The McCune-Albright syndrome (MAS) was described independently by Fuller Albright and Donovan McCune in 1937 (1,2). The classical triad of MAS, firstly reported in 1937 and subsequently confirmed in several reports, consists of polyostotic fibrous dysplasia (FD), skin hyperpigmentation (cafe-au-lait spots), and endocrine dysfunction (3-5). Typical endocrinopathies are precocious puberty, especially seen in females, hyperthyroidism, growth hormone excess, hyperprolactinemia, and hypercortisolism. The onset of these manifestations is usually during infancy and childhood. Since specific treatment is required, the prognosis depends on the severity of each individual endocrine manifestation. Among non-endocrine manifestations, fibrous dysplasia of bone (FD) is mostly polyostotic and frequently causes fractures needing surgical and orthopedic treatment. Since previous studies have suggested the overall prognosis of patients with McCune-Albright syndrome to be non-fatal, recent data have drawn the attention to non-endocrine affections, including hepatobiliary dysfunction and cardiac disease, which are probably important risk factors for early death (6).

Patients with MAS display mosaicism of activating somatic mutations of the gene encoding the alpha-subunit of Gs (GNAS1) (7,8). Mutations of GNAS1 have been detected in all affected subjects and Arg²⁰¹ is the only location so far reported. Mutant Gsa is expressed in the affected endocrine organs, as well as in tissues not classically involved in MAS, the highest proportion of mutant alleles being found in regions of abnormal proliferation. This mosaic distribution is consistent with the hypothesis that this syndrome is due to a somatic mutation in Gsa gene occurring as an early postzygotic event. Thus, the clinical presentation of each individual is dependent on the particular distribution of affected cells, causing a broad spectrum of endocrine and non-endocrine manifestations, ranging from one or two mild clinical signs with excellent long-term prognosis to a severe life-threatening multiorgan disease.
This review will briefly revisit the clinical manifestations of the disease (summarized in table 1), as well as recent data on genetics and molecular diagnostic.

Table 1

Endocrine dysfunction
Precocious pseudopuberty
         Precocious puberty is the most frequent endocrinopathy in females with MAS and it was described in the first reports as a hallmark of the disease (1,2). It is estimated that its prevalence ranges from 64 to 79% in girls, whereas it is much rarer in boys (15%) (reviewed in ref. 5). Pubertal signs often onset before the age of 4 years and, typically, they are characterized by alternate phases of sexual maturation progression and regression. Ovaries of affected girls show multiple autonomous follicular cysts that secrete estrogen and are therefore accompanied by pre-pubertal levels of serum gonadotropins. Curiously, these cysts spontaneously enlarge and regress, thus explaining the atypical clinical course of hyperestrogenism. It is also frequent to observe a precocious shift from a GnRH-independent puberty to a GnRH-dependent puberty. Independently from the cause, precocious puberty often leads to definitive short stature (5,9-12).
         In boys, precocious activation of Leydig cell androgen secretion results in pubertal spermatogenesis, leading to testicular enlargement, and in the development of secondary sex characteristics. However, sexual precocity is rare in MAS males while isolated testicular enlargement is frequently observed. In a boy with macro-orchidism and signs of Sertoli cell hyperactivity but no signs of hyperandrogenism, microdissection of a testicular biopsy demonstrated that the mutated GNAS1 allele was present only in Sertoli cells, resulting in isolated Sertoli cell hyperfunction (13,14). Lack of occurrence of the mutation in Leydig cells may explain why sexual precocity is rarely observed in boys with MAS.

Thyroid disorders
         Nodular and diffuse goiter, with or without hyperthyroidism, has been reported in association with MAS and, taken together, these abnormalities represent the second most endocrinopathy associated with MAS. Pathophysiology consists of autonomous production of thyroid hormones due to GNAS1 mutations that activate the TSH-mediated intracellular signaling, thus determining both thyroid hyperfunction and growth. Thyroid disorders are generally more common in girls than in boys, and the spectrum of clinical presentation ranges from asymptomatic subclinical hyperthyroidism to thyrotoxic crisis. Thyroid dysfunction, like that of the ovaries, is associated with structural abnormalities in the gland itself, together with suppressed levels of the respective stimulating hormone. Its prevalence has been overall estimated from 2.7 to 21.9% (5). The largest review of thyroid disorders in MAS includes all the cases reported in the literature since the first report in 1936 up to 1997, and it includes 64 cases, 41 females and 23 males, with a median onset age of 10 years (range: birth to 48 years) (15). Ultrasonography revealed thyroid abnormalities in most patients, with nodular goiter in 19 subjects (14 with and 5 without hyperthyroidism), diffuse goiter in 23 patients (20 with and 3 without hyperthyroidism), and 22 cases with subclinical or clinical hyperthyroidism without thyroid enlargement (15). Overall, the prevalence of a real goiter is still controversial, ranging from very low rates to 71.4% (5,15,16). The reason why the same GNAS1 mutation, that presumably affects all thyrocytes, may determine such variable clinical manifestations either in thyroid function and in thyroid growth is still unknown.
         The differential diagnosis between MAS-related thyropathies and other forms of neonatal/juvenile hyperthyroidism are summarized in Table 2 (17).

Table 2:

Interestingly, a report by Feuillan and colleagues described 8 girls with hyperthyroidism and MAS in whom only tri-iodothyronine was elevated in the presence of normal thyroxine levels, postulating a high deiodinase 2 activity in MAS (16). This hypothesis has not been demonstrated so far and the pathophysiology of this phenomenon does not seem clear anyway. There are no data on the natural history of the disease, since treatment is always started in symptomatic disease. A definitive therapy such as thyroidectomy or radioactive iodine is often required, since hyperthyroidism tends to recur after antithyroid drug withdrawal (15,18).
         Finally, two cases of thyroid carcinoma arisen from a nodule bearing the GNAS1 activating mutation have also been reported in patients with MAS (19).

Growth hormone (GH) and prolactin (PRL) excess
         GH hypersecretion in MAS was first described by Scurry and colleagues in 1964 (20). Since then, most of the data on GH excess in MAS come from single case reports, with the exception of one large series including 12 patients (21), with therefore non-definitive data on this aspect of the disease (22). According to the largest study, the incidence of GH excess among patients with MAS has been assessed as up to 21% with an equal sex ratio (21). The age of onset is usually adolescence, before the age of 20 years, thus leading to either acromegaly or gigantism depending on bone age. The clinical expression of GH excess can be masked because of precocious puberty or craniofacial fibrous dysplasia, indicating the necessity for routine screening in all MAS patients. Hyperprolactinemia is an accompanying finding in most patients (>80%), whereas it has never been reported as an isolated form (23). The pathogenesis of GH hypersecretion in MAS is not completely understood as many findings, such as GH responsiveness to GHRH and preserved nocturnal GH increase, seem to indicate abnormal hypothalamic GHRH release rather than primary pituitary dysfunction. Moreover, pituitary tumors have been found in some patients on CT scans or MRI but much less frequently than in non-MAS patients with GH excess. In 1984, Kovacs and colleagues reported mammosomatotropic hyperplasia in the excised pituitary from a 11-year-old girl with MAS (24). The transition from hyperplasia to adenoma could explain the variety of sellar radiographic findings in such patients.
         Medical treatment is often the only option in MAS patients with GH excess, as trans-sphenoidal surgery is usually restricted due to both massive thickening of the skull base and the frequent absence of documented pituitary tumors. The use of bromocriptine, cabergoline and octreotide, or the combination of these, has shown variable results, whereas pegvisomant, a GH receptor antagonist, is a new promising option, having been recently tested in a subset of patients with MAS (25,26).

Hypercortisolism
         ACTH-independent Cushing’s syndrome may occasionally occur in patients with MAS, its prevalence being quite low (around 5%). Cushing’s syndrome is diagnosed in most cases during the neonatal period or infancy, often being, when present, the first clinical sign of the disease (27). Patients have the typical clinical and laboratory signs of Cushing’s syndrome, including severe effects on bone density, with frequent spontaneous fractures and delayed bone maturation (28). There is evidence of autonomous cortisol secretion due to activating GNAS1 mutations in the adrenal gland, leading to macronodular adrenal hyperplasia (27). Despite occasional reports on spontaneous resolution, most patients require early adrenalectomy. Recently, treatment with metyrapone has been proposed as an alternative option in these patients (29).

Non-endocrine dysfunction
Fibrous dysplasia (FD)
FD is a focal and benign fibrous bone lesion that was first described in 1942 (30; reviewed in refs. 4&5). While most patients with isolated FD have a single bone lesion, FD associated with MAS is predominantly characterized by multiple lesions (polyostotic fibrous dysplasia) (4,31). Prevalence of FD in MAS ranges from 46-98% with an onset of symptoms mostly during infancy (5). FD lesions are typically found in the long bones of the extremities, the femur being affected in virtually all cases, the ribs, and craniofacial bones while they are rarely found in hands, feet, or spine (31-33). FD lesions may be asymptomatic but often lead to bone deformity, pain and pathological fractures with a peak incidence between 7 and 12 years age (31-33). In addition, cranial nerve compression syndromes due to progressive FD lesions have been reported (34).
FD is a lesion composed mainly of fibrous tissue that originates in the medullary cavity and expands concentrically outward into the surrounding cortical bone through the bone-resorbing activity of osteoclasts, which are present in greater numbers in the periphery (35,36). Most of the cells are immature mesenchymal cells with a spindle-shaped fibroblastic appearance and express alkaline phosphate and other osteoblast-specific proteins (36). The involvement of the proto-oncogene c-fos and cytokines such as IL-6, with subsequent hyperproliferation and incomplete differentiation of osteoblasts together with osteoclast activation,  have been suggested to play a role in the biochemical pathways leading to FD (37,38).
Bisphosphonates have been shown to have therapeutic benefit, presumably due to their antiresorptive activity (reviewed in ref. 39). Rarely, these lesions expand beyond the normal boundaries of the cortical bone or undergo malignant degeneration (4). In any case, there is a tendency of extension and progression of FD lesions, with deformities and physical impairment that often lead to the need of a wheelchair (33).

Skin hyperpigmentation
         The café-au-lait spots are one of the most obvious signs of MAS and present as single or multiple tan-brown hyperpigmented flat macules with irregular ("coast of Maine") borders developing during infancy and becoming even more obvious with age or with sun exposure (1,2). Their prevalence in MAS has been estimated from 53.1-92.5% (5). These lesions are often limited to one side of the body, which usually corresponds to the side with bone involvement and generally do not cross the midline. Moreover, they are typically arranged in a segmental pattern, which follows the developmental lines of Blaschko (40). Malignant transformation of these lesions has not been described. Melanocytes cultured from these lesions show increased intracellular cAMP levels, increased numbers of dendrites and melanosomes, and increased levels of tyrosinase, the rate-limiting enzyme for the production of melanin (41).

Hyperphosphaturic hypophosphatemia
Hyperphosphaturic hypophosphatemic rickets or osteomalacia has been associated with MAS and polyostotic FD, with a prevalence of renal phosphate wasting up to 50% of patients (42,43). Increased intracellular cAMP levels in renal proximal tubules leading to decreased phosphate reabsorption, even in the absence of hyperparathyroidism, has been proposed as one potential mechanism for hypophosphatemia in MAS patients, but this hypothesis has not been confirmed (4). In addition to increased phosphate clearance, patients have other evidence of renal tubular dysfunction, including aminoaciduria and mild proteinuria (42). Recently, the factor causing hypophosphatemia in MAS was indicated to be fibroblast-growth factor 23 (FGF-23), although the possibility of some other humoral factors has not been excluded (44,45). Serum levels of FGF-23 are increased in MAS patients with FD compared to normal age-matched controls, and are significantly higher in MAS patients with renal phosphate wasting compared to those without (44).
Phosphate loss leads to profound skeletal effects, such as weakening of the mechanical resistance of bone and promotion of bowing and deformity. Thus, evaluation of phosphate metabolism is mandatory in all patients with MAS.

Other non-endocrine manifestations
The abnormalities in MAS patients are generally restricted to bone, skin, and endocrine organs, and therefore there is little effect on mortality (3,32). However, some patients also develop one or more non-endocrine abnormalities that may markedly increase morbidity and mortality (6). Non-endocrine organs that may be affected in MAS include the liver, heart, thymus, spleen, bone marrow, gastrointestinal tract, and brain (5-7). Liver abnormalities associated with MAS include severe neonatal jaundice and persistently elevated liver enzymes, with histological findings ranging from normal to giant cell hepatitis (6,45). Cirrhosis with liver failure and need for transplantation has been reported in one case, but it was in association with hepatitis C (6). Cardiac abnormalities perhaps represent the major risk factors for long-term survival, their clinical spectrum including hypertension, cardiomegaly associated with atypical myocyte hypertrophy, persistent tachycardia, and sudden infant death (SIDS) (6).

Other rare features of MAS include thymic hyperplasia, myelofibrosis, gastrointestinal polyps, pancreatitis, breast cancer, microcephaly, and other neurological abnormalities (1,2,6). Very recently, testicular microlithiasis in boys affected with MAS was also reported, but the pathogenesis of this defect remains unclear (47).

Genetics and molecular diagnosis
Genetics
Activating mutations in GNAS1 (the so-called gsp oncogene) (48) are known to be involved in the pathogenesis of different human endocrine diseases, such as sporadic endocrine tumors, in particular GH-secreting pituitary adenomas and autonomous thyroid adenomas, and of course MAS. GNAS1 activating mutations are missense mutations leading to amino acid substitution of either residue Arg201 or Gln227 (Arg201 only in MAS). These two residues are catalytically important for GTPase activity; therefore, these mutations cause constitutive activation by disrupting the signalling turn-off mechanism. Growth and hormone release in many endocrine glands are stimulated by trophic hormones that activate Gsa-cAMP pathways. As a matter of fact, in MAS endocrine manifestations affect those glands sensitive to trophic agents acting through cAMP-dependent pathway, leading to autonomous hyperfunction of gonads, pituitary, thyroid and adrenal cortex (7,8). Somatic gsp mutations are also present in FD lesions from patients with or without other features of MAS (49,50). MAS is virtually never inherited, and germ-line gsp mutations are considered lethal (40), although a possible germ-line mutation was reported in one patient with severe manifestations (51).
The human Gsα gene maps on a locus under complex imprinting control with multiple maternally, paternally and biallelically alternatively spliced transcripts (reviewed in ref. 4). Recent reports demonstrated that in the thyroid, the gonad and the pituitary Gsa transcription mainly derives from the maternal allele (52-55). Moreover, it has been demonstrated that in most gsp positive GH-secreting pituitary tumors the mutation occurs on the maternal allele (52,53), most likely indicating that the same mutations on paternal allele are clinically silent. As a matter of fact, in MAS, gigantism/acromegaly seem to occur only in those patients carrying the activating mutation on the maternal allele, while gsp mutations may indifferently lay on the paternal or the maternal allele in all the other patients (56). It is therefore conceivable that paternal mutations in tissues such as thyroid and gonad with variable, but not negligible paternal contribution to Gsa expression (about 20-30% in our laboratory, ref. 53), are still able to have clinical significance.

Molecular diagnosis
Accuracy and sensitivity in the molecular diagnosis of MAS is mandatory for optimal therapeutic strategy and adapted follow-up, especially for incomplete clinical forms of MAS. The somatic nature of mutations in the GNAS gene in McCune-Albright syndrome and isolated fibrous dysplasia makes their identification often very difficult. Conventional methods for the detection of mosaic mutations of GNAS have required polymerase chain reaction analysis of genomic DNA from affected tissues or multiple rounds of tandem polymerase chain reaction and endonuclease digestion to enrich for mutant alleles DNA from other tissues (57). Most recently, a new diagnostic method using peptidic nucleic acid (PNA) primers that specifically block synthesis from the wild type allele, has been tested to detect low copy numbers of mutant GNAS alleles in DNA from peripheral blood cells from patients with MAS and FD (58,59). More than 100 patients have been screened so far with promising results, indicating PNA clamping as a rapid, reliable, and economical method to diagnose MAS.

Acknowledgements