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

McCune-Albright Syndrome

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
Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals

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.

Differential Diagnoses

Other Problems to Be Considered

In a typical case, the diagnosis of McCune-Albright syndrome (MAS) 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

Laboratory 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 (total and bone-specific fractions), osteocalcin, and serum adenosine 3,'5'-cyclic monophosphate (cAMP)¹² levels are elevated.
• Urinary excretion of hydroxyproline, N-telopeptides, pyridinium X-links, and cAMP is elevated. Depending on the extent of coexisting osteomalacia, serum calcium may be normal or slightly reduced. Typically, the rickets/osteomalacia associated with McCune-Albright syndrome is hypophosphatemic and hyperphosphaturic.

Imaging Studies

• In McCune-Albright syndrome (MAS), plain bone radiographs 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 (MFD) is more common than the polyostotic form. MFD is not associated with other findings that are 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. However, an abdominal ultrasonogram that reveals multiple hypoechoic cystic lesions within the uterus and upper vaginal vault is characteristic of embryonal rhabdomyosarcoma.
• Computed tomography (CT) scans and magnetic resonance imaging (MRI) 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.
• Reports suggest that the MRI may be useful to define the extent of bony disease, similar to bone scanning.¹³
• Radionuclide bone scans (technetium-99m [^99m Tc]–labeled methylene diphosphonate scans) in patients with polyostotic fibrous dysplasia appear as areas of increased activity. This is helpful in defining 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 polyostotic fibrous dysplasia has areas of fibrous metaplasia within flat and tubular bones. The basic anomaly in fibrous dysplasia 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, they are 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

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 NIH for this indication.

Management of growth hormone excess in the setting of MAS should be achieved using pharmacotherapeutic agents, because this excess is invariably the result of diffuse nodular pituitary hyperplasia rather than of 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 bones affected by fibrous dysplasia. No systemic investigation into the use of 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; the doses begin with 50 mcg administered every 8 hours subcutaneously and is 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.¹⁴

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 (a pediatrician or an 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.¹⁵
• 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 in the 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 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 the use of antiandrogen and antiestrogen preparations, typically 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. (Hyperthyroidism secondary to multinodular toxic goiter is the second most common endocrinopathy in patients with McCune-Albright syndrome, following precocious puberty.) 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 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 bisphosphonates¹ (particularly pamidronate and alendronate) may have beneficial effects on the bone disease, including with regard to reducing bone pain and the frequency of pathologic fractures, as well as to 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 the following:
• Hypogonadism - For which appropriate hormone replacement therapy should be instituted
• Hypophosphatemia with hyperphosphaturia - Which is managed aggressively with oral phosphorus replacement
• Hypophosphatemic rickets - Which is managed with appropriate vitamin D, calcium, and phosphate repletion
• 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 McCune-Albright syndrome (MAS).
• When medical therapy fails, ovariectomy or ovarian cystectomy may be used as a last resort for the control of precocious puberty. Despite this approach, most female patients with MAS who have had this surgery have retained 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 nonhyperfunctioning), progressively increasing goiter, and, of course, the very rare cases of coexisting thyroid carcinoma.

Diet

No specific dietary therapy is necessary for patients with McCune-Albright syndrome.

Activity

• Encourage patients with McCune-Albright syndrome 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 polyostotic fibrous dysplasia.
• Make individual recommendations that patients avoid various contact sports, games, and pastimes associated with fracture risk.

Medication

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

Aromatase inhibitors

Testolactone typically is administered at a low dose of approximately 10 mg/kg/d and is 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.

Testolactone (Teslac)

Synthetic antineoplastic agent that is structurally distinct from the androgen steroid nucleus in possessing a 6-membered lactone ring in place of the usual 5-membered carbocyclic D-ring.
Although the precise mechanism by which testolactone produces a clinical antineoplastic effect has not been established, its principal action is reported to be the inhibition of steroid aromatase activity and the consequent reduction in estrone synthesis from adrenal androstenedione, the major source of estrogen in postmenopausal women.
Based on in vitro studies, the aromatase inhibition may be noncompetitive and irreversible. This phenomenon may account for the persistence of testolactone's effect on estrogen synthesis after drug withdrawal. Despite some similarity to testosterone, testolactone has no in vivo androgenic effect. No other hormonal effects have been reported in clinical studies in patients receiving testolactone. In one study, testolactone administered orally (1000 mg/d) was reported to increase the renal tubular reabsorption of calcium but had no effect on serum calcium concentration. The mechanism of hypocalciuric effect is unknown. No clinical effects of testolactone on adrenal function have been reported in humans; however, one study noted an increase in the urinary excretion of 17-ketosteroids in most patients treated with 150 mg/d PO.
Typically, testolactone is administered at a low dose of approximately 10 mg/kg/d and is increased gradually over a period of 3-4 wk to an ultimate dose of 40 mg/kg/d. With an 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 y, when epiphysial fusion plate has occurred.
Testolactone is well absorbed from the GI tract. It is metabolized to several derivatives in the liver, all of which preserve the lactone D-ring. These metabolites, as well as some unmetabolized drug, are excreted in the urine. No clear manifestation of androgenic, estrogenic or antiestrogenic, progestational or antiprogestational, and gonadotropinlike or antigonadotropic effects have been reported. Testolactone does not demonstrate anti-inflammatory, mineralocorticoidlike, or glucocorticoidlike properties. Available for PO administration as tabs, providing 50 mg testolactone per tab.

