eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

McCune-Albright Syndrome

Author: Gabriel I Uwaifo, MBBS, Clinical and Research Attending, Assistant Professor of Medicine and Endocrinology, MedStar Clinical Research Center, MedStar Research Institute and Washington Hospital Center
Coauthor(s): Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Contributor Information and Disclosures

Updated: Dec 18, 2008

Introduction

Background

McCune-Albright syndrome (MAS) is defined as the association of polyostotic fibrous dysplasia (PFD) (see Image 1), 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 puberty³ 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.⁴ Some severely affected patients may present with associated hepatic, cardiac, and GI dysfunction (ie, elevated hepatic transaminases, GI polyposis, and cardiomyopathy).

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.^5,6 First described in 1926 by Henschen, this syndrome has been associated with precocious puberty and with café au lait spots (see Image 2) 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.

Pathophysiology

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.⁷

Precocious puberty associated with MAS is gonadotrophin independent. In girls, it is the result of estrogen excess from ovarian follicular cysts. 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.

Clinical

History

• The clinical presentation of McCune-Albright syndrome (MAS) is highly variable, depending on which of the various potential components of the syndrome predominate.
• In cases where polyostotic fibrous dysplasia (PFD) is marked, multiple pathologic fractures are prominent early in the history (usually in childhood).
  • Bony involvement often is unilateral in distribution, although in many cases, it is found to predominate clinically on 1 side.
  • The potential presenting features include gait anomalies (eg, a limp), visible bony deformities, bone pain, and joint stiffness with pain, most often the result of secondary osteoarthrosis.
• Symptoms begin during childhood, although in some cases, the disease is clinically silent and is discovered on routine radiographs obtained for an unrelated reason.
• In other cases, the phenotypic affectation is mild and the onset of symptoms is considerably delayed; subtle findings can include mild facial asymmetry, dysmorphism, and a small difference in limb length.
• Spontaneous improvement or resolution of the bony lesions does not occur. Existing bony lesions may slowly worsen or remain static, or new lesions may develop.
• Bony lesions have been noted to worsen during pregnancy and other settings of estrogen excess. This may be due to the trophic effects of estrogen on fibrous dysplastic bone, which does possess estrogen receptors.
• Rarely, MAS has been associated with high-output congestive heart failure similar to that seen in Paget disease.
• Other endocrinopathies associated with MAS include the following:
  • Goiters, with or without hyperthyroidism, usually due to toxic multinodular goiter
  • Diabetes mellitus
  • Acromegaly
  • Cushing syndrome
  • Thyroid nodules (ie, adenomas, goitrous colloid/hypertrophic nodules, thyroid cancer [although this last disorder occurs only rarely])
• The clinical history and physical examination findings may appropriately vary based on the patient's syndrome(s). The cardinal paradigm is that the endocrine gland's hyperfunction is the result of autonomous functioning nodular disease in all of these conditions.
• Patients with myxomas often present with a history of palpable masses in the limbs, anterior abdominal wall, and/or back. These often are otherwise asymptomatic and may be painful.
• Thyroid anomalies are found in 30-40% of patients with MAS. The incidence of these lesions is higher in males than in females.
• The precocious puberty that characterizes MAS presents as premature thelarche or menarche, often in girls as young as 2-3 years.
• Growth hormone excess coexisting with MAS is uncommon and generally is not found until early adulthood or midadulthood.
  • Usually, premature vaginal bleeding occurs before the onset of breast development. In some of these patients, the vaginal bleeding remains intermittent and irregular, while in others, it assumes a cyclical fashion typical of menstrual periods.
  • Other patients may have cyclical vaginal bleeding and breast enlargement related to fluctuations in serum estrogen levels.
  • Some of these patients may have normal onset of puberty at a normal age.
  • Forms of sexual precocity are observed in more than 50% of women with the syndrome.⁸ Sexual precocity also occurs in male patients but is less common.
  • Patients with MAS and growth hormone excess present with the same paradoxical responses as regular patients with acromegaly upon thyrotropin-releasing hormone stimulation and upon oral glucose tolerance tests.
  • In the absence of a well-defined, surgically excisable pituitary adenoma (ie, producing growth hormone), octreotide is the treatment modality of choice. In fact, most patients present with diffuse pituitary hyperplasia rather than with the typical solitary macroadenoma of patients with sporadic acromegaly.
• The skull and parasellar bone fibrous dysplasia (FD) that often coexist with this disorder (see Image 4) require technically demanding surgical treatment that is associated with a significantly increased potential for complications. The potential risk for secondary bony neoplasms precludes the use of radiation therapy in patients with MAS and pituitary adenomas.⁹
• Bromocriptine and the other dopamine receptor agonists are useful therapeutic modalities in the setting of hyperprolactinemia due to prolactinomas.
• Preliminary studies suggest that the new dopamine agonist cabergoline may have utility in the treatment of cosecretory somatomammotropinomas.
• Particularly in the setting of hyperprolactinemia, associated hypogonadotropic hypogonadism may be present.
• Hyperprolactinemia in the absence of acromegaly has not been described in patients with MAS.
• MAS typically is sporadic and is therefore very rarely associated with transmission from generation to generation.

