Endocrine Abstracts

Fibrous dysplasia (FD) is a focal bone lesion composed of immature mesenchymal osteoblastic precursor cells which may occur at one site (monostotic) or multiple sites (polyostotic) in individual patients. Polyostotic FD may also be associated with other manifestations, including hyperpigmented (café-au-lait) skin lesions, gonadotropin-independent sexual precocity, and/or other endocrine and nonendocrine manifestations, and these constellation of features are known as the McCune–Albright syndrome (MAS). Other endocrine manifestations may include TSH-independent thyroid nodules with hyperthyroidism, ACTH-independent adrenal adenomas or hyperplasia with hypercortisolism, and growth hormone-secreting pituitary tumors. The underlying genetic mutations in MAS/FD lead to constitutive activation of G_sα, the ubiquitously expressed G protein α-subunit which couples receptors to intracellular cAMP generation, via amino acid substitutions that disrupt the intrinsic GTPase ‘turn-off’ mechanism. These mutations are somatic and dominant-acting, and in MAS occur during early development resulting in a widespread mosaic of normal and mutant-bearing cells. Similar mutations, presumably occurring in later development and therefore with a more limited tissue distribution, are also present in 40% of growth hormone-secreting pituitary tumors, monostotic and polyostotic FD, intramuscular myxomas, and less commonly in other endocrine tumors. The constitutive activation of G_sα explains why MAS patients have stimulation of multiple peripheral endocrine glands in the absence of circulating stimulatory pituitary hormones and increased skin pigment, which is normally induced by melanocyte-stimulating hormone via G_sα/cAMP. Increased cAMP in bone marrow stromal cells leads to FD by increased proliferation and abnormal differentiation of these cells. As G_sα is imprinted and expressed only from the maternal allele in some tissues (eg. pituitary somatotrophs), parental origin of the mutated allele may also affect the clinical presentation.