Klinefelter's syndrome is named after Harry F. Klinefelter (cline-felter) who first described the syndrome in the USA in 1942.[i] It is a genetic disorder that only affects male. Normally a person, whether male or female, has a total of 46 chromosomes in the nucleus, which is the control centre of each cell. Chromosomes are the genetic material that contain the code of life: Deoxyribonucleic acid, better known as DNA. Of those 46 chromosomes, 44 are grouped in a total of 22 pairs and are called autosomes, the name given to the non-sex determining chromosomes that determine other characteristics. In addition there are normally two sex chromosomes, females having two X chromosomes and males having one X and one Y. Each chromosome is made up of genes, each of which has a specific role to perform. The Y chromosome contains the male determining gene. Of the 46 chromosomes, half come from the mother and half from the father. A normal male would have 44 autosomes and the X and Y sex chromosomes, making a total of 46. This is expressed as 46,XY and is known as that individual's karyotype (carry-o-type). In Klinefelter's syndrome however, due to one of nature's accidents, when the male sperm fuses with the female egg, the fetal cells have at least one extra X chromosome. The most common number of chromosomes found in KS is 47, that is 44 autosomes and 3 sex chromosomes giving a karyotype of 47,XXY.
The extra X chromosome can come from either a sperm or an egg, with a 50:50 chance. However as maternal age increases so does the risk of having a boy with KS. The same risk does not however occur as men get older. Because KS is not passed on but occurs by accident, it is said to be congenital, which means that it is not inherited, that is, it is not an hereditary disorder. This means that the parents of a boy who has Klinefelter's syndrome need not be anxious about having more children as the likelihood of having another KS boy is minimal.
What is a Mosaic/Mosaicism ?
Some KS males have what is known as mosaicism (mose-aia-sisem) which means that some of the cells in their body are ordinary 46,XY whilst others are, for example, 47,XXY. This example would be expressed as 46,XY/47,XXY. Some of these individuals, because of where the normal 46,XY cells are located, are able to produce sperm and father children, whereas the majority who are non-mosaic are sterile, that is, they are unable to produce sperm and father children.
KS is estimated to be found in 1 in 1000 (0.1%) [ii], [iii] of live male births, but other studies have suggested that the figure may be as high as 1 in 700 (approximately 0.14%) [iv] . The most common karyotype is 47,XXY [v] A minority of KS males have a relatively low IQ below 80 [vi] (a measure of intelligence relative to the rest of the population; the average is normally 100, give or take 15).
Delayed language development occurs in 50% of cases [vii], [viii]. Breast development, known as gynæcomastia (guy-na-co-mastia) occurs in some cases, however during adolescence it can be a temporary finding (usually 40% of boys) [ix]. Examples [x] of other KS karyotypes are: 48,XXXY, 46,XX (male), 46,XxY, 46,XX/47,XXY.
Boys with KS
Boys with KS have a normal male body shape and are thus referred to as being phenotypically (fee-no-typically) male. They may experience learning difficulties, especially with verbal or spoken skills, which may require appropriate speech therapy. They may have difficulty in concentrating for more than a few minutes on any single topic. They may have problems in socialising with other children of their own age group. Boys with KS may have difficulties in specific areas of learning, especially those that are based upon a facility with language. This affects their ability to learn to read and spell, as well as their ability to learn arithmetic skills. Remedial teaching (learning support) may be beneficial for such children, and a Statement of Special Educational Needs is often appropriate [xi].
At puberty, blood testosterone levels are normal initially but may fail to rise into the normal adult range from age 14 onwards. A boy's hips may develop fatty deposits (although this can occur in non-KS males) so that the boys assume more of a female pear shape (described as eunuchoid) and they may develop breast enlargement, though this is also a common finding in non-KS boys. If testosterone is low, muscle development and beard growth may be reduced, and sexual interest lowered. Before puberty a KS boy's testes have a lower number of sperm producing cells (spermatogonia) than his peers, but after puberty has begun fibrosis & hyalinization (hialin-i-zation) of the seminiferous (semi-nif-er-ous) tubules begins, a process which results in sterility. In simple terms hyalinization means that the seminiferous tubules become filled with a substance called hyalin which hardens & blocks the tubules. Fibrosis means that the tissue or cells surrounding the tubules (called connective tissue) shrink & become permanently scarred or damaged.
