The Journal of clinical endocrinology and metabolism | 2021
Progression of PTH-resistance in autosomal dominant pseudohypoparathyroidism type Ib due to maternal STX16 deletions.
Abstract
CONTEXT\nMaternally inherited STX16 deletions that cause loss-of-methylation at GNAS exon A/B and thereby reduce Gsα expression are the most frequent cause of autosomal dominant pseudohypoparathyroidism type 1B (AD-PHP1B). Early identification of these disease-causing variants in the children of affected and unaffected female carriers would prompt treatment with calcium and calcitriol, once PTH levels increase, thereby preventing hypocalcemia and associated complications.\n\n\nOBJECTIVES\nDetermine when PTH and calcium abnormalities develop after birth if a STX16 deletion is inherited maternally.\n\n\nPATIENTS AND METHODS\nForty-four children of affected (n=7) or unaffected (n=7) females with a STX16 deletion were investigated for the presence of these variants. If a deletion was identified, measurement of PTH, calcium, phosphate, and TSH was advised.\n\n\nRESULTS\nThe STX16 deletion that causes AD-PHP1B was identified in 25 children. Pre-treatment laboratory results were available for 19 of those cases. Elevated PTH levels were detected by 2 years of age and these were progressively higher if laboratory testing was first performed after establishing the genetic defect later in life. Total serum calcium levels remained within normal limits until about five years of age. TSH levels showed no consistent rise over time.\n\n\nCONCLUSION\nEstablishing whether a STX16 deletion is inherited from a female carrier of a disease-causing variant rapidly establishes the diagnosis of AD-PHP1B. Several years before overt hypocalcemia developed, PTH levels increased thereby establishing the onset of PTH-resistance. Our findings provide diagnostic guidance and when treatment with calcium and calcitriol should be considered, in order to prevent hypocalcemia and associated sequelae.