ANNUAL CLINICAL FOCUS Klinefelter Syndrome DANIEL J. WATTENDORF, MAJ, MC, USAF, and MAXIMILIAN MUENKE, M.D. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland To complement the 2005 Annual Clinical Focus on medical genom- ics, AFP is publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. This review discusses Klinefelter syndrome. (Am Fam Physician 2005;72:2259-62 Copyright © 2005 American Academy of Family Physicians.) This article exem- linefelter syndrome is caused by Body habitus may be feminized (Figure 1). plifies the AAFP 2005 an additional X chromosome in In childhood, when there is a relative quies- Annual Clinical Focus on the legal, social, clinical, males (47,XXY). Clinical findings cence in the hormonal milieu, ascertainment and ethical issues of medi- are nonspecific during childhood; of the syndrome may be difficult because the cal genomics. Kthus, the diagnosis commonly is made during effects of hypogonadism (i.e., small external A glossary of genomics adolescence or adulthood in males who have genitalia and firm testes) may be subtle or terms is available online small testes with hypergonadotropic hypogo- not present at all. at http://www.aafp.org/ nadism and gynecomastia. Virtually all men Persistent androgen deficiency in adult- afpgenglossary.xml. with Klinefelter syndrome are infertile. hood may result in loss of libido, decreased muscle bulk and tone, decreased bone Epidemiology mineral density, a propensity for thrombo- Approximately one in 1,000 boys is born with embolism, and an increased risk of mor- an additional X chromosome—47,XXY, the tality from diabetic and cardiovascular karyotype that causes Klinefelter syndrome.1 complications.4 This karyotype is detected at or before birth in 10 percent of affected boys, and it is found during adulthood in 25 percent of affected TABLE 1 men.2 Almost all men with a 47,XXY karyo- Klinefelter Syndrome: Characteristic type will be infertile; Klinefelter syndrome Clinical Findings accounts for 3 percent of male infertility.3 Klinefelter syndrome is common in infertile Infertility (azoospermia or oligospermia) men with oligospermia or azoospermia (5 to Small, firm testes 10 percent).2 Hypergonadotropic hypogonadism Gynecomastia Clinical Presentation Tall, slender body habitus with long legs The most overt phenotypic features of Kline- and shorter torso felter syndrome are caused by testosterone Osteoporosis (in young or middle-age men) deficiency and, directly or indirectly, by Motor delay or dysfunction unsuppressed follicle-stimulating and lutein- Speech and language difficulties izing hormones. Affected men typically have Attention deficits (in decreasing order of frequency): infertility, Learning disabilities small testes, decreased facial hair, gynecomas- Dyslexia or reading dysfunction tia, decreased pubic hair, and a small penis Psychosocial or behavioral problems (Table 1).2 Because of their long legs, men with Klinefelter syndrome often are taller Information from reference 2. than predicted based on parental height. December 1, 2005 U Volume 72, Number 11 www.aafp.org/afp American Family Physician 2259 Klinefelter Syndrome speech, and language), Klinefelter syndrome Normal karyotype Klinefelter syndrome (46,XY) (47,XXY) has been identified in 0.4 percent of boys with special education needs and no known diagnosis, and in 1.2 percent of boys with Y Y mental retardation of unknown etiology. In X X X these cases, the boys initially were referred for consideration of fragile X syndrome.6,7 Tall stature Of note, the 0.4 percent of boys with Kline- Narrow shoulders felter syndrome in the special-education Gynecomastia Small testes cohort is likely to represent less than half the Infertility actual prevalence, because only paternally acquired disease was identified. Magnetic resonance imaging has identi- fied a specific brain morphology associated with Klinefelter syndrome.8 An increased risk of psychiatric disorders also has been reported in affected men.9 Diagnosis Because most boys with Klinefelter syndrome appear similar to boys with normal karyo- types, the disorder typically is identified in adulthood, when infertility or gynecomas- tia are common presentations. However, ILLUSTRATION BY DARRYL LEJA DARRYL BY ILLUSTRATION by this time, a therapeutic window during Figure 1. Characteristic clinical findings in men with Klinefelter syn- adolescence for treatment of hypogonadism, drome. Note that there are no facial characteristics that suggest a diagnosis of Klinefelter syndrome. Therefore, particular attention to cognitive impairments, and psychosocial fac- physical examination