During puberty a KS boy may begin to have problems at school if he has to participate in school sport. If physical differences are present, these can attract the unpleasant attention of his classmates and can result in teasing and social isolation. Before puberty it is desirable to discuss this in confidence with his headteacher and those other members of staff who need to know. Should gynæcomastia develop to a degree where it causes unhappiness to the boy, testosterone treatment and surgery should be considered and the implications fully discussed and understood by an affected adolescent before any final decision is taken. If surgery is chosen, it is important to ensure that the surgeon who will be operating has some experience in doing so, as poor surgery can create worse psychological problems than existed prior to the operation.
Men with KS
Men with KS are usually sterile. They tend to have longer arms and legs and tend to be taller than their peers. Lack of emotion, fatigue and apathy are common [xii] and other problems such as an increased tendency to develop psychiatric disorders, [xiii] may occur as a result of the syndrome.
General information - introduction
A number of other characteristics may be associated with Klinefelter's syndrome that are dealt with briefly. In the past, too much attention may have been paid to problems affecting one or two individuals who also happened to have KS, which has led to suggestions of associations between the syndrome and other diseases (however see below). Follow-up investigations have not necessarily confirmed such findings, demonstrating a need for both parents, affected individuals and those professionals working with them to be open minded and not take what they read or hear necessarily as fact. Corroboration of research by other researchers is desirable before any suggested association between KS and something else is accepted. An additional problem often encountered is inaccurate information published in some medical reference books aimed at the general public. Authors have not always checked their facts and this had led to unnecessary anxiety in readers. Similar problems are beginning to appear with some medical information on the internet, with opinion sometimes presented as fact.
Disorders of the body's defence system with antibodies attacking the body itself, appear to be more common in KS with a greater tendency to develop breathing (ie respiratory) disorders such as asthma.
There seems to be a higher risk of developing diseases affecting the veins: hypostatic leg ulcers and thrombophlebitis (throm-bo-flea-bite-is) seem to be more common. In thrombophlebitis the wall of a vein can become inflamed and this can lead to the liquid blood becoming solidified and causing a blood clot that impedes the progress of the blood in the affected area.
There appears to be a higher risk of developing osteoporosis (also known as brittle bone disease) in which the bones gradually weaken and are more likely to break. Men with KS who only have moderately low levels of natural testosterone may have normal bone density whilstthose with lower bone density seem to have an increased bone turnover[xiv]. Treatment with testosterone (more later) may prevent this from developing. However there is evidence which suggests that only early testosterone treatment prevents reduced bone density. Later treatment (after puberty) seems to offer no benefits.[xv], [xvi]. Decreasing bone mass which can lead to osteoporosis, can be automatically measured by a bone density scanner. A new test has also been developed which analyses a urine sample for the presence of a collagen breakdown product, which indicates the development of osteoporosis [xvii].
It has been suggested that diabetes mellitus is associated with Klinefelter's syndrome but the connection may be linked with the greater tendency for KS men to be overweight as this disorder can occur in such individuals. As yet there is no sound evidence linking diabetes with KS.
There is a slightly higher risk of developing the following two types of cancer. Male breast cancer is more common in KS than in the normal male population. Almost 1% of all breast cancers are in men [xviii]. Breast cancer is 20 times more common in KS than in non-KS males. This means that roughly 3% of KS men will develop breast cancer [xix]. Whilst this poses a risk, it needs to be looked at in the context that it is estimated that 1 in 12 (around 9% of) women will develop breast cancer over their lifetime. [xx] That is, they have three times the risk KS men have. The reported average age the cancer starts is later than that found in women who develop breast cancer [xxi]. Circumstantial evidence suggests a link with gynæcomastia [xxii] but this is open to question [xxiii]. Removal of the breasts may not eliminate the risk as it has been suggested that the cause of the cancer may be linked to the hormonal imbalances in KS, causing cells to become cancerous [xxiv]. In women, a longer than normal menopause can increase the risk because of fluctuating ostrogen levels, [xxv] and this may have its equivalent in KS men.
Germ cell cancers are those which originate in the sperm producing cells. Whilst most of these cells are situated in the testes, a few are in the body cavity below the lungs where organs such as the liver are situated, called the mediastinum. In KS there is a very small risk of developing germ cell cancer originating in the mediastinum, a risk that is greatly reduced after the age of thirty years. The peak risk group are aged between 15 and 30 years old. [xxvi].
