Progressive Development of PTH Resistance in Patients With Inactivating Mutations on the Maternal Allele of GNAS.

Context: Parathormone (PTH) resistance is characterized by hypocalcaemia, hyperphosphatemia, and elevated PTH in the absence of vitamin D deficiency. Pseudohypoparathyroidism type 1A [PHP1A, or inactivating parathormone (PTH)/PTHrp signaling disorder 2, according to the new classification (iPPSD2)], is caused by mutations in the maternal GNAS allele.

Objective: To assess PTH resistance over time in 20 patients affected by iPPSD2 (PHP1A), diagnosed because of family history, ectopic ossification, or short stature, and carrying a GNAS mutation.

Methods: We gathered retrospective data for calcium, phosphate, thyrotropin (TSH), and PTH levels at regular intervals. PTH infusion testing (teriparatide) was performed in 1 patient.

Results: Patients were diagnosed at a mean age of 3.9 years and had a mean follow-up of 2 years. TSH resistance was already present at diagnosis in all patients (TSH, 13.3 ± 9.0 mIU/L). Over time, PTH levels increased (179 to 306 pg/mL; P < 0.05), and calcium levels decreased (2.31 to 2.21 mmol/L; P < 0.05), but phosphate levels did not decrease with age as expected for healthy individuals. One patient born with ectopic ossifications showed an increase in cyclic adenosine monophosphate upon PTH infusion, similar to that of controls, at 7 months of age, but an impaired response at 4 years of age.

Conclusions: In patients with iPPSD2 (PHP1A), PTH resistance and hypocalcemia develop over time. These findings highlight the importance of screening for maternal GNAS mutations in the presence of ectopic ossifications or family history, even in the absence of PTH resistance and hypocalcemia. The follow-up of these patients should include regular assessments of calcium, phosphate, and PTH levels.