Klinefelter Syndrome refers to XXY chromosome in men leading to Klinefelter syndrome symptoms and lower testosterone levels due to 47 chromosomes.

Klinefelter Syndrome

Online Consultation

Iqra Mazhar

Overview

<p>Klinefelter syndrome first entered medical literature in 1942 when American physician Harry Klinefelter described the case of 9 patients with gynecomastia, small testes, azoospermia, and tall stature<sup><a href="#accordion">[1]</a></sup>. Although initially considered an endocrine disorder, researchers managed to discover the syndrome&rsquo;s specific genetic etiology in 1959.&nbsp;</p>

<p>The National Organization for Rare Disorders defines it as a group of chromosomal disorders characterized by one or more extra X chromosomes in males<sup><a href="#accordion">[2]</a></sup>. As a result, instead of the individual possessing 46, XY (the normal male karyotype), they have a 47, XXY karyotype.&nbsp;</p>

<p>With an estimated prevalence of 1 in 500-1000 men, Klinefelter syndrome is the most common chromosomal disorder in humans&nbsp;and a common cause of infertility and hypogonadism in men<sup><a href="#accordion">[3][4]</a></sup>. However, it is a highly underdiagnosed condition, with approximately two-thirds of cases going unnoticed<sup><a href="#accordion">[4]</a></sup>. The majority of the patients are diagnosed in adulthood during fertility workups; only 10% are identified before puberty<sup><a href="#accordion">[5]</a></sup>.&nbsp;</p>

<p>In Pakistan, Down&rsquo;s syndrome and Turner syndrome account for a greater number of chromosomal abnormalities than Klinefelter syndrome<sup><a href="#accordion">[6]</a></sup>. An observational study conducted at an endocrine clinic in Pakistan reported the syndrome in 15% of patients with hypogonadotropic hypogonadism, while 27% had Turner syndrome<sup><a href="#accordion">[7]</a></sup>.&nbsp;</p>

<p>As per the 6th National Population and Housing Census, Pakistan&rsquo;s transgender population stood at 10,418 in 2017<sup><a href="#accordion">[8]</a></sup>. These individuals have a higher prevalence of Klinefelter syndrome compared to the general population<sup><a href="#accordion">[9][10]</a></sup>.&nbsp;</p>

<p>In recent years, researchers have reported a rise in the incidence of Klinefelter syndrome<sup><a href="#accordion">[11]</a></sup>. This is likely due to greater awareness of the disease and increased prenatal diagnostic testing.&nbsp;</p>

<div>&nbsp;</div>

<p>Approximately 80-90% of men with Klinefelter syndrome have 47, XXY karyotype, while the rest have a mosaic karyotype with some cells containing 46, XY and other 47, XXY<sup><a href="#accordion">[2]</a></sup>. However, some may have structural chromosomal abnormalities or additional X chromosomes (48, XXXY or 49, XXXXY). The severity of symptoms increases with the number of X chromosomes in cells.&nbsp;</p>

<p>&nbsp;</p>

Signs And Symptoms

<p>People with Klinefelter syndrome often have no specific defining features at birth or even later in life. Symptoms mostly appear during puberty or in adulthood when men face problems fathering a child. Moreover, the symptoms tend to vary by age.</p>

<p>&nbsp;</p>

<p><strong>In newborns and infants</strong>, Klinefelter syndrome may present with:</p>

<ul>
	<li>Reduced muscle tone</li>
	<li>Delayed milestones (e.g., taking longer to crawl and walk) due to slow motor development</li>
	<li>Delayed speech and language</li>
	<li>Undescended testis</li>
	<li>Hypospadias</li>
	<li>Cleft palate</li>
</ul>

<p>&nbsp;</p>

<p><strong>During puberty,</strong> boys can experience:</p>

<ul>
	<li>Tall stature&nbsp;</li>
	<li>Delayed or incomplete puberty</li>
	<li>Sparse facial and body hair</li>
	<li>Small testes and penis</li>
	<li>Poor coordination and balance</li>
	<li>Breast growth (<a href="https://www.merisehat.pk/disease/gynecomastia" target="_blank">gynecomastia</a>)</li>
	<li>Difficulty socializing</li>
	<li>Heavier around the thighs and hips</li>
	<li>Weak bones</li>
</ul>

<p>&nbsp;</p>

<p><strong>In adults,</strong> Klinefelter syndrome results in:</p>

<ul>
	<li>Low sex drive</li>
	<li>Sexual dysfunction</li>
	<li>Low or no sperm count</li>
	<li>Small testicles and penis</li>
	<li><a href="https://www.merisehat.pk/disease/gynecomastia" target="_blank">Gynecomastia</a></li>
	<li>Fewer muscles&nbsp;</li>
	<li>Weak bones</li>
	<li><a href="https://www.merisehat.pk/disease/infertility-in-men" target="_blank">Infertility</a></li>
</ul>

<div>&nbsp;</div>

Causes

<p>A person&rsquo;s biological sex is determined by the absence or presence of the Y chromosome. Biological females have a 46, XX karyotype while males have 46, XY. In Klinefelter syndrome, a nondisjunction error during the division of sex chromosomes in the egg or sperm results in an extra X chromosome in males.&nbsp;</p>