Dosing

Adult

250 mg PO qid

Pediatric

Presently not approved for routine use in children except in the setting of research protocols; regimen developed by Feuillan and colleagues involves use of starting dose of 10 mg/kg, which is then increased over a period of 3-4 wk, with final intended dose of 40 mg/kg in 4 divided doses; medication should be used for a trial period of at least 6 mo before a decision is made whether to stop or maintain treatment

Interactions

May increase the effects of oral anticoagulants (monitor INR and adjust anticoagulant dosage accordingly)
Certain signs and symptoms have been reported in association with the use of this drug, but determining the relationship of underlying disease and drug administration to a reported reaction is often impossible; such reactions include maculopapular erythema, increase in blood pressure, paresthesia, aches and edema of the extremities, glossitis, anorexia, and nausea and vomiting; alopecia, either alone or with associated nail growth disturbance, has been reported rarely; these adverse effects subsided without interruption of treatment

Contraindications

Documented hypersensitivity; males with breast cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Plasma calcium levels should be monitored routinely in any patient receiving therapy for mammary cancer, particularly during periods of active remission of bony metastases (if hypercalcemia occurs, appropriate measures should be instituted); drug/laboratory test; physiologic effects of testolactone may result in decreased estradiol concentrations with radioimmunoassays for estradiol, increased plasma calcium concentrations, and increased 24-h urinary excretion of creatine and 17-ketosteroids.
Carcinogenesis, mutagenesis, and impairment of fertility may occur (no long-term animal studies have been performed to evaluate carcinogenic potential or mutagenesis; testolactone did not affect fertility in male or female rats)
Because many drugs are excreted in human milk, a decision should be made whether to discontinue breastfeeding
Certain signs and symptoms have been reported in association with the use of this drug, but determining the relationship of the underlying disease and drug administration to a reported reaction is often impossible; such reactions include maculopapular erythema, increased blood pressure, paresthesia, aches and edema of the extremities, glossitis, anorexia, and nausea and vomiting; alopecia, either alone or with associated nail growth disturbance, has been reported rarely; these adverse effects subsided without interruption of treatment
Among potential adverse effects are transient abdominal cramping, diarrhea, and mild hepatic inflammation evidenced by elevated SGOT, SGPT, and GGT levels

Follow-up

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 polyostotic fibrous dysplasia.

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 polyostotic fibrous dysplasia (PFD) is osteosarcoma, most often in the setting of irradiation of PFD-affected bones. It is very uncommon; the overall incidence rate of sarcomatous degeneration in the setting of PFD is 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 with increased perioperative mortality and those patients who develop malignancies, McCune-Albright syndrome is not associated with a significantly increased mortality risk.
• Deformities associated with polyostotic fibrous dysplasia result in variable degrees of morbidity, ranging from mild to very severe.

Miscellaneous

Medicolegal Pitfalls

• Early recognition of McCune-Albright syndrome (MAS) 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 of the bone unless the treatment is absolutely necessary, because irradiation may increase the risk for sarcomatous degeneration.
• For most physicians who are not endocrinologists, the crucial point in the management of MAS is the recognition of the disease and the referral of the patient to an endocrinologist who is experienced in its management. The endocrinologist will, in turn, offer other referrals as indicated (eg, to an experienced orthopedic surgeon).
• Consider the diagnostic possibility of MAS in all patients with recurrent fractures, particularly if the fractures occur in the setting of minimal trauma or without trauma. The common pitfall is to simply refer the patient for orthopedic procedures whenever a fracture occurs, without considering the underlying primary diagnosis.

Multimedia

Media file 1: Base of the skull computed tomography scan showing extensive fibrous dysplasia. 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.

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.

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

Media file 4: This plain skull radiograph 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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Keywords

McCune-Albright syndrome, hyperthyroidism, gynecomastia, thyroid gland, hyperparathyroidism, acromegaly, dysplasia, endocrine glands, Cushing syndrome, Cushing's syndrome, precocious puberty, fibrous dysplasia, endocrine gland, thyroid glands, cafe au lait spots, café au lait spots, endocrinopathy, McCune Albright syndrome, hyperprolactinemia, polyostotic fibrous dysplasia, Mazabraud syndrome

Contributor Information and Disclosures

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
Gabriel I Uwaifo, MBBS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, American Society of Hypertension, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Nicholas J Sarlis, MBBS, MD, PhD, FACP, Medical Director, Department of Oncology-US Medical Affairs Department, Sanofi-Aventis Pharmaceuticals
Nicholas J Sarlis, MBBS, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American Federation for Medical Research, American Head and Neck Society, American Medical Association, American Society for Therapeutic Radiology and Oncology, American Society of Clinical Oncology, American Thyroid Association, Association for Psychological Science, Endocrine Society, European Society for Medical Oncology, New York Academy of Sciences, and Royal Society of Medicine
Disclosure: Sanofi-Aventis Salary Employment

Medical Editor

Ghassem Pourmotabbed, MD†, Former Associate Professor, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Tennessee School of Medicine and Health Science Center
Ghassem Pourmotabbed, MD† is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, and Endocrine Society
Disclosure: Nothing to disclose.

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Managing Editor

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, American Society of Law Medicine and Ethics, Endocrine Society, and International Society for Clinical Densitometry
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CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Related eMedicine topics:
Albright Syndrome
Café Au Lait Spots
Fibrous Dysplasia [Orthopedic Surgery]
Fibrous Dysplasia [Radiology]
Gigantism and Acromegaly
McCune-Albright Syndrome [Pediatrics: General Medicine]
Precocious Pseudopuberty
Precocious Puberty

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