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Although considered the most common chromosomal disorder in humans, the subtle symptoms of Klinefelter syndrome can result in a man living with the condition his entire life without ever being diagnosed.

Klinefelter affects only males. Instead of having the usual XY chromosome pattern of most males, boys are born with an extra X chromosome in most of their cells, causing an XXY pattern. The exact cause of the extra X chromosome is unknown, but an estimated one in 500 males has the extra X, which can come from either parent. The syndrome, however, is a random occurrence and is not inherited.

Also called the XXY condition or 47, XXY, Klinefelter syndrome gets its name from physician Harry Klinefelter, who published a paper in 1942 about several men with enlarged breasts and small testes and an inability to produce sperm. Whether a man will have these traits or others, such as sparse facial and body hair or poor motor skills and weak muscle tone, depends on the number of XXY cells he has and the amount of testosterone he produces. Many men, however, don't have noticeable symptoms.

"The traits are not recognizable unless they are severe," said Ilene Fennoy, M.D., a clinical professor of pediatrics at Columbia University Medical Center in New York, who specializes in treating boys with the disorder.

"About 66 percent of males with Klinefelter syndrome are never diagnosed, and only about 10 percent are diagnosed prior to puberty," she said. The majority of cases detected before a boy reaches puberty are detected during prenatal amniocentesis, according to Fennoy.

Many other cases are diagnosed when men undergo fertility testing. Although XXY males can have normal sex lives, between 95 and 99 percent are infertile because they produce no or minimal sperm. Klinefelter is a leading cause of male infertility.

Young boys with the disorder, however, are likely to have language, social, or physical development problems. Symptoms include delayed speech, ADHD, motor delays, sensitivities to sounds or touch, and learning disabilities.

Symptoms like these led to the diagnosis of Roberta Rappaport's son at age 12. His pediatrician ﬁrst noticed early language delays and suggested speech therapy. His nursery school teacher was next to point out that the child was "not settling down like he should by his age."

"We kept telling our pediatrician about comments we'd get from teachers or things we noticed. Finally at our son's 12-year check-up, his doctor linked the symptoms together and sent us for genetic testing," recalled Rappaport, who with her husband founded the Chicagobased American Association of Klinefelter Syndrome Information & Support.

Pediatricians, endocrinologists, geneticists, speech therapists, psychologists, and other medical experts may be involved in assessing a boy for the condition.

Fennoy said she prefers to treat young patients with "psychiatric therapy and behavioral counseling rather than medical interventions." Some physicians, however, suggest starting testosterone replacement at the onset of puberty to allow a boy to undergo the physical changes that usually occur at puberty, such as increasing muscle mass, developing a deeper voice, and growing facial and body hair.

Researchers are currently studying the efﬁcacy of testosterone replacement therapy in the pediatric population. A clinical trial at the University of Colorado at Denver is currently enrolling 50 XXY adolescent males, ages 8-18, to determine whether testosterone replacement therapy leads to changes in psychological factors and motor skills. The study will be completed in February 2017.

Another trial at Denmark's Aarhus University will conclude in July 2014. It is investigating the quality of life in adult males with Klinefelter. Participants are being surveyed on their marital status, fatherhood, education, and mental and physical health.

Rappaport says her son, now 44, is a talented handyman, but has poor organizational skills. "Klinefelter is a spectrum disorder, meaning it goes in a bell curve," she said. "I also know many men who function well as doctors and lawyers, so it's not insurmountable."

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Although considered the most common chromosomal disorder in humans, the subtle symptoms of Klinefelter syndrome can result in a man living with the condition his entire life without ever being diagnosed. Klinefelter affects only males. Instead of having the usual XY chromosome pattern of most males, boys are born with an extra X chromosome in...

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The Association for X and Y Chromosome Variations

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The Association for X and Y Variations (AXYS) is an advocacy, education and support organization for individuals with X and Y chromosome variations and their families.

AXYS is a nonprofit 501(c)(3) organization formed by the merger of KS&A (formerly Klinefelter Syndrome and Associates) and AAKSIS (American Association for Klinefelter Syndrome Information and Support). The XXYY Project maintains separate 501(c)(3) status but partners with AXYS on programs, administration, advocacy and support efforts.

Klinefelter Syndrome and Associates was founded in 1989 by Melissa Aylstock, the mother of an adolescent with Klinefelter syndrome. Her goal was to provide support for other families, raise awareness among the public, and promote education and research. KS&A began to include other SCA conditions, and eventually merged efforts with AAKSIS and the XXYY project to form AXYS.

The X and Y variations are also known as "supernumerary sex chromosome aneuploidy" (SCA). They include the trisomies of 47,XXY (Klinefelter syndrome), 47,XYY, and 47,XXX (Trisomy X). Also included are the more rare 48- and 49-chromosome variations 48,XXYY; 48,XXXY; 48,XXXX; 49,XXXXY; and 49,XXXXX.

Mission Statement

The mission of AXYS is to help individuals with one or more extra X and/or Y chromosomes and their families to lead fuller, more productive lives.

