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

Center of Molecular and Vascular Biology (K.F., B.I., C.T., C.W., C.V.G.) and Department of Pediatrics (J.J., M.V.H., F.d.Z., C.V.G.), University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Kathleen Freson, Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: Kathleen.freson{at}med.kuleuven.be.

Context: Pseudohypoparathyroidism type Ia 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 -subunit of the stimulatory G protein (Gs) 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 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.