Physical

• Café au lait spots, the classic symptom of McCune-Albright syndrome (MAS), often predominate ipsilateral to the side with more bony fractures and deformity.
  • These spots are fairly prominent, with irregular edges, and consequently are called the "coast-of-Maine" variants (as distinguished from the smaller, rounded, smooth-edged "coast-of-California" café au lait spots associated with neurofibromatosis type 1 [NF-1]).
  • These café au lait spots are larger and less numerous than are those in patients with neurofibromatosis.
  • They are difficult to notice in very young patients but can become more prominent with age.
  • The spots terminate abruptly at the midline and are most common on the side with the dominant amount of bony involvement.
  • The lesions are arranged in a segmental fashion that coincides with the developmental lines of Blaschko.
  • Common areas to look for subtle café au lait spots include the nape of the neck and the nasal clefts. However, these pigmented lesions are absent in 10-20% of patients and can be detected (by a formal dermatologic assessment) in as many as 10% of healthy subjects, making their diagnostic utility limited when unassociated with other features of MAS.
• A few cases have been described in which MAS has been associated with either patchy or diffuse alopecia (first described by Shelley and Wood).
• Patients with precocious puberty invariably are taller as children. However, as a result of a combination of precocious puberty, recurrent fractures, and hypophosphatemic rickets, the majority of patients with MAS have a final height below that of their peers and below their projected mid-parental height.
• One important setting in which a patient with MAS attains normal height is that in which there is a coexisting growth hormone excess (a clinical pearl that aids in diagnosis).

Causes

• McCune-Albright syndrome (MAS) is presumed to result from a postzygotic mutational event occurring in a mosaic fashion early in embryonic life. Because of the sporadic distribution of the responsible somatic genetic mutations, it is impossible, based on the present body of knowledge, to predict the degree, extent, and type of tissue affliction.
• The cardinal pathogenetic mechanism appears to be an activating somatic mutation of the cellular Gs alpha gene.¹⁰ This results in constitutive hyperfunction of the cell that bears the mutated gene and expresses its product.
• These activating Gs alpha mutations are demonstrated in the café au lait skin lesions, the fibrous dysplastic bony lesions, the gonadal tissues, and in various hyperfunctioning endocrine glands, including the thyroid and adrenal glands.
• The finding of Gs alpha mutations is not entirely predictive of the pathologic changes associated with MAS.
  • In patients with MAS, multiple tissues are described that do not possess the mutations, in organs that seem to be clinically affected by the manifestations of the syndrome and vice versa.
  • Happle suggested that MAS results from a dominant lethal gene defect that persists by mosaicism.
  • Seven familial MAS cases have been described in the literature, suggesting a 2-hit mutation hypothesis for the pathogenesis.
• Cases of MAS described in monozygotic twins are associated with different phenotypic manifestations.¹¹
  • This suggests an initial, dominant, inherited mutation, which is responsible for the primary gene defect, followed by a somatic, sporadic cellular mutation that results in mosaicism and the variegated clinical phenotype.
  • This second hit is presumed to occur early in somatic division, as do the sporadic noninherited variants.
• The basis for myxomas in association with polyostotic fibrous dysplasia in the setting of MAS is somewhat unclear. Mazabraud suggested that dysplasia of the tendon-to-muscle junctions may be the basis. Others have suggested that the myxomas may be caused by mechanical factors within the muscle fibers or at the tendon-muscle interface.
• Other potential hypotheses include metabolic anomalies in soft tissues and bone during the growth period.
• No consistent association exists of myxomas with intralesional Gs alpha mutations.
• High oncogene expression is observed in the bony lesions, especially the c-fos oncogene. This finding may be due to secondary activation of the above oncogenes.

• Search for CME/CE on This Topic »

• McCune-Albright Syndrome (Pediatrics: General Medicine)
• Albright Syndrome (Dermatology)
• Precocious Pseudopuberty (Pediatrics: General Medicine)
• Cafe Au Lait Spots (Pediatrics: General Medicine)

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