Gynaecomastia and Klinefelter Syndrome

Question 1

Approach to Gynaecomastia

Answer 1

A. Breast enlargement
1. Site: left or right, asymmetry/symmetry
2. Onset and duration
3. Character: pain
4. Nipple discharge
5. Overlying skin changes, lump
6. Other palpable masses

Examination:
- Palpation of quadrants, axilla
- Areola examination - thumb and forefinger on opposite sides - firm disc of mobile glandular tissue
- Differentiates from pseudogynaecomastia

B. Gonadal examination
1. Body hair - lack of facial/body hair
2. Testicular volume - small or large, tumour

C. Overall appearance
1. Klinefelter - tall, feminine voice

D. Secondary hyperandrogenism
1. CKD - look for RRT modality
2. CLD - stigmata, HCC
3. Thyrotoxicosis - thyroid status, goitre, thyroid eye signs
4. Lung carcinoma - clubbing, tar staining, cachexia

E. Past Medical History
1. Diseases and medication use - digoxin, spironolactone

F. Family History - genetic component

G. Social History - sexual performance, libido
- Are you able to achieve an erection?

Question 2

What are the differential diagnosis of gynaecomastia?

Answer 2

1. Genetics - Klinefelter syndrome
2. Puberty and obesity
3. Chronic liver disease and cirrhosis
4. Primary hypogonadism
5. Secondary hypogonadism - prolactinoma, Kallman’s syndrome, haemochromatosis
6. Chronic kidney disease
7. Graves disease
8. Androgen insensitivity syndrome
9. Tumours - germ cell, Leydig cell, Sertoli cell, adrenal
10. Drugs - anti-androgens, chemotherapy, cimetidine/ranitidine, spironolactone, digoxin, amiodarone, metronidazole, ketoconazole, HAART (PI), metoclopramide, TCA

Question 3

How does prolactin cause gynaecomastia

Answer 3

1. Reduced gonadotrophin -> secondary hypogonadism
2. Stimulates breast tissue milk production

Question 4

Why does gynaecomastia increases with age?

Answer 4

1. Increasing body fat and aromatase activity -> increased conversion of androgens to estrogen
2. Increased exposure to gynaecomastia inducing drugs

Question 5

Investigations of gynaecomastia

Answer 5

1. Offer US/mammogram if red flag features present
2. Review medication use
3. Hormone tests - FSH, LDH, testosterone, estrogen, hCG
4. Genetic testing - Klinefelter, androgen insensitivity
5. Semen analysis for younger patient
6. Pituitary panel and MRI as necessary
7. Renal panel and liver function test

Question 6

Gynaecomastia with testicular enlargement

Answer 6

1. Infection - orchitis
   - Trial of antibiotics
2. Suspicious for malignancy
   - Tumour markers - BhCG, LDH, AFP
   - Imaging: US, CT/MRI
   - Orchidectomy

Question 7

What is Klinefelter’s syndrome?

Answer 7

Additional X chromosome 47, XXY

• Occasional mosaicism - mitotic non-disjunction)
• Rarely 48, XXYY or even 49 XXXXY

Question 8

Clinical Features of Klinefelter’s syndrome

Answer 8

1. Tall, disproportionate lower limbs to upper limbs
2. Gynaecomastia (30-50%)
3. Secondary sexual characteristics:
   - Reduced muscle tone
   - Reduced facial/axillary/pubic hair
   - High pitched voice
   - Broad hips
4. Small testes and penis, infertility
5. Associated conditions
   - Autoimmune: RA, SLE, Sjogren, Hashimoto, DM
   - MVP
   - Varicose veins
   - Osteoporosis
6. Additional features which might present:
   - Cognitive deficit
   - Mental restriction (XXXY)
   - Very tall stature or aggressive behaviour (XXYY)

Question 9

What is the difference between primary and secondary hypogonadism?

Answer 9

Primary hypogonadism
- Defect in gonads -> reduced androgens, with high gonadotrophins

Secondary hypogonadism
- Defect in hypothalamic-pituitart function -> reduced both androgens and gonadotrophins

Question 10

Primary hypogonadism in males

Answer 10

1. Infection - mumps, orchitis -> destruction
2. Testicular torsion - look for orchidectomy
3. Cryptorchidism (undescended testes)
4. Klinefelter’s syndrome
5. Noonan syndrome - short stature, webbed neck, right cardiac defect, testicular failure
6. Varicocoele - damages seminiferous tubules
7. Myotonic dystrophy
8. Radiation
9. Chemotherapy and drugs

Question 11

Secondary hypogonadism

Answer 11

1. Kallman’s syndrome
2. Prader-Willi syndrome
3. Dandy-Walker malformation
4. Isolated LH deficiency
5. Hypopituitarism
6. Hyperprolactinaemia
7. Haemochromatosis
8. Morbid obesity
9. Malnutrition

Question 12

Why is gynaecomastia not usually seen in secondary hypogonadism?

Answer 12

Serum FSH and LH not high -> unable to stimulate testicular aromatase to convert testosterone to oestradiol

Question 13

What are causes of tall stature?

Answer 13

1. Normal variant
2. Klinefelter’s syndrome
3. Marfan’s syndrome
4. Homocysteinuria
5. MEN 2B
6. Precocoius puberty
7. Hyperthyroidism
8. Gigantism