Klinefelter's syndrome (KS) is the constellation of symptoms associated with an extra sex chromosome, the 47, XXY karotype, compared to the usual male configuration, XY. This group of symptoms, which include gynecomastia, increased height, sparse facial and body hair, reduced sperm count, and diminutive testicular size, was originally observed in nine patients by Dr. Harry Klinefelter in 1942. Many men live with this abnormality and never become aware of the genetic difference physically or recognize the associated symptoms (Table 1). Genetic screening for the chromosomal abnormality began in the 1970s in newborn males via organizations such as the National Institute of Child Health and Human Development. KS is not considered an inherited condition. About 25% of the expected incidence of KS is diagnosed in adulthood. Women who give birth to an infant with KS do not have a greater risk of recurrence in a later pregnancy than the risk in the general population.1-3
This genetic abnormality occurs frequently, in 1:500 to 1:1,000 male births. About 3% of the infertile male population has this condition. The "syndrome" terminology has lost favor in the literature, since many patients lack clinical evidence of the extra sex chromosome in youth and may or may not grow to develop symptoms with age. The nomenclature is now replaced with "XXY males." Research illustrates that half of the incidence of KS derives from the father's genetic lineage. An increased risk of KS is linked to advanced maternal age.1
The abnormality is conferred when genetic material is exchanged during meiosis. This process involves the separation of one cell (46 chromosomes) into two new cells (23 chromosomes each). During the exchange between male and female chromosomes, faulty pairing can occur, leading to an egg with two X chromosomes or to a sperm with an X and Y chromosome. When a sperm with an XY chromosome fertilizes an egg with a traditional single X chromosome, or a traditional Y-bearing sperm fertilizes an egg with two X chromosomes, an XXY male is conceived. A secondary etiology of this syndrome is an error of parental gametogenesis, when a sperm or egg carries an extra X chromosome with the normal single-sex chromosome.
Occasionally, variations of the XXY abnormality may occur. The most common is the XY mosaic. Some cells are XXY, and some are XY. While similar outcomes exist between the variations, fertility is likely improved with the mosaic abnormality (Table 2).2,4
Primary physical features of XXY males are gynecomastia (breast enlargement), sparse facial and body hair, rounded body type due to excess weight, and taller appearance (around 6 feet) than expected based on paternal and sibling familial history. Approximately 10% of XXY males will seek medical care due to breast enlargement.
Symptoms associated with cognitive and motor skills include language impairment, which often requires special educational needs early in childhood development, and delays in toddlers' ability to walk. Language problems may be seen in school by delays in speech development and reading and writing abilities. If a child cannot communicate effectively with single words by 18 to 24 months of age, parents should consult a speech therapist or language pathologist. Mood can also be negatively affected in adolescents who develop KS. Teenagers often understand more than they can articulate in words, compared to their peers. The temperament and disposition that children display tend to pervade throughout their life.
Testosterone levels are usually low or below normal, with elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) reaching five to 10 times the normal range by midpuberty. Testosterone decline is due to failure of the Leydig's cells to function properly. The pituitary-gonadal system functions effectively through puberty but begins to change when testosterone falls below normal range, leading to an overproduction of gonadotropins. The increased production of FSH and LH leads to hyalinization and fibrosis in the seminiferous tubules, where the sperm are normally located.
Some clinical features of XXY males are associated with various health conditions. Incomplete masculinization, a prominent feature of KS, is linked to infertility, and decreased libido is associated with osteoporosis. The learning, emotional, and mental disorders of XXY males are related to taurodontism. Low energy, another clinical feature of the syndrome, is linked to autoimmune disease.1-7
Some males may be asymptomatic in self-reporting based on physical differences or cognitive function. The likelihood of diagnosis is greatest during birth (before or after), early childhood, adolescence, or adulthood when testing for infertility. Before birth, diagnosis can be assessed through amniocentesis or chorionic villus sampling. These procedures are usually reserved for high-risk pregnancies associated with familial genetic mutations, pregnant women older than age 35, or other medical indications that require a sample of amniotic fluid surrounding the fetus. A definitive diagnosis can be made through a blood sampling procedure referred to as karotype. White blood cells can be separated and incubated to detect the extra X chromosome.
