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Context: Several endocrine disorders that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). PHP type I, associated with blunted PTH-induced nephrogenous cAMP formation and phosphate excretion, is subdivided according to the presence or absence of additional endocrine abnormalities, Albright’s hereditary osteodystrophy (AHO), and reduced Gsα activity caused by GNAS mutations.

Objective: We sought to identify the molecular defect in four unrelated patients who were thought to have PHP-Ia because of PTH and TSH resistance and mild AHO features.

Methods: Gsα activity and mutation analysis, and assessment of GNAS haplotype, methylation, and gene expression were performed for probands and family members.

Results: Two patients showed modest decreases in erythrocyte Gsα activity. Instead of Gsα point mutations …