<p>The genes present on the X chromosome are responsible for growth, brain development, and testes function. An additional X chromosome results in primary gonadal failure that leads to testosterone deficiency. The lack of testosterone then causes symptoms such as small testes and penis, sparse facial and body hair, and breast growth.&nbsp;</p>

<div>&nbsp;</div>

<p>Approximately, two-thirds of Klinefelter syndrome cases go undiagnosed<sup><a href="#accordion">[3]</a></sup>. However, prenatal testing can lead to a timely diagnosis. The following tests can be done prior to birth:</p>

<p>&nbsp;</p>

<ul>
	<li><strong>Amniocentesis:</strong> Samples of the amniotic fluid are examined for chromosomal abnormalities.</li>
	<li><strong>Chorionic Villus Sampling:</strong> The test involves taking samples of the chorionic villi lining the placenta and then examining them for chromosomal abnormalities.&nbsp;</li>
</ul>

<p>&nbsp;</p>

<p>The issue is these tests pose a risk of miscarriage in pregnant women<sup><a href="#accordion">[12]</a></sup>.&nbsp;Therefore, they are only conducted on those with a history of chromosomal disorders or women above 35 years of age.&nbsp;</p>

<div>&nbsp;</div>

Diagnosis

<p>In patients suspected of having 47, XXY karyotype, the doctor may conduct diagnostic testing. The main diagnostic test for Klinefelter syndrome is karyotyping. It involves an analysis of peripheral blood lymphocytes for the shape and number of chromosomes.&nbsp;</p>

<p>Other than karyotype analysis, individuals may also undergo a complete hormonal workup to get an assessment of the levels of various hormones, such as FSH, LH, testosterone, prolactin, and estradiol.&nbsp;</p>

<div>&nbsp;</div>

Treatment

<p>There is no cure for the syndrome. However, different treatments can help prevent complications and improve a person&rsquo;s overall quality of life.</p>

<p>&nbsp;</p>

<h5><strong>Hormone Replacement Therapy</strong></h5>

<p>Supplemental testosterone is typically administered at the onset of puberty. The treatment can help invoke pubertal changes, such as a deepening of the voice, growth of facial and body hair, an increase in muscle mass, and improvement in energy. It can also improve the individual&rsquo;s bone density and decrease the risk of fractures. Infertility and testicle size remain unaffected by testosterone therapy.&nbsp;</p>

<p>&nbsp;</p>

<h5><strong>Physical Therapy&nbsp;</strong></h5>

<p>For individuals with decreased muscle tone, physical therapy can help with motor skills and can also help build muscles.&nbsp;</p>

<p>&nbsp;</p>

<h5><strong>Counseling</strong></h5>

<p>Therapeutic support helps people come to terms with their diagnosis and reduce any emotional issues caused by the syndrome. Moreover, it can help them develop social skills and answer any questions about their gender identity.&nbsp;</p>

<p>&nbsp;</p>

<h5><strong>Speech And Language Therapy</strong></h5>

<p>Some children may face dyslexia or speech delay as children. A combination of speech-language therapy and counseling can help them overcome their learning predicament.&nbsp;</p>

<p>&nbsp;</p>

<h5><strong>Fertility Treatment</strong></h5>

<p>Azoospermia is a common feature of Klinefelter syndrome. Hence, these men are unable to have a child. Procedures, such as intracytoplasmic sperm injection, may be used to assist these men to father a child.&nbsp;</p>

<p>&nbsp;</p>

<h5><strong>Breast Reduction Surgery</strong></h5>

<p>Surgical removal of breast tissue can help treat gynecomastia and reduce the risk of breast cancer in the patient.&nbsp;</p>

<div>&nbsp;</div>

<p>People with Klinefelter syndrome are at an increased risk of:</p>

<ul>
	<li><a href="https://www.merisehat.pk/disease/infertility-in-men" target="_blank">Infertility</a></li>
	<li>Sexual dysfunction (e.g., <a href="https://merisehat.pk/disease/erectile-dysfunction" target="_blank">erectile dysfunction</a> and diminished libido)</li>
	<li><a href="https://www.merisehat.pk/disease/hernia#diagnosis-5984" target="_blank">Hernia</a></li>
	<li>Speech and language delay</li>
	<li>Weak bones (e.g., <a href="https://www.merisehat.pk/disease/osteoporosis-80" target="_blank">osteoporosis</a>, osteopenia)</li>
	<li><a href="https://www.merisehat.pk/disease/breast-cancer" target="_blank">Breast cancer</a></li>
	<li><a href="https://www.merisehat.pk/disease/diabetes-type-1-and-2" target="_blank">Type II diabetes</a></li>
	<li><a href="https://www.merisehat.pk/disease/hypertension-57" target="_blank">Hypertension</a></li>
	<li>High <a href="https://www.merisehat.pk/disease/cholesterol#causes-5532" target="_blank">cholesterol </a>and triglycerides</li>
	<li><a href="https://www.merisehat.pk/disease/anxiety" target="_blank">Anxiety </a>and <a href="https://www.merisehat.pk/disease/depression" target="_blank">depression</a></li>
	<li>Behavioral problems</li>
	<li>Lung disease</li>
	<li>Oral problems</li>
	<li>Autoimmune conditions (e.g.,<a href="https://www.merisehat.pk/disease/systemic-lupus-erythematosus" target="_blank"> systemic lupus erythematosus</a>)</li>
</ul>

