🦴 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

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Pseudo(pseudo)hypoparathyroidism