Klinefelter Syndrome
Etiology
Klinefelter syndrome is the most common sex chromosomal aneuploidy in males, with an incidence of 0.1–0.2% in the general population (1 in 500-1,000) and rising to 4% among infertile males and 10–11% in those with oligospermia or azoospermia. Approximately 80% of them have a 47,XXY chromosome complement, whereas mosaics and higher degrees of poly-X are seen in the remaining 20%. Even with as many as 4 X chromosomes, the Y chromosome determines a male phenotype. The chromosomal aberration most often results from meiotic nondisjunction of an X chromosome during parental gametogenesis; the extra X chromosome is maternal in origin in 54% and paternal in origin in 46% of patients. A national study in Denmark revealed a prenatal prevalence of 213 per 100,000 male fetuses, but in adult men the prevalence was only 40 per 100,000, suggesting that only 1 in 4 adult males with Klinefelter syndrome was diagnosed. The incidence of KS increases with maternal age and possibly also with paternal age.
Clinical Manifestations
In patients who do not have a prenatal diagnosis, the diagnosis is rarely made before puberty because of the paucity or subtlety of clinical manifestations in childhood. Behavioral or psychiatric disorders may be apparent long before defects in sexual development. These children tend to have learning disabilities and deficits in executive function (concept formation, problem solving, task switching, and planning), and the condition should be considered in males with psychosocial, learning, or school adjustment problems. Affected children may be anxious, immature, or excessively shy and tend to have difficulty in social interactions throughout life. In a prospective study, a group of children with 47,XXY karyotypes identified at birth exhibited relatively mild deviations from normal during the first 5 yr of life. None had major physical, intellectual, or emotional disabilities; some were inactive, with poorly organized motor function and mild delay in language acquisition. Problems often first become apparent after the child begins school. Full-scale IQ scores may be normal, with verbal IQ being somewhat decreased. Verbal cognitive defects and underachievement in reading, spelling, and mathematics are common. By late adolescence, many males with Klinefelter syndrome have generalized learning disabilities, most of which are language based. Despite these difficulties, most complete high school. The patients tend to be tall, slim, and have a specific tendency to have long legs (disproportionate to the arms, and longer than those seen with other causes of hypogonadism), but body habitus can vary markedly. The testes tend to be small for age, but this sign may become apparent only after puberty, when normal testicular growth fails to occur. The phallus tends to be smaller than average, and cryptorchidism is more common than in the general population. Bone mineral density may be low in adults with Klinefelter syndrome, and this correlates with lower testosterone levels.
Pubertal development may be delayed, although some children undergo apparently normal or nearly normal virilization. Despite normal testosterone levels, serum LH and FSH concentrations and their responses to gonadotropinreleasing hormone (GnRH) stimulation are elevated starting at around 13 yr of age. Approximately 80% of adults have gynecomastia; they have sparser facial hair, most shaving less often than daily. The most common testicular lesions are spermatogenic arrest and Sertoli cell predominance. The sperm have a high incidence of sex chromosomal aneuploidy. Azoospermia and infertility are usual, although rare instances of fertility are known. It is now clear that germ cell numbers and sperm counts are higher in early puberty and decline with age. Testicular sperm extraction followed by intracytoplasmic sperm injection can result in the birth of healthy infants, with success rates declining with increasing age. In nonmosaic Klinefelter patients, most testicular sperm (94%) have a normal pattern of sex chromosome segregation, indicating that meiotic checkpoints can remove most aneuploid cells. Antisperm antibodies have been detected in 25% of tested specimens.
There is an increased incidence in adulthood of central adiposity, metabolic syndrome, pulmonary disease, varicose veins, and cancer of the breast. Among 93 unselected male breast cancer patients, 7.5% were found to have Klinefelter syndrome. Mediastinal germ cell tumors have been reported; some of these tumors produce hCG and cause precocious puberty in young males. They may also be associated with leukemia, lymphoma, and other types of hematologic neoplasia. The highest cancer risk (relative risk: 2.7) occurs in the 15-30 yr age group. A large cohort study in Britain demonstrated an overall significantly increased standardized mortality ratio (1.5), with increases in deaths from diabetes, epilepsy, peripheral and intestinal vascular sufficiency, pulmonary embolism, and renal disease. Mortality from ischemic heart disease was decreased. In adults, structural brain abnormalities correlate with cognitive deficits.
In adults with XY/XXY mosaicism, the features of Klinefelter syndrome are decreased in severity and frequency. Children with mosaicism have a better prognosis for virilization, fertility, and psychosocial adjustment.
