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11/14/24, 10\:58 AM Klinefelter Syndrome

Klinefelter Syndrome

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Klinefelter Syndrome (KS)\: chromosomal disorder with karyotype 47, XXY, a
Aetiology\: extra X chromosome due to meiotic non-disjunction or mosaicism; longer CAG repeats in androgen receptor
gene correlate with severity.
Risk factor\: advanced maternal age.
Neonates\: may have cryptorchidism, micropenis, hypospadias; otherwise, typically normal at birth.
Puberty\: delayed/absent secondary sexual characteristics, small testicular size, gynaecomastia, taller stature due to
delayed epiphyseal fusion.
Adults\: infertility, androgen de
Investigations\: karyotyping (prenatal and postnatal), serum FSH/LH (high), SHBG (high), total/free testosterone (low),
semen analysis (azoospermia).
Management\: testosterone therapy, multidisciplinary team input (paediatricians, endocrinologists, psychologists, fertility
experts), addressing complications.
Complications\: cardiovascular disease (mitral valve prolapse, venous thromboembolism), endocrine disorders (diabetes,
hypothyroidism, obesity), increased cancer risk (breast cancer, lymphoma), cognitive/neuropsychiatric issues
(developmental delay, psychiatric disorders).
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A comprehensive topic overview

Introduction

Klinefelter Syndrome (KS) is a chromosomal disorder which occurs when an individual’s karyotype is XY (male), and there
is at least one additional X chromosome.
1
The incidence of KS is estimated to be about 1.5 in 1000 live-born males. 1,2
While the clinical manifestations of KS vary
widely, its subtle signs and phenotype may not be apparent until adulthood. Only 25 to 50% of a
obtain a diagnosis during their lifetime.
3

Aetiology

The X and Y chromosomes are the sex chromosomes, with females having XX sex chromosomes and males having XY
sex chromosomes.
In Klinefelter syndrome, there is the presence of at least one additional X chromosome, resulting in a karyotype of 47, XXY
(or, rarely, even more, extra X chromosomes).
1
KS typically occurs via one of the following processes\:
1,4
Meiotic non-disjunction of the X chromosome from the maternal or paternal side, leading to the formation of sperm or
egg cells with an abnormal number of chromosomes during gametogenesis (80-90%)
Mosaicism during early foetal growth (10%)
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KS typically have longer cytosine, adenine and guanine (CAG) repeats in the androgen receptor gene. The shorter the
CAG repeat, the more sensitive the androgen receptor is towards testosterone. Therefore, in the case of KS, the severity of
the phenotype is inversely proportional to the long length of the CAG repeat.
5,6
It is important to note that, like other chromosomal abnormalities, Klinefelter syndrome a
but around 60% of these will spontaneously abort.

Risk factors

Advanced maternal age is the only evidence-based risk factor for KS.
7,8

Clinical features

Due to the variability in phenotype severity and di
around 30.
1
Otherwise, the typical presentations di
is a
5,6

History

Neonates and pre-pubertal boys
Only the most severe phenotypes of KS are recognised before puberty. In young boys, there may be noticeable language
delay and behavioural abnormalities.
9,10
Puberty
Patients with KS will often have abnormal pubertal development, and so may report symptoms related to delayed
development of secondary sexual characteristics, or issues such as gynaecomastia. 11,12
Issues with developmental delay
and behaviour may also become more noticeable as patients age.
Adults
Most adult men present with infertility and signs and symptoms of androgen de
sexual complaints, most commonly erectile dysfunction and reduced libido.

Clinical examination

Neonates and pre-pubertal boys
Most children appear to be normal at birth. 13,14
The most distinguishing features of hypogonadism in the neonate are
genital anomalies\:
11
Cryptorchidism
Micropenis (\<1.9cm in full-term neonates)
Hypospadias
Puberty
Many a
11,12
Small testicular size
Incomplete virilization (e.g. decreased pubic and facial hair, micropenis)
Gynaecomastia
The patient may also be taller than expected based on mid-parental height due to the lack of testosterone, leading to
delayed epiphyseal fusion.
12
Adults
Evaluation of genitalia would reveal\:
12-14
Small, ≀4 mL each
Inadequate phallic growth
This occurs due to extensive and progressive
spermatogenesis.
14
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Di

The main di
17
Another di
experience androgen insensitivity because of deactivating mutations in the androgen receptor gene.
18

Investigations

Prenatal investigations

Prenatal screening can be done by testing the maternal blood sample for the foetus’ cell-free DNA (cfDNA) that the
placenta would have released into the mother’s bloodstream. 1,19
Karyotyping may then be carried out.
The diagnosis may be further con
1

Postnatal investigations

KS is often diagnosed based on the clinical presentation and con
karyotyping. 1
Evaluation of the sex chromosomes would demonstrate more than one X chromosome plus a Y
chromosome.
1,4
This test can be carried out at any age of males in whom a diagnosis of KS would be possible.

