Compound Heterozygous Mutations in the GNAS Gene of a Boy with Morbid Obesity, Thyroid-Stimulating Hormone Resistance, Pseudohypoparathyroidism, and a Prothrombotic State

Context: Pseudohypoparathyroidism type la and pseudopseudohypoparathyroidism are characterized by Albright's hereditary osteodystrophy (AHO), respectively, with and without hormone resistance. Both clinical conditions result from decreased expression or function of the alpha-subunit of the stimulatory G protein (Gs alpha) of adenylyl cyclase due to heterozygous inactivating mutations in GNAS. Homozygous GNAS defects have not been described. Objective: A genetic and functional GNAS study was undertaken in a boy with morbid obesity (body mass index Z-score of 5 at the age of 3 yr, with a body fat fraction of 40%, which is more than twice normal), TSH resistance, pseudohypoparathyroidism, and a prothrombotic state. Results: The boy was found to be a first case with a compound heterozygous GNAS defect: a de novo R231C mutation on the paternal allele and on the other allele a maternally inherited unique combination of three C to T nucleotide substitutions in exon 7 (I185I), intron 7 (IVS7 + 31), and exon 13 (N371N) leading to aberrant splicing of GNAS. Platelets of this boy displayed a pronounced Gs alpha hypofunction and were spontaneously hyperreactive resulting in a prothrombotic state due to extremely low cAMP levels. Conclusion: This report expands the human GNAS genotype-phenotype spectrum to include compound heterozygosity and a prothrombotic state. (J Clin Endocrinol Metab 93: 4844-4849, 2008)