AXYS fulfills this mission by satisfying previously unmet needs and improving the lives of those impacted by the X and Y chromosome aneuploidies including Klinefelter syndrome (47,XXY), Trisomy X (47,XXX), 47,XYY syndrome, 48,XXYY, and related genetic conditions through:

Support geared to the needs of individuals, their families, and the professionals who serve them

Education that provides current, scientifically accurate information to our constituents and to the public

Promoting research that advances knowledge of the field

Improving treatment options and access for those affected by the conditions

AXYS celebrates the diversity of the human family, including sex and gender, skin color, ethnicity, religion, sexual orientation, gender identity, age, socioeconomic status, physical characteristics and mental abilities.
AXYS X and Y Chromosome Variations Brochure
Trifold brochure printing instructions: Be sure you are printing in two-sided (duplex) mode, and to select the "Flip on Short Edge" or "Short-Edge Binding" option, if available in the Print dialog box or any associated dialog boxes.

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The Association for X and Y Variations (AXYS) is an advocacy, education and support organization for individuals with X and Y chromosome variations and their families. AXYS is a nonprofit 501(c)(3) organization formed by the merger of KS&A (formerly Klinefelter Syndrome and Associates) and AAKSIS (American Association for

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Currently researchers are studying the effectiveness of testosterone replacement therapy. AXYS or The Association for X and Y Chromosome Variations is a support organization for individuals and families who have X and Y chromosome variations. AXYS has nationwide support groups helping and shining line on the many variations of KS as well as other chromosome variations.

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The following information may help to address your question:

What is Klinefelter syndrome?

Klinefelter syndrome (KS) is a condition that occurs in males when they have an extra X chromosome. Some males with KS have no obvious signs or symptoms while others may have varying degrees of cognitive, social, behavioral, and learning difficulties. Adults with Klinefelter syndrome may also have primary hypogonadism (decreased testosterone production), small and/or undescendent testes (cryptorchidism), enlarged breast tissue ( gynecomastia), tall stature, and/or inability to have biological children (infertility), as well as an abnormal opening of the penis (hypospadias), and an small penis (micropenis). KS is not inherited, but usually occurs as a random event during the formation of reproductive cells (eggs and sperm) that results in the presence of one extra copy of the X chromosome in each cell (47,XXY). KS treatment is based on the signs and symptoms present in each person. Life expectancy is usually normal and many people with KS have normal life. There is a very small risk of developing breast cancer and other conditions such as a chronic inflammatory disease called systemic lupus erythematosus.

In some cases, there is more than one X chromosome in each cell (for example, 48,XXXY or 49,XXXXY). These conditions, which are often called "variants of Klinefelter" syndrome usually have more serious problems ( intellectual disability, skeletal problems, and poor coordination) than classic Klinefelter syndrome (47,XXY).

What are the signs and symptoms of Klinefelter syndrome?

The signs and symptoms of Klinefelter syndrome (KS) vary among affected people. Some men with KS have no symptoms of the condition or are only mildy affected. In these cases, they may not even know that they are affected by KS. When present, symptoms may include:

Small, firm testicles

Delayed or incomplete puberty with lack of secondary sexual characteristics resulting in sparse facial, body, or sexual hair a high-pitched voice and body fat distribution resulting in a rounder, lower half of the body, with more fat deposited in the hips, buttocks and thigh instead of around the chest and abdomen

Breast growth (gynecomastia)

Reduced facial and body hair

Infertility

Tall stature

Abnormal body proportions (long legs, short trunk, shoulder equal to hip size)

Learning disablity

Speech delay

Crypthochirdism

Opening (meatus) of the urethra (the tube that carries urine and sperm through the penis to the outside) on the underside of the penis (hypospadias) instead of the tip of the head of the penis

Social, psychologic and behavioral problems

Whether or not a male with KS has visible symptoms depends on many factors, including how much testosterone his body makes, if he is mosaic (with both XY and XXY cells), and his age when the condition is diagnosed and treated. Some people have a slightly increased risk of developing breast cancer, a rare extragonadal germ cell tumor, lung disease, varicose veins and osteoporosis as well as some autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome.
Some people with features of Klinefelter syndrome have more than one extra X chromosome in each cell (such as 48,XXXY or 49,XXXXY). In these cases, known as "variants of Klinefelter syndrome", the signs and symptoms can be more severe and may include:

Intellectual disability

Distinctive facial features

Skeletal abnormalities

Poor coordination

Severe speech difficulties

Behavioral problems

Heart defects

Teeth problems.

What causes Klinefelter syndrome?

Klinefelter syndrome usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. For example, an egg or sperm cell may gain one or more extra copies of the X chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have one or more extra X chromosomes in each of the body's cells.

Most often, Klinefelter syndrome is caused by a single extra copy of the X chromosome, resulting in a total of 47 chromosomes per cell. Males normally have one X chromosome and one Y chromosome in each cell (46, XY), while females have two X chromosomes (46, XX). People with Klinefelter syndrome usually have two X chromosomes and one Y chromosome (47, XXY). Some people with Klinefelter syndrome have the extra X chromosome in only some of their cells; these people are said to have mosaic Klinefelter syndrome.

