Men with Klinefelter's syndrome (KS) have an extra X chromosome, having the 47,XXY karyotype.
The prevalence of the syndrome is about 1/600 newborn boys. It is the most common numerical chromosome aberration in men.
Nearly all men with the syndrome have small testicles and hypergonadotropic hypogonadism and are infertile. Other symptoms vary greatly.
A significant percentage of the men (50-75%) live their lives without knowing about the chromosomal aberration.
Men with 47,XXY usually have mild symptoms but due to certain increased risks of disease, the chromosomal aberration should be taken into consideration when monitoring their health in adulthood.
Aetiology
KS is not hereditary but an incidental chromosomal aberration usually occurring due to disturbed gamete division.
The 47,XXY karyotype is the most common.
Some patients (about 15%) have a mosaic 47,XXY that occurs in some cells, only; in such cases, symptoms may be milder.
Higher numbers of extra chromosomes, such as 48,XXXY or 49,XXXXY, are rarer and often produce more severe symptoms.
Diagnosis
KS is sometimes diagnosed as an incidental finding in association with chromosome analysis done for some other reason during pregnancy or childhood.
Most commonly, it is found when examining the cause of azoospermia causing infertility.
It can be found by chromosome analysis (karyotype test) in blood (or other tissue, such as the placenta or amniotic fluid), and it can also be detected by molecular karyotyping (array comparative genomic hybridization, arrayCGH).
A diagnosis made during pregnancy should be confirmed by chromosome analysis of a blood sample after birth.
Chromosome analysis should be done as part of investigations for azoospermia or severe oligozoospermia as well as for primary hypogonadism or elevated LH or FSH levels.
Signs and symptoms
In childhood and school age
Usually not detectable in infancy or childhood
Signs of the syndrome may include undescended testes, hypospadia or, more rarely, small penis.
Some patients have slightly delayed motor or speech development.
In school age, there is an increased risk of learning disorders, particularly ones related to reading or writing.
There may be features of autism spectrum disorders, activity or attention disorders, or challenges related to social skills or emotions.
Patients often grow taller than expected, with long limbs.
In puberty and adolescence
Puberty usually begins normally.
In many boys with KS, testosterone production does not increase normally in puberty, hypergonadotropic hypogonadism develops around mid-puberty, and the development of secondary sex characteristics is impaired: the testes are small and firm, muscles often weak, and the growth of beard and other hair may be lesser than normal Pubertal Development and its Disturbances.
Some boys have gynaecomastia, mostly mild and requiring no intervention.
The adult height usually exceeds the expected height slightly (average height about 186 cm).
The syndrome does not prevent attending military service.
In adulthood
Most of the men are infertile due to lack or insufficient production of sperm; only less than 10% have been found to have a very low number of sperm in their semen.
Testosterone levels are often low in adulthood but not all patients have symptoms of hypogonadism or have no low testosterone levels either; even if not, LH and FSH levels are usually elevated.
The share of body fat, particularly around the trunk, and visceral fat is usually increased, as are the risks of type 2 diabetes and cardiovascular disease.
Osteopenia or osteoporosis is found in about 40% of patients; this does not necessarily correlate with serum testosterone levels.
The risk of autoimmune diseases, such as rheumatoid arthritis, Sjögren's syndrome or SLE, is somewhat increased.
Sexual disturbances, such as decreased libido or erectile dysfunction, appear to be slightly more common. Testosterone treatment will correct these but not always completely, at least not erectile dysfunction.
The risk of psychological symptoms, such as depression or anxiety, is increased in adulthood.
Due to elevated oestrogen levels, the risk of breast cancer may be slightly increased but still clearly below the general risk of breast cancer in women, and routine follow-up by imaging is not recommended.
Klinefelter's syndrome has no effect on life expectancy.
Treatment
In childhood and school age, some of the boys need speech therapy or learning support; the need for such measures should be assessed without hesitation.
If a boy is known to have a chromosomal aberration, he should be referred for assessment by a paediatric endocrinologist before the beginning of puberty. Development in puberty should be followed and testosterone treatment considered if the onset or process of puberty is delayed or if hypogonadism is detected.
The boy or young adult, at the latest, should be provided with age-appropriate counselling on issues and treatment possibilities related to fertility.
If there is severe gynaecomastia, surgical treatment can be considered but this is rarely necessary.
Microdissection testicular sperm extraction (MD-TESE) combined with intracytoplasmic sperm injection (ICSI) may provide some patients with the opportunity to have their own biological children.
Other options for the treatment of childlessness are sperm donation and adoption.
Deep-freezing semen containing a few sperm in puberty, before starting testosterone treatment, may provide a chance for treating childlessness in the future.
In adulthood, testosterone treatment appears to benefit at least men with hypogonadism. Treatment should be provided as for hypogonadism in general Male Hypogonadism and Hormone Replacement. Testosterone treatment usually improves the quality of life of men with hypogonadism.
Men with 47,XXY or the parents of a boy with the karyotype should be offered genetic counselling.
Follow-up
Blood glucose and lipid levels should be regularly monitored in adulthood.
Lifestyle guidance and good treatment of any diabetes, overweight or dyslipidaemia are important.
In follow-up, other increased risks of disease (osteoporosis, autoimmune diseases, psychiatric disease) should be considered.
If no testosterone treatment is being used in adulthood, LH, FSH and testosterone levels and any symptoms of hypogonadism should be monitored regularly.
References
Brinton LA. Breast cancer risk among patients with Klinefelter syndrome. Acta Paediatr 2011;100(6):814-8. [PubMed]
Zitzmann M, Rohayem J. Gonadal dysfunction and beyond: Clinical challenges in children, adolescents, and adults with 47,XXY Klinefelter syndrome. Am J Med Genet C Semin Med Genet 2020;184(2):302-312. [PubMed]
Pizzocaro A, Vena W, Condorelli R et al. Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis. J Endocrinol Invest 2020;43(12):1675-1687. [PubMed]
Berglund A, Stochholm K, Gravholt CH. The epidemiology of sex chromosome abnormalities. Am J Med Genet C Semin Med Genet 2020;184(2):202-215. [PubMed]
Zitzmann M, Aksglaede L, Corona G et al. European academy of andrology guidelines on Klinefelter Syndrome Endorsing Organization: European Society of Endocrinology. Andrology 2021;9(1):145-167. [PubMed]