<div>&nbsp;</div>

<p>Klinefelter syndrome is not an inherited condition; instead, it occurs due to a random error during cell division. Therefore, there are no specific risk factors for the disorder. However, older women have been known to have a higher risk of giving birth to children with Klinefelter syndrome<sup><a href="#accordion">[13]</a></sup>.&nbsp; &nbsp;</p>

<p>&nbsp;</p>

<p>There is currently no way to prevent Klinefelter syndrome from developing. However, prenatal screening can help diagnose the disorder earlier and lead to a better prognosis.&nbsp;</p>

<p>&nbsp;</p>

Key Points

<ul>
	<li>Klinefelter syndrome is a genetic condition that results in an extra sex chromosome in males. As a result, the individual has a 46, XXY chromosome composition.&nbsp;</li>
	<li>Gynecomastia, sparse facial and body hair, and hypogonadism are the primary symptoms of the genetic disorder. Other symptoms include poor muscle tone in children, tall stature in children, and low or zero sperm count in adults. However, due to the variability of symptoms, most cases go undiagnosed until puberty or even later in adulthood.</li>
	<li>Common complications of Klinefelter syndrome are infertility, decreased libido, <a href="https://www.merisehat.pk/disease/diabetes-type-1-and-2" target="_blank">type II diabetes</a>, <a href="https://www.merisehat.pk/disease/osteoporosis-80" target="_blank">osteoporosis</a>, <a href="https://www.merisehat.pk/disease/breast-cancer" target="_blank">breast cancer</a>, <a href="https://www.merisehat.pk/disease/hernia#diagnosis-5984" target="_blank">hernia</a>, <a href="https://www.merisehat.pk/disease/anxiety" target="_blank">anxiety </a>and <a href="https://www.merisehat.pk/disease/depression" target="_blank">depression</a>, and autoimmune problems (e.g., SLE, <a href="https://www.merisehat.pk/disease/rheumatoid-arthritis" target="_blank">rheumatoid arthritis</a>).</li>
	<li>Screening tests for Klinefelter syndrome involve prenatal diagnostic methods, such as amniocentesis or chorionic villus sampling. Since they are invasive and can lead to miscarriages, they are only conducted on pregnant women with a history of chromosomal abnormalities or those older than 35 years.&nbsp;</li>
	<li>The main diagnostic test for Klinefelter syndrome is karyotyping and it involves an analysis of peripheral blood lymphocytes for the shape and number of chromosomes. Other than karyotype analysis, individuals may also undergo a complete hormonal workup to assess the levels of various hormones, such as FSH, LH, testosterone, prolactin, and estradiol.&nbsp;</li>
	<li>Although there is no cure for the disease, treatments such as testosterone replacement therapy, counseling, speech-language therapy, and fertility treatments can prevent complications and improve the individual&rsquo;s overall quality of life.</li>
</ul>

<div>&nbsp;</div>

[1] Bonomi M, Rochira V, Pasquali D, et al. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. J Endocrinol Invest. 2017;40(2):123-134.

[2] 47,XXY (Klinefelter syndrome). NORD (National Organization for Rare Disorders).

[3] Maiburg M, Repping S, Giltay J. The genetic origin of Klinefelter syndrome and its effect on spermatogenesis. Fertility and Sterility. 2012;98(2):253-260.

[4] Los E, Ford GA. Klinefelter Syndrome. [Updated 2022 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

[5] Aksglaede L, Link K, Giwercman A, Jørgensen N, Skakkebaek NE, Juul A. 47, XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. Am J Med Genet C Semin Med Genet. 2013;163C(1):55-63.

[6] Khan G, Ansari JA, Salman M, Ranjha MA, Tahir F. A Six-year Analysis Report at the Cytogenetics Department of National Institute of Health Islamabad, Pakistan. Pakistan Journal of Medical Research. 2018;57(4).

[7] Zahra F, Ahsan T, Lal Rehman U, Jabeen R. Clinical Spectrum and Causes of Delayed Puberty Among Patients Presenting to the Endocrine Clinic at Jinnah Postgraduate Medical Centre. Cureus. 2022;14(1):e21574. Published 2022 Jan 24.

[8] Population, labour force & employment - ministry of finance.

[9] Liang B, Cheung AS, Nolan BJ. Clinical features and prevalence of Klinefelter syndrome in transgender individuals: A systematic review. Clinical Endocrinology. 2022;97(1):3-12.

[10] Fazil H. A road map for the access and inclusion in education for persons with Klinefelter syndrome (gender disorder). Pakistan Social Sciences Review. 2020;4(IV):113-133.