AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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 hyperactivity of various endocrine glands. 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 and Albright hereditary osteodystrophy (AHO) is important. AHO also is a GS alpha gene defect that results in pseudohypoparathyroidism or pseudopseudohypoparathyroidism.

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

Fewer than 10 well-documented cases exist of MAS associated with Cushing syndrome. This syndrome is distinct, unlike all the 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 have been identified. This is called Mazabraud syndrome (MS). First described in 1926 by Henschen, this syndrome has been associated with both precocious puberty and 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 as 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. Malignancies described in this 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 increased risk for thyroid (a novel finding by the US National Institutes of Health group) and 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. The hyperphosphaturia in patients with MAS 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 are the result of a noninherited postzygotic activating mutation of the GS alpha gene, resulting in overproduction of a variety of protein products in a fashion independent from normal feedback control mechanisms. The GS alpha subunit is the 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.

Precocious puberty associated with the condition 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 MAS in the United States and internationally is unknown. It is thought to be a very rare disorder.

International

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

Mortality/Morbidity

Mortality and morbidity are associated with the fractures, malignancies, endocrine disorders, and other conditions associated with this syndrome.

Race

MAS has no specific ethnic predisposition.

Sex

Both sexes are affected, but girls have been reported more frequently than boys, presumably due to the dramatic presentation characterized by early onset of puberty, menarche, and thelarche.

Age

The disease can be diagnosed at birth (presence of café au lait spots) and can be definitely diagnosed by early childhood in cases with severe PFD or by adolescence (due to the development of precocious puberty).

• 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 early-to-late teenage years tends to be associated with clinically attenuated phenotypes.

CLINICAL

Section 3 of 11  

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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 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 one side.
  
  
  
  • The potential presenting features include gait anomalies (including limps), 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 discovered on routine x-rays obtained for an unrelated reason.



• In other cases, the phenotypic affectation is mild and the onset of symptoms is considerably delayed, including subtle findings such as mild facial asymmetry, dysmorphism, and mild unequal 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, rarely thyroid cancer)
     
• 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 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.



• Precocious puberty that characterizes MAS presents as premature thelarche or menarche in girls often as young as 2-3 years.



• Growth hormone excess coexisting with MAS is an uncommon association, and it generally is not found until early or mid adulthood.
• • 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 cyclic 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. 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 cases present with diffuse pituitary hyperplasia rather than the typical solitary macroadenoma of patients with sporadic acromegaly.
     
• The skull and parasellar bone FD that often coexist with this disorder (see Image 4) require technically demanding surgical treatment that is associated with 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.



• 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 hypogonadotrophic hypogonadism may be present.



• Hyperprolactinemia in the absence of acromegaly has not been described in patients with MAS.



• MAS typically is sporadic and, thus, very rarely associated with transmission from generation to generation.



• Growth hormone excess coexisting with MAS is uncommon and, typically, is not found until early or mid adulthood.

Physical

• Café au lait spots, the classic symptom, often predominate on the side ipsilateral to the side with more bony fractures and deformity.
• • These are fairly prominent and have irregular edges, giving an appearance 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 those in patients with neurofibromatosis.

  • They are difficult to notice in very young patients but can become more prominent with age.

  • They often 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 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 of MAS associated with either patchy or diffuse alopecia (first described by Shelley and Wood).
• As a result of the combination of precocious puberty, recurrent fractures, and hypophosphatemic rickets, the majority of these patients are short in stature.
• One important setting in which a patient with MAS has normal height is the coexistence of growth hormone excess, which is a clinical pearl that aids in diagnosis.

Causes

• MAS is presumed to be the result of a postzygotic mutational event occurring in a mosaic fashion early in embryonic life. Because of the sporadic distribution of the responsible somatic genetic mutations, predicting the degree, extent, and type of tissue affliction based on the present body of knowledge is impossible.
• The cardinal pathogenetic mechanism appears to be an activating somatic mutation of the cellular GS alpha gene. This results in constitutive hyperfunction of the cell bearing the mutated gene and expressing 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 without the mutations in organs that seem clinically affected by the manifestations of the syndrome and vice-versa.

