Pediatric McCune-Albright Syndrome Follow-up

The following is recommended in patients with McCune-Albright syndrome:

• 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 as 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 the 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.
• Fibrous dysplasia: Outpatient care of the child with fibrous dysplasia depends on the severity and location of the lesions. Closely monitor vision and hearing 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.
• Hyperthyroidism: Closely monitor children treated with either thyroidectomy or radioactive iodine for hyperthyroidism to 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

  • Monitor children treated with bilateral adrenalectomy for infantile Cushing syndrome for adequate adrenal steroid replacement. Attention to growth rate is important as both undertreatment and overtreatment with glucocorticoids can result in decreased growth velocity. Slight undertreatment (hydrocortisone at 10-12 mg/m²/d) should provide adequate maintenance replacement without growth suppression.
  • Carefully monitor mineralocorticoid treatment because overtreatment with Florinef can result in hypertension. Confirm adequate mineralocorticoid replacement by monitoring blood pressure in addition to periodic assessment of plasma renin activity.
  • Increased doses of steroids are required during times of stress. During febrile illnesses, both hydrocortisone and Florinef doses should be doubled. During times of severe stress (eg, trauma, surgery), administer hydrocortisone doses at approximately 10 times maintenance levels.
• Gigantism/acromegaly: Monitor individuals with growth hormone (GH) excess for signs of increased tumor growth and subsequent effect on visual acuity. Repeat imaging of the pituitary by MRI should be obtained at intervals to ensure adequate suppression of adenoma growth. In addition, medical therapy can be optimized by intermittent measurement of GH and/or insulinlike growth factor (IGF)-1.

Medications include the following:

• Testolactone: Consider aromatase inhibitors in cases of persistent estrogen secretion.
• Antithyroid agents: Tapazole or propylthiouracil can be used as temporizing therapy in severe hyperthyroidism associated with McCune-Albright syndrome.
• GH-suppressing agents: Sandostatin can decrease adenoma growth and GH secretion in somatotroph adenomas. Bromocriptine sometimes is added as adjunctive therapy.
• Hydrocortisone: This is used for glucocorticoid replacement perioperatively and postoperatively in infantile Cushing syndrome.
• Florinef: This is used postoperatively in infantile Cushing syndrome for mineralocorticoid replacement.

The extent and severity of McCune-Albright syndrome depends on the degree of involvement and tissue distribution of the activating alpha subunit of G protein (Gsa) mutations.

