A patient with Pseudohypoparathyroidism type 1a (PHP-1a) has elevated PTH but hypocalcaemia. The primary biochemical defect is:

• A Absence of PTH receptor at target cells
• B Deficiency of calcitriol synthesis in the kidney
• C Loss-of-function mutation in Gs-alpha, impairing cAMP generation despite PTH binding ✓
• D Excess phosphaturia from a gain-of-function FGF-23 mutation

Explanation

PHP-1a results from a heterozygous inactivating mutation in GNAS1 (Gs-alpha gene, maternally inherited allele). Although PTH binds its receptor normally, the downstream Gs-alpha cannot adequately stimulate adenylyl cyclase, so cAMP production is blunted. Consequently, target tissues (renal tubule, bone) are resistant to PTH, causing hypocalcaemia and hyperphosphataemia despite high PTH. The patients also show Albright hereditary osteodystrophy (short stature, brachydactyly).

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.