ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Clin Endocrinol. 2018;89:56–64.

McCune Albright syndrome (MAS) is a rare disorder caused by somatic gain-of-function mutations of the GNAS gene [1]. This gene encodes the α-subunit of the Gs protein and its mutations are responsible for persistent stimulation of adenylyl cyclase and dysregulated production of cyclic AMP leading to persistent overactivity in the target tissues. The extent of the disease is determined by the proliferation, migration and survival of the cell in which the mutation spontaneously occurs during embryonic development. Therefore, patients with GNAS mutations show a wide range of phenotypes, differing in the degree of severity and the age at onset of the disease. The disease is characterized by a variable association of café-au-lait skin spots, hyperfunctioning endocrinopathies and skeletal lesions with fibrous dysplasia involving one (monostotic) or multiple (polyostotic) bones.

Approximately 20% of subjects with MAS have GH excess, which can worsen craniofacial bone disease leading to vision and hearing deficits related to cranial expansion [2]. Early diagnosis and management of GH excess improve clinical outcomes and decrease the incidence of optic neuropathy [3]. Treatment options include medical management, surgery, and radiotherapy. Somatostatin analogues represent the first line agents followed by Pegvisomant, alone or in combination.

This retrospective, multicentric cross-sectional study was performed in three different MAS cohorts (from Italy, USA and Australia) and included 195 patients. 37 subjects with MAS and GH excess were identified and compared to 34 subjects with MAS without GH excess, as control group. The aim was to define the impact of GH hyperactivity and its therapeutic management on the development of MAS comorbidities. All patients underwent a comprehensive characterization including baseline and dynamic hormone assessment, bone fibrous dysplasia imaging, audiology, neuro-ophthalmology and pain assessment.

GH excess was more common in males and was associated with increased head circumference, hearing defects, optic neuropathy, facial asymmetry and malignancies. Medical therapy (Octreotide alone 10–30 mg or associated with Pegvisomant 10–20 mg) was effective in lowering IGF-I levels within the treatment target (IGF-I Z-score between −2 and +2 SDS). Early start of treatment (below the age of 16) was associated with lower risk of optic neuropathy and reduced growth of pituitary adenomas. The clinical value of this paper is further strengthened by the diagnostic flow chart provided to drive the physicians in the management of MAS patients with suspicion of GH excess.

References: 1. Javaid MK, Boyce A, Appelman-Dijkstra N, Ong J, Defabianis P, Offiah A, Arunde P, Shaw N, Pos VD, Underhil A, Portero D, Heral L, Heegaard AM, Masi L, Monsell F, Stanton R, Dijkstra PDS, Brandi ML, Chapurlat R, Hamdy NAT, Collins MT. Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet J Rare Dis 2019;14:139.

2. Akintoye SO, Chebli C, Booher S, Feuillan P, Kushner H, Leroith D, Cherman N, Bianco P, Wientroub S, Robey PG, Collins MT. Characterization of gsp-mediated growth hormone excess in the context of McCune-Albright syndrome. J Clin Endocrinol Metab 2002;87:5104–5112.

3. Boyce AM, Glover M, Kelly MH, Brillante BA, Butman JA, Fitzgibbon EJ, Brewer CC, Zalewski CK, Cutler Peck CM, Kim HJ, Collins MT. Optic neuropathy in McCune-Albright syndrome: effects of early diagnosis and treatment of growth hormone excess. J Clin Endocrinol Metab 2013;98:E126–134.