  • Happle suggested that MAS is the result of 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.
• • 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 PFD in the setting of MAS is somewhat unclear. Mazabraud suggested that dysplasia of the tendon-to-muscle junctions may be the basis. Others suggest that they may be the result of 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.

DIFFERENTIALS

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Other Problems to be Considered

In a typical case, the diagnosis usually is not in doubt. However, in atypical cases, the combination of cutaneous pigmentation, bony lesions, and soft-tissue masses may suggest systemic mastocytosis and neurofibromatosis.

Particularly when associated with a great degree of deformity, other important diagnostic considerations include the following:

Ossifying fibromas of the bone
Paget disease of bone: This typically has onset in adulthood, unlike MAS, which more typically begins in childhood.
Proteus syndrome
Stein-Leventhal syndrome
Thyrotoxicosis
Various congenital syndromes associated with hydrocephalus

If multiple bony fractures and deformity predominate, MAS may be mistaken for a milder form of osteogenesis imperfecta.

If precocious puberty predominates, the differential diagnosis becomes even wider and includes congenital adrenal hyperplasia.

Vaginal bleeding in neonates and infants is one of the typical presentations of MAS. In this setting, rhabdomyosarcoma of the vaginal tract is an important differential. This typically appears as a "bunch of grapes," hence the name sarcoma botryoides.

WORKUP

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Lab Studies

• In patients with sexual precocity, baseline gonadotropin (ie, luteinizing hormone and follicle-stimulating hormone) 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. These findings can be of a transitory nature, particularly in female patients.



• Androgen levels in female patients remain within normal limits.



• Blood and urinary chemistries show evidence of excessive bone turnover and elevated indicators for bone formation and resorption (eg, urinary N-telopeptide, pyridinolines, deoxypyridinolines). Serum alkaline phosphatase levels (both total and bone-specific fractions), osteocalcin, and serum adenosine 3,'5'-cyclic monophosphate (cAMP) levels are elevated.



• Urinary excretion of hydroxyproline, N-telopeptides, pyridinium X-links, and cAMP is elevated. Serum calcium may be normal or slightly reduced depending on the extent of coexisting osteomalacia. Typically, the rickets/osteomalacia associated with McCune-Albright syndrome (MAS) is hypophosphatemic and hyperphosphaturic.

Imaging Studies

• In this condition, plain bone x-rays typically show multiple patchy areas of bony lysis (see Image 3) and sclerosis. The findings are consistent with bone dystrophy (ie, areas of hypertrophy, geodes bounded by fine sclerotic rims).
• • Mixed radiopaque and radiolucent areas with thin or hypertrophic cortices are present.
  
  
  
  • Virtually any bone in the body may be affected. Monostotic fibrous dysplasia is more common than PFD. Monostotic fibrous dysplasia is not associated with the other findings typical of MAS.
  
  
  
  • Commonly affected bones include the femur, tibia, ribs, and facial bones. Involvement of the small bones of the hands and feet account for 50% of cases.
  
  
  
  • Long-bone lesions are more frequent in the metaphyseal and diaphyseal regions. The individual lesions may be trabeculated, with thin cortices and ground-glass appearance.


• Formal bone-age estimations may be higher in patients with sexual precocity.



• Ultrasonography may be a useful diagnostic adjunct to evaluate patients with historical or examination evidence of soft-tissue swelling. Myxomas in the context of MS can be seen as sharply defined hypoechoic masses with a few central fluid-filled cavities.



• CT scans and MRI scans also show hypoechoic areas in the setting of myxomas. These are hypointense or isointense on T1-weighted imaging with gadolinium enhancement or on T2-weighted imaging.



• Recent reports suggest that the MRI may be useful to define the extent of bony disease, similar to bone scanning.



• Radionuclide bone scans (technetium 99m-labeled methylene diphosphonate scans) in patients with PFD appear as areas of increased activity. This is helpful to define the extent of disease activity after the diagnosis is made. The poor specificity of increased patchy bone activity on bone scans precludes use for screening/exact diagnosis.

