Hypocalcaemia, pseudohypoparathyroidism, pseudo-pseudo

Question 1

Physiological action of parathyroid hormone

Answer 1

PTH is stimulated by hypocalcaemia via calcium-sensing receptor on parathyroid gland

Effects of PTH on calcium and phosphate metabolism via type 1 PTH receptor
1. Bone
- Sustained PTH causes bone resorption and release calcium stores
- Intermittent PTH stimulates bone formation

2. Kidneys - calcium resorption from distal tubules, inhibits phosphate resorption
3. Vitamin D metabolism - renal synthesis of 1-a-hydroxylase to convert calcidiol to calcitriol
   - Calcitriol negative feedback reduces PTH secretion

Question 2

Pseudohypoparathyroidism is the target tissue PTH resistance due to GNAS gene mutations (defective PTH signaling by type 1 PTH receptor)

There are 3 types of GNAS gene mutations:
1. Pseudohypoparathyroidism type 1a
2. Pseudohypoparathyroidism type 1b
3. Pseudo-pseudohypoparathyroidism

Answer 2

Question 3

Pseudohypoparathyroidism type 1a is also known as Albright’s hereditary osteodystrophy

Characterised by:
1. Skeletal abnormalities
2. Hypocalcaemia with elevated PTH level
3. Additional hormonal resistance: TSH, ADH, sex hormones, ACTH, GHRH

Deficiency in alpha subunit of Gs protein that couples PTH receptor to adenylcyclase limits cAMP production
(This also affects multiple hormones, but most patients have unaffected ACTH and glucagon)

Question 4

Pseudohypoparathyroidism type 1b is characterised by end organ PTH resistance without skeletal abnormalities.

This is due to defect in PTH receptor, not Gs protein expression disorder

Question 5

Pseudo-pseudohypoparathyroidism occurs in 1st degree relatives of patients with PHP type 1a

Characterised by:
1. Skeletal abnormalities
2. No end organ resistance to PTH, no hypocalcaemia

Question 6

Clinical features of pseudohypoparathyroidism

Answer 6

Look - face, skeletal, dermatological abnormalities
Ask patient to stand - short stature, ankylosing spondylitis

1. Round face
2. Obesity
3. Short stature
4. Shortening of 4th metacarpal (symmetrical or asymmetrical)
   - Archibald sign - ask patient to make a fist
5. Shortening of distal phalanx of thumb - ratio of width of nail to length is increased
   - Murderer’s thumb or potter’s thumb
6. Palpable subcutaneous calcifications
7. Hypocalcaemia - Chvostek sign and Trousseau sign
8. Hypothyroidism

Question 7

Differential diagnoses of round facies

Answer 7

1. Pseudohypoparathyroidism
2. Cushing’s syndrome
3. Beta thalassaemia (chipmunk facies)
4. Myxoedema
5. Nephrotic syndrome (periorbital swelling)

Question 8

Differential diagnoses of subcutaneous calcification

Answer 8

1. Pseudohypoparathyroidism
2. Gouty tophi
3. Systemic sclerosis calcified nodules
4. Ehlers-Danlos syndrome
5. Pseudoxanthoma elasticum
6. Dermatomyositis
7. Soft tissue sarcoma

Question 9

Causes of hypocalcaemia

Answer 9

1. Hypoalbuminaemia - reduced albumin-bound calcium
2. Vitamin D deficiency
3. Acute pancreatitis
4. Hypoparathyroidism
5. Hypomagnesaemia - PTH resistance
6. Acute hyperphosphataemia - renal failure, rhabdomyolysis, tumour lysis syndrome
7. Drugs - cisplatin, biphosphonates, foscarnet
8. Autosomal dominant hypercalciuric hypocalcaemia (opposite of familial hypocalciuric hypercalcaemia)