Klinefelter Syndrome: Symptoms, Causes, Diagnosis, and Treatments

Most young men feel a varying degree of anxiety during puberty. They ask themselves if they are going through a normal process.

They compare body hair and other secondary sexual characteristics, and there is always someone who is apparently “more advanced” in puberty. But what if boys don’t grow any facial hair at all? What if their voice doesn’t change, and they start developing breasts?

In these cases, it may be important to rule out Klinefelter syndrome. What is it? How do you suspect Klinefelter syndrome, and what can you do about it?

What is Klinefelter syndrome?

Klinefelter syndrome is the most common sex chromosome disorder in humans. It happens when the normal karyotype in males contain one extra X chromosome or more. This usually happens in one for every 500 men and is typically associated with infertility, man boobs, and other symptoms.

Most young men with hypogonadism are probably associated with a chromosomal disorder. And Klinefelter is the most common by far.

Klinefelter syndrome was originally described by Dr. Klinefelter back in 1942. At that time, they didn’t know the cause and suspected it was only a hormonal problem. Then, Dr. Jacobs and his research team found out that it was due to an extra X chromosome (1). 

Contrary to what most people believe, Klinefelter syndrome is a group of chromosomal abnormalities, not only one. These patients may have up to four X chromosomes instead of one. But of course, having more than two is highly unlikely, even in Klinefelter syndrome. Thus, the incidence reduces for each additional X chromosome (2).


Klinefelter’s syndrome has a series of physical traits and characteristic symptoms. The majority of them become evident after puberty. In most cases, what brings patients to the doctor is a combination of gynecomastia, infertility, and other symptoms of hypogonadism.

The list of signs and symptoms and physical traits include (2, 3):

  • Very tall individuals with long legs and arms

  • Sparse body hair and facial hair

  • Very late and usually incomplete pubertal changes

  • Erectile dysfunction and sexual disturbances

  • Osteoporosis

  • Gynecomastia (man’s boobs), and sometimes breast cancer

  • Language and speech difficulties

  • Low IQ and learning problems

  • Anxiety, depression, self-esteem issues

Androgen deficiency caused by Klinefelter syndrome causes a series of problems in the body. For example, in most cases, these patients have a lower bone density compared to other males. They have a higher incidence of several diseases, including obesity, diabetes, and hypothyroidism.

They also have a higher incidence of autoimmune disease, including rheumatoid arthritis and lupus. Cryptorchidism (undescended testes) is also more prevalent in males with Klinefelter syndrome.

Some people believe that this problem causes a short height, but it’s quite the opposite. Most children have normal height, and adults are usually taller than average. However, patients with 4 X chromosomes (49, XXXXY) may have a shorter height.

Low IQ is not rare in Klinefelter, but not mandatory, either. Most males with Klinefelter’s syndrome have an average intellectual function. However, the higher the number of X chromosomes, the higher the chance of learning disability. In most cases, learning disabilities are minor and are sometimes disregarded by patients and their families.

But perhaps the most important is sexual characteristics because KS is a cause of genital ambiguity. You can have a micropenis, true hermaphroditism, and even a complete sex reversal. Male sexual characteristics are absent or incomplete. Thus, males can have a high-pitched voice, sparse body hair, and female body fat (3).

In most cases, these males are also infertile. They can have a complete seminiferous tubules atrophy or another testicular problem. However, you can also have a fertile male with Klinefelter syndrome in specific cases (mosaic Klinefelter syndrome).

We can have different symptoms according to age (2,3):

  • Babies: They usually have prolonged motor development and weak muscles. They can have undescended testes and a delay in their speaking skills.

  • Teenagers: Average or taller stature than the average with longer legs and arms. Puberty is incomplete or delayed and less facial and body hair after puberty: smaller testicles and penis, larger breast tissue, and weak bones.