Procedures

• Bone biopsy may be necessary to rule out malignancy in a patient with a rapidly expanding lesion. It can be used clinically to aid in the diagnosis of osteomalacia and has been used for research purposes in an academic setting.
• Similarly, a rapidly expanding myxoma may require a muscle or soft-tissue biopsy.
• Enlarging thyroid nodules or hypofunctioning solitary thyroid nodules warrant a fine-needle aspiration biopsy.

Histologic Findings

The bone affected by PFD has areas of fibrous metaplasia within flat and tubular bones. The basic anomaly in FD lesions is a progressively expanding fibrous lesion of bone-forming mesenchyme. The lesions typically expand concentrically from the medullary cavity outwards (ie, towards the cortex). The bony lesions are well defined, although invariably not encapsulated. The lesions are rich in spindle-shaped fibroblasts, with a swirled appearance within the marrow space and erratically arranged "tongues" of woven bone. Islands of cartilaginous tissue also may be interspersed within the lesions. Some parts of the affected bones may have cystic lesions lined by multinucleated giant cells akin to osteitis fibrosa cystica (of severe hyperparathyroidism) but with a paucity of osteoblasts.

TREATMENT

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Medical Care

No specific medications are available to treat the bone manifestations of McCune-Albright syndrome (MAS). Antiresorptive agents (eg, alendronate and its congeners [bisphosphonates]) are currently in phase 2 trials at the US National Institutes of Health.

Management of growth hormone excess in the setting of MAS should be achieved using pharmacotherapeutic agents, because this is invariably the result of diffuse nodular pituitary hyperplasia rather than a single definitive adenoma. Surgical removal of adenomas, even if apparently present on radiologic testing, may be complicated by coexisting fibrous dysplasia involving the skull bones that distorts anatomical planes and increases the potential for torrential intraoperative bleeding. Irradiation of the pituitary is also not ideal given the potential risk of inducing sarcomatous degeneration in fibrous dysplasia affected bones. No systemic investigation of using focused gamma knife–based pituitary irradiation has been done because this condition is so uncommon.

The vast majority of patients with growth hormone excess in the setting of MAS are treated with octreotide in doses similar to those used in regular acromegaly; beginning at 50 mcg every 8 hours subcutaneously, then titrated to response based on IGF-1 and postinjection growth hormone levels to doses as high as 1,500 mcg every day. Long-acting somatostatin analogues, such as Sandostatin LAR and lanreotide, have also been used on a case-by-case basis.

High-dose dopamine agonists, including bromocriptine, cabergoline, and pergolide, have also been demonstrated to have utility either as adjuncts to somatostatin analogues or as monotherapy. They appear to have particular utility in the setting of prolactin and growth hormone cohypersecretory states suggestive of somatomammotropinomas.

No systemic data are presently available on the utility or place of growth hormone receptor antagonists such as pegvisomant in managing MAS-associated growth hormone excess. It is not contraindicated; however, the fact that these agents do not control growth hormone levels would probably make their use as monotherapy in this setting inadvisable.

• MAS is a multisystemic condition with a host of variable presentations. Management often is challenging and requires a multidisciplinary approach.
  
  
  • Orthopedic surgical care for multiple bony fractures and deformities plays a major role.
    
  
  
  • The endocrinologist should screen and search for various endocrinopathies that worsen the clinical presentation.
    
  
  
  • An astute primary care physician (pediatrician or internist, depending on the age of the patient) who will coordinate the various aspects of the patient's care also is necessary.
     
• Therapy for precocious puberty is available and should be tried; however, it is still largely experimental.
  
  
  • Because precocious puberty in patients with MAS is gonadotrophin-independent, continuous GnRH therapy has little utility.
    
    
  • For female patients, the central theme is to block estrogen effects. Testolactone, a competitive aromatase inhibitor, is used for this purpose.
    
    
  • Preliminary data from the testolactone therapeutic trials suggest that this medication causes reduction in estradiol and estrone levels, with reduced frequency of menses and reduction in growth and bone maturation. Testolactone also may cause elevations in measured urinary 17-ketosteroid (U-17KS) and 17-hydroxysteroid (U-17OHCS) levels.
    