Klinefelter Variants and Other Poly-X Syndromes
When the number of X chromosomes exceeds 2, the clinical manifestations, including intellectual disability and impairment of virilization, are more severe. Height decreases with increasing number of X chromosomes. The XXYY variant is the most common variant (1 in 18,000-40,000 male births). In most, intellectual disability occurs with IQ scores between 60 and 80, but 10% have IQs greater than 110. The XXYY male phenotype is not distinctively different from that of the XXY patient except that XXYY adults tend to be taller than the average XXY patient. The 49,XXXXY variant is sufficiently distinctive to be detected in childhood. Its incidence is estimated to be 1 in 80,000-100,000 male births. The disorder arises from sequential nondisjunction in meiosis. Affected patients are severely cognitively impaired and have short necks and typical coarse facies. The eyes are wide-set, with a mild upward slant of the fissures as well as epicanthus and strabismus; the nose is upturned, wide, and flat; also noted is a large open mouth and large malformed ears. The testes are small and may be undescended, the scrotum is hypoplastic, and the penis is very small. Defects suggestive of Down syndrome (short, incurved terminal 5th phalanges, single palmar creases, and hypotonia) and other skeletal abnormalities (including defects in the carrying angle of the elbows and restricted supination) are common. The most frequent radiographic abnormalities are radioulnar synostosis or dislocation, elongated radius, pseudoepiphyses, scoliosis or kyphosis, coxa valga, and retarded bone age. Most patients with such extensive changes have a 49,XXXXY chromosome karyotype; several mosaic patterns have also been observed: 48,XXXY/49,XXXXY; 48,XXXY/49,XXXXY/50,XXXXXY; and 48,XXXY/49,XXXXY/50,XXXXYY. Prenatal diagnosis of a 49,XXXXY infant has been reported. The fetus had intrauterine growth retardation, edema, and cystic hygroma colli.
The 48,XXXY variant is relatively rare. The characteristic features are generally less severe than those of patients with 49,XXXXY and more severe than those of 47,XXY patients. Mild intellectual disability, delayed speech and motor development, and immature but passive and pleasant behavior are associated with this condition.
Very few patients have been described with 48,XYYY and 49,XXYYY karyotypes. Dysmorphic features and cognitive impairment are common to both.
Laboratory Findings
Most males with Klinefelter syndrome go through life undiagnosed. The chromosomes should be examined in all patients suspected of having Klinefelter syndrome, particularly those attending child guidance, psychiatric, and cognitive disability clinics. In infancy, inhibin B and AMH levels are normal but testosterone levels are lower than in controls. Before 10 yr of age, males with 47,XXY Klinefelter syndrome have normal basal plasma levels of FSH and LH. Responses to gonadotropin-stimulating hormone and to hCG are normal. The testes show normal growth early in puberty, but by midpuberty the testicular growth stops, gonadotropins become elevated, and testosterone levels are slightly low. Inhibin B levels are normal in early puberty, decrease in late puberty, and are low in adults with the syndrome. Elevated levels of estradiol, resulting in a high ratio of estradiol to testosterone, account for the development of gynecomastia during puberty. Sex hormone–binding globulin levels are elevated, further decreasing free testosterone levels. A long androgen receptor polyglutamine (CAG) repeat length is associated with the more severe phenotype, including gynecomastia, small testes, and short penile length. Testicular biopsy before puberty may reveal only deficiency or absence of germinal cells. After puberty, the seminiferous tubular membranes are hyalinized and there is adenomatous clumping of Leydig cells. Sertoli cells predominate. Azoospermia is characteristic, and infertility is the rule.
Management
Males known to have Klinefelter syndrome should be monitored closely for speech, learning, and behavioral problems; they should be referred for early evaluation and treatment as needed. Testosterone, LH, and FSH levels should be checked at 11-12 yr of age; replacement therapy with a testosterone preparation is recommended once FSH and LH begin to rise above normal. Fasting glucose, lipids, and hemoglobin A1C should also be obtained, as these children are at risk for central adiposity and metabolic syndrome. A baseline dual-energy x-ray absorptiometry scan to assess bone density is also recommended by some authorities. Although testosterone treatment will normalize testosterone levels, stimulate the development of secondary sexual characteristics, increase bone mass and muscle mass, and improve body composition, it will not improve fertility (and will, in fact, suppress spermatogenesis). There is some evidence that it also improves mood and may have a positive effect on cognition and social functioning, but the findings are not conclusive at this time. Either long-acting testosterone injections or a daily application of testosterone gel may be used (testosterone patches have a high incidence of skin rash and are not frequently used in pediatrics). Testosterone enanthate or cypionate ester may be used in a starting dose of 25-50 mg injected intramuscularly every 3-4 wk, with 50-mg increments every 6-9 mo until a maintenance dose for adults (200-250 mg every 3-4 wk) is achieved. At that time, testosterone patches or testosterone gel may be substituted for the injections. Depending on patient and physician preference, transdermal testosterone may also be used as initial treatment instead of injections. For older males, larger initial doses and increments can achieve more rapid virilization. The various transdermal preparations differ somewhat from each other and standard references should be consulted for recommendations regarding dosage and mode of application.
Gynecomastia may be treated with aromatase inhibitors (which will also increase endogenous testosterone levels), but medical treatment is not always successful and plastic surgery may be needed. Fertility is usually not an issue in the pediatric age group, but adults can father children using testicular sperm extraction followed by intracytoplasmic sperm injection. Because sperm counts decrease rapidly after the onset of puberty in children with Klinefelter syndrome, sperm banking during early puberty is an option that can be discussed with a fertility specialist. Sperm counts can be stimulated using hCG treatment prior to testicular sperm extraction. Therapy, counseling, and psychiatric services should be provided as needed for learning difficulties and psychosocial disabilities.
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