It is estimated that about half of the time, the cell division error occurs during development of the sperm, while the remainder are due to errors in egg development. Women who have pregnancies after age 35 have a slightly increased chance of having offspring with this syndrome.

The features of Klinefelter syndrome are due to the extra copies of genes on the extra X chromosome, which can alter male sexual development.

Some people with features of Klinefelter syndrome have conditions known as "variants of Klinefelter syndrome" where there is more than one extra sex chromosome in each cell ( 48,XXXY, 48,XXYY and 49,XXXXY).

How might Klinefelter syndrome be treated?

Because symptoms of Klinefelter syndrome (KS) can sometimes be very mild, many people are never diagnosed or treated. When a diagnosis is made, treatment is based on the signs and symptoms present in each person, especially the problems related to hypogonadism, gynecomastia, and psychosocial problems. Treatment may include:

Testosterone replacement: About half of people with SK have low testosterone levels, which may be raised by taking supplemental testosterone. Having a more normal testosterone level can help affected people develop bigger muscles, a deeper voice, and facial and body hair, and may also increase sexual desire, enlarge the testes, improve mood, self-image, and behavior; it may also protect against osteoporosis and decrease the risks of autoimmune disease and breast cancer.

Breast removal or reduction surgery.

Educational interventions: As children, many people with Klinefelter syndrome qualify for special services to help them in school. Teachers can also help by using certain methods in the classroom, such as breaking bigger tasks into small steps.

Several forms of therapy such as physical, speech, occupational, behavioral, mental health, and family therapy can often help reduce or eliminate some of the symptoms of Klinefelter syndrome such as poor muscle tone; speech and language problems; or low self-confidence.

What is the long-term outlook for people with Klinefelter syndrome?

Babies with the 47, XXY form of Klinefelter differ little from healthy children. The results of one study on non- mosaic XXY infants younger than 2 years indicated that most XXY babies had normal external genitalia and facial features with height and weight in the normal range. Genetic testing had been performed due to a delay in walking and/or speech. Early diagnosis of Klinefelter syndrome is shown to be important to monitor potential developmental problems.

Boys with the 47, XXY karyotype may struggle through adolescence with academics, various frustrations, and, in a few instances, serious emotional or behavioral difficulties. However, most move toward full independence from their families as they enter adulthood. Some have completed graduate education and have a normal level of functioning. Lifespan is not affected by Klinefelter syndrome.

How can I find a genetics professional in my area?

We hope this information is helpful. We strongly recommend you discuss this information with your doctor. If you still have questions, please contact us.

Warm regards,
GARD Information Specialist

Please see our Disclaimer.

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The following information may help to address your question: What is Klinefelter syndrome? Klinefelter syndrome (KS) is a condition that occurs in males when they have an extra X chromosome. Some males with KS have no obvious signs or symptoms while others may have varying degrees of cognitive, social, behavioral, and learning difficulties.

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Although KS doesn't affect lifespan, it can affect the learning abilities and emotional difficulties for a boy at a young age. As a male grows older their learning abilities can improve as well as emotional and behavioral issues.

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Diagnosis

Your doctor will likely do a thorough physical exam and ask detailed questions about symptoms and health. This may include examining the genital area and chest, performing tests to check reflexes, and assessing development and functioning.

The main tests used to diagnose Klinefelter syndrome are:

Hormone testing. Blood or urine samples can reveal abnormal hormone levels that are a sign of Klinefelter syndrome.

Chromosome analysis. Also called karyotype analysis, this test is used to confirm a diagnosis of Klinefelter syndrome. A blood sample is sent to the lab to check the shape and number of chromosomes.

A small percentage of males with Klinefelter syndrome are diagnosed before birth. The syndrome might be identified in pregnancy during a procedure to examine fetal cells drawn from the amniotic fluid (amniocentesis) or placenta for another reason - such as being older than age 35 or having a family history of genetic conditions.

Klinefelter syndrome may be suspected during a noninvasive prenatal screening blood test. To confirm the diagnosis, further invasive prenatal testing such as amniocentesis is required.

Treatment

If you or your son is diagnosed with Klinefelter syndrome, your health care team may include a doctor who specializes in diagnosing and treating disorders involving the body's glands and hormones (endocrinologist), a speech therapist, a pediatrician, a physical therapist, a genetic counselor, a reproductive medicine or infertility specialist, and a counselor or psychologist.

Although there's no way to repair the sex chromosome changes due to Klinefelter syndrome, treatments can help minimize its effects. The earlier a diagnosis is made and treatment is started, the greater the benefits. But it's never too late to get help.

Treatment for Klinefelter syndrome is based on signs and symptoms and may include:

Testosterone replacement therapy. Starting at the time of the usual onset of puberty, testosterone replacement therapy can be given to help stimulate changes that normally occur at puberty, such as developing a deeper voice, growing facial and body hair, and increasing muscle mass and sexual desire (libido). Testosterone replacement therapy can also improve bone density and reduce the risk of fractures, and it may improve mood and behavior. It will not improve infertility.

