McCune-Albright Syndrome Treatment & Management

Updated: May 18, 2023
  • Author: Ranjodh Singh Gill, MD, FACP, CCD; Chief Editor: George T Griffing, MD  more...
  • Print

Approach Considerations

McCune-Albright syndrome (MAS) is a multisystemic condition with a host of variable presentations. Diagnosis and treatment of this syndrome require a high index of suspicion in any patient with characteristic café-au-lait spots and endocrine dysfunction or pathologic fractures. No interventions are available to prevent MAS; however, appropriate care must be taken for fracture prevention in patients with severe polyostotic fibrous dysplasia (PFD) and in treating and correcting any endocrinologic abnormalities.

For most physicians who are not endocrinologists, the crucial treatment aims are recognition of MAS and prompt referral of the patient to an endocrinologist who is experienced in its management. The endocrinologist, in turn, arranges other referrals (eg, to an orthopedic surgeon or neurosurgeon) if and as indicated. A 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 is an integral part of the medical care team of a patient with MAS.

No specific medications are available to treat the bone manifestations of MAS. Antiresorptive agents (eg, alendronate and its congeners [bisphosphonates]) are being evaluated for this indication and have great palliative value owing to their pain-controlling attributes in this disease. Transsphenoidal surgery, if needed, remains difficult secondary to massive thickening of the skull base. Irradiation of the bone should be avoided unless the treatment is absolutely necessary, because irradiation may increase the risk for sarcomatous degeneration. [18]

The precocious puberty of MAS generally does not respond to gonadotropin-releasing hormone (GnRH) agonists, and short-acting aromatase inhibitors have had limited effectiveness. Inconsistent results have been reported with bromocriptine, cabergoline, octreotide, or a combination of these. Pegvisomant, a growth hormone (GH) receptor antagonist, is a possibility, though it has not been specifically evaluated for treatment of MAS with GH pathology. [18]


Pharmacologic Therapy

Precocious puberty

Therapy for precocious puberty is available and should be tried; however, it is still largely experimental. Precocious puberty in MAS is gonadotropin-independent and therefore does not respond to the gonadotropin-releasing hormone (GnRH) agonist therapy that is so successful with gonadotropin-dependent central precocious puberty, [11] though one study did find GnRH analogue therapy for children to have some success in girls with MAS. [46]

For female patients, the central aim is to block estrogen effects. To this end, the aromatase inhibitors have been the mainstay of therapy in girls with persistent estradiol elevation.

Patients who respond to treatment should continue therapy until the age of normal puberty or until a bone age of 15-16 years.

A GnRH analogue may be added to aromatase inhibitors as an adjunct in the treatment of precocious puberty to suppress pituitary gonadotropin production. Depot leuprolide acetate at a dosage of 7.5 mg (300-500 µg/kg) every 28 days is a typical regimen; the dosage can be adjusted upward or downward on the basis of clinical and laboratory findings.

Preliminary trials of other aromatase inhibitors have been initiated with the aim of achieving better management of precocious puberty. [47] In 1 clinical trial, fadrozole, a more potent aromatase inhibitor, was ineffective in preventing progression of precocious puberty [48] ; however, anastrozole, a highly selective aromatase inhibitor, significantly slowed precocious puberty in 1 case and offered the added benefit of once-daily dosing. [49] The third-generation aromatase inhibitor letrozole has had some success. [50]

Ketoconazole was used in 1 study as an alternative therapy in 2 girls, who also showed significant improvement in signs of precocious puberty. [51] Unfortunately, ketoconazole’s dosing frequency is 3 times daily, which is a drawback in comparison with the once-daily dosing of anastrozole or tamoxifen.

Estrogen receptor antagonists, such as tamoxifen, may have a therapeutic role but have not yet been systematically investigated. Tamoxifen has shown some evidence of efficacy for treating precocious puberty in girls with MAS. In a multicenter study that used a regimen of 20 mg of tamoxifen once daily, the investigators reported significant improvement in growth velocity and rate of skeletal maturation. [52]

Other pilot clinical trials have been performed, in which the antiandrogen cyproterone acetate was used to block pubertal development in young female patients, while ketoconazole was used in males.

Adequate response to these therapies can be assessed by administering serial GnRH stimulation tests after 3-6 months of therapy.

Additional treatment options include medroxyprogesterone acetate, which is particularly useful for controlling menstrual bleeding. The preferred agent is Depo-Provera in intramuscular (IM) doses of 4-15 mg/kg monthly. No definitive clinical trials have determined the efficacy of this medication in the setting of MAS.