  • Adults: Low sperm count, small penis and testicles, low sexual drive. Males still have the same incomplete secondary sexual changes and are usually less muscular. Increased abdominal fat and less body hair and facial hair.

Risk factors

Klinefelter syndrome is a random genetic problem of the sex chromosomes. Thus, there is limited control over what parents could do to prevent this issue. However, there is only one risk factor currently recognized for Klinefelter syndrome:

Women who get pregnant after 40 years old have a higher chance of Klinefelter syndrome. The risk increases 4-fold in these women. In their case, the X chromosomes in the ovum are not correctly divided into two single units. Instead, they have two X chromosomes in the ovum. The sperm cells come with one Y chromosome, and the result is an XXY karyotype (2).

Some studies would also suggest that older parents also have a higher risk of having a baby with Klinefelter syndrome. However, the possibility is still higher for an older woman (4).


According to studies dating back from 1959, the cause of Klinefelter syndrome is an extra X chromosome. These males have one Y chromosome and at least two X chromosomes. The most common is an XXY male karyotype (1).

The reason why they get aberrant sex genes is due to a problem in oogenesis or spermatogenesis. These processes produce female eggs and male sperm cells. Klinefelter syndrome is one of the possible outcomes when sex chromosomes fail to separate in this process. It can be maternal or paternal nondisjunction, but after diagnosis, it is impossible to tell.

It is also possible to have a nondisjunction after fertilization. In simple words, the egg and the sperm are both normal. They are meant to give birth to a boy with a normal karyotype. However, something happens in between.

A few cells in the newly formed zygote go through cell division problems. They give rise to cells with an extra X chromosome, while others are completely normal. This is called mosaic Klinefelter syndrome. It is a milder form of the disease, and some of these men are completely fertile and have a relatively normal life. Approximately 10% of KS cases are due to mosaicism (5).


We often consider the sexual characteristics associated with Klinefelter syndrome. However, this health problem is associated with severe health problems. Moreover, there is also an increased risk of severe disorders:

  • Motor dysfunction: Motor skills are difficult to develop in children with Klinefelter Syndrome (KS). However, some KS patients still have tremors and severe motor problems as adults (6,7). 

  • Cognitive dysfunction: As adults, KS patients can develop severe memory problems. Oral language production and complex grammatical constructions may become very challenging for them (8).

  • Emotional and psychiatric problems: These patients often develop severe self-esteem problems. They may even develop psychiatric problems such as bipolar disorder and schizophrenia (9).

  • Tumors and cancer: Breast cancer tumors are common in males with KS. However, there are other tumors prevalent in this group. For example, mediastinal tumors can be found in the thorax. They also have a higher risk of teratomas (10).

  • Endocrine diseases: The most common endocrine-related problem is osteoporosis. There is not sufficient sex hormone, and bone density is severely reduced. These patients may also develop diabetes, metabolic syndrome, thyroid problems, and other metabolic diseases (11).

  • Cardiovascular problems: There is a higher risk of varicose veins and deep vein thrombosis. KS patients may also have a higher risk of heart attack, pulmonary embolism, and other problems (12).

  • Autoimmune disorders: Klinefelter syndrome is associated with a higher risk of autoimmune disease. The most common is systemic lupus erythematosus and rheumatoid arthritis (13). 


The diagnosis of this XXY condition has two different phases. In phase one, doctors make a thorough physical exam. They evaluate the sexual characteristics and other signs and symptoms described above.

Out of many signs and symptoms, the ones with a higher predictive value are:

  • Small testes as the most important feature

  • Man boobs, clinically known as gynecomastia

  • Evaluation of height, arms, and legs

  • Deficits in language or cognitive function

  • Behavioral and psychosocial difficulties associated with KS

  • Academic problems and learning challenges

  • Infertility

Depending on age, the diagnosis may need to evaluate different aspects:

  • Infants: Undescended testicles, micropenis, smaller testicles.

  • Toddlers: Hypotonia and delay in language skills and verbal expression.