Breast tissue removal. In males who develop enlarged breasts, excess breast tissue can be removed by a plastic surgeon, leaving a more typical-looking chest.

Speech and physical therapy. These treatments can help boys with Klinefelter syndrome who have problems with speech, language and muscle weakness.

Educational evaluation and support. Some boys with Klinefelter syndrome have trouble learning and socializing and can benefit from extra assistance. Talk to your child's teacher, school counselor or school nurse about what kind of support might help.

Fertility treatment. Most men with Klinefelter syndrome are typically unable to father children because few or no sperm are produced in the testicles. For some men with minimal sperm production, a procedure called intracytoplasmic sperm injection (ICSI) may help. During ICSI, sperm is removed from the testicle with a biopsy needle and injected directly into the egg.

Psychological counseling. Having Klinefelter syndrome can be a challenge, especially during puberty and young adulthood. For men with the condition, coping with infertility can be difficult. A family therapist, counselor or psychologist can help work through the emotional issues.

Coping and support

Treatment, health education and social support can greatly benefit individuals with Klinefelter syndrome.

Boys with Klinefelter syndrome

If you have a son with Klinefelter syndrome, you can help promote healthy mental, physical, emotional and social development.

Learn about Klinefelter syndrome. Then you can provide accurate information, support and encouragement.

Monitor your son's development carefully. Seek help for problems you notice, such as trouble with speech or language.

Keep regular follow-up appointments with medical professionals. This may help prevent future problems.

Encourage participation in sports and physical activities. These activities will help build muscle strength and motor skills.

Encourage social opportunities and participation in group activities. These activities can help develop social skills.

Work closely with your son's school. Teachers, school counselors and administrators who understand your son's needs can make a big difference.

Learn what support is available. For example, ask about special education services, if needed.

Connect with other parents. Klinefelter syndrome is a common condition, and you - and your son - aren't alone. Ask your doctor about internet resources and support groups that may help answer questions and ease concerns.

Men with Klinefelter syndrome

If you have Klinefelter syndrome, you may benefit from these self-care measures:

Work closely with your doctor. Appropriate treatment can help you maintain your physical and mental health and prevent problems later in life, such as osteoporosis.

Investigate your options for planning a family. You and your partner may want to talk to a doctor or other health professional about your options.

Talk with others who have the condition. There are a number of resources that provide information about Klinefelter syndrome and can offer the perspectives of other men and their partners who cope with the condition. Many men also find it helpful to join a support group.

Preparing for your appointment

If you notice symptoms of Klinefelter syndrome in yourself or your son, talk to your health care professional. You may be referred to a specialist for testing and diagnosis.

Here's some information to help you get ready for your appointment. If possible, bring a family member or friend with you. A trusted companion can help you remember information and provide emotional support.

What you can do

Before the appointment, make a list of:

Signs or symptoms that concern you

Medications, including over-the-counter medications, vitamins, herbs or other supplements, and the dosages

Ages when you or your son reached certain puberty milestones, such as the development of pubic and armpit hair, growth of the penis, and increased testicle size

Questions to ask the doctor to make the most of your appointment

Questions to ask might include:

Do the symptoms indicate Klinefelter syndrome?

What tests are needed to confirm the diagnosis?

What are other possible causes for the symptoms?

Is a specialist needed?

What treatments are necessary?

What are the side effects and expected results of treatment?

What kind of special therapies do you recommend?

What kind of support is available?

How can I learn more about this disorder?

Don't hesitate to ask other questions during the appointment.

What to expect from your doctor

Your doctor may ask questions such as:

When did you first notice that something may be wrong?

What signs and symptoms have you noticed?

When did you (or your child) meet growth and developmental milestones?

Do you have problems with fertility?

Have you had any previous tests or treatments?

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Your doctor will likely do a thorough physical exam and ask detailed questions about symptoms and health. This may include examining the genital area and chest, performing tests to check reflexes, and assessing development and functioning. The main tests used to diagnose Klinefelter syndrome are: Hormone testing.

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Abstract

Nearly 70 years after its description, Klinefelter's syndrome (KS) remains a largely undiagnosed condition. In addition to its typical characteristics of increased follicle-stimulating hormone secretion and small and firm testes, the syndrome presents an extremely wide spectrum of phenotypes. This could be explained by the possible presence of chromosomal mosaicism, androgen receptor polymorphisms and related heterogeneous endocrine abnormalities. The varied but relatively mild physical abnormalities also explain why many patients do not receive clinical attention until adulthood, when they seek medical advice on small testes or infertility. Diagnosis is also hindered by the low awareness of the disease among health professionals. This paper aims to review the possible signs of KS at different stages of life that could help achieve an early (or at least earlier) diagnosis. It has been demonstrated that the early diagnosis of KS improves patients' quality of life and enables better medical treatment. To achieve this, it is crucial to increase both medical and general awareness of the disease, including through use of the media and patients' associations.

