Pseudohypoparathyroidism type 1B caused by methylation changes at the GNAS complex locus.

Area of Science:

• Endocrinology
• Genetics
• Epigenetics

Background:

• Pseudohypoparathyroidism type 1B (PHP1B) is a rare genetic disorder characterized by parathyroid hormone (PTH) resistance.
• PHP1B is associated with epigenetic alterations, specifically methylation changes at the GNAS locus, leading to impaired PTH signaling.

Observation:

• This report details a sporadic case of PHP1B presenting with broad GNAS methylation changes.
• The patient experienced autoimmune negative hypothyroidism years before developing PTH resistance.
• The methylation changes were presumed to stem from an unidentified genetic mutation outside the GNAS locus.

Findings:

• The GNAS methylation abnormalities resulted in PTH resistance primarily in the proximal renal tubules.
• Patients exhibit reduced urinary calcium excretion and efficient calcium and phosphate mobilization from bone.
• Treatment involved calcium supplementation and calcitriol administration.

Implications:

• This case expands the understanding of the genetic heterogeneity underlying PHP1B.
• It underscores the potential for extragenic mutations to cause GNAS methylation defects.
• Early recognition of PHP1B and its associated endocrine and autoimmune conditions is crucial for management.