There is a condition, thought to be common in KS called taurodontism(toro-dont-ism), which literally means "bull teeth". In this condition the dental pulp - the living part of the tooth which contains a nerve, occupies a greater area than normal. This results in a thinner layer of the hard enamel which leads to an increased risk of tooth decay [xxvii].
There is another condition, very rare in KS, called radial ulnar synostosis in which the radius and ulnar bones in the forearm are fused together. This prevents rotation of the forearm.
Emotional and behavioural aspects
There are a number of emotional and behavioural problems associated with KS such as shyness, difficulties in forming relationships, a lack of visible facial emotion and of motivation. Low self-esteem may be an issue for adolescents. Little is yet understood about the reasons for these difficulties; some may be directly related to the chromosomal abnormality and its influence on brain development. Others are secondary to hormonal changes, and their effect on physical development and maturation [xxviii].
Biology of male reproductive organs & testosterone.
Testosterone (test-os-ter-own) is a natural chemical which is produced by the body and in males mostly comes from the testes (singular: testis), the male sex organs. It is what is known as an androgen (and-row-jen), one of a number of hormones responsible for activating both the growing male sex organs and at puberty, beard growth and voice deepening, for example. It is mainly produced in the testes (95%) by the Leydig cells which are situated around the seminiferous tubules (see below) in response to the reception of luteinizing (loot-en-i-zing) hormone (or LH for short) produced by a part of the brain called the anterior pituitary gland. Each testis is divided into a series of chambers called lobules, each of which contains coiled seminiferous tubules. Within these tubules are two types of cell: the spermatogenic cells which develop into sperm by a process called spermatogenesis, of which more later; and the Sertoli cells, which nourish the maturing sperm cells. The Sertoli cells also perform a number of other functions which include releasing a hormone called Inhibin, which controls the release from the Pituitary gland, of Follicle Stimulating Hormone (or FSH). The seminiferous tubules are surrounded by blood capillaries and groups of Leydig cells, which release androgens, or sex hormones, one of which is testosterone. Most of the remaining testosterone is produced in the adrenal cortex, which is situated on the upper surface of each kidney.
Spermatogenesis is the name given to the process that occurs in the seminiferous tubules, which produces sperm. This process goes on all the time from the onset of puberty, in fertile males. Sperm producing cells upon exposure to testosterone, divide to produce two "daughter" cells, as they are called (although this in no way implies any gender). These "daughter" cells contain the full set of 23 pairs of chromosomes (total = 46 chromosomes). One of these "daughter" cells is a new sperm producing cell, whilst the other cell further divides to form two new cells, each with only one member of each chromosome pair. As the unfertilised egg also contains only one member of each chromosome pair, the act of fertilisation re-institutes an embryo with 46 chromosomes.
Now I shall discuss the male hormone testosterone, which is known as an anabolic steroid as one of its effects is to promote muscle growth. It should not be confused with the drugs abused by some athletes and bodybuilders.
Testosterone is usually given orally (in the form of tablets, by mouth), intramuscular injections (into the muscle), implantation of pellets or in the form of a transdermal (ie skin) patch. Testosterone is given in the form of one or more of its compounds, that is basic testosterone in a different form which affects how the body deals with it. These compounds are known as esters and some are utilised by the body more quickly than others. Testosterone preparations such as Sustanon* contain a relatively fast acting and a slow acting form, which are designed so that the drug can begin to work within hours of injection, lasting from a few days (eg. Testosterone propionate), to a few weeks (eg. Testosterone enanthate).
One of the problems with testosterone given by mouth is that it has to be given in relatively high doses to have an effect as the liver, the organ which removes poisonous substances from the blood, also inactivates testosterone. Testosterone undecanoate (Restandol*) is given by tablets. Each tablet lasts for between 2 to 6 hours normally requiring between 2 and 4 tablets, taken at intervals, a day. It is more effective if each tablet is taken with food, as this reduces the amount destroyed by the liver. Men often find tablet treatment is not strong enough to restore libido. * note: these are the brand names for these medicines in the United Kingdom. They may be known by different names elsewhere.
The implantation of testosterone pellets is another method, ideally being inserted in the wall of the abdomen under local an æsthetic. An implant containing 600mg to 1200mg of testosterone can last for between 4 and 6 months or more and it has been suggested that this is the best form (in 1990) in which it can be given [xxix]. The main problem with implants is their tendency to come out and need reinsertion. However a new method of having testosterone became available in the UK in 1996, called Andropatch*, which as a transdermal patch delivers testosterone through the skin and one or more patches is worn every day.
