Pediatric McCune-Albright Syndrome Clinical Presentation

A complete medical history is important in the evaluation of apparent endocrine hyperfunction such as that seen in McCune-Albright syndrome. A detailed history is often more important in ruling out other causes of endocrine hyperfunction than in diagnosing McCune-Albright syndrome.

Precocious puberty can result from either central gonadotropin-dependent or peripheral gonadotropin-independent causes.

Symptoms of an intracranial process, such as abrupt vision changes, nighttime headaches, or nighttime emesis, are suggestive of hypothalamic lesions that can lead to gonadotropin-dependent precocious puberty and are not consistent with McCune-Albright syndrome. Previous brain injury due to infection or trauma is also associated more often with central precocious puberty.

Although the following pattern is not conclusive, puberty in McCune-Albright syndrome is seen more frequently with vaginal bleeding and/or breast development unaccompanied by growth of pubic hair and tends to occur at an earlier age than central gonadotropin-dependent precocious puberty. Furthermore, vaginal bleeding often occurs before the onset of breast development and tends to be irregular. Bleeding episodes may be isolated or frequently recurrent, with very little pattern or predictability.

Consider other possible causes of estrogen excess with precocious vaginal bleeding and/or breast development. Accidental ingestion of estrogen supplements can cause some breast development, increase in height velocity, and maturation of the endometrial lining. As estrogen levels decrease, a withdrawal-bleeding episode can occur. If vaginal bleeding occurs in the absence of other signs of estrogen excess (eg, breast development, increased height velocity), a careful history mindful of possible trauma or sexual abuse should be obtained.

Evaluation of café au lait pigmentation requires a detailed family history because neurofibromatosis also produces multiple café au lait spots. Unlike McCune-Albright syndrome, which occurs sporadically, neurofibromatosis is an autosomal dominant condition. Consider a diagnosis of neurofibromatosis if a family history of café au lait pigmentation is noted. Do not discount the possibility of neurofibromatosis when precocious puberty occurs with café au lait spots. Hypothalamic optic gliomas with neurofibromatosis can lead to gonadotropin-dependent precocious puberty.

Hyperthyroidism in McCune-Albright syndrome rarely occurs without several other features of the syndrome. With hyperthyroidism, a family history of autoimmune thyroid disorders supports a diagnosis of Graves disease, although Graves disease can be seen without a family history. If no other features of McCune-Albright syndrome are present, autoimmune thyroid disease is far more likely. Also consider surreptitious administration of thyroid hormone in unexplained hyperthyroidism. Again, this explanation would be more likely in the absence of physical findings of McCune-Albright syndrome.

Infantile Cushing syndrome may initially be seen without other signs of McCune-Albright syndrome. Cortisol excess should be considered in any infant with profound failure to thrive, hypertension, muscle weakness, and easy bruising. Unlike older children with cortisol excess, infants may have decreased appetite and food intake. Consider exogenously administered steroids in the absence of other signs of McCune-Albright syndrome before attributing excess cortisol to an activating alpha subunit of the stimulatory G protein (Gsa) mutation. Injections of steroids can be long lasting; triamcinolone acetonide has caused Cushing syndrome for well over 1 year after the final injection, presumably due to an inability to metabolize and excrete the steroid.

Diagnosis of McCune-Albright syndrome depends on finding at least 2 of the phenotypic features associated with activating Gsa mutations. The presence of 2 distinct physical findings consistent with autonomous function increases the likelihood that the single underlying cause is an activating Gsa mutation rather than activating mutations in genes (ie, receptors) specific to a tissue type. Although an activating Gsa mutation can be isolated in only one tissue type, confirmation requires molecular analysis of that specific tissue. Additionally, certain physical findings should lead away from the diagnosis of McCune-Albright syndrome.

Precocious puberty in girls with McCune-Albright syndrome is indicated by the appearance of signs of estrogen excess for age, including breast development, genital maturation, and increased height velocity. Pubic hair growth may or may not be present. Both breast diameter and Tanner staging should be recorded at each clinic visit as a gauge of ongoing estrogen exposure. If necessary, genital maturation can be determined by examination of the vaginal mucosa. A pink mucosa with mucous covering is consistent with estrogen stimulation, whereas a glistening red appearance is indicative of a thin, non–estrogen-stimulated mucosa.

Examination of the vaginal mucosa should be performed with extreme care to avoid traumatizing the patient. Frequently, the introitus can be examined with the patient lying on her back with heels together and legs externally rotated. Very gentle traction of labia majora may be necessary. Bimanual or speculum examinations should not be attempted. Only trained individuals should perform more detailed vaginal examinations with the patient under light general anesthesia.

If precocious puberty and café au lait pigmentation are the only features, neurofibromatosis cannot be ruled out. The café au lait spots in McCune-Albright syndrome are pigmented macules with irregular outlines (see the image below).

Color ranges from light brown to dark brown and may not be apparent in very young patients. A Wood lamp can help to detect subtle lesions. Pigmented areas are often few but can be quite large. These lesions often display a segmental distribution and frequently predominate on one side of the body.

Individual lesions generally do not cross the midline. Café au lait spots in McCune-Albright syndrome are characterized by an irregular outline, described as coast of Maine, whereas spots in neurofibromatosis tend to be smaller and have a smooth outline, described as coast of California. However, this distinction may not hold true in all cases. The presence of axillary or inguinal freckling, pigmented iris hamartomas (Lisch nodules) or cutaneous neurofibromas are suggestive of neurofibromatosis.

Fibrous dysplasia in McCune-Albright syndrome ranges from asymptomatic lesions to markedly disfiguring involvement of the skull, spine, and long bones. Involvement of the skull can be particularly problematic, with lesions of the orbit resulting in visual loss and/or proptosis, and lesions of the ear resulting in deafness and vertigo. As with the cutaneous lesions, the bony lesions are not uniformly distributed and tend to be unilateral.

Hyperthyroidism in McCune-Albright syndrome is uncommon, appearing as a hypermetabolic state. Findings may include tachycardia, hypertension, hyperthermia, tremor, sleeplessness, and weight loss. Infants with hyperthyroidism often have failure to thrive. Hyperthyