McCune-Albright Syndrome 

McCune-Albright syndrome (MAS) is defined as the association of polyostotic fibrous dysplasia (PFD) (see image below), precocious puberty, café au lait spots, and other endocrinopathies due to the hyperactivity of various endocrine glands.^{[1, 2]}

Fuller Albright first described this syndrome in 1937. The first case described by Donovan McCune had the classic triad and hyperthyroidism. Other cases have been retrospectively identified since antiquity, such as the Tegernsee Giant, who probably had MAS and acromegaly.

MAS has been shown to be due to a postzygotic activating mutation of the Gs alpha gene in the affected tissues. For semantic reasons, differentiating MAS from Albright hereditary osteodystrophy (AHO) is important. AHO, which also is caused by a Gs alpha gene defect, results in pseudohypoparathyroidism or pseudopseudohypoparathyroidism.

The precocious puberty^{[3, 4]} associated with MAS typically is gonadotrophin independent. Among the endocrine syndromes described in association with MAS are (1) hyperthyroidism, (2) acromegaly, (3) gonadotropinomas, (4) hyperprolactinemia, (5) Cushing syndrome, (6) hyperparathyroidism, (7) gynecomastia, and (8) hypophosphatemic rickets.^{[5, 6]} Some severely affected patients may present with associated hepatic, cardiac, and GI dysfunction (ie, elevated hepatic transaminases, GI polyposis, and cardiomyopathy).^[7]

There exist fewer than 10 well-documented cases of MAS associated with Cushing syndrome. This syndrome is distinct, unlike all other endocrinopathies of MAS, which are slowly progressive and persistent without treatment. Interestingly, several cases of Cushing syndrome in the context of MAS have regressed within the first few years following onset. Cushing syndrome associated with MAS is predominantly due to adrenocortical hyperfunction. Most of these cases have been described in infants or children, and the medical management has been suboptimal. Bilateral adrenalectomy is the usual method of treatment. In some cases, Cushing syndrome is of a transitory nature. Pituitary-based Cushing disease in the setting of MAS is far less common. In fact, no cases of Cushing disease have been described in patients with MAS thus far in the literature.

Approximately 30 well-documented cases of fibrous dysplasia (FD) associated with single or multiple intramuscular or juxtamuscular myxomas (Mazabraud syndrome [MS]) have been identified.^{[8, 9]} First described in 1926 by Henschen, this syndrome has been associated with precocious puberty and with café au lait spots (see image below) and occurs in association with MAS. The myxomas associated with this condition can occur in virtually any location in the muscular system. The exact etiopathogenesis of MS is unclear, because no activating mutations of the Gs alpha gene have been demonstrated in patients with this clinical variant.

Simple myxomas typically are benign and solitary, with peak incidence in the sixth and seventh decades. The age of peak incidence for this syndrome is young adulthood, and the tumors commonly are multiple.

The main sites of involvement by the myxomas are the large muscles of the thighs, buttocks, and shoulders. They often are located close to FD lesions but typically remain separate from them. They commonly recur, even after attempts at surgical resection.

Only a few cases of malignant transformation of skeletal lesions have been described in the setting of MAS. Observed malignancies include (1) osteosarcomas (most common), (2) chondrosarcomas, (3) fibrosarcomas, and (4) liposarcomas. These malignancies occur most commonly in the setting of therapeutic irradiation exposure.

Females may have a greater risk for breast cancer, probably due to their prolonged exposure to elevated estrogen levels. The underlying Gs alpha gene mutation also may play a role in this. For the same reasons, these patients also appear to be at an increased risk for thyroid malignancies (a novel finding by the US National Institutes of Health [NIH]) and for secondary osseous malignancies.

Hypophosphatemic rickets is another potential complication that may worsen the bone disease associated with PFD. This is due to tubulopathy characterized by hyperphosphaturia. In patients with MAS, hyperphosphaturia may be due to a phosphatonin similar to that seen in patients with tumor-induced osteomalacia, which appears to be fibroblast growth factor 23 (FGF-23). While on vitamin D and phosphorus supplements, patients with MAS and hypophosphatemic rickets must be monitored closely for hypercalcemia and secondary hyperparathyroidism.

Most of the clinical features of McCune-Albright syndrome (MAS) are caused by a noninherited postzygotic activating mutation of the Gs alpha gene that results in overproduction of a variety of protein products in a fashion independent from normal feedback control mechanisms.^[1] The Gs alpha subunit is a component of the G-protein complex, which couples hormone receptors to adenylate cyclase (the intracellular second messenger) in a submembrane site. It then mediates the cellular effects of hormone binding. These genetic findings have been noted and confirmed in various tissue specimens from patients with MAS.^[10]

Precocious puberty associated with MAS is gonadotrophin independent. In girls, it is the result of estrogen excess from ovarian follicular cysts.^[11] Because the sexual precocity associated with MAS is gonadotrophin independent, it is more accurately described as pseudoprecocious puberty.

Frequency

United States

The exact incidence or prevalence of McCune-Albright syndrome in the United States and internationally is unknown. It is thought to be a very rare disorder.^[1]

International

Fibrous dysplasia is an infrequent, nonmalignant condition of the bone. In a review of radiographs from 82,000 patients, only 23 cases of polyostotic FD (PFD) were found. Polyostotic variants of the disease are uncommon, and McCune-Albright syndrome is even less common. The relative incidence of monostotic fibrous dysplasia is 70%, while those of PFD and MAS are 30% and less than 3%, respectively.

Mortality/Morbidity

Mortality and morbidity related to McCune-Albright syndrome result from the fractures, malignancies, endocrine disorders, and other conditions associated with this syndrome.

Race

McCune-Albright syndrome has no ethnic predilection.

Sex

Both sexes are affected by McCune-Albright syndrome, but cases involving females have been reported more frequently than have those involving males, presumably due to the dramatic presentation characterized by early onset of puberty, menarche, and thelarche.

Age

McCune-Albright syndrome (MAS) can be diagnosed at birth (if café au lait spots are observed). In addition, MAS can be definitely diagnosed by early childhood in patients with severe polyostotic fibrous dysplasia (PFD) or, due to the development of precocious puberty, by adolescence.

• Most commonly, MAS onset occurs in early childhood. The age of onset typically is earlier in girls than in boys.
• In female patients, onset as early as infancy, with per vaginal bleeding, has been described.
• Later-onset disease, in a patient's early to late teenage years, tends to be associated with clinically attenuated phenotypes.