XXY males will enter puberty normally without delay of physical maturity. As puberty progresses, they fail to keep pace with other males. Normally, testes gradually increase in size from the initial volume of 2 mL to about 15 mL. In XXY males, while the penis is a normal size, the testes remain small at 2 mL without a sufficient quantity of testosterone. To confirm a diagnosis of KS, a thorough medical history should be conducted to assess developmental abnormalities at birth, rate and extent of virilization at puberty, sexual functioning, secondary sex characteristics, beard growth, muscle strength, and energy level.
Endocrine studies primarily illustrate hyper gonado tropic hypogonadism secondary to testicular failure. In adult males, the normal LH is 1.5 to 9 mIU/mL; FSH is 2.0 to 9.2 mIU/mL. In males with KS, basal serum concentrations of LH and FSH are moderately elevated. Serum testosterone concentration is usually decreased (<300 ng/dL in adults), whereas the normal range in adult males is 350 to 1,030 ng/dL. The human chorionic gonadotropin (hCG) stimulation test typically shows a low to subnormal testosterone response, with little or no elevation of serum testosterone concentration after intramuscular (IM) injection of hCG.1-3
The majority of XXY males do not produce enough sperm for fertility. XXY males also have a higher risk of autoimmune diseases (e.g., type 1 diabetes mellitus, lupus erythematosus, and thyroiditis); this risk is correlated with lower testosterone and higher estrogen levels. Other hypotheses suggest lymphocyte irregularities. Patients with hypotestosterone may encounter the onset of osteoporosis later in life, and bone mineral density has been found to be 12% to 15% lower than normal. Taurodontism, an enlargement of the pulp of the teeth with surface thinning, is common in KS and can be diagnosed by dental x-rays. Cerebrovascular accidents are more prevalent in XXY males, as well as breast cancer, rheumatoid arthritis, leukemia, and Hodgkin's and non-Hodgkin's lymphoma. Other systemic, chronic conditions that correlate to KS include lung cancer, breast cancer, diabetes mellitus, cerebrovascular disease, vascular insufficiency, nonischemic heart disease, and circulatory diseases.7
Learning disabilities, despite normal or high IQ, are common. The risk of dyslexia and attention-deficient/hyperactivity disorder may also be higher. In addition, psychological problems such as depression are linked to most sexual disorders.
Testosterone: The primary clinical symptoms of KS are treatable. While surgery can correct gynecomastia, testosterone injections can correct hair loss and promote muscle mass. Testosterone supplementation should begin in puberty (optimally at age 11 or 12) but is also beneficial in adulthood. Hormonal screening can assess testosterone levels performed in the morning. The average male produces 4 to 7 mg of testosterone per day in a circadian pattern that peaks in the morning and is minimal in the evening. However, testicular size, sterility, and gynecomastia will not be affected by testosterone supplementation.
Testosterone can be administered as oral, buccal, injectable, and transdermal formulations. IM preparations of enanthate or cypionate are commonly used (Table 3) and have similar pharmacokinetics and safety profiles. Oral preparations are infrequently prescribed due to elevations in liver function tests and the risk of hepatotoxicity. Peak serum levels are achieved in two to five days and return to baseline approximately two weeks after injection. The typical dose is 200 mg every two weeks. If initiated during puberty, the dose is lowered to 50 to 100 mg every four weeks, then every two weeks until adulthood. Transdermal testosterone may not be an optimal option due to the scrotal surface area. It is also a more expensive formulation and is not well studied in patients younger than 18 years.
