Klinefelter syndrome

Klinefelter syndrome should be considered by GPs in male patients presenting with any relevant symptoms or signs

Most diagnoses of Klinefelter syndrome occur either prenatally, around the expected time of puberty or in association with infertility

Accurate measurement of testicular volume (using an orchidometer; Image 1) during routine physical examination would likely improve detection of Klinefelter syndrome, thereby facilitating simple, effective treatment with life-long benefit

GPs are ideally placed to perform clinical assessments, order laboratory investigations, refer for specialist assessment and initiation of testosterone replacement therapy, and coordinate ongoing management of Klinefelter syndrome

Klinefelter syndrome is the most common cause of androgen deficiency in men

Klinefelter syndrome refers to a collection of characteristics in males caused by the presence of two or more X chromosomes

The most common (80-90%) karyotype of males with Klinefelter syndrome is 47,XXY. Some males with Klinefelter syndrome have more than two X chromosomes, or chromosomal mosaicism

Klinefelter syndrome prevalence is estimated to be 1 in 500 males, with only around half of those affected ever diagnosed

Klinefelter syndrome is characterised by impaired testosterone production and spermatogenesis

Classical features of Klinefelter syndrome (Image 2) are present to differing degrees in individuals

The only consistent feature of Klinefelter syndrome is small testes volume (< 4 mL)

The subtle effects of Klinefelter syndrome in many men account for low rates of diagnosis and illustrates the importance of genital examination as part of routine clinical exams

Men with Klinefelter syndrome benefit from testosterone replacement therapy

Infertility is common in men with Klinefelter syndrome, due to oligi- or azoospermia, but paternity may be possible with assisted reproductive technologies using sperm collected by microdissection testicular sperm extraction (microTESE) 

1. Pubertal development (poor progression)

2. Sexual function (low libido)

3. Degree of virilisation

4. Psychosocial (learning, schooling and behaviour)

5. Infertility

Examination

1. No hormonal features prior to puberty

2. Undescended testes

3. Rarely, ambiguous genitalia

1. Small testes (< 4 mL) are a characteristic feature from mid puberty

2. Poor pubertal progression and facial, body and pubic hair relative to age

3. Gynaecomastia

4. Feminine fat distribution

5. Taller than average height

6. Poor muscle development

1. Small testes (typically < 4 mL)

2. Reduced facial, body and pubic hair

3. Gynecomastia

4. Feminine fat distribution and weight gain

5. Taller than average height

6. Poor muscle development

Testicular volume is assessed using an orchidometer

Normal testicular volume range:
– Childhood 3 mL or smaller
– Puberty 4–14 mL
– Adulthood 15–35 mL

Small testes:
– 4 mL is the only consistent feature of Klinefelter syndrome (Image 2)

The testes may start to develop in early puberty, but soon regress to 4 mL by mid puberty

Two fasting, morning samples of serum total testosterone, taken on different days

Total serum testosterone, low or low normal from mid puberty (normal range typically 8–27 nmol/L)

Serum LH, elevated from mid puberty (normal range 1-8 IU/L)

Serum FSH, elevated from mid puberty (normal range 1-8 IU/L)

Karyotype (47,XXY)
– 10% mosaic 46,XY/47,XXY

Bone densitometry, DEXA (osteoporosis)

Semen analysis if fertility is an issue (usually azoospermic)

Thyroid function tests (hypothyroidism)

Fasting blood glucose (diabetes)

TRT is lifelong and may be started from mid puberty, although many boys initially virilise normally

Gynecomastia is an indication to start TRT (see below)

Teenage boys usually start on a low dose and build to full adult dose as puberty progresses

Even if measured testosterone concentrations are normal, there is evidence that bone density is reduced in the presence of chronically raised LH levels, suggesting that TRT is indicated

In adults, consult with a fertility specialist (if appropriate) to develop a plan for fertility preservation prior to TRT, as TRT will suppress spermatogenesis

Gynaecomastia may be transient, lasting one to three years

Adequate testosterone replacement often results in complete resolution over 12 months

Surgical removal, mastectomy (do not refer for early surgery as it may resolve naturally or following TRT)

Men with Klinefelter syndrome are less likely to die from prostate cancer, and restoring testosterone levels to the normal range is likely only to return their risks to those of their eugonadal peers

Subject to the same advice about testing for prostate cancer as their peers (PSA)

Exclusion of significant prostate pathology is essential for those aged >40 years at the commencement of therapy

Aside from cognitive and behavioural features, it is important to note that despite the following recognised disease associations with Klinefelter syndrome, the absolute risk is low

Tumours: leukaemia, mediastinal germ cell tumours, lymphoma, teratoma and breast cancer

Endocrine: hypothyroidism and diabetes mellitus
(Type 1 is rare and Type 2 is often affected by obesity)

Cardiovascular: venous ulcers and venous thromboembolic disease

Auto-immune: systemic lupus erythematosis (SLE) and coeliac disease

Refer to a paediatric endocrinologist

Refer for educational and allied health assistance if needed

Develop a plan in consultation with an endocrinologist for assessment and management of:
– Hormone deficiency
– Infertility
– Osteoporosis
– Cardiovascular risk

Refer to a fertility specialist +/- urologist, as appropriate, for sperm recovery from testis or donor sperm

Most men are azoospermic

Sperm are rarely found in the ejaculate but in 30-50% of cases sperm can be found with microdissection testicular sperm extraction. Access to surgical expertise and high costs can make this prohibitive for many affected men. Where sperm is found, Intracytoplasmic Sperm Injection (ICSI) fertility treatment would be required

ICSI — the risk of 47,XXY offspring is low

Donor insemination

Counselling may be necessary

Difficulties with speech and reading

Delayed motor development

Reduced attention span

Behavioural problems (particularly in adolescence)

Requirement for educational and allied health assistance