Pseudo hypo parathyroid
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pseudohypoparathyroidism types pathophysiology PTH resistance
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pseudohypoparathyroidism clinical features diagnosis treatment Albright hereditary osteodystrophy
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pseudohypoparathyroidism type 1a 1b 2 Gs alpha GNAS mutation pseudo-pseudohypoparathyroidism
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Pseudohypoparathyroidism (PHP)
Overview
Pseudohypoparathyroidism is a group of inherited disorders characterized by end-organ resistance to PTH rather than PTH deficiency. The result is a biochemical picture resembling hypoparathyroidism — hypocalcemia + hyperphosphatemia — but with elevated PTH levels (Harrison's, p. 11611).
Pathophysiology
PTH normally binds its receptor on proximal renal tubule cells and activates a Gs-protein → adenylyl cyclase → cAMP → PKA cascade. In PHP, a defect in this pathway (usually at the Gsα protein level, encoded by GNAS) prevents PTH from:
- Increasing intracellular cAMP
- Stimulating 1,25(OH)₂D (calcitriol) production
- Promoting phosphaturia
This leads to insufficient calcitriol → impaired intestinal calcium absorption, and phosphate retention → hyperphosphatemia (Harrison's, p. 11611, 11614).
Classification
| Type | Mutation / Defect | AHO Features | PTH Resistance | Other Hormone Resistance |
|---|---|---|---|---|
| PHP Type Ia (PHP1A) | GNAS loss-of-function (maternal allele) → ↓ Gsα activity (~50%) | Yes | Yes (renal PTH) | Yes (TSH, LH/FSH, glucagon — multi-hormone) |
| Pseudo-PHP (PPHP) | GNAS loss-of-function (paternal allele) | Yes | No | No |
| PHP Type Ib (PHP1B) | Methylation defect at GNAS locus (imprinting) | No | Yes (primarily PTH) | Mild TSH in some |
| PHP Type Ic | Gsα activity normal but downstream effector defect | Yes | Yes | Yes |
| PHP Type II | Defect distal to cAMP production; cAMP rises but PKA response fails | No | Yes | No |
Key distinction: PHP1A and Pseudo-PHP arise from mutations in the same gene (GNAS) but on different parental alleles (genomic imprinting). Gsα is predominantly expressed from the maternal allele in the kidney — so only maternal GNAS mutations cause renal PTH resistance.
Albright's Hereditary Osteodystrophy (AHO)
Present in PHP1A, PHP1C, and Pseudo-PHP. Features include:
- Short stature
- Obesity
- Round facies
- Brachydactyly (especially shortening of 4th and 5th metacarpals/metatarsals — "knuckle-knuckle-dimple-dimple" sign)
- Subcutaneous ossifications
- Intellectual disability (variable)
- Dental anomalies
Clinical Presentation
Symptoms arise from hypocalcemia:
- Neuromuscular: tetany, carpopedal spasm, paresthesias, seizures
- Chvostek's sign (facial nerve tap → facial twitch)
- Trousseau's sign (BP cuff inflation → carpal spasm)
- Cataracts (chronic hypocalcemia)
- Basal ganglia calcifications (on CT)
- Prolonged QTc on ECG
- In PHP1A: features of multi-hormone resistance (hypothyroidism from TSH resistance, hypogonadism)
Laboratory Findings
| Parameter | Finding |
|---|---|
| Serum calcium | Low |
| Serum phosphate | High |
| PTH | Elevated (↑↑) |
| 1,25(OH)₂D (calcitriol) | Low or low-normal |
| 25-OH Vitamin D | Normal |
| Urinary cAMP after PTH infusion | ↓ (PHP I) / Normal (PHP II) |
| TSH | ↑ in PHP1A/1B (TSH resistance) |
Ellsworth-Howard Test: IV PTH infusion → measure urinary cAMP and phosphate excretion. In PHP type I, cAMP response is blunted; in PHP type II, cAMP rises but phosphaturia is absent.
Diagnosis
- Biochemistry: hypocalcemia + hyperphosphatemia + elevated PTH
- AHO features on examination
- Ellsworth-Howard test to subtype
- Genetic/molecular testing: GNAS sequencing and methylation analysis to confirm subtype
- Imaging: hand X-ray (brachydactyly), CT brain (basal ganglia calcifications), DXA (bone density)
Differentials
- True hypoparathyroidism (low PTH)
- Vitamin D deficiency (low 25-OH D; PTH elevated but responds to supplementation)
- Hypomagnesemia (causes functional PTH resistance)
- Renal failure (hyperphosphatemia + low Ca but different context)
Management
Acute Hypocalcemia (symptomatic/tetany)
- IV calcium gluconate (10 mL of 10% solution over 10 min, then infusion)
Chronic Management
| Treatment | Details |
|---|---|
| Calcitriol (1,25(OH)₂D) | Drug of choice; 0.25–2 µg/day — bypasses the defective PTH→calcitriol step |
| Calcium supplementation | 1–3 g/day elemental calcium |
| Monitor | Serum Ca, phosphate, urinary calcium (24h), renal function |
| Thiazide diuretics | Sometimes used to reduce hypercalciuria |
| Treat hypothyroidism | Levothyroxine if TSH resistance present (PHP1A) |
| Avoid | High-phosphate diet; use phosphate binders if needed |
Target: serum calcium in low-normal range (avoid overcorrection → hypercalciuria and nephrolithiasis, since PTH-driven renal calcium reabsorption is impaired).
Key Distinctions to Remember
| Hypoparathyroidism | PHP | Pseudo-PHP | |
|---|---|---|---|
| PTH level | ↓ | ↑↑ | Normal |
| Calcium | ↓ | ↓ | Normal |
| Phosphate | ↑ | ↑ | Normal |
| AHO features | No | Yes (PHP1A) | Yes |
| Gsα activity | Normal | ↓ | ↓ |
Pseudo-PHP has the same genetic defect and AHO phenotype as PHP1A but normal calcium/phosphate — because the paternal GNAS allele is affected, which is expressed in tissues other than kidney. No renal PTH resistance occurs.
Sources: Harrison's Principles of Internal Medicine, 21st Edition, pp. 11611, 11614.
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