TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib)

Area of Science:

• Endocrinology
• Genetics
• Epigenetics

Background:

• Pseudohypoparathyroidism type Ib (PHP-Ib) is characterized by parathyroid hormone (PTH) resistance, leading to hypocalcemia and hyperphosphatemia.
• This rare disorder stems from GNAS gene methylation abnormalities, potentially affecting other hormone pathways like thyroid-stimulating hormone (TSH).
• Clinical manifestations of hormone resistance beyond PTH are often diagnosed late, after hypocalcemia becomes apparent.

Purpose of the Study:

• To investigate the potential of hypothyroidism as an initial clinical presentation of PHP-Ib.
• To identify GNAS methylation changes and STX16 deletions in pediatric patients initially diagnosed with hypothyroidism.
• To emphasize the importance of monitoring PTH, calcium, and phosphate levels in patients with unexplained hypothyroidism.

Main Methods:

• Analysis of GNAS methylation patterns (loss of methylation [LOM] and gain of methylation) at specific exons (AS, XL, A/B, NESP55).
• Genetic analysis to detect STX16 deletions.
• Clinical and laboratory data review of pediatric patients with subclinical or overt hypothyroidism.

Main Results:

• Four pediatric patients initially diagnosed with hypothyroidism later developed overt PTH resistance consistent with PHP-Ib.
• Epigenetic GNAS abnormalities (LOM at AS, XL, A/B; gain of methylation at NESP55) were found in three patients.
• A maternally inherited STX16 deletion was identified in the fourth patient.
• No GNAS methylation changes were detected in a larger cohort of patients with subclinical hypothyroidism.

Conclusions:

• Hypothyroidism can be the primary presenting symptom of PHP-Ib, preceding PTH resistance.
• Comprehensive genetic and epigenetic evaluation, including GNAS methylation analysis, is essential for diagnosing PHP-Ib in patients with unexplained hypothyroidism.
• Monitoring PTH, calcium, and phosphate levels is critical for early detection and management of PHP-Ib to prevent hypocalcemia.