Peripubertal and adult investigations

The typical
Serum FSH and LH\: high in Klinefelter Syndrome
2,4,14
Serum sex hormone-binding globulin (SHBG)\: high in Klinefelter Syndrome
2
Serum total and free testosterone\: both are low in Klinefelter Syndrome; however, due to SHBG concentrations being
elevated, the serum free testosterone concentrations are disproportionately less than the serum total testosterone
concentrations
2,4,14
The elevated gonadotropins and decrease in androgen production, is known as hypergonadotropic hypogonadism, and is
a hallmark for the characteristic phenotype of a man with KS.
1,2,7,8,20,21
Semen analysis test\: azoospermia is usually reported on sperm count analysis
1

Diagnosis

As discussed above, the diagnosis of KS would be con
karyotyping of an individual with a Y chromosome.
If genetic mosaicism is suspected as the cause, then karyotyping is often carried out on cells from the patient's oral
mucosa to con

Management

The current guidelines present recommendations for managing patients with KS, according to age of diagnosis, severity of
phenotype and desired clinical endpoint.
24
Patients require multidisciplinary team input, and those involved may include\:
1,2,24
Paediatricians
GPs
Endocrinologists
Psychologists
Speech and language therapists
Specialist nurses
Fertility experts
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Testosterone therapy is routinely o
long-term management for the possible consequences of hypogonadism. In boys of pubertal age and men, the goal would
be to stimulate the gradual development of secondary sexual characteristics while also preventing the frequent
associated comorbdities.
1,2,8,9,24
Males who are infertile and interested in having children should be guided about the current options available.
1,9,24
In addition to the above, patients will require management for the complications and co-morbidities associated with KS.

Complications

KS is associated with several complications and co-morbidities in many systems of the body\:
1,2,9,11,14,17,20,21,22,23

Cardiovascular disease

Mitral valve prolapse
Short QTc interval\: may predispose to arrhythmias and sudden cardiac-related death
Increased incidence of venous leg ulcers
Increased incidence of venous thromboembolism\: deep vein thrombosis (DVT) and pulmonary embolism (PE)

Endocrinological disease

Obesity
Diabetes mellitus
Hypothyroidism
Deranged lipid pro\: may predispose to myocardial infarction and stroke

Cancer risk

Increased risk, particularly that of breast cancer
Non-Hodgkin's lymphoma
Germ cell tumours of the mediastinum

Cognitive and neuropsychiatric abnormalities

Developmental delay\: particularly verbal communication
Learning disability
Increased incidence of psychiatric disorders\: schizophrenia, psychotic disorders, depression and attention de
hyperactivity disorder

Key points

Klinefelter Syndrome occurs when there is a at least one extra X chromosome in an individual with Y chromosomes.
Clinical features are of varying severity, including signs of primary hypogonadism.
The diagnosis is often missed due to the subtle clinical manifestation of the Klinefelter syndrome.
If suspected, Klinefelter syndrome is con
Multiple comorbidities have been linked to Klinefelter syndrome, including cardiovascular, endocrinological,
oncological and neuropsychiatric abnormalities.
Management should be tailored for the patient’s needs and the importance of a multi-disciplinary team should not be
underestimated. Testosterone therapy is also often considered.

References

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Zitzmann, M., Aksglaede, L., Corona, G., Isidori, A. M., Juul, A., T’Sjoen, G., Kliesch, S., D’Hauwers, K., Toppari, J., SƂowikowska-
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https\://app.geekymedics.com/notebook/2817/ 5/611/14/24, 10\:58 AM Klinefelter Syndrome

Reviewer

Dr John Torpiano
Consultant Paediatric Endocrinologist

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Contents

Introduction
Aetiology
Risk factors
Clinical features
Di
I ti ti
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