• Precocious puberty: In addition to early breast development and vaginal bleeding, increased estrogen secretion in precocious puberty can result in an initial increase in height velocity. Although early height percentiles are greater than expected, a rapid advancement of bone age results in an ultimate loss of adult height potential. Early estrogen exposure may also mature the hypothalamic-pituitary-gonadal axis and result in earlier than expected central puberty. Furthermore, precocious puberty can have a profound psychological and social effect on a young patient experiencing puberty before she is intellectually ready.
• Fibrous dysplasia: Lesions in fibrous dysplasia range from relatively benign and asymptomatic to serious and debilitating, depending on the location. Lesions in weight-bearing bones can cause pathologic fractures. Fibrous dysplasia in the skull can be quite disfiguring and impinge on optic and auditory nerves, thus affecting sight and hearing. Rarely, compression fractures in the spine with impingement on spinal nerves have been reported.
• Hyperthyroidism: Hyperthyroidism in McCune-Albright syndrome can cause severe failure to thrive in infants and young children. Elevated thyroid levels result in a hypermetabolic state with possible weight loss, anxiety, tremor, tachycardia, and sleeplessness. Decreased attention span often results in poor school performance. Osteoporosis can also result from a prolonged hyperthyroid state. Of particular concern, however, is the possibility that the tachycardia resulting from severe hyperthyroidism may complicate or trigger a cardiac event. Individuals with severe manifestations are at risk of sudden death from presumed cardiac involvement. Hyperthyroidism could increase the risk of these events in susceptible individuals.
• Infantile Cushing syndrome: Infantile Cushing syndrome also presents with severe growth failure, although the weight for height percentile deviations are not as significant as in hyperthyroidism in infancy. Infants with Cushing syndrome often have poor muscle tone and may have hypertension and bruise easily. Long-term untreated hypercortisolism also can result in death. Blood pressure, muscle tone, and growth should all improve with adrenalectomy, although some permanent effect on growth potential may occur.
• Gigantism/acromegaly: GH excess associated with a somatotroph adenoma leads to gigantism and/or acromegaly, depending on the age of initial presentation. In addition to the tall stature and coarse facial features associated with GH excess, individuals are at risk of developing glucose intolerance, hypertriglyceridemia, hypertension, and mild myopathy. The adenoma itself may interfere with the production of other pituitary hormones. Extension of the tumor above the sella can compromise the optic chiasm, resulting in visual field defects, most commonly bitemporal homonymous hemianopsia.
• Hypophosphatemia: Hypophosphatemia as a result of increased urinary phosphate losses causes severe rickets and short stature. Although phosphate replacement and vitamin D treatment improve growth and heal the rickets, overall growth potential is reduced.
• Sudden death: More severe presentations of McCune-Albright syndrome are clearly associated with sudden death. Although no arrhythmias have been detected in individuals with McCune-Albright syndrome, this is the presumed mechanism of sudden death. The stimulatory G protein is one of the primary intracellular signal transducers of the beta-adrenergic receptor. Constitutive activation of adrenergic signaling could result in a refractory and pathologic arrhythmia. Further study is needed to reach a conclusive understanding of sudden death in this syndrome.

The prognosis varies, as follows:

• Precocious puberty: Prognosis depends on the duration of premature estrogen exposure. Early puberty is not a life-threatening condition and does not seem to lead to problems after true, centrally mediated puberty begins at an appropriate age. Reduction of height potential depends on the degree of bone age advancement that occurs during the periods of early estrogen exposure.
• Fibrous dysplasia: Fibrous dysplasia is difficult to treat effectively. Current therapies focus on the treatment of complications of fibrous dysplasia (eg, pathologic fractures), rather than prevention. Current studies using bisphosphonates are promising, although it is unclear if bisphosphonates significantly reduce morbidity associated with these lesions.
• Hyperthyroidism: Radioiodine ablation or thyroidectomy treats hyperthyroidism effectively. Long-term prognosis is excellent with adequate thyroid hormone replacement.
• Infantile Cushing syndrome: Comorbid heart and liver disease are poor prognostic markers and may indicate the need for prompt adrenalectomy.^[6] Cushing syndrome is effectively treated with bilateral adrenalectomy. Long-term prognosis depends on adequate replacement of both mineralocorticoids and glucocorticoids. Individuals remain at risk for significant morbidity or mortality due to adrenal insufficiency during times of severe stress and should receive stress doses of hydrocortisone emergently.
• Acromegaly/gigantism: GH secretion in McCune-Albright syndrome is difficult to treat effectively. Sandostatin has proven effective in many but not all cases. Furthermore, radiation treatment of the adenoma increases the risk of malignant change in areas of fibrous dysplasia in the radiation field. Long-term prognosis in refractory cases of acromegaly is poor, with an increased risk of diabetes and heart disease.

Educational requirements depend on the phenotypic expression of McCune-Albright syndrome. Instruct individuals with fibrous dysplasia in critical weight bearing areas to avoid activities (eg, contact sports) that put their skeleton at risk for pathologic fracture.

Patients that have undergone bilateral adrenalectomy for Cushing syndrome need clear instructions on changing steroid dosing for febrile illnesses. Furthermore, these individuals need to wear medic alert identification bracelets or necklaces in case of severe illness or trauma to inform medical personnel of the requirement for stress doses of hydrocortisone.

For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.