Of all these products, Sustanon is the cheapest, followed by Restandol which is quite expensive whilst the Andropatch appears to be the most expensive of these three common forms of testosterone. This should not be a problem however if you use the UK's National Health Service. The following price comparisons (at 1998 prices [xxx]) should give you an idea of the relative prices of these three commonly prescribed forms of testosterone.
Andropatch (transdermal) costs £48.00 for either a box of 60 x 2.5mg, or a box of 30 x 5.0mg patches
Restandol (tablet) costs £8.69 for 28, or £17.38 for 56 tablets
Sustanon (injection) costs £3.67 for 3 x 1ml ampoules of Sustanon 100, or £8.60 for 3 x 1ml ampoules of Sustanon 250
Do I need testosterone treatment ?
Not necessarily. As mentioned earlier, testosterone offers the possibility of preventing the development of fatty deposits round the hips & breast development, where these occur. It can ensure normal development of the penis if administered under the guidance of a doctor [xxxi] In adults it may reduce fatigue etc., prevent osteoporosis [xxxii] and help ensure satisfactory sexual activity. However it should only continue to be taken if you and your doctor feel it has benefited you. The amount of testosterone produced in the testes by adult KS males varies between individuals. You may find that you may need testosterone treatment, but it may also offer no real benefit and you may even experience unwanted side effects (see below) [xxxiii]. The dose needed will vary between individuals and should be adjusted accordingly.
What type of testosterone form should I ask my doctor for ?
Different forms (also called esters) of testosterone can have different effects on different individuals. One form may suit one person whilst causing problems or having little effect on another. The type chosen may be influenced by your preference as to how it should be administered. You may find an injection into your muscle (an intramuscular injection) more convenient, or you may prefer to have tablets (oral administration) or a (transdermal) skin patch, for example. Certain combinations of testosterone esters in a product may prove less satisfactory and even undesirable. What you should be aiming at is a product that gives a more or less steady level of serum (a component of blood) testosterone.
Possible dangers from prolonged use of testosteroneXXXX
Unlike naturally occurring testosterone, that introduced into the body as a result of testosterone treatment can cause some long term problems [xxxiv]. Heart problems, hypertension and the build-up of fluid in the body (ie: odema) can occur as a result of salt and water retention by the body. There may be an increased risk of atherosclerosis (are-thur-o-scler-o-sis) in which the walls of the arteries narrow as the result of a build up of fat, which increases the risk of a stroke. There is also evidence of polycythemia (poly-sigh-theme-e-a) in which there is a higher concentration of red blood cells in the blood than normal, though the evidence suggests the link is with older men [xxxv]. In some men there is a risk that too high a dose of testosterone (including in the short term) could result in aggression, psychosis (sigh-co-sis) and mania [xxxvi]. There is a slight risk that testosterone might cause problems for someone undergoing anti-coagulant treatment. There may also be a risk of liver damage.
Is there a link between KS and criminality ?
The simple answer to this question is no. One problem is that KS is sometimes confused with a different condition known as XYY syndrome. Some early research in the 1960s suggested a link between the possession of an extra Y chromosome (as in XYY syndrome) and aggression.[xxxvii] While some research has shown a higher number of XYY men had been found in high security prisons and special hospitals, other studies do not support this view. Later research found little evidence linking XYY syndrome with criminality.[xxxviii] Whilst early research suggested a link between criminality and KS, such as that by Nielsen[xxxix] who found that 38% of KS compared to 6% of XY males committed crimes, later research has not supported this.[xl] It is also necessary to remember that KS males are often less mature, passive, impressionable and more dependent on others, often having few or no friends, and are therefore more vulnerable to group pressure.[xli] Current thinking accepts that any association is controversial[xlii] and more research would be needed before any firm conclusions could be drawn.
All internet addresses (URLs) given in this document were correct when this document was issued in July 1998.