In males, adequate medical therapy for precocious puberty consists of the use of antiandrogen and antiestrogen preparations, typically a combination of spironolactone and aromatase inhibitors. Alternative antiandrogens (eg, ketoconazole) may also be used, in a dosage range of 600-800 mg/day. In one report, combined treatment with ketoconazole and cyproterone acetate was used in a boy with MAS and peripheral precocious puberty, with some positive effect. [53]

Polyostotic fibrous dysplasia

The bony disease associated with MAS (PFD) is very difficult to treat. Currently, no clinically proven medical therapies are available. Studies of oral and intravenous (IV) bisphosphonates (particularly pamidronate, alendronate, and zoledronate) suggest that these agents may have beneficial effects on the bony disease, with regard to reducing both bone pain and the frequency of pathologic fractures, as well as to slowing the evolution of the bony disease. [54, 8] However, data on the ability of bisphosphonates to heal fibrous dysplasia are conflicting.

One study found that long-term bisphosphonate treatment had beneficial effects on bone health in MAS; fracture rate and bone pain were reduced, and radiologic evidence of long-bone pathology resolution was observed. [55] Another suggested that bisphosphonate may be helpful. [56] A 2011 case report found continuous low-dose oral alendronate to be helpful in a 79-year-old woman with PFD. [57]

However, another study found that bisphosphonate treatment of PFD in children with MAS did not arrest progressive bone pathology. [58]  Similarly, a study by Florenzano et al reported that bisphosphonates did not affect disease burden progression in pediatric patients with FD. Moreover, although the investigators found that in adults with FD there was a decrease in bone-turnover markers and other disease-activity markers, these changes were determined to be age related and not significantly associated with bisphosphonate treatment. [59]

Nonetheless, a literature review by Chapurlat and Legrande indicated that, based on observational studies, IV therapy with pamidronate can significantly reduce bone pain and bone resorption in patients with FD/MAS. However, reports regarding the oral bisphosphonates alendronate and risedronate did not find these to effectively decrease bone pain, although several studies did indicate that, like pamidronate, the oral bisphosphonates can increase bone mineral density at FD sites. [60]

Tocilizumab, an interleukin-6 blocker used for rheumatoid arthritis, has been employed as a treatment for a polyostotic variant of bone fibrous dysplasia. [61]


As a rule, hyperthyroidism in the setting of MAS is treated with the same medication options as regular hyperthyroidism, including thionamides (eg, propylthiouracil) and methimazole.

Hyperthyroidism due to functional thyroid follicular adenomas can be treated medically. Antithyroid medications can be used to decrease thyroid hormone production. Unlike Graves disease, hyperthyroidism secondary to a GNAS1 mutation is unlikely to go into remission. Therefore, patients probably should use antithyroid drugs indefinitely. A more permanent treatment of the hyperthyroidism, including radioiodine therapy or thyroidectomy, should be considered if a diagnosis of MAS is confirmed.

Hyperthyroidism usually occurs in the context of toxic multinodular goiter. Notably, hyperthyroidism secondary to toxic multinodular goiter is the second most common endocrinopathy in MAS, after precocious puberty. Although radioiodine can be effective in controlling hyperthyroidism, it is a less popular option, because high doses or repeated administration may be necessary. Obvious issues arise with regard to the safety of radioiodine in children, especially in view of the potential for benign and malignant thyroid nodules to develop after radioiodine therapy.

Infantile Cushing syndrome

No effective medical treatment for adrenocorticotropic hormone (ACTH)-independent Cushing syndrome is available, and the currently recommended treatment is bilateral adrenalectomy.

During the procedure and afterwards, the patient needs replacement of both glucocorticoids and mineralocorticoids in appropriate amounts. Stress doses of glucocorticoid (approximately 10 times maintenance) should be administered perioperatively and slowly reduced to maintenance levels (eg, hydrocortisone 12-16 mg/m2/day in 3 divided doses). Mineralocorticoid replacement (eg, fludrocortisone 0.05-0.1 mg/day) should be started soon after surgery as the hydrocortisone dose is weaned toward maintenance levels.

Gigantism and acromegaly

Management of GH excess in the setting of MAS should be achieved by using pharmacotherapeutic agents because such excess is invariably the result of diffuse nodular pituitary hyperplasia rather than of a single definitive adenoma. Surgical removal of adenomas, even if they appear to be present on radiologic testing, may be complicated by coexisting fibrous dysplasia (FD) involving the skull bones that distorts anatomic 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 FD. No systemic investigation into the use of focused gamma knife–based pituitary irradiation has been done, because this condition is so uncommon.

