In patients with sexual precocity, baseline gonadotropin (ie, LH and FSH) and gonadotropin levels stimulated by gonadotropin-releasing hormone (GnRH) are below normal limits. In females who are affected, estrogen levels are elevated above the age-adjusted expected level. Similarly, males who are affected have elevated serum free and total testosterone levels. Androgen levels in female patients remain within normal limits.
Precocious puberty in MAS is gonadotropin-independent. Therefore, the finding of elevated estradiol levels and suppressed or undetectable gonadotropin levels is diagnostic of gonadotropin-independent puberty. However, estrogen secretion is frequently episodic in MAS; thus, multiple assays over time may be necessary to demonstrate an elevation in estradiol levels.
Because secretion of LH and FSH is pulsatile, random gonadotropin levels in early puberty are often equal to prepubertal levels. Additionally, significant pulses may only occur at night in early puberty. An LH-releasing hormone (LH-RH) stimulation test (gonadorelin hydrochloride 100 mg intravenously [IV]) can help to differentiate between central gonadotropin-dependent and gonadotropin-independent precocious puberty.
In this test, serum is sampled for LH and FSH at 0 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after administration of LH-RH. Suppressed or undetectable levels of LH and FSH after administration of LH-RH are consistent with MAS.
-
Base of the skull computed tomography scan showing extensive fibrous dysplasia in McCune-Albright syndrome. Note the asymmetrical affectation, with near-total obliteration of various neural foramina at the base of the skull. This degree of fibrous dysplasia can result in multiple cranial nerve compression neuropathies, of which blindness and deafness (from involvement of cranial nerves II and VIII) are among the most disabling.
-
Café au lait spot. This is a fairly large, irregular-edged ("coast-of-Maine" variety) lesion. It presents as a brownish, otherwise-asymptomatic macule/patch. The degree of pigmentation is fairly uniform.
-
Fibrous dysplasia of a long bone characterized by focal bony expansion, patchy areas of sclerosis, and bony cyst formation in McCune-Albright syndrome.
-
Plain skull radiograph in a typical McCune-Albright syndrome case shows marked macrocrania, frontal bossing, and markedly thickened bony table in patchy areas, particularly at base of skull and occiput. Skull also shows hair-on-end appearance, which needs to be differentiated from similar radiologic appearances in Paget disease or poorly controlled hemoglobinopathy (eg, beta-thalassemia, sickle cell disease).
-
Large café-au-lait patches around shoulder in child with McCune-Albright syndrome.
-
Lucency characteristic of polyostotic fibrous dysplasia in patient with McCune-Albright syndrome.
-
Café-au-lait pigmentation in case of McCune-Albright syndrome. Lesion does not cross midline, which is typical of pigmented lesions in this syndrome.
-
Adrenal hyperplasia with nodular elements in adrenal gland isolated from infant with infantile Cushing syndrome in the context of McCune-Albright syndrome. DNA isolated from nodular tissue was determined to have activating Gs alpha mutation (GNAS1), whereas DNA isolated from surrounding tissue did not contain this mutation.
-
The G protein cycle begins with ligand binding to a 7-transmembrane domain G protein-coupled receptor (GPCR). Binding of the cognate ligand forms a ligand-receptor complex, which then stimulates an exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the alpha subunit of the stimulatory G protein (Gs alpha). This activates the alpha subunit, which subsequently stimulates adenylyl cyclase (AC) to increase production of cyclic adenosine monophosphate (cAMP). The alpha subunit contains intrinsic guanosine triphosphatase (GTPase) activity, which cleaves a phosphate group from GTP, converting it to GDP, and thus inactivates the alpha subunit. The inactivated alpha subunit is now ready to be reactivated by ligand-receptor binding, so that the next cycle of signal transduction can occur.
-
Mutations in McCune-Albright syndrome inactivate intrinsic guanosine triphosphatase (GTPase) activity, thus preventing inactivation of the "turned-on" Gs alpha subunit. Once activated, the mutated Gs alpha subunit is able to continuously stimulate adenylyl cyclase, even in absence of ligand binding to its cognate GPCR receptor. The result is elevation of intracellular cyclic adenosine monophosphate (cAMP) and continual stimulation of downstream cAMP signaling cascades.