[i] original paper: Klinefelter, H.F. et al: Syndrome Characterized by Gynecomastia, Aspermatogenesis without A-Leydigism, & increased Excretion of Follicle Stimulating Hormone; J.of Clinical Endocrinology, 1942 (2) no.11: 615-627
[ii] Bock, R: Understanding Klinefelter's Syndrome: A Guide for XXY males & their families; National Institutes of Health, USA, 1993 (NIH Pub.no: 93-3202) also available at: http://www.iacnet.com/health/15097321.htm
[iii] Sørensen, K: Klinefelter's Syndrome in Childhood, Adolescence & Youth: A genetic, clinical, developmental, psychiatric & psychological study; Parthenon, 1987
[iv] Ratcliffe, S.G et al: Edinburgh Study of Growth & Development of Children with Sex Chromosome Abnormalities III (in: Children with Sex Chromosome Aneuploidy: Follow-up studies), March of Dimes Birth Defects Foundation: Original Article Series, 1986; 22(3):73-118 (eds. Ratcliffe, S.G & N. Paul)
[v] see Sørensen above
[vi] see Bock above
[vii] Oxford Textbook of Medicine; Sir David Weatherall et al (eds), OUP, 1987 (2nd edition)
[viii] see Sørensen above
[ix] Ratcliffe, S.G et al: Edinburgh Study of Growth & Development of Children with Sex Chromosome Abnormalities IV (in: Children & Young Adults with Sex Chromosome Aneuploidy: Follow-up Clinical & Molecular studies), March of Dimes Birth Defects Foundation: Original Article Series, 1991; 26(4):1-44 (eds. Evans, J.A et al)
[x] personal communication with Professor M.A.Ferguson-Smith
[xi] information supplied by Professor David Skuse
[xii] see Weatherall above
[xiii] Martinus, J: Psychiatric Aspects of Klinefelter's Syndrome in Adolescence; from Klinefelter's Syndrome eds. Bandmann, H.-J & R.Breit, Springer, 1984
[xiv] Luisetto G. et al: Bone mass and mineral metabolism in Klinefelter's syndrome; Osteoporos Int 1995;5(6):455-461
[xv] Kubler A. et al: The influence of testosterone substitution on bone mineral density in patients with Klinefelter's syndrome; Exp Clin Endocrinol 1992;100(3):129-132
[xvi] This is supported by research by Wong, F.H. et al: Loss of bone mass in patients with Klinefelter's syndrome despite sufficient testosterone replacement; Osteoporosis Int 1993, Jan; 3(1): 3-7
[xvii] OsteosalT is used with the electronic reader InstaQuantT developed by Cortecs Diagnostics Limited, who can be contacted either by E-mail at: [email protected] or by post at: Newtech Square, Deeside Industrial Park, Deeside, CH5 2NT, United Kingdom.
[xviii] Sasco, Annie J. et al: Review article: Epidemiology of male breast cancer. A meta-analysis of published case-controlled studies & discussion of selected ætiological factors; Int.J.Cancer, 1993 (53): 538-549; see also: Genetics of breast & ovarian cancer (Male breast cancer); British Medical Bulletin (50) no.3: 668; also personal communication with Professor H.S.Jacobs (UCL Medical School) (1996)
[xix] research by Hultborn et al in 1997 suggests the risk of male breast cancer in KS males may be as high as 7.5%, though it has been acknowledged that methodological differences may account for that figure. see: Hultborn, R. et al: Prevalence of Klinefelter's syndrome in male breast cancer patients; Anticancer Res, Vol 17, Nov.1997: 4293-4297
[xx] Whitehouse, David & Maurice Slevin: Cancer: the facts; OUP, 1996 (2nd edition)
[xxi] Scheike, O et al: Male breast cancer; Acta Pathol Microbiol Scand, 1975 Suppl 251: 3-35 found an average age of 65.2 years out of 257 cases, whereas Hultborn et al (see reference above) found the average age to be 72 out of 93 cases
[xxii] see Scheike above
[xxiii] van Geel, A.N et al: A retrospective study of male breast cancer in Holland; Br J Surgery, 1985 Sept; 72(9): 724-727
[xxiv] Thomas, David B: Breast cancer in men; Epidemiological Reviews, 1993 (15) no.1: 220-231; for more information on male breast cancer see: http://interact.withus.com/interact/mbc/index.html; see also: Volm, M.D. et al: Pituitary adenoma and bilateral male breast cancer: an unusual association; J.Surg.Oncol: Jan.1997, 64(1): 74-78 [xxv] see Whitehouse above
[xxvi] ? Hasle, H et al: Cancer incidence in men with Klinefelter syndrome; Br.J.Cancer 1995 Feb; 71(2): 416-420; , Hasle, H et al: Mediastinal germ cell tumour associated with Klinefelter syndrome. A report of case and review of the literature; Eur.J.Pediatr. 1992 Oct; 151(10): 735-739; f Nichols, C.R et al: Klinefelter's syndrome associated with mediastinal germ cell neoplasms; J. Clinical Oncology 1987; 5(8): 1290-1294; For more information on germ cell tumours generally, see: http://www.mc.vanderbilt.edu/peds/pidl/hemeonc/germcell.html note: Approximately 20% of non-seminomatous malignant germ cell tumours are associated with Klinefelter's syndrome (47,XXY). At least 8% of primary mediastinal germ cell tumours are in men with KS.