Introduction

Klinefelter's syndrome (KS) was first described by Harry Klinefelter in 1942 ( Klinefelter et al., 1942) as a condition characterized by gynaecomastia, small, firm testes, hypogonadism and a high level of FSH. It is the most common chromosomal disorder, affecting 1 in 500 men ( Lanfranco et al., 2004), and is a frequent cause of hypogonadism and infertility. It is caused by the presence of extra X chromosomes, usually acquired through non-disjunction during maternal or paternal gametogenesis. The most common karyotype is 47,XXY. Recent findings suggest that the prevalence of diagnosed KS, but not of XXX or XYY aneuploidies, has increased in recent decades, probably due to both the increased prevalence of paternal meiotic alterations and a greater number of routinely performed prenatal investigations ( Morris et al., 2008). Nevertheless, the true prevalence of this aneuploidy is still considered to be underestimated ( Abramsky and Chapple, 1997).

As its clinical presentation may be subtle, many of those affected may be unaware or diagnosed only during evaluation for hypogonadism and/or infertility. It has been demonstrated that KS is one of the most frequent causes of infertility, affecting ∼11% of azoospermic and ∼3.1% of all infertile men (Lanfranco et al., 2004).

Abramsky and Chapple (1997) showed that up to 64% of KS patients are never diagnosed, whereas 10% of those affected are diagnosed prenatally and only 26% are diagnosed in prepuberty or adulthood. A very large study of the Danish national registry recently confirmed these data and showed that KS is often undiagnosed and seldom predicted before puberty ( Bojesen et al., 2003).

The aim of this paper is to review the possible signs of KS in the different phases of life, to help achieve an early diagnosis.

Prenatal diagnosis

Only a marginal percentage of males with KS are diagnosed prenatally, when amniocentesis is performed due to advanced maternal age. Since the maternal age effect is weaker in KS than in other chromosome disorders, such as Down syndrome ( Hook, 1981; Visootsak et al., 2001), prenatal KS is mainly a chance finding. So far, no specific ultrasound (US) features or serum screening markers suggesting the presence of KS have been found, meaning that there is no effective way to screen the population prenatally, apart from karyotype analysis ( Abramsky and Chapple, 1997). Moreover, it has been observed that chromosome analyses are usually performed due to suspicions other than KS and their frequency increases with maternal age.

The techniques that can be used for prenatal diagnosis-chorionic villus sampling, amniocentesis and cordocentesis-are all invasive procedures and carry some risks. They all need to be accompanied by suitable genetic counselling and clinical support.

The benefit of prenatal identification of KS mainly lies in the opportunity to prepare the parents and provide a dedicated clinical path for the affected infant. The aim is to make the parents aware of their son's disorder, reduce their anxiety and provide appropriate social and educational support. Early diagnosis thus allows physicians and parents to treat the affected boys in time and prevent the majority of complications associated with late intervention.

Parents will also be able to: However, some aspects of prenatal diagnosis are the object of discussion, such as the resulting increase in terminations, estimated in some reports as up to 70% of prenatally diagnosed KS ( Bojesen et al., 2003). The decision to terminate a pregnancy due to sexual abnormalities and aneuploidies with a low risk of abnormal phenotype seems to be related to the parents' social and cultural background, local laws and the genetic counselling strategy (Table I). The way that information about the condition is conveyed by medical staff also plays a critical role in this decision ( Quadrelli et al., 2007). This is why parents should be given adequate time to reflect and all decisions should be made only after they have been given thorough information and any prejudices and mistaken affirmations have been addressed.

have their KS son start any necessary speech therapy as soon as possible, aiming for early and complete rehabilitation, and plan an educational strategy, given that the percentage of patients with learning or language difficulties tends to be lower when patients are diagnosed by amniocentesis (Girardin et al., 2009);

promote physical activity in order to contain the effects of any motor dyspraxia;

monitor pubertal development with the help of an endocrinologist;

plan, with the help of a psychologist, the best time to tell their son about his condition.

If the diagnosis is not made prenatally, it is unlikely to be made during the first 10 years of life and ∼75% of the estimated cases are never diagnosed at all (Abramsky and Chapple, 1997). The rare early diagnosis of KS highlights the need to identify the early features of typical and atypical post-natal presentation, with the aim of appropriate treatment and prevention of possible complications.

Diagnosis at birth

Diagnosis in infancy

KS infants have variable phenotypic features and do not have obvious facial dysmorphology; thus they are usually indistinguishable from other boys with normal karyotype.

Infants with 47,XXY aged 1-23 months may exhibit smaller testicular and penile size. As growth of the penis in-uterus and during childhood is a good bioassay for endogenous testosterone as well as androgen receptor responsiveness, reduced penile growth in early childhood may indicate androgen deficiency (Ross et al., 2005).

