Pediatric McCune-Albright Syndrome Treatment & Management

Treatment of McCune-Albright syndrome includes the following:

• Precocious puberty

  • Precocious puberty in McCune-Albright syndrome 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.
  • The aromatase inhibitor testolactone has been the mainstay of therapy in girls with persistent estradiol elevation. Aromatase inhibitors block the conversion of testosterone to estradiol, thus lowering circulating estrogen levels. Doses beginning at 20 mg/kg/d, divided in 3-4 doses, as much as 40 mg/kg/d are used. Although fairly effective, the large amount of medication required and the frequency of dosing make compliance difficult.
  • Fadrozole, a more potent aromatase inhibitor, was shown in a clinical trial to be ineffective in preventing progression of precocious puberty. However, anastrozole, a highly selective aromatase inhibitor, was successful in significantly slowing precocious puberty in one case. It also had the added benefit of once daily dosage.
  • Tamoxifen, an antiestrogen that was initially developed for use in estrogen–sensitive breast cancer, has been shown to be effective in treating precocious puberty in girls with McCune-Albright syndrome. One multicenter study was performed using 20 mg of tamoxifen once a day.^[4] They found significant improvement in growth velocity and rate of skeletal maturation.
  • Ketoconazole was used in one study as an alternative therapy in 2 girls.^[5] They also showed significant improvement in signs of precocious puberty. Unfortunately, ketoconazole's dosing is 3 times daily, which is a drawback compared to the daily dosing of anastrozole or tamoxifen. Additional clinical studies of newer and more potent aromatase inhibitors, as well as antiestrogens and other therapies, continue to be pursued.
• Fibrous dysplasia: Symptomatic fibrous dysplasia is difficult to treat medically. Currently, no clinically proven medical therapies are available. Studies using both oral and intravenous bisphosphonates are encouraging. Conflicting data regarding the ability of bisphosphonates to heal fibrous dysplasia have been reported. Some studies have shown no improvement in bone mineral density, whereas others have shown significant improvement in bone mineral density in the areas of fibrous dysplasia. However, bisphosphonates do make the lesions less painful.
• Hyperthyroidism: Hyperthyroidism due to functional thyroid follicular adenomas can be treated medically. Antithyroid medications, such as propylthiouracil and methimazole, can be used to decrease thyroid hormone production. Unlike Graves disease, hyperthyroidism secondary to an activating mutation of the alpha subunit of g protein (Gsa) is unlikely to go into remission. Therefore, patients probably should use antithyroid drugs indefinitely. Consider a more permanent treatment of the hyperthyroidism, including I131 therapy or thyroidectomy, if a diagnosis of McCune-Albright syndrome is confirmed.
• Hypophosphatemic rickets: The treatment for severe hypophosphatemia is similar to that used in X-linked dominant hypophosphatemic rickets. Phosphate supplementation (approximately 1.5-2.5 g/d divided in 5 doses) is given in addition to 1,25 dihydroxy vitamin D (calcitriol 0.25-0.5 mg/d).
• Infantile Cushing syndrome: No effective medical treatment for adrenocorticotropic hormone (ACTH)-independent Cushing syndrome is available, and the current recommendation for treatment is bilateral adrenalectomy. During the adrenalectomy and afterwards, the patient needs replacement of both glucocorticoid and mineralocorticoid in appropriate amounts. Stress doses of glucocorticoid (approximately 10 times maintenance) should be administered perioperatively and slowly reduced to maintenance replacement levels (hydrocortisone at 12-16 mg/m²/d divided in 3 doses). Mineralocorticoid replacement (Florinef at 0.05-0.1 mg/d) should be started soon after surgery as the hydrocortisone dose is weaned toward maintenance levels.
• Gigantism/acromegaly: Medical treatment is the most effective for growth hormone (GH)-producing adenomas. Radiation therapy may cause sarcomatous changes in the surrounding dysplastic bone if fibrous dysplasia is present. Octreotide, the long-acting somatostatin analogue, has been used with variable success in decreasing GH secretion from these tumors. Octreotide has been successful in lowering GH levels in many cases but rarely has normalized GH secretion. Dopamine agonists, such as bromocriptine and cabergoline, have also been used to decrease GH secretion. They 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. Combination octreotide and cabergoline therapy has shown additional improvement in GH secretion compared with monotherapy but, in general, was not successful in bringing levels down to normal.

Surgical treatment in McCune-Albright syndrome may include the following:

• Precocious puberty: Historically, wedge resection of the ovary was performed if a single large follicular cyst was found. Unfortunately, this often only temporarily treated the estrogen hypersecretion and other large follicular cysts subsequently formed. Therefore, surgical treatment currently is not recommended to treat precocious puberty in McCune-Albright syndrome.
• 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 require surgically placed fixation devices. Rarely, severe and progressive malformation of the femur can occur. These lesions usually are painful because of the multiple small fractures associated with them and may need to be removed surgically. Routine removal of most polyostotic dysplastic lesions generally is not warranted and can result in the lesion recurring at the same site.
• Hyperthyroidism: Ablative therapy is warranted in treatment of hyperthyroidism due to McCune-Albright syndrome, either by radioactive iodine treatment or by thyroidectomy. A near total thyroidectomy should be considered, because any cells left behind containing activating Gsa mutations result in adenoma formation and recurrence of hyperthyroidism.
• Infantile Cushing syndrome: The current recommendation for treatment is bilateral adrenalectomy. See Medical Care for details on perioperative replacement of hormones.
• Gigantism/acromegaly: Consider surgical removal only if the tumor is threatening vision because removal is rarely curative.

Pediatric endocrine consultation should be considered in any child with McCune-Albright syndrome to evaluate for and manage the myriad potential endocrinopathies. Furthermore, new medical therapies to treat estrogen hypersecretion and fibrous dysplasia are being proposed in clinical studies that are available through some pediatric endocrine programs.

Consider consultation with a pediatric orthopedic surgeon experienced in the management of polyostotic fibrous dysplasia prior to any major surgical procedure on dysplastic bone lesions. These lesions can be difficult to treat because of the soft nature of the dysplastic bone.

No special dietary considerations are noted.

Activity is not limited unless the patient has fibrous dysplasia located at critical sites in the skeleton. Because fibrous dysplasia can weaken the bone, the presence of a lesion in a weight bearing bone can increase the risk of a pathologic fracture. Therefore, limiting activities (eg, contact sports) in these cases should be considered.