  • Schoolboys: Impaired social development, learning problems, mild autism spectrum disorder.

  • Adolescents: Delayed or incomplete puberty, tall stature, small testes, gynecomastia, high-pitched voice, sparse face, and body hair.

  • Adults: Very low or absent sperm count, breast malignancy, mood disorders, testicular failure.

After a primary suspicion of KS, phase two rules out other diagnoses, it is essential to perform a testosterone and LH/FSH measure. This is the only way to know what’s wrong.

The results will tell doctors whether or not the testes are healthy and work as they should. KS is a type of hypogonadotropic hypogonadism. This means that LH/FSH levels are normal, but the testicles are unable to release testosterone. Chromosome analysis is then performed to confirm the diagnosis.

Other tests and screening methods that may be useful in these cases include:

  • Androgen receptor gene quantitative real-time polymerase chain reaction

  • Serum osteocalcin levels

  • Bone density screening

  • Coagulability tests


Patients with Klinefelter syndrome can have successful treatment. This treatment is based on solving three main aspects of KS: hypogonadism, psychosocial issues, and gynecomastia.

Hypogonadism is mainly treated by using testosterone replacement therapy. Speech therapy and others can address psychosocial issues. Gynecomastia is often solved by using surgical procedures. Additionally, some men may also request for infertility treatment.

Testosterone treatment is usually started as soon as KS is detected. But there should be very close monitoring of the natural process of puberty. The decision should not be delayed, but not rushed, either. In some cases, males may need gender counseling as well (14).

Testosterone therapy is usually performed with testosterone enanthate. But other types of testosterone may also be applied. It does not only speed up sexual development. According to studies, testosterone therapy may also improve depression, anxiety, and social problems. Contrary to what people may think, there is no significant increase in aggressive behaviors (15).

Speech therapy and behavioral therapy are more complex and require a multidisciplinary team. It is important to assess social anxiety and depression problems as a part of the disease. In some cases, language therapy is very helpful and required to understand complex grammar. The goal of the psychoeducational treatment is to evaluate strengths and weaknesses. Then, therapists will create an appropriate plan to address the issue.

As for gynecomastia, it is important to practice mastectomy. This reduces the chance of breast cancer in males with Klinefelter syndrome. After a mastectomy, males will also reduce their anxiety and psychological strain. 


An endocrinologist should do the management of Klinefelter syndrome. A speech therapist also needs to be a part of the team. It is important to go through behavioral consultation and sometimes physical therapy, too.

In male patients that request for fertility procedures, it is possible to use various methods. Half of the men with Klinefelter syndrome can be enabled to have children. This is achieved by microsurgical sperm extraction and in-vitro fertilization.

Intracytoplasmic sperm injection is the procedure typically used to achieve fertilization. Surely, before injecting sperm cells, they should be selected for viability. It is also essential to talk to a genetic counselor before going through that step.

Patients with Klinefelter syndrome do not have a shorter lifespan. They can live a relatively healthy life after going through therapy for their condition. No special diet is required, and they are not restricted from doing any activity. They usually need close contact with a multidisciplinary team consisting of a genetic counselor, an endocrinologist, and a surgeon to remove breast tissue, a psychologist, and a speech therapist (14). 


Klinefelter syndrome is a genetic condition that affects one male for every 500. It is a random sex chromosome abnormality in which there are one or more extra X chromosomes.

The most common is an XXY karyotype. However, we can have up to 4 X chromosomes in rare cases. There’s also a mosaic Klinefelter syndrome with milder symptoms and a combination of normal and abnormal cells.

In these patients, testosterone levels are deficient, and testicle function is inadequate. They are often recognized during puberty years. They either have a delayed or an incomplete puberty.

Having very scarce body hair, small penis, and very small testicles, tall stature, and man boobs (gynecomastia) can be suspicious of KS. However, an endocrinologist may need to evaluate each particular case to know whether or not it requires testing to rule out KS.