Most patients with GH excess in MAS are treated with octreotide in dosages similar to those used in regular acromegaly, beginning at 50 µg subcutaneously (SC) every 8 hours and then titrated to response (on the basis of insulinlike growth factor 1 [IGF-1] and postinjection GH levels) to levels as high as 1500 µg/day. Octreotide successfully lowers GH levels in many cases but rarely normalizes GH secretion. Long-acting somatostatin analogues (eg, depot octreotide and lanreotide) have also been used on a case-by-case basis. [62]

The dopamine agonists bromocriptine and cabergoline have also been used to decrease GH secretion. (A third dopamine agonist, pergolide, was withdrawn from the US market in March 2007.) These agents appear to have particular utility in the setting of prolactin and growth hormone co-hypersecretory states suggestive of somatomammotropinomas.

Dopamine agonists have been used as monotherapy but are typically used in conjunction with octreotide. A study showed that cabergoline was able to decrease GH secretion but was unsuccessful in bringing GH secretion down to normal. Combined octreotide-cabergoline therapy has yielded additional improvement in GH secretion in comparison with monotherapy, but in general, it has not been successful in bringing levels down to normal.

No systemic data are presently available on the utility or place of GH receptor antagonists (eg, pegvisomant [63] ) in managing MAS-associated GH excess. Such therapy is not contraindicated; however, the inability of these agents to control GH levels would probably make their use as monotherapy in this setting inadvisable.

Other manifestations

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 and recommended treatments include the following:

  • Hypogonadism - Appropriate hormone replacement therapy

  • Hypophosphatemia with hyperphosphaturia - Aggressive oral phosphorus replacement

  • Hypophosphatemic rickets - Appropriate calcium supplementation, phosphate repletion, and calcitriol administration

  • Hyperparathyroidism (primary or secondary)


Surgical Interventions

Precocious puberty

The need for excision of hyperfunctioning endocrine tissue is directed by the severity of the patient’s endocrine imbalance and the efficacy of medical treatment. When medical therapy fails, oophorectomy or ovarian cystectomy has been 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.

Historically, wedge resection of the ovary was performed if a single large follicular cyst was found. Unfortunately, this approach was often only temporarily successful in treating the estrogen hypersecretion, and other large follicular cysts subsequently formed. Accordingly, many advise against surgical treatment of precocious puberty in MAS.

Laparoscopy minimizes surgical aggression and allows the acquisition of tissue biopsy specimens for molecular analysis. [64] Additionally, hyperestrogenism can be arrested with the excision of hyperactive ovarian tissue. In girls younger than 3 years, laparoscopy can be performed by using the transumbilical laparoscopic ovarian cystectomy approach. In older females, traditional techniques are used.

Polyostotic fibrous dysplasia

Fracture is the primary indication for surgical treatment of dysplastic lesions. Most fractures are treated with traction. However, proximal fractures of the femur may have to be treated with surgically placed fixation devices. [65] Rarely, severe and progressive malformation of the femur can occur. These lesions are usually painful (because of the multiple small fractures associated with them) and may have to be removed surgically. For most PFD lesions, routine removal is not warranted; after removal, the lesion may recur at the same site.

En bloc resection and free metatarsal transfer have been used to treat FD of the fourth metacarpal associated with MAS. [66]

A study by Gorgolini et al ultimately advised that following surgical correction of lower limb deformities in patients with PFD or MAS, individuals with residual valgus deformities of more than 15° should undergo additional surgical correction in order to provide functional and cosmetic improvement. The investigators state that for such corrections, the treatment of choice is osteotomy of the distal femur or proximal tibia, although the tibial osteotomy cannot be carried out if an intramedullary nail is present. [67]

A study by Dalle Carbonare and Manisali of craniofacial fibrous dysplasia, including monostotic, polyostotic, and syndromic (ie, MAS), found that in the syndromic and nonsyndromic types radical resection led to a lower recurrence rate than did conservative surgery. Moreover, postoperative outcomes were better in both types following therapeutic optic nerve decompression than after prophylactic decompression. In addition, asymptomatic syndromic and nonsyndromic patients achieved excellent outcomes with watchful waiting. [68]


Ablative therapy (either radioiodine treatment or thyroidectomy) is warranted for the treatment of hyperthyroidism due to MAS. Any cells left behind that contain GNAS1 mutations may result in adenoma formation and recurrence of hyperthyroidism.

