Pediatric McCune-Albright Syndrome 

McCune-Albright syndrome in its classic form consists of at least 2 features of the triad of polyostotic fibrous dysplasia, café au lait skin pigmentation, and autonomous endocrine hyperfunction.^[1] Reports of similar cases were published before McCune and Albright separately reported the most complete early descriptions of the syndrome in 1937.^{[2, 3]} Later findings broadened the spectrum of the McCune-Albright syndrome. Although changes in ovary, bone, and skin tissue are most common, other endocrine and nonendocrine tissues may also be affected, including the adrenal, thyroid, pituitary, liver, and heart.

The most common form of autonomous endocrine hyperfunction in this syndrome is gonadotropin-independent precocious puberty, but affected individuals also may have hyperthyroidism, hypercortisolism, pituitary gigantism, or acromegaly. Nonendocrine abnormalities in this disorder include hypophosphatemia, chronic liver disease, tachycardia, and, rarely, sudden death, possibly from cardiac arrhythmias.

Precocious puberty, the most common endocrine feature of McCune-Albright syndrome, is a result of gonadotropin-independent autonomous ovarian or testicular function. Precocious puberty caused by this condition is far more common in girls than in boys. Girls as young as 4 months with McCune-Albright syndrome can have breast development or vaginal bleeding. A dominant ovarian cyst develops independent of stimulation by gonadotropins. This cyst secretes estradiol, which causes sexual precocity. In addition, excess estrogen exposure often stimulates increased growth velocity and can result in a marked advancement in skeletal maturity.

Adrenocorticotropic hormone (ACTH)–independent Cushing syndrome generally results in growth failure and hypertension in infancy. The adrenal glands are bilaterally enlarged and contain multiple small nodules in the cortex.

Hyperthyroidism typically occurs later in childhood, although it can occur within the first year of life. As in Cushing syndrome and precocious puberty, hyperthyroidism associated with McCune-Albright syndrome is a result of one or more autonomous hyperfunctioning nodules.

Growth hormone (GH) excess from somatotroph adenomas in the pituitary can occur at any age, resulting in gigantism and/or acromegaly.

Fibrous dysplasia in the McCune-Albright syndrome can involve any bone but most commonly affects the long bones, ribs, and skull. Fibrous dysplasia ranges from small asymptomatic areas detectable only by bone scan to markedly disfiguring lesions that can result in frequent pathologic fractures and impingement on vital nerves.

Café au lait spots in McCune-Albright syndrome are large melanotic macules. Except for hyperpigmentation of the basal layer, no abnormal pathology is seen.

Hypophosphatemia is a result of decreased reabsorption of phosphate in the renal tubule, similar to the phosphaturia seen with hyperparathyroidism. Parathyroid hormone levels are not elevated, suggesting parathyroid hormone-independent stimulation of phosphaturia.

Hepatic abnormalities range from mild elevation of hepatic transaminases to severe neonatal jaundice and chronic cholestasis. Although some liver biopsies appear normal, others reveal mild biliary abnormalities or fatty liver. One case report described fatty liver in an infant with Cushing syndrome. Therefore, the fatty liver may have been secondary to glucocorticoid excess. Elevated transaminases in this infant, however, persisted long past correction of the glucocorticoid excess with adrenalectomy.

Many case reports, including some originally reported by McCune and Albright, describe sudden death. Most of these episodes of sudden death have occurred in patients with multiple endocrine and nonendocrine manifestations of the syndrome. Persistent tachycardia has been observed in addition to mild-to-moderate cardiomegaly. Although the cause of death in these patients is unclear, it is presumed to be secondary to cardiac arrhythmia.

McCune-Albright syndrome is the result of a postzygotic somatic mutation in the gene that codes for the alpha subunit of the stimulatory G protein (Gsa). G proteins are involved in transmitting hormone signals intracellularly by coupling cell surface receptors to intracellular signaling cascades. The specific mutations that cause McCune-Albright syndrome cause constitutive activation of these intracellular signaling cascades in the absence of hormone stimulation. For further details of the molecular mechanisms behind stimulatory G protein function and McCune-Albright syndrome, see Causes.

Frequency

United States

McCune-Albright syndrome is a rare, sporadically occurring genetic disorder. The exact incidence is unknown.

Mortality/Morbidity

In precocious puberty, early breast development and vaginal bleeding can be accompanied by loss of adult height potential. Some of the most severe effects of fibrous dysplasia are pathologic fractures, facial disfigurement, and vision and hearing problems. Hyperthyroidism can cause severe failure to thrive in infants and young children, decreased attention span, and osteoporosis. Tachycardia resulting from severe hyperthyroidism may complicate or trigger a cardiac event. Infantile Cushing syndrome can cause severe growth failure, poor muscle tone, and hypertension. Permanent effect on growth potential is also possible. Long-term untreated hypercortisolism can result in death. Gigantism or acromegaly can occur, with a risk of developing glucose intolerance, hypertriglyceridemia, hypertension, and mild myopathy. Hypophosphatemia causes rickets and short stature.

Sudden death has frequently been associated with more severe disease. Although no arrhythmias have been detected in individuals with McCune-Albright syndrome, this is the presumed mechanism of sudden death.

Race

McCune-Albright syndrome occurs equally in all races.

Sex

Gonadotropin-independent precocious puberty is far more common in affected girls than in boys. Other manifestations of McCune-Albright syndrome probably occur equally in both sexes.

Age

Severe cases involving multiple endocrine tissues may be recognized shortly after birth. Cases of infantile Cushing syndrome and hyperthyroidism have also been reported in the neonatal period. Additionally, fibrous dysplasia, café au lait pigmentation, liver disease, and hypophosphatemia can initially be seen in infancy.

Less severe findings of McCune-Albright syndrome can occur at almost any time during childhood. Precocious puberty in girls can be seen in infants as young as 4 months, although it frequently occurs in girls older than 1 year. Café au lait pigmentation is more likely to become apparent later in the progression of the syndrome.

GH-producing pituitary tumors and functional-thyroid adenomas secondary to activating Gsa mutations can occur in individuals at any age.