Adverse effects of testosterone use include allergic reactions (Table 4). The testosterone formulation may be dissolved in an oil base, causing painful injection site reactions. Weight gain may also occur from lean body mass and fluid accumulation. Due to increased androgen accumulation from testosterone, acne may occur. Androgens can lower high-density lipoprotein levels; thus, close monitoring of lipid profiles with advancing age is recommended. Continued use of testosterone beyond age 40 may be linked to benign prostatic hyperplasia. A prostate-specific antigen and digital rectal exam should be conducted after three to six months of testosterone therapy in men older than 40 years and annually thereafter. Nadir testosterone levels should be captured three to four months prior to the next injection. Levels that exceed 500 ng/dL or that are less than 200 ng/dL should be dose-adjusted or altered in frequency. Testosterone is contraindicated in men with breast cancer or known or suspected prostate cancer. It is also prohibited for use in men with bladder outlet obstruction, as seen with benign prostatic hypertrophy. Testosterone supplementation can correct anemia, which is present due to androgen deficiency from puberty. Hematocrit levels should be monitored, since elevations above normal range (erythrocytosis) can precipitate an increase in blood viscosity, aggravating vascular disease in the periphery, heart, and brain (Table 5).1,2,4,8 Although the etiology is unclear, testosterone may cause or worsen obstructive sleep apnea.1-4,7 Testosterone replacement does not mimic normal physiologic sex-steroid production. Thus, mood fluctuations and physical functioning may be affected.1-4,8
Notably, medications may also contribute to signs and symptoms of secondary hypogonadism. The patient's medical history should be screened to avoid exacerbation of testosterone deficiency. These medications include ketoconazole, glucocorticoids, spironolactone, cimetidine, phenytoin, opioids, alcohol, and anabolic steroids.
Fertility Treatment: Advances in fertility treatment, such as sperm extraction, in vitro fertilization (IVF), and intracytoplasmic sperm insertion (ICSI), can result in conception without abnormalities or mutations of chromosomes. Additional options are donor insemination or adoption.
IVF is commonly used for male and female infertility. Often, the major obstacle for male infertility is the point of fertilization. IVF is a form of assisted reproductive technology that combines male sperm with a mature egg in a laboratory dish for fertilization. The pre-embryo is then transferred to the uterus for implantation.
Through ICSI, a single sperm can be directly injected into an oocyte (egg). This procedure is usually a second-line option after IVF has failed, or for males with a severe reduction in sperm count, which can apply to patients with KS. ICSI does not guarantee pregnancy or fertilization; it has about a 50% fertilization rate and upward of a 40% pregnancy rate.9,10
Research indicates that the best time for parents or health care professionals to reveal the presence of KS may be mid- to late adolescence.1,5,6 At this age, an XXY male is old enough to understand the condition and may be better equipped to decide whom he wishes to inform. When educating patients about KS, males should be reassured that small testes will not interfere with the ability to have a normal sex life. Patients who develop gynecomastia should be encouraged to conduct regular breast self-examinations. Concerning testosterone use, patients can be counseled on painful injection site reactions, since testosterone may be dissolved in an oil base. Furthermore, pharmacists can warn patientsthat testosterone may influence mood and physical function.1-4,8
Counseling a patient with KS may prove challenging to a female pharmacist due to patient sensitivity discussing sexual and/or fertility difficulties. Female pharmacists may also face unique challenges in assisting males with KS regarding treatment and education. Table 6 lists counseling tips that address reproductive health concerns, as well as therapy and fertility options.
The American Association for Klinefelter Syndrome exists to support research efforts and patient education. Services include regional support for patients and caregivers, continuing education, telephone support, referrals, list-serves, and periodic newsletters. The links listed above can provide patients and parents with useful information and referral resources.
1. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med.1998;158:1309-1314.
2. Staessen C, Coonen E, et al. Preimplantation diagnosis for X and Y normality in embryos from three Klinefelter patients. Hum Reprod. 1996;11:1650-1653.
3. Matsumoto AM. Hormonal therapy of male hypogonadism. Endocrinol Metab Clin North Am. 1994;23:857-875.
4. Ghusn HF, Cunningham GR. Evaluation and treatment of androgen deficiency in males. Endocrinologist. 1991;1:399-405.
5. Smyth CM. Diagnosis and treatment of Klinefelter syndrome. Hosp Pract. 1999;34:111-120.
6. Staessen C, Tournaye H, et al. PGD in 47, XXY Klinefelter's syndrome patients. Hum Reprod Update. 2003;9:319-330.
7. Bojesen A, Juul S, et al. Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab. 2004;89:3830-3834.
8. Tenover JS. Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab. 1992;75:1092-1098.
9. The management of infertility in teritart care. Royal College of Obstetricians and Gynecologists-Medical Specialty Society. January 2000.
10. The initial investigation and management of the infertile couple. Royal College of Obstetricians and Gynecologists-Medical Specialty Society. Oct. 1998.
11. American Association of Clinical Endocrinologists and the American College of Endocrinology. AACE Clinical Practice Guidelines for the Evaluation and Treatment of Hypogonadism in Adult Male Patients. ED81843; 1196.
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