It has been assumed that genital development is due to the activation of the hypothalamus-pituitary-gonad (HPG) axis during the first months of life. In the healthy male infant, gonadotrophins, testosterone (T) and inhibin B increase to pubertal or even adult levels at about 3 months of age ( minipuberty); serum levels of FSH, LH and T then decrease in the following 3-6 months until the HPG axis reactivates in puberty. Although serum inhibin B levels decrease from 3 (or 6) months of age, they remain elevated even after levels of the other three hormones decrease to within the range observed later in childhood ( Andersson et al., 1998a, b). The described post-natal increase in sex hormones represents a window where it is possible to study the function of the axis ( Main et al., 2002).

A very early reduction in Leydig cell activity has been postulated in KS, based on initial findings of low T serum levels in umbilical cord ( Sørensen et al., 1981). However, subsequent studies showed that the differences in umbilical cord T levels between healthy and affected boys were not statistically significant ( Ratcliffe, 1982).

Conflicting data have been reported on hormone levels in KS infants. Aksglæde et al. (2007) found high-normal serum levels of total and free-T and elevated levels of gonadotrophins in 3-month-old KS infants when compared with healthy controls. However, Lahlou et al. (2004) observed that the T surge in the first 3 months of life was somewhat lower than in normal infants; in contrast, LH levels were considered similar to those found in normal infants, suggesting that KS causes the Leydig cells to develop some degree of LH resistance. As with the controls, inhibin B levels increased significantly from birth to 4 months and then decreased progressively. At the same time, anti-Müllerian hormone (AMH) levels increased progressively from birth to 8 months and then remained stable for the next 2-3 years. The normal level of gonadotrophins, inhibin B and AMH suggests that the Sertoli cells are qualitatively and quantitatively normal in KS children during infancy ( Lahlou et al., 2004).

In summary, as hormonal variations are similar to those of healthy infants, at this stage KS is unlikely to be suspected, unless on the basis of clinical signs.

Diagnosis in childhood

The school-aged child with KS presents learning disabilities, verbal cognitive deficits, speech difficulties and trouble in spelling, reading and mathematics. A variable degree of difficulty in expressing feelings and socializing is often observed. In this respect, KS males are at higher risk of behavioural disorders and psychiatric problems than the general population (Visootsak et al., 2001). Early detection of the syndrome is important because it allows prompt identification of speech problems and scholastic difficulties that require speech therapy and educational support.

Genital abnormalities associated with KS have been reported sporadically, but they are not mentioned as features of the condition in the reference textbooks. However, the older child or adolescent should be evaluated for signs of delayed or incomplete pubertal development. Physical abnormalities such as a slightly smaller penile length, a lower than normal testicular volume, a taller stature and a reduced upper to lower segment ratio could be the basis for a vague suspicion.

Diagnosing the condition in childhood offers important advantages:

it enables early initiation of language therapy; this is particularly important in helping the child develop more advanced language comprehension and expression skills, in order to prevent social isolation ( Visootsak et al., 2001; Girardin et al., 2009);

it enables the child to be monitored and supported during the peripubertal period;

it enables better management of these patients during puberty, the preservation of fertility and the initiation of androgen replacement therapy before signs and symptoms of hypogonadism develop (Ferlin et al., 2008).

Diagnosis in puberty

The onset of puberty in KS boys is usually spontaneous and occurs at the expected age. However, from adolescence onwards, the testes become increasingly firm and never reach the size observed in normal adults.

It should be clarified that according to Tanner's definition of puberty in normal subjects, various elements need to be taken into account: pubic hair distribution (P) and morphology and size of external genitals (G). The beginning of puberty is conventionally defined as the attainment of a testicular volume of 4 ml ( Marshall and Tanner, 1970). In KS subjects testicular volume generally stops at about 4-5 ml ( Wikström et al., 2004; Aksglæde et al., 2008a, b). However, T production is sufficient for the development of normal primary and secondary sexual characteristics, attainment of puberty stage P5 and completion of epiphyseal closure, even if this tends to take place 3-4 years later than in 46,XY males ( Hall et al., 2001). At some stage during pubertal maturation, these compensatory efforts may fail to maintain sufficient circulating T levels and a normal estrogen (E2)/T ratio. This can cause features of eunuchoidism and gynaecomastia to develop. This situation results in sparse facial, body and genital hair. The described incidence of gynaecomastia in KS varies between 50 and 88%, depending on how it is evaluated ( Smyth and Bremner, 1998; Ratcliffe, 1999; Visootsak et al., 2001); the differences between the caseloads could be due to the difficulty in distinguishing between gynaecomastia and pseudogynaecomastia, unilateral and bilateral, transient and stable and painful and non-painful forms. Gynaecomastia may also be caused by an imbalance between estrogen receptors and androgen receptors, leading to excessive estrogen action, deficient androgen action or a combination of these effects. However, the development of unilateral or bilateral gynaecomastia could be one of the most common signs leading boys and their parents to consult a doctor ( Visootsak and Graham, 2006).

It has recently been demonstrated that gonadal transformation can be followed by US. Several observations demonstrate that prepubertal testes appear identical in affected and unaffected subjects. However, with the onset of puberty, the increase in gonadotrophins alters the echotexture of the testicles, which become inhomogeneous with scattered hypoechoic areas. In this respect, US may suggest KS as early as puberty stage G2, before any signs are seen on clinical examination (Isidori and Lenzi, 2008).

