McCune-Albright Syndrome Treatment & Management

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.^[18]

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.

Pergolide was withdrawn from the US market  March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess patients' need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.

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.^[19]
  • 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 bisphosphonates^[1] (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

• 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.

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

• 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.