of the body habitus is necessary for diagnostic tors has been missed. Late or incomplete consideration. puberty should prompt further examination. Testicular size can be measured with a Prader Specific cognitive deficits in language orchidometer or ultrasonography. Middle comprehension and executive functioning school–age boys with Klinefelter syndrome are part of the Klinefelter syndrome pheno- often will have elevated follicle-stimulat- type.5 Although most studies describe only ing and luteinizing hormone levels and low mild cognitive impairment (e.g., mild global plasma testosterone levels. Subclinical values delay in gross and fine motor development, on laboratory indices may be found in these patients; therefore, a karyotype with instruc- tions to count sex chromosomes in 50 cells The Authors is useful for diagnosis, especially in patients DANIEL J. WATTENDORF, MAJ, MC, USAF, is a family physician and clinical with mosaicism. geneticist. He is assistant professor in the Department of Family Medicine at the Uniformed Services University of the Health Sciences, F. Edward Hébert School of Causes of Klinefelter Syndrome Medicine, Bethesda, Md., and attending clinical geneticist at the National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda. The additional sex chromosomes in men with Klinefelter syndrome results from non- MAXIMILIAN MUENKE, M.D., is a pediatrician and clinical geneticist. He is disjunction during meiosis and may have chief of the Medical Genetics Branch at the National Human Genome Research Institute, NIH, and director of the medical genetics residency and fellowship a paternal (50 to 60 percent) or maternal training programs at NIH. (40 to 50 percent) origin. This contrasts with Down syndrome, which is caused pre- Address correspondence to Maximilian Muenke, M.D., Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 35 dominantly by maternal nondisjunction Convent Dr. – MSC 3717, Building 35, Room 1B-203, Bethesda, MD 20892-3717 and inheritance of the extra chromosome (e-mail: [email protected]). Reprints are not available from the authors. 21 from the mother. 2260 American Family Physician www.aafp.org/afp Volume 72, Number 11 U December 1, 2005 Klinefelter Syndrome Although Klinefelter syndrome encom- The prepubertal testosterone deficit results passes the specific clinical consequences in impaired bone mineral density and skel- observed in men with an XXY karyotype, etal muscle development. Decreased energy there are variant karyotypes that can include and libido, which are associated with post- additional X chromosomes (e.g., XXXY, pubertal testosterone deficit, improve with XXXXY) or additional X and Y chromo- hormone therapy and often are accompa- somes (e.g., XXYY). Men with these karyo- nied by improved confidence and sense of types have similar but often more severe well-being.10 phenotypes compared with those with the Androgen therapy should be started when XXY karyotype. there is direct laboratory evidence of a tes- Physical manifestations of Klinefelter syn- tosterone deficit or when hypergonadotro- drome are relatively moderate compared phism, which suggests such a deficit, is with autosomal trisomies (e.g., Down syn- present. This may occur by the time the drome) because when additional X chro- patient begins middle school (i.e., 12 to mosomes are present, one is predominantly 14 years of age). Physical differences in males inactivated. However, the entire X chromo- with Klinefelter syndrome often are evident some is not inactivated. As the number of after the onset of puberty. However, the X chromosomes increases, the phenotypic characteristic phenotypic findings (e.g., lack severity increases as well. As a result, cogni- of gonadal development; sparse or absent tive and gonadal development is impaired, facial hair; and thin, long-limbed body habi- and cardiovascular and skeletal manifesta- tus) usually are subtle. Consideration of tions often are present. Klinefelter syndrome as a diagnosis and Mosaicism occurs in 15 percent of men investigation with a standard karyotype are with an additional X chromosome and gen- important because of the therapeutic benefit erally results in a milder phenotype. When of testosterone supplementation. Clinical mosaicism occurs, cells with two or more suspicion warrants diagnostic investigation karyotypes are distributed. Most often, a to ensure appropriate surveillance for tes- normal chromosome number (46,XY) is tosterone deficit. identified in cells from a sample that also Because gynecomastia predisposes men to contains hyperdiploid cells (i.e., a Kline- breast cancer—the