There is a critical time during pubertal development when a sufficient androgen level is necessary for normal bone mineralization. This may explain the gravity of impaired androgen secretion at the critical stage of bone maturation, which leads to such a deficiency of mineralization that subsequent androgen replacement in adults may not be sufficient to restore normal bone mass (Seo et al., 2007). This highlights the importance of a preventive study of body composition and bone mineral content in adolescents with KS before and around the time of puberty.

The hormonal pattern of adolescent KS boys is quite distinctive, showing a progressively increasing difference from euploid boys. Mid-puberty is characterized by a gradual increase in blood LH, which reflects the compensatory feedback mechanism in maintaining sufficient Leydig cell function, and a surge in FSH, which indicates progressive tubular damage, resulting in a hypergonadotropic hormonal pattern by late puberty. Abnormally high concentrations of serum FSH and LH should without doubt prompt the general practitioner to request supplementary investigations, ultimately leading to diagnosis.

At puberty, after activation of the HPG axis the serum T concentration rises and reaches normal or near-normal levels, but as T levels increase, inhibin B levels drop significantly and soon become undetectable ( Christiansen et al., 2003). During this phase, AMH also decreases and a strong inverse nonlinear relationship between T and both AMH and inhibin B has been described ( Wikström et al., 2004). During prepuberty and early puberty, this hormonal pattern shows the functional integrity of the Sertoli cells, with normal down-regulation of AMH and inhibin βB-subunit expression that becomes germ cell dependent ( Andersson et al., 1998a, b). The dramatic drop in inhibin B demonstrates germ cell apoptosis.

In conclusion, quantification of AMH ( Lee et al., 1996; Wikström and Dunkel, 2008) and inhibin B ( Aksglæde et al., 2008a, b) could identify the best time for cryopreservation of testicular tissue.

Diagnosis in puberty has the following important advantages:

prevention of the long-term consequences of gonadal insufficiency;

attainment of the correct peak bone density (Seo et al., 2007);

development of psychological and sexual identity;

prevention of infertility, if possible, through cryopreservation of testicular tissue at early puberty and of semen samples containing very low numbers of spermatozoa as soon as possible ( Lanfranco et al., 2004; Aksglæde et al., 2008a, b);

prevention of metabolic syndrome signs and symptoms (Ishikawa et al., 2008).

Diagnosis in adulthood

The adult KS phenotype is typically characterized by tall stature, narrow shoulders, broad hips, sparse body hair, gynaecomastia, small and firm testes. However, its high variability and the fact that symptoms rarely present simultaneously can make diagnosis more difficult. Many cases remain undiagnosed and only 26% of the estimated number of KS adults are detected by late adulthood, leading to severe complications and a more difficult clinical management (Bojesen et al., 2006b). The hormonal patterns and the timing and severity of the androgen deficiency could in part explain the high variability of the clinical picture, with putative alterations in secretory activity, or receptor responsiveness at multiple endocrine sites. In adult patients, physical examination and serum hormone quantification definitely help confirm the diagnosis of hypergonadotropic hypogonadism.

As the testicles are invariably small and firm, US can be used to confirm any substantial changes in their echotexture. They are generally hypoechoic and inhomogeneous, with multiple scattered hypoechoic foci. These changes are often proportionate to the length of exposure to elevated gonadotrophin levels and are the result of the changes beginning during pubertal development ( Isidori and Lenzi, 2008; Fig. 1).

Investigation of the hormonal pattern and a chromosome analysis is recommended for all patients with small testes attending an infertility clinic (Lanfranco et al., 2004).

With regard to fertility, although a complete absence of spermatozoa is usually observed in the ejaculate, focal spermatogenesis has occasionally been reported. Testicular sperm extraction associated with intra-cytoplasmic sperm injection offers KS patients the possibility of fatherhood ( Ramasamy et al., 2009) as reported by Palermo et al. ( 1998), when the first pregnancy was described. Unsuccessful sperm recovery has an important emotional impact on patients with KS, so predictive factors for sperm recovery need to be established. Clinical and biological parameters such as testicular volume, patient age, serum FSH, LH, T and inhibin B have been studied as predictive factors, but the results of various series were contradictory. Patient age is one of the few parameters that has a significant correlation with successful sperm retrieval ( Ferhi et al., 2009; Emre et al., 2006; Ramasamy et al., 2009). KS patients may benefit from early diagnosis, giving them the chance to bank their sperm cells before the onset of azoospermia. It was recently debated whether early treatment of hypogonadism in KS patients affects sperm cell retrieval. Incomplete data from mixed populations (including non-KS subjects) seem to suggest that testosterone treatment may have a negative effect on fertility; however, this is unlikely to apply to KS subjects and further studies are warranted ( Ramasamy et al., 2009).