    
  • Other preliminary trials of other aromatase inhibitors, such as fadrozole and anastrazole, are underway with the goal of achieving better management of precocious puberty.
    
    
  • Estrogen receptor antagonists, such as tamoxifen, may have a therapeutic role but have not yet been systematically investigated.
    
    
  • Other pilot clinical trials also have been performed, in which antiandrogen cyproterone acetate was used to block pubertal development in young female patients, while ketoconazole was used in males.
    
    
  • GnRH analogues may be added to testolactone as an adjunct for treatment of precocious puberty to suppress pituitary gonadotrophin production. Depot leuprolide acetate at a dose of 7.5 mg (300-500 mcg/kg) every 28 days is a typical regimen, the dose of which can be adjusted upwards or downwards based on clinical and laboratory findings.
    
    
  • Adequate response to these therapies can be assessed by serial GnRH stimulation tests following 3-6 months of therapy.
    
    
  • Other alternative treatment options include medroxyprogesterone acetate, which is particularly useful for controlling menstrual bleeding. The preferred agent is Depo-Provera in intramuscular doses of 4-15 mg/kg monthly. No definitive clinical trials have determined the efficacy of this medication in the setting of MAS.
    
    
  • Adequate medical therapy for precocious puberty in males consists of both antiandrogen and antiestrogen preparations. This typically consists of a combination of spironolactone and testolactone. Alternative antiandrogens, such as ketoconazole, also may be used in a dose range of 600-800 mg daily.
     
• Hyperthyroidism in the setting of MAS is treated with the same medication options as regular hyperthyroidism, including thionamides (eg, propylthiouracil) and methimazole.
  
  
  • Thyroidectomy or hemithyroidectomy is the treatment of choice for hyperthyroidism associated with a goiter in patients with MAS.
    
  
  
  • Hyperthyroidism usually occurs in the context of toxic multinodular goiter. Although radioiodine can be effective in controlling hyperthyroidism, it is a less popular treatment option because high doses or repeated administrations of radioiodine may be necessary. Obvious issues arise with regard to the safety of radioiodine in children, especially in view of the potential for the development of both benign and malignant thyroid nodules over time following radioiodine therapy.
     
• The bony disease associated with MAS is very difficult to treat.
  
  
  • Some preliminary data suggest that bisphosphonates (particularly pamidronate and alendronate) may have beneficial effects on the bone disease, including reducing bone pain, reducing frequency of pathologic fractures, and slowing the evolution of the bone disease.
    
    
  • In patients with MAS, other identified comorbidities that may be significantly affecting the bone density in a negative way must be identified and aggressively managed. Major morbidities include (1) hypogonadism, for which appropriate hormone replacement therapy should be instituted; (2) hypophosphatemia with hyperphosphaturia, which is managed aggressively with oral phosphorus replacement; (3) hypophosphatemic rickets, which is managed with appropriate vitamin D, calcium, and phosphate repletion; and (4) hyperparathyroidism, which may be primary or secondary.

Surgical Care

• Standard orthopedic surgical practice is used to manage the various fractures and deformities seen in patients with MAS.
• Ovariectomy or ovarian cystectomy may be used as a last resort for control of precocious puberty when medical therapy fails. Despite this approach, most female patients with MAS who have had this surgery retain normal fertility.
• Bilateral adrenalectomy is the treatment of last resort for poorly controlled Cushing syndrome (ie, when this occurs in the context of MAS).
• Partial or total/near-total thyroidectomy may be necessary for the control of thyrotoxicosis or the removal of multiple benign thyroid adenomas (even when they are non–hyperfunctioning), progressively increasing goiter, and, of course, the very rare cases of coexisting thyroid carcinoma.

Diet

No specific dietary therapy is necessary for patients with MAS.

Activity

• Encourage patients to maintain a high degree of physical activity and a regular exercise program. However, this may be unrealistic for the majority of patients with severe generalized PFD.
• Make individual commendations that patients avoid various contact sports, games, and past-times associated with fracture risk.