[xxvii] Paulsen, C.Alvin & S.R.Plymate: Klinefelter's syndrome; from The Genetic Basis of Common Diseases, eds. King, et al (Oxford Monographs on Medical Genetics, 1992) chapter 44
[xxviii] see Skuse above
[xxix] Handelsmann, David J: Pharmacology of testosterone pellet implants; in 'Testosterone: action, deficiency, substitution' eds. E. Nieschlag & H.M.Behre, Springer, 1990
[xxx] MIMS, June 1998: 190-193
[xxxi] see Ferguson-Smith above
[xxxii] Aspray, T.J. et al: Consequences of withholding testosterone treatment; Lancet, 1996 (348): 609
[xxxiii] see Ferguson-Smith above
[xxxiv] Gooren, Louis J.G. & Kaas H. Polderman: Safety aspects of androgen therapy; in 'Testosterone: action, deficiency, substitution' eds. E. Nieschlag & H.M.Behre, Springer, 1990
[xxxv] Hajjar, R.R. et al: Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis; J.Clin.Endocrinol.Metab, Vol 82, Nov.1997: 3793-3796; Drinka, P.J. et al: Polycythemia as a complication of testosterone replacement therapy in nursing home men with low testosterone levels; J.Am.Geriatr.Soc, Vol 43, Aug.1995: 899-901
[xxxvi] there may be an association between KS and bipolar disorder: see: Everman, D.B. & Stoudemire, A: Bipolar disorder associated with Klinefelter's syndrome and other chromosomal abnormalities; Psychosomatics, Vol 35, Jan.1994: 35-40; Bekaroglu, M. et al: Bipolar affective disorder associated with Klinefelter's syndrome - a case report; Isr.J.Psychiatry Relat.Sci., Vol 34(4) 1997: 308-310
[xxxvii] Wilson, J.Q. & Herrnstein, R.J: Crime and Human Nature; Touchstone, 1986
[xxxviii] Owen, R.D: The 47,XYY male: a review; Psychological Bulletin, Vol 78, 1972: 209-233; Thielgaard, R: Aggression and XYY personality; Int.J.of Law and Psychiatry, Vol 6, 1983: 413-421
[xxxix] Nielsen, Johannes et al: A Psychiatric-Psychological Study of 50 Severely Hypogonadal Male Patients, Including 34 with Klinefelter's Syndrome, 47,XXY; Acta Jutlandica XLI: 3, Skrifter fra Århus Universititet, Munksgaard 1969
[xl] Forssman, H. et al: Children with supernumary X-chromosome. A ten-year follow-up study of schoolchildren in special classes; J.Ment.Defic.Res, Vol 23, Sept.1979: 189-193; Nielsen, Johannes & Pelsen, B: Follow-up 20 years later of 34 Klinefelter males with karyotype 47,XXY and 16 hypogonadal males with karyotype 46,XY; Hum.Genet, Vol 77, Oct.1987: 188-192
[xli] see Sørensen above
[xlii] personal correspondence with Professor P.A.Jacobs
- Concise Medical Dictionary (Oxford Reference) (4th edition) OUP, 1994
- Human Anatomy and Physiology by: Carola, Harley & Noback: (2nd edition) McGraw-Hill, 1992
- Nielsen, J: Klinefelter's syndrome: an orientation; Gallo Tryk, Denmark, 1991 (2nd edition); latest edition available through
- Turner Centre's internet site at: http://www.aaa.dk/turner/tfsen.htm or free for KS men or the parents of KS boys, via E-mail at: [email protected] or by writing to: Turner Centeret, Skovagervej 2, DK-8240 Risskov, Denmark. (tel: +45 86 17 77 77 ext 3684 - Danish time = GMT +1 hour)