The Clinical Spectrum of McCune-Albright Syndrome and Its Management

Abstract

McCune-Albright syndrome (MAS) is a rare, mosaic disorder presenting along a broad clinical spectrum. Disease arises from somatic-activating GNAS mutations, leading to constitutive Gαs activation and ligand-independent signaling of the Gαs-coupled protein receptor. The phenotype is largely determined by location and extent of tissues in which the GNAS mutation is expressed, as well as the pathophysiologic effects of Gαs activation within these tissues. Patients pre-sent clinically with a variable combination of fibrous dysplasia of bone (FD), café-au-lait skin macules, and hyperfunctioning endocrinopathies. In bone, Gαs leads to impaired differentiation of skeletal stem cells and formation of discrete, expansile FD lesions, resulting in fractures, pain, and functional impairment. A systematic approach to diagnosis and management is critically important to optimize outcomes for patients with FD/MAS. There are no medical therapies capable of altering the disease course in FD; however, screening and treatment for endocrinopathies can mitigate some skeletal morbidities. This review summarizes current understanding of MAS pathophysiology, describes the spectrum of clinical features, and includes a detailed discussion of the recommended approach to diagnosis and management.

Keywords: Fibroblast growth factor 23; Fibrous dysplasia; Gαs; Metabolic bone disease; Mosaicism.

Figure 1.. Radiographic and histologic features of fibrous dysplasia (FD).

(A) Axial CT with diffuse skull base FD. Note the characteristic homogeneous, “ground glass” appearance of FD bone. (B) Radiograph of the spine with scoliosis secondary to vertebral FD (white arrow). (C) Femoral FD with a classic varus (“shepherd’s crook”) deformity (white arrow). (D, E) FD histology: H&E stain demonstrating classic curvilinear trabeculae and hypercellular fibrous stroma; (D) low power view and (E) high power view demonstrating signs of increased remodeling including Sharpey fibers (open arrows) and abundant osteoclasts (closed arrows).

Figure 2.. Clinical and radiographic features of McCune-Albright Syndrome (MAS).

(A) An infant with a typical appearing café-au-lait macule and breast budding; (B) corresponding pelvic ultrasound shows a large estrogen-producing ovarian cyst. (C) Adolescent with typical appearing café-au-lait macules affecting her neck and jaw, and a goiter (arrow) consistent with hyperthyroidism; (D) corresponding thyroid ultrasound demonstrating an abnormal, heterogenous cystic gland. (E) Patient with uncontrolled growth hormone excess resulting in macrocephaly and vision loss; (F) T1-weighted MRI with large growth hormone-secreting pituitary adenoma (arrow) and thickened cranial base secondary to fibrous dysplasia.