Knowledge of co-morbidity related to KS could help diagnosis. Several cross-sectional studies found a strong correlation between circulating T and cardiovascular risk factors due to the effects of androgens on adipose tissue, insulin sensitivity, endothelial function, vascular tone, atherosclerosis and left ventricular dysfunction. Hypogonadism in KS may lead to an elevated incidence of metabolic syndrome, diabetes mellitus and cardiovascular diseases ( Swerdlow et al., 2005; Bojesen et al., 2006a,b; Ishikawa et al., 2008).

Moreover, sex hormones play an important role in the development of muscle, bone and joint mass; KS patients have increased body fat mass and decreased muscle mass ( Bojesen et al., 2006b), as well as an increased risk of osteoporosis and a precocious onset of bone diseases: up to 40% of patients may have osteopenia ( Breuil and Euller-Ziegler, 2001). A significantly lower BMD has been found in patients who had never received T treatment or when therapy was commenced late in life, suggesting that bone loss is related to androgen deficiency rather than the chromosome abnormality ( Seo et al., 2007). For this reason the finding of altered bone density and body composition should prompt further evaluations to investigate KS.

Finally, hypoandrogenism developing later in life in undiagnosed KS could precipitate sexual dysfunction and mood disorders and deeply affect quality of life (QoL). Even though few studies have examined the relationship between KS and QoL, the negative impact of long-term hypogonadism on physical, social, emotional, cognitive and sexual function has been amply described (Maggi et al., 2007).

The advantage of early diagnosis and careful follow-up in KS patients is that it enables earlier detection of any co-morbidities and interventional strategies to be established to counteract late-onset complications. Early lifelong replacement therapy is thus indicated to prevent related symptoms and improve QoL of patients with androgen deficiency. Therapy has a positive effect on mood and behaviour, improves goal-directed thinking and self-esteem and reduces fatigue and irritability (Nielsen et al., 1988).

Even though no specific studies have evaluated the economic impact of increased morbidity and mortality in KS, early diagnosis and treatment of androgen deficiency may have a positive effect on the healthcare system (Maggi et al., 2007).

Diagnosis in early adulthood could offer the following advantages:

Conclusions

This review highlighted the features that may prompt physicians to suspect KS at various ages of presentation (Table II). It has been demonstrated that there are benefits in diagnosis and proper follow-up and treatment at all stages and that 'it is never too late'. Clearly, the earlier the diagnosis is made, the greater the benefits.

In this respect, the most productive strategies are to increase awareness: not only in paediatricians, gynaecologists and fertility doctors, but also in general practitioners.

One of the most common erroneous beliefs is that KS is diagnosed only at puberty. This review shows that various hormonal and clinical features do exist that can lead to diagnosis of a 47,XXY male earlier in life.

It has been shown that KS males may come to medical attention through bone fractures or sexual dysfunctions. For this reason diagnosis could be improved by informing general practitioners of the different pictures that it can present, at all stages in life. Our experiences highlight the importance of strong cooperation between affected males and both family doctors and patient associations.

Many of the advantages of strategies to boost early diagnosis strategies lie in the opportunity to boost the medical care of patients with KS and their QoL.

Finally, more research is needed on the best interventional approaches to prevent complications. A trial addressing the differential contribution of behavioural approaches versus androgen therapy in the prevention of cardio-metabolic complications is currently in progress.

The early use of androgen treatment is still an open issue, as it is strongly related to the preservation of testicular sperm retrieval later in life. Although this aspect will be clarified through future controlled randomized trials, very early diagnosis still seems the most appropriate strategy at the current time, and can be achieved through increasing awareness of the condition among specialists and general practitioners.

Acknowledgements

Thanks to Marie-Hélène Hayles for the language revision.

References

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Strategies and advantages of early diagnosis in Klinefelter's syndrome

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Nearly 70 years after its description, Klinefelter's syndrome (KS) remains a largely undiagnosed condition. In addition to its typical characteristics of increased follicle-stimulating hormone secretion and small and firm testes, the syndrome presents an extremely wide spectrum of phenotypes. This could be explained by the possible presence of chromosomal mosaicism, androgen receptor polymorphisms and related heterogeneous endocrine abnormalities.

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Prenatal tests for this disorder are available though only few males can be diagnosed prenatally.  Some tests that can be done are chorionic villus sampling, amniocentesis, and cordocentesis. Some treatments that can tend to KS are testosterone replacement therapy, breast tissue removal, speech and physical therapy, and more.

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Klinefelter is often diagnosed in adulthood and through lab tests and scannings.

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-reduced muscle mass
-less facial and body hair
-broad hips
-enlarged breasts
-increased belly fat

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It's when a person, usually male, have an extra X chromosome and one Y chromosome.  Some nicknames for Klinefelter Syndrome include 47,XXY, XXY Syndrome, XXY Trisomy, or KS.

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Other physical changes associated with Klinefelter syndrome are usually subtle. Older children and adults with the condition tend to be somewhat taller than their peers. Other differences can include abnormal fusion of certain bones in the forearm (radioulnar synostosis), curved pinky fingers (fifth finger clinodactyly ), and flat feet ().