Thyroidectomy or hemithyroidectomy is the treatment of choice for hyperthyroidism associated with a goiter in patients with 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 not hyperfunctioning), progressively increasing goiter, and, of course, the very rare cases of coexisting thyroid carcinoma.

Other manifestations

The current recommendation for treatment of infantile Cushing syndrome in the context of MAS is bilateral adrenalectomy. Perioperative replacement of hormones is indicated (see Pharmacologic Therapy).

In MAS patients with gigantism or acromegaly, surgical removal should be considered only if the tumor is threatening vision; removal is rarely curative.


Diet and Activity

No specific dietary therapy is necessary for patients with MAS.

In general, patients should be encouraged to maintain a high degree of physical activity and a regular exercise program. Activity need not be limited unless the patient has PFD located at critical sites in the skeleton. Because this process can weaken bone, the presence of a lesion in a weight-bearing bone can increase the risk of a pathologic fracture and thus potentially warrant some restriction of activity. Patients may be advised, on an individual basis, to avoid certain contact sports, games, and pastimes associated with fracture risk.



Consultation with an endocrinologist is indicated because patients may have multiple endocrine defects, which may necessitate careful orchestration of treatment. Consultation with an orthopedist is indicated for pathologic fractures.

In children with MAS, a pediatric endocrine consultation should be considered for aid in evaluating and managing the myriad potential endocrinopathies. Furthermore, new medical therapies to treat estrogen hypersecretion and PFD may be available through some pediatric endocrine programs. Before any major surgical procedure on dysplastic bone lesions, a pediatric orthopedic surgeon experienced in managing PFD should be consulted. These lesions can be difficult to treat because of the soft nature of the dysplastic bone.


Long-Term Monitoring

Endocrinology follow-up care for MAS patients is lifelong. Ablation of hyperfunctioning endocrine tissue should be arranged early. These patients have an increased incidence of breast cancer and osteosarcoma and thus require lifelong follow-up screening.

Precocious puberty

Routine monitoring of growth and development is important in the long-term management of individuals with gonadotropin-independent precocious puberty. Careful attention to growth velocity is warranted; early estrogen exposure can inappropriately advance skeletal maturity and decrease adult height potential.

In addition, early estrogen exposure can advance the maturity of the hypothalamic-pituitary-gonadal axis and result in precocious onset of gonadotropin-dependent puberty. Because adult height potential often is already diminished by premature estrogen exposure, consideration should be given to suppression of early onset of puberty to prevent further compromise of adult height.

Polyostotic fibrous dysplasia

Outpatient care of a child with PFD depends on the severity and location of the lesions. Vision and hearing should be closely monitored if lesions are located near the orbit or bones surrounding the middle and inner ear. Progressive deformities or increasing pain at other sites may indicate pathologic fractures and warrant evaluation by a pediatric orthopedist.


After treatment of hyperthyroidism with either thyroidectomy or radioactive iodine, close monitoring is warranted ensure appropriate replacement of thyroid hormone. In children younger than 3 years, thyroid hormone is very important for normal brain growth. Schedule office visits every 3 months with careful physical examination and thyroid function tests. In children older than 3 years, routine visits can be decreased to every 4-6 months.

Infantile Cushing syndrome

After treatment of infantile Cushing syndrome with bilateral adrenalectomy, monitoring is warranted to ensure adequate adrenal steroid replacement. Attention to growth rate is important: Both undertreatment with glucocorticoids and overtreatment can result in decreased growth velocity. Slight undertreatment (hydrocortisone 10-12 mg/m2/day) should provide adequate maintenance replacement without growth suppression.

Mineralocorticoid treatment should be carefully monitored; overtreatment with fludrocortisone can result in hypertension. Adequate mineralocorticoid replacement is confirmed by monitoring blood pressure and periodically assessing plasma renin activity.

Increased doses of steroids are required during times of stress. During febrile illnesses, both hydrocortisone and fludrocortisone doses should be doubled. During times of severe stress (eg, trauma or surgery), hydrocortisone doses should be administered at approximately 10 times maintenance levels.

Gigantism and acromegaly

Individuals with GH excess should be monitored for signs of increased tumor growth and subsequent effect on visual acuity. Repeat magnetic resonance imaging (MRI) of the pituitary should be obtained at intervals to ensure adequate suppression of adenoma growth. Medical therapy can be optimized by periodically measuring levels of GH, IGF-1, or both.