pseudohypoparathyroidism

**Pathophysiology** - PTH normally binds the PTH1 receptor (a GPCR) on kidney and bone. The receptor signals through Gsα, which activates adenylyl cyclase, raises cAMP, and activates PKA. In the proximal tubule this reduces phosphate reabsorption (phosphaturia). In the distal tubule it increases calcium reabsorption. It also stimulates 1α-hydroxylase to make active vitamin D. - In PHP the target tissues do not respond to PTH. Calcium falls, phosphate rises, and the parathyroids respond with high PTH.

**Lab pattern (vs. hypoparathyroidism)** - Ca²⁺ is low, phosphate is high, and 1,25-(OH)₂D is low. PTH is HIGH in PHP but low in true hypoparathyroidism. Magnesium is normal. - Ellsworth-Howard test: give exogenous PTH and measure urinary cAMP and phosphate. - Type 1 (Ia, Ib, Ic): urinary cAMP does not rise, because the defect is at or before cAMP generation. - Type 2: cAMP rises but phosphaturia does not, because the defect is downstream of cAMP.

**Subtypes** - **PHP type 1a (Albright hereditary osteodystrophy, AHO)** - Cause: heterozygous loss-of-function mutation in GNAS, which encodes Gsα. This is the classic board answer. - Inheritance: autosomal dominant with genomic imprinting. In the proximal renal tubule, thyroid, and pituitary, the paternal GNAS allele is silenced, so only the maternal allele is expressed there. A maternally inherited mutation therefore gives full PHP1a, with AHO plus resistance to PTH, TSH, GHRH, and gonadotropins (hypothyroidism, short stature, hypogonadism). - AHO features: - Short stature - Round facies - Obesity - Brachydactyly (shortened 4th and 5th metacarpals and metatarsals) - Subcutaneous ossifications - Intellectual disability - Hypocalcemia symptoms: perioral paresthesias, tetany, Chvostek and Trousseau signs, seizures, prolonged QT. - **Pseudopseudohypoparathyroidism (PPHP)** - Same GNAS mutation, but inherited from the father. - The patient has the AHO phenotype with normal Ca²⁺, phosphate, and PTH, because the maternal allele is intact in the kidney. - Classic imprinting example: the same mutation produces different disease depending on the parent of origin. - **PHP type 1b** - Isolated renal PTH resistance, usually from a methylation defect at the GNAS locus on the maternal allele. - No AHO phenotype. - **PHP type 2** - Defect is downstream of cAMP, so the Ellsworth-Howard test shows normal cAMP but no phosphaturia.

**Management** - Oral calcium plus calcitriol (active vitamin D). - Keep PTH in the upper-normal range to avoid hypercalciuria and nephrocalcinosis. - Treat other hormone resistances, such as levothyroxine for hypothyroidism. - Acute symptomatic hypocalcemia is treated with IV calcium gluconate.

**High-yield associations and differentials** - Hypocalcemia with HIGH PTH suggests PHP, vitamin D deficiency, or CKD. Hyperphosphatemia with low Ca²⁺ and high PTH points to PHP or CKD. - Pseudohypoparathyroidism is a PTH-resistance state, not an autoimmune or surgical cause of low PTH. - Gsα (stimulatory) mutations cause different diseases depending on whether function is lost or gained: - Loss of function: PHP1a. - Activating (gain-of-function) mutations: McCune-Albright syndrome (somatic mosaic), with polyostotic fibrous dysplasia, café-au-lait spots, and precocious puberty. - Other causes of AHO-like short 4th metacarpals: Turner syndrome. Fourth-metacarpal shortening can also be a clue in other conditions. - Hypomagnesemia can cause functional PTH resistance and should be excluded.

**Board pearl** A child or young adult with hypocalcemic seizures or tetany, short stature, round face, a short 4th metacarpal, obesity, and elevated TSH has PHP1a. Labs show high PTH, high phosphate, and low calcium. The defect is Gsα (GNAS) on the maternal allele.