lupus 2002;11:95–101.

18. Seabright M. A rapid banding technique for human chromosomes.Lancet 1971;2:971–2.

19. Jacobs PA, Bacino C, Hassold T, Morton NE, Keston M, Lee M.A cytogenetic study of 47,XXY males of known origin and theirparents. Ann Hum Genet 1988;52(Pt 4):319–25.

20. Hopkinson ND, Doherty M, Powell RJ. Clinical features andrace-specific incidence/prevalence rates of systemic lupus ery-thematosus in a geographically complete cohort of patients. AnnRheum Dis 1994;53:675–80.

21. Johnson AE, Gordon C, Palmer RG, Bacon PA. The prevalenceand incidence of systemic lupus erythematosus in Birmingham,England: relationship to ethnicity and country of birth. ArthritisRheum 1995;38:551–8.

22. Lopez P, Mozo L, Gutierrez C, Suarez A. Epidemiology ofsystemic lupus erythematosus in a northern Spanish population:gender and age influence on immunological features. Lupus2003;12:860–5.

23. Petri M. Epidemiology of systemic lupus erythematosus. Best PracRes Clin Rheumatol 2002;16:847–58.

24. Rovensky J. Rheumatic diseases and Klinefelter’s syndrome. Au-toimmun Rev 2006;6:33–6.

25. Lahita RG. The importance of estrogen in systemic lupus erythem-atosus. Clin Immunol Immunopathol 1992;63:17–8.

26. Lahita RG. Sex steroids and SLE: metabolism of androgens toestrogen. Lupus 1992;1:125–7.

27. Price WH, Clayton JF, Wilson J, Collyer S, De May R. Causes ofdeath in X chromatin positive males (Klinefelter’s syndrome). JEpidemiol Community Health 1985;39:330–6.

28. Langlands AO, MacLean N, Kerr GR. Carcinoma of the malebreast: report of a series of 88 cases. Clin Radiol 1976;27:21–5.

29. Engelberth O, Charvat J, Jezkova, Z, Raboch J. Autoantibodies inchromatin-positive men. Lancet 1966;2:1164–7.

30. Kocar IH, Yesilova Z, Ozata M, Turan M, Sengul A, Ozdemir I.The effect of testosterone replacement treatment on immunolog-ical features of patients with Klinefelter’s syndrome. Clin ExpImmunol 2000;121:448–52.

31. Olsen NJ, Kovacs WJ. Case report: testosterone treatment ofsystemic lupus erythematosus in a patient with Klinefelter’s syn-drome. Am J Med Sci 1995;310:158–6.

32. Petri MA, Mease PJ, Merrill JT, Lahita RG, Iannini MJ, YocumDE, et al. Effects of prasterone on disease activity and symptomsin women with active systemic lupus erythematosus: results of amulticenter randomized, double-blind, placebo-controlled trial.Arthritis Rheum 2004;50:2858–68.

33. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med1998;158:1309–14.

34. Mok CC, Lau CS. Profile of sex hormones in male patients withsystemic lupus erythematosus. Lupus 2000;9:252–7.

35. Tojo K, Kaguchi Y, Tokudome G, Kawamura T, Abe A, Sakai O.47 XXY/XY mosaic Klinefelter’s syndrome presenting with mul-tiple endocrine abnormalities. Intern Med 1996;35:396–402.

36. Sarri C, Cote GB, Mengreli C, Lambadidis I, Pantelakis S.Hypothyroidism and sex chromosomes. J Med Genet 1988;25:247–9.

37. Takegami T, Nakao K, Nagayama Y, Fujita T, Hoshino T,Tsunematsu T, et al. A case of SLE associated with Turner’ssyndrome of 45, XO/46, XXq� mosaicism. Nippon Naika GakkaiZasshi 1980;69:861–6. In Japanese.

38. Itani S, Hoshino T. Unusual X chromosome, anomaly 45, X, X, t(X;X) (q26;q26) and systemic lupus erythematosus in a womanwith gonadal dysgenesis. Jpn J Hum Genet 1979;24:175.

39. Elsheikh M, Wass JA, Conway GS. Autoimmune thyroid syn-drome in women with Turner’s syndrome—the association withkaryotype. Clin Endocrinol (Oxf) 2001;55:223–6.

40. Invernizzi P, Miozzo M, Battezzati PM, Bianchi I, Grati FR,Simoni G, et al. Frequency of monosomy X in women with primarybiliary cirrhosis. Lancet 2004;363:533–5.

41. Invernizzi P, Miozzo M, Selmi C, Persani L, Battezzati PM, ZuinM, et al. X chromosome monosomy: a common mechanism forautoimmune disease. J Immunol 2005;175:575–8.

42. Petri M, Buyon JP, Kim M, Kalunian K, Grossman J, Hahn B, etal. Combined oral contraceptives (OC) are not associated with anincreased rate of flare in SLE patients in SELENA [abstract].Arthritis Rheum 2004;50 Suppl 9:S239–40.

KLINEFELTER’S SYNDROME AND SLE 2517