Pseudohypoparathyroidism Diagnosis
Diagnose pseudohypoparathyroidism (PHP) by demonstrating the biochemical triad of hypocalcemia, hyperphosphatemia, and elevated or inappropriately normal PTH levels, then confirm with genetic testing of the GNAS locus when feasible. 1
Diagnostic Criteria
Essential Biochemical Features
Measure serum calcium (corrected for albumin) and intact PTH simultaneously to establish the diagnosis. 1 The characteristic biochemical pattern includes:
- Hypocalcemia (low serum calcium corrected for albumin) 2, 3
- Hyperphosphatemia (elevated serum phosphate) 4, 2
- Elevated PTH despite hypocalcemia, indicating end-organ resistance to PTH rather than PTH deficiency 2, 3
This biochemical constellation distinguishes PHP from hypoparathyroidism, where PTH would be low or absent. 1
Critical Differential Considerations
Always assess vitamin D status before finalizing the diagnosis, as vitamin D deficiency can cause secondary hyperparathyroidism with similar biochemical features and complicate PTH interpretation. 1, 5 Aim for 25-OH vitamin D levels >20 ng/mL (50 nmol/L). 6, 5
Evaluate dietary calcium intake through detailed dietary history, as calcium deprivation can mimic PHP biochemically. 6, 5 Low urinary calcium suggests inadequate calcium intake rather than true PHP. 5
Check serum magnesium levels, as hypomagnesemia can cause functional hypoparathyroidism with a similar presentation. 4
Confirmatory Testing
Perform genetic analysis of the GNAS gene to confirm the diagnosis and classify the PHP subtype. 2, 7 Molecular testing can identify:
- GNAS mutations (PHP1A) - found in approximately 38% of PHP patients 2
- Epigenetic abnormalities at the GNAS locus (PHP1B) - found in approximately 58% of PHP patients 2
- Loss of methylation at the A/B differentially methylated region (DMR) specifically confirms PHP1B 7
If genetic testing is unavailable, the clinical diagnosis relies on the biochemical triad plus demonstration of PTH resistance. 1 The classic PTH infusion test (Ellsworth-Howard test) shows blunted urinary cAMP and phosphate excretion responses to exogenous PTH administration. 4
Clinical Phenotype Assessment
PHP1A Features
Patients with PHP1A typically present with Albright hereditary osteodystrophy (AHO) features, which are notably absent in PHP1B. 2 Look for:
- Brachydactyly (shortened metacarpals/metatarsals, especially 4th and 5th) 3
- Round facies and short stature 3
- Subcutaneous ossifications (ectopic bone formation) 3
- Early-onset obesity 2, 3
- Intellectual disability (variable severity) 3
- Multi-hormonal resistance (TSH, gonadotropins, GHRH) beyond PTH resistance 2
- Hypertension (more common in PHP1A than PHP1B) 2
PHP1B Features
PHP1B patients typically have isolated PTH resistance without AHO features. 2, 7 They present with:
- Absence of dysmorphic features 7
- Normal stature and intelligence 7
- Isolated biochemical abnormalities (hypocalcemia, hyperphosphatemia, elevated PTH) 7
Age at Presentation
PHP1A is typically diagnosed earlier in life due to the obvious physical features of AHO, while PHP1B may present later (often in adolescence) when symptomatic hypocalcemia develops. 2, 7
Radiological Evaluation
Skeletal Manifestations
Obtain skeletal radiographs if rickets or osteomalacia is suspected clinically. 4 PHP can present with:
- Rickets-like changes in children (epiphyseal enlargement, bowing of long bones, failure of epiphyseal calcification) 4
- Osteomalacia in adults (generalized demineralization, pseudofractures) 4
- Subperiosteal erosions reflecting secondary hyperparathyroidism 4
Consider bone biopsy if radiological findings are equivocal, which may show increased osteoid seams consistent with osteomalacia. 4
Ectopic Calcifications
Obtain brain imaging (CT or MRI) to assess for intracerebral calcifications, which occur in approximately 72% of PHP patients with no significant difference between PHP1A and PHP1B subtypes. 2 The presence of cerebral calcifications shows a borderline association with older age at diagnosis. 2
Renal imaging is generally not necessary, as renal calcifications are uncommon in PHP despite chronic hyperphosphatemia. 2 This distinguishes PHP from primary hyperparathyroidism, where nephrocalcinosis and nephrolithiasis are frequent complications. 8
Laboratory Monitoring Strategy
Initial Workup
Beyond the essential calcium, phosphate, and PTH measurements, obtain:
- Serum albumin to correct calcium values 1
- 25-OH vitamin D to exclude vitamin D deficiency 1, 5
- Serum magnesium to exclude hypomagnesemia 4
- Alkaline phosphatase (often elevated, reflecting bone disease) 4
- Serum creatinine and eGFR to assess renal function 5
- 1,25-dihydroxyvitamin D (may be inappropriately low for age despite normal adult range) 4, 9
PTH Assay Considerations
Be aware that different PTH assay generations have variable sensitivity to PTH fragments, which can affect interpretation. 6, 1 Second-generation assays may overestimate PTH in some patients due to cross-reactivity with PTH fragments. 6 Always use assay-specific reference ranges when interpreting PTH values. 6, 1
Common Diagnostic Pitfalls
Do not use calcimimetics (cinacalcet) in PHP, as the problem is PTH resistance at the end-organ level, not excessive PTH production. 1 Calcimimetics would be counterproductive and potentially harmful.
Do not delay diagnosis in patients presenting with symptomatic hypocalcemia (tetany, seizures, paresthesias), as severe hypocalcemia requires urgent treatment regardless of the underlying etiology. 7
Do not assume PHP is excluded by normal calcium levels in infants, as serum phosphate may be in the normal range within the first 3-4 months of life in conditions like X-linked hypophosphatemia. 6 However, this is less relevant for PHP, where hypocalcemia is the hallmark.
Do not confuse PHP with primary hyperparathyroidism, which presents with hypercalcemia and elevated PTH rather than hypocalcemia. 6, 8 The calcium level immediately distinguishes these conditions.