Congenital
Acquired
Klinefelter syndrome
Trauma
Cryptorchidism
Orchitis
Immune polyglandular failure
Spinal cord injury
Congenital anorchia
Medications: ketoconazole, cancer chemotherapy
Noonan’s syndrome
X-irradiation
Lawrence–Moon–Bardet–Biedl syndrome
Retroperitoneal fibrosis
Myotonic dystrophy
Amyloidosis
Sickle cell disease
AIDS
Noonan syndrome
Alcoholic liver disease
Chronic kidney disease
Lessons Learned
In 1942 Klinefelter et al. described nine unrelated adult men with gynecomastia, small firm testes, scant body hair, and elevated FSH levels (a bioassay for FSH in urine based on the development of the reproductive tract in mice was performed at that time). While the authors wrote that “nothing has been found in these patients to explain the testicular lesion”, after an inactivated X-chromosome was identified in normal women (Barr body) in 1949, the 47,XXY chromosomal basis of the disorder was described in 1959. It is now known that KS syndrome is the most common form of congenital male hypogonadism and X and Y chromosome variation, and accounts for approximately 11 % of azoospermic men. The prevalence in the general population is 0.1–0.2 %. Intrauterine mortality does not appear to be a feature of Klinefelter syndrome (KS). The diagnosis is made in the course of prenatal screening, in newborns with cryptorchidism or microphallus, in boys with language delay, learning disabilities, or behavioral problems, as teenagers with delayed or incomplete pubertal development or gynecomastia, or in adults with hypogonadism or infertility. Bojesen et al. [3] estimated that only one fourth of adult men in Denmark with KS are ever diagnosed.
Genetics/Etiology
In individuals with more than one X chromosome, all in excess of one condense to form Barr bodies, a darkly staining mass of chromatin at the cell’s nuclear rim. A karyotype is performed using rapidly dividing T-lymphocytes in peripheral blood that are chemically arrested in metaphase and stained to establish the diagnosis. The extra X chromosome in KS results from nondisjunction during meiotic division in germ-cell development, or in less than 5 %, during early embryonic mitotic division. About half of the cases are paternally derived and result from the formation of an XY sperm in meiosis-1, whereas maternal XX oocytes can result from errors in either meiosis-1 or meiosis-11. The risk of KS appears to increase in mothers older than age 40.
About 10 % of men with KS have a mosaic peripheral blood karyotype, usually 47,XXY/46,XY, and have a milder phenotype. The karyotype may occasionally be normal, especially if only 20 cells are counted, and a karyotype of skin fibroblasts or testicular biopsy specimen may be needed to confirm the mosaic diagnosis. Higher grade chromosome aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY) also produce the Klinefelter phenotype, but are rare, and cause psychomotor retardation.
When two X chromosomes are present, most genes on one X are silenced as a result of the X-chromosome inactivation. Some genes escape X-inactivation, however, and are expressed from both the active and inactive X chromosome. About 15 % of X-chromosome genes, especially genes in the pseudoautosomal region, escape X-inactivation in KS, and thus have a higher level of expression than in normal men. The overexpression of these genes in various tissues of the body, together with the hypogonadism, produce the Klinefelter phenotype.
Some men with primary testicular failure have a 46,XX karyotype. This condition generally results from the translocation during paternal meiosis of the distal end of the short arm of the Y chromosome, containing the testis determining gene (SRY), to the X chromosome, or sometimes to an autosome.
Phenotypic Manifestations
The major manifestations of KS are listed in Table 35.2 [4]. In general, the greater the number of X chromosomes, the more marked are the phenotypic consequences. While stature and body hair are variable polygenic traits, all men with classical 47,XXY KS can be readily diagnosed because they have small firm testes.
Feature | Frequency % | Feature | Frequency % |
|---|---|---|---|
Infertility | 91–99 | Cryptorchidism | 27–37 |
Small testes (bitesticular size <6 ml) | >95 | Learning disabilities (children) | >75 |
Increased gonadotropins | >95 | Delay of speech development (children) | 40 |
Azoospermia | >95 | Psychiatric disturbances | 25 |
Decreased testosterone | 63–85 | Increased height (prepubertal, adults) | 30 |
Decreased facial hair | 60–80 | Abdominal adiposity (adults) | ∼50 |
Decreased pubic hair | 30–60 | Metabolic syndrome (adults) | 46 |
Gynecomastia | 38–75 | Osteopenia (adults) | 5–40 |
Breast cancer | 30× incr | Type 2 diabetes (adults) | 10–39 |
Mediastinal cancers | 50× incr | Decreased penile size (children) | 10–25 |
Klinefelter patients are often tall, but rather than classic eunuchoidal skeletal proportions (arm span at least 6 cm >height), they have exaggerated pubis-floor growth. Even prepubertal boys with KS may have long legs, implying that this abnormality may not be from a sex hormone disturbance. Long legs are instead thought to be due to overexpression of short stature homeobox (SHOX) gene, on pseudoautosomal region1 of the X chromosome that plays a major role in growth [5].
Gynecomastia
While breast enlargement was the essential finding in the cases reported by Klinefelter et al., not all men with KS have gynecomastia. Early studies found elevated circulating estradiol levels whereas more recent studies report normal estradiol levels in KS men. However, all cases have low testosterone in relation to estradiol levels. It is also possible that gynecomastia is due partly to effects on the breast of X-linked genes that escape silencing. Breast pain may occur, and gynecomastia can be psychologically disturbing, especially to adolescents. Long-standing gynecomastia generally contains extensive fibrous stroma as well as glandular tissue, and may be irreversible, and claims that antiestrogens or aromatase inhibitors substantially decrease breast tissue mass have come from open labeled uncontrolled trials with self-reported outcomes. These drugs are unapproved for this purpose and cannot be recommended at this time. Plastic surgery techniques restore the breast contour with minimal scarring and protect areolar anatomy and sensation. Subcutaneous mastectomy with liposuction through a circum-areolar approach is most often used. Corrective surgery will often favorably impact the emotional disturbance and academic difficulties that these boys endure.
Bone mineral density is reduced, and osteoporosis occurs more often in men with KS than in normal men, and the age-related decrease in bone mass is thought to be more pronounced [6]. Free testosterone levels are inversely correlated with bone mineral density in some studies; however, testosterone deficiency alone does not appear to explain the low bone mass in KS. BMD may increase after the initiation of testosterone replacement especially in younger men.
Language-based learning disabilities, reading disorders, developmental dyspraxia with neuromotor dysfunction, speech and language abnormalities, and social dysfunction are common in KS. 47,XXY individuals have lower verbal IQ than performance IQ with normal full-scale IQ whereas patients with higher grade aneuploidies tend to be mentally retarded. Babies with KS tend to have expressive language delay, while school-age boys demonstrate a verbal cognitive deficit with significant underachievement in reading, spelling, and writing. Some also have reduced mathematical ability. These learning disabilities lead to poor school performance and to less skilled occupations in adulthood. Behavioral problems and difficulty with social relationships may accompany academic underachievement. Many patients are quiet, sensitive and insecure, with lack of insight and poor judgment. On the other hand, some men with KS are intelligent, and professionally and financially successful. Between- subject variability in the overexpression of X-chromosome genes, and variable CAG repeat length in the androgen receptor promoter are thought to account for the inconstant phenotype. It is often written that quality of life would be considerably more favorable if the diagnosis were made in childhood, and information, counseling, support, and hormone treatment were given beginning at an early age; but this is unproven.
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