A child with features of Albright hereditary osteodystrophy (short stature, short 4th metacarpal, subcutaneous ossifications) has elevated PTH with hypocalcaemia but a normal PTH receptor gene. The molecular defect most likely involves:

• A Loss-of-function mutation in the PTHR1 gene encoding the PTH receptor
• B Autoimmune destruction of parathyroid glands reducing PTH secretion
• C Loss-of-function mutation in the GNAS gene encoding the Gsα subunit, causing pseudohypoparathyroidism type Ia ✓
• D Gain-of-function mutation in the calcium-sensing receptor (CaSR) simulating hypercalcaemia

Explanation

Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited inactivating mutations in GNAS, encoding the Gsα protein. Despite normal PTH and normal PTHR1, the signal cannot propagate to adenylyl cyclase, so cAMP is not produced in target tissues. The result is end-organ resistance to PTH: hypocalcaemia, hyperphosphataemia, and elevated PTH. The somatic phenotype (Albright osteodystrophy) results from Gsα haploinsufficiency in other tissues. CaSR gain-of-function causes autosomal dominant hypocalcaemia, not the Albright phenotype.

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

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Written and medically reviewed by the StethoPrep medical team.