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Characterization of gsp-Mediated Growth Hormone Excess in the Context of McCune-Albright Syndrome

Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research (S.O.A., N.C., P.G.R., M.T.C.), National Institutes of Health (NIH), Bethesda, Maryland 20892-4320; Department of Nursing (S.B.), Developmental Endocrinology Branch (P.F.), National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892-4320; Molecular Endocrinology Branch (D.L.), National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-4320; Department of Orthopedic Surgery, University of Maryland (C.C.), Baltimore, Maryland 21201; Biomedical Computer Research Institute (H.K.), Philadelphia, Pennsylvania 19115; Department of Experimental Medicine (P.B.), University of Rome "La Sapienza," I-100161 Rome, Italy; and Department of Pediatric Orthopedic Surgery (S.W.), Dana Children’s Hospital, Tel Aviv Medical Center, 64139 Tel Aviv, Israel

Address all correspondence and requests for reprints to: Michael T. Collins, M.D., Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30, Room 228, MSC 4320, Bethesda, Maryland 20892-4320. E-mail: mcollins{at}dir.nidcr.nih.gov.

Abstract

McCune-Albright syndrome (MAS) is a disorder characterized by the triad of café-au-lait skin pigmentation, polyostotic fibrous dysplasia of bone, and hyperfunctioning endocrinopathies, including GH excess. The molecular etiology of the disease is postzygotic activating mutations of the GNAS1 gene product, G_s. The term gsp oncogene has been assigned to these mutations due to their association with certain neoplasms. The aim of this study was to estimate the prevalence of GH excess in MAS, characterize the clinical and endocrine manifestations, and describe the response to treatment.

Fifty-eight patients with MAS were screened, and 22 with stigmata of acromegaly and/or elevated GH or IGF-I underwent oral glucose tolerance testing. Twelve patients (21%) had GH excess, based on failure to suppress serum GH on oral glucose tolerance test, and underwent a TRH test, serial GH sampling from 2000–0800 h, and magnetic resonance imaging of the sella.

We found that vision and hearing deficits were more common in patients with GH excess (4 of 12, 33%) than those without (2 of 56, 4%). Of interest, patients with a history of precocious puberty and GH excess who had reached skeletal maturity achieved normal adult height despite a history of early epiphyseal fusion. All 9 patients tested had an increase in serum GH after TRH, 11 of 12 (92%) had hyperprolactinemia, and all 8 tested had detectable or elevated nighttime GH levels. Pituitary adenoma was detected in 4 of 12 (33%) patients. All patients with elevated IGF-I levels were treated with cabergoline (7 patients), long-acting octreotide (LAO; 8 patients), or a combination of cabergoline and LAO (4 patients). In six of the seven patients (86%) treated with cabergoline, serum IGF-I decreased, but not to the normal range. In the eight patients treated with LAO alone, IGF-I decreased, and, in four, returned to the normal range. The remaining 4 patients were treated with a combination of cabergoline and LAO. For them, symptoms of GH excess diminished, and IGF-I decreased further, but did not enter the normal range.

GH excess is common in MAS and results in a distinct clinical phenotype characterized by inappropriately normal stature, TRH responsiveness, prolactin cosecretion, small or absent pituitary tumors, a consistent but inadequate response to treatment with cabergoline, and an intermediate response to LAO.

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