KLINEFELTER'S SYNDROME

Introduction

This page seeks to provide not only more up-to-date information about Klinefelter's syndrome (KS) but also to give some background as to why people have KS and the reasons for their infertility. The information has been obtained from a wide variety of sources and this sheet aims to present it in a matter of fact manner. Throughout this document the emphasis is on the word may. The problems given in this document do not represent everyone with KS. It states what problems may occur in some individuals. Some may have one or two of the problems, others several and yet others still have none except infertility.

Many men with KS live normal lives, oblivious to the fact that they have KS. Of those who find out, it is often when they seek help for infertility, which may be their only problem. Many are able to do ordinary jobs, either as employees, self-employed or even employers, in both the public and private sectors, whether or not they also have other conditions that may impair them. Many KS men also get married or live in other relationships. Many KS males have medical problems that are probably unconnected with having KS and this should be borne in mind when reading this sheet.

Basic genetics

Klinefelter's syndrome is named after Harry F. Klinefelter (cline-felter) who first described the syndrome in the USA in 1942. It is a genetic disorder that only affects boys and men. 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.

Basic statistics

KS is estimated to be found in 1 in 1000 (0.1%) of live male births, but other studies have suggested that the figure may be as high as 1 in 700 (approximately 0.14%).

The most common karyotype is 47,XXY.

A minority of KS males have a relatively low IQ below 80 (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.

Breast development, known as gynaecomastia (guy-na-co-mastia) occurs in some cases, however during adolescence it can be a temporary finding (usually 40% of boys).

Examples of other KS karyotypes are: 48,XXXY, 46,XX (male), 46,XxY, 46,XY/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.

At puberty

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 gynaecomastia 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 K S 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 and other problems such as an increased tendency to develop psychiatric disorders, 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.

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.

I: illnesses and related subjects

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 whilst those with lower bone density seem to have an increased bone turnover. 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. 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.

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. 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. 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. 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. Circumstantial evidence suggests a link with gynaecomastia but this is open to question. 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. In women, a longer than normal menopause can increase the risk because of fluctuating oestrogen levels, 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.

II: physical impairments

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.

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.

III: 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.

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.

In adults it may reduce fatigue etc., prevent osteoporosis 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. 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 testosterone

Unlike naturally occurring testosterone, that introduced into the body as a result of testosterone treatment can cause some long term problems [34]. Heart problems, hypertension and the build-up of fluid in the body (ie: oedema) 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. 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. 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. 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. Whilst early research suggested a link between criminality and KS, such as that by Nielsen who found that 38% of KS compared to 6% of XY males committed crimes, later research has not supported this.

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. Current thinking accepts that any association is controversial and more research would be needed before any firm conclusions could be drawn.

What about information on KS that is available on the Internet?

A word of caution, especially for those with only rudimentary experience of the internet. It is always worth looking at the source of the information as not all information about KS and other medical topics on the internet, is accurate.

Periodically you may encounter personal opinions expressed as facts. You will also find that by using different search engines you gather more information than you would by just relying on one alone as material referenced in one may be unavailable in another. Finally, you should not take the number of items displayed when you have conducted a search, as the total number of different items available.

The same information can appear several times in different formats. These comments aside, the internet can be a very useful source of information if used correctly.