Testosterone replacement is one of the main treatments available for KS. Most of these patients live a relatively normal life after testosterone replacement. They can have a normal lifespan and may even have children. However, appropriate genetic counseling should be requested, and sometimes patients have severe behavioral and psychiatric problems we need to take care of. 


  1. Jacobs, P. A., & Strong, J. A. (1959). A case of human intersexuality having a possible XXY sex-determining mechanism. Nature, 183(4657), 302-303.
  2. Visootsak, J., & Graham, J. M. (2006). Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet journal of rare diseases, 1(1), 1-5.
  3. Bojesen, A., & Gravholt, C. H. (2007). Klinefelter syndrome in clinical practice. Nature Clinical Practice Urology, 4(4), 192-204.
  4. Lowe, X., Eskenazi, B., Nelson, D. O., Kidd, S., Alme, A., & Wyrobek, A. J. (2001). Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. The American Journal of Human Genetics, 69(5), 1046-1054.
  5. Paduch, D. A., Fine, R. G., Bolyakov, A., & Kiper, J. (2008). New concepts in Klinefelter syndrome. Current Opinion in Urology, 18(6), 621-627.
  6. Robinson, A., Bender, B. G., Linden, M. G., & Salbenblatt, J. A. (1990). Sex chromosome aneuploidy: the Denver Prospective Study. Birth defects original article series, 26(4), 59.
  7. Visootsak, J., Aylstock, M., & Graham Jr, J. M. (2001). Kilnefelter syndrome and its variants: an update and review for the primary pediatrician. Clinical pediatrics, 40(12), 639-651.
  8. Graham, J. M., Bashir, A. S., Stark, R. E., Silbert, A., & Walzer, S. (1988). Oral and written language abilities of XXY boys: implications for anticipatory guidance. Pediatrics, 81(6), 795-806.
  9. Boks, M. P., de Vette, M. H., Sommer, I. E., van Rijn, S., Giltay, J. C., Swaab, H., & Kahn, R. S. (2007). Psychiatric morbidity and X-chromosomal origin in a Klinefelter sample. Schizophrenia research, 93(1-3), 399-402.
  10. Völkl, T. M., Langer, T., Aigner, T., Greess, H., Beck, J. D., Rauch, A. M., & Dörr, H. G. (2006). Klinefelter syndrome and mediastinal germ cell tumors. American Journal of Medical Genetics Part A, 140(5), 471-481.
  11. Gravholt, C. H., Chang, S., Wallentin, M., Fedder, J., Moore, P., & Skakkebæk, A. (2018). Klinefelter syndrome: integrating genetics, neuropsychology, and endocrinology. Endocrine Reviews, 39(4), 389-423.
  12. Calogero, A. E., Giagulli, V. A., Mongioì, L. M., Triggiani, V., Radicioni, A. F., Jannini, E. A., & Pasquali, D. (2017). Klinefelter syndrome: cardiovascular abnormalities and metabolic disorders. Journal of Endocrinological Investigation, 40(7), 705-712.
  13. Seminog, O. O., Seminog, A. B., Yeates, D., & Goldacre, M. J. (2015). Associations between Klinefelter’s syndrome and autoimmune diseases: English national record linkage studies. Autoimmunity, 48(2), 125-128.
  14. Nieschlag, E., Ferlin, A., Gravholt, C. H., Gromoll, J., Köhler, B., Lejeune, H., … & Wistuba, J. (2016). The Klinefelter syndrome: current management and research challenges. Andrology, 4(3), 545-549.
  15. Ross, J. L., Kushner, H., Kowal, K., Bardsley, M., Davis, S., Reiss, A. L., … & Roeltgen, D. (2017). Androgen treatment effects on motor function, cognition, and behavior in boys with Klinefelter syndrome. The Journal of pediatrics, 185, 193-199.


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