MEDICATION

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The goals of pharmacotherapy are to prevent complications and to reduce morbidity.

Drug Category: Aromatase inhibitors

Testolactone typically is administered at a low dose of approximately 10 mg/kg/d and increased gradually over a period of 3-4 weeks to an ultimate dose of 40 mg/kg/d. With adequate treatment response, serum estrone and estradiol levels are reduced. Patients who respond to treatment should continue therapy until the age of normal puberty or until bone age of 15-16 years, when epiphysial fusion plate has occurred. Among the potential adverse effects associated with medication use are transient abdominal cramping, diarrhea, and mild hepatic inflammation evidenced by elevated SGOT, SGPT, and GGT.

FOLLOW-UP

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Deterrence/Prevention

• No measures are available to prevent McCune-Albright syndrome (MAS); however, appropriate care must be taken for fracture prevention in patients with severe PFD.

Complications

• Depending on the specific bone involved and the specific location, potential complications of fractures include secondary osteomyelitis, compressive neuropathy, Volkmann contractures, sympathetic algodystrophy, myositis, ligamentous ossifications, and pseudoarthrosis.
• The most dreaded complication of PFD is osteosarcoma, most often in the setting of irradiation to PFD-affected bones. It is very uncommon, with an overall incidence rate of sarcomatous degeneration in the setting of PFD of less than 1%. Most frequently, it involves the bones of the face and femur.
• Skull involvement can be associated with blindness due to optic nerve compression. Deafness also can occur and is associated with vestibulocochlear nerve compression. Other potential complications can result from compressive neuropathies of the cranial nerves located at the base of the skull.
• A small subset of patients has significant risk for perioperative sudden death. This is presumed to be secondary to either cardiomyopathy or arrhythmia from excess cAMP expression in cardiac tissue. This is a direct consequence of the constitutive activation of adenylate cyclase by the GS alpha mutation within the cardiac myocytes.

Prognosis

• Apart from the small subgroup of patients that has increased perioperative mortality and those who develop malignancies, MAS is not associated with a significantly increased mortality risk.
• Deformities associated with PFD result in variable degrees of morbidity, ranging from mild to very severe.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Early recognition of McCune-Albright syndrome is vital. Consider the possibility of the diagnosis in the appropriate setting. The physician should have a high index of suspicion for other endocrinopathies associated with the condition.



• Emphasize the need to avoid irradiation to the bone unless absolutely necessary because this may increase the risk for sarcomatous degeneration.



• For most physicians who are not endocrinologists, the crucial point in the management of the condition is to recognize the disease and refer the patient to an endocrinologist experienced in its management, who will, in turn, offer other referrals as indicated (ie, to an experienced orthopedic surgeon).



• Consider the diagnostic possibility in all patients with recurrent fractures, particularly if they occur in the setting of minimal to no trauma. The common pitfall is to simply refer the patient for orthopedic procedures whenever a fracture occurs, without considering the underlying primary diagnosis.

MULTIMEDIA

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Media file 1:  Base of the skull CT scan showing extensive fibrous dysplasia. Note the asymmetric 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.
	View Full Size Image
Media type:  CT

Media file 2:  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.
	View Full Size Image
Media type:  Photo

Media file 3:  Fibrous dysplasia of a long bone characterized by focal bony expansion, patchy areas of sclerosis, and bony cyst formation.
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Media type:  X-RAY

Media file 4:  This plain skull x-ray film shows marked macrocrania, frontal bossing, and a markedly thickened bony table in patchy areas, particularly at the base of the skull and occiput. The skull also shows the hair-on-end appearance suggestive of Paget disease or poorly controlled hemoglobinopathy (eg, beta thalassemia, sickle cell disease).
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Media type:  X-RAY

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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• Whyte MP. Rare disorders of skeletal formation and homeostasis. In: Becker KL, Bilezikian JP, Hung W, Kahn CR, Bremmer WJ, eds. Principles and Practice of Endocrinology and Metabolism. 2nd ed. Philadelphia, Pa: JB Lippincott; 1995:. 594-606.

Article Last Updated: May 22, 2006