Makindo Medical Notes

Related Subjects: |PTH Physiology |Calcium Physiology |Magnesium Physiology |Calcitonin |Hypocalcaemia |Hypercalcaemia |Hypomagnesaemia |Hypermagnesaemia |Primary Hyperparathyroidism |Familial hypocalciuric hypercalcaemia (FHH) |Sarcoidosis

🦴 Pseudohypoparathyroidism (PHP) is a rare inherited disorder where the body fails to respond to parathyroid hormone (PTH). Despite high circulating PTH, target organs (bone, kidney) are resistant, leading to hypocalcaemia and hyperphosphataemia.

📖 About

• First described in 1942 (Albright’s hereditary osteodystrophy).
• Autosomal dominant inheritance, most often due to defects in the GNAS1 gene.
• Failure of PTH action → ↓ Ca²⁺, ↑ phosphate, ↑ PTH (secondary hyperparathyroidism).
• ⚠️ Always exclude hypomagnesaemia as a cause of apparent PTH resistance.

🧬 Aetiology & Pathophysiology

• Mutations in GNAS1 gene (chromosome 20q13) → defective G-protein signalling.
• End-organ insensitivity to PTH at the renal tubule and bone.
• Impaired cAMP generation in the proximal tubule after PTH binding.
• Subtype classification: PHP type 1a, 1b, 2 based on genetics and biochemical response.

⚡ Pseudopseudohypoparathyroidism (PPHP): patients share the same physical phenotype (short stature, round face, short 4th/5th metacarpals) but have normal biochemistry. Caused by the same GNAS1 mutations but with paternal imprinting differences.

🩺 Clinical Features

• Symptoms of hypocalcaemia: tetany, carpopedal spasm, seizures, paraesthesia.
• Albright hereditary osteodystrophy phenotype:
  • Short stature
  • Rounded facies
  • Shortened 4th or 5th metacarpals/metatarsals ("knuckle knuckle dimple knuckle")
  • Obesity, dental hypoplasia
  • Subcutaneous calcifications, cataracts
• Cognitive impairment in some cases.
• Soft tissue calcifications and basal ganglia calcification → movement disorders.

🔬 Investigations

• Biochemistry: ↓ calcium, ↑ phosphate, ↑ PTH, ↑ ALP.
• Magnesium: ensure normal (exclude Mg deficiency as cause of resistance).
• Ellsworth-Howard Test: IV PTH →
  • Normal response: ↑ urinary phosphate & cAMP.
  • PHP: no rise in phosphate/cAMP.
• Imaging: CT/MRI may show basal ganglia calcification.
• Genetic testing can confirm GNAS1 mutations.

💊 Management

• 🎯 Goal: normalise calcium and phosphate, relieve symptoms.
• Calcium supplementation + activated vitamin D (calcitriol).
• Low phosphate diet and phosphate binders if needed.
• Monitor for nephrocalcinosis and hypercalciuria during treatment.
• Growth hormone may help with short stature in selected cases.

📚 References

• Albright F, et al. Pseudohypoparathyroidism — an example of "Seabright-Bantam syndrome". Endocrinology, 1942.
• Thakker RV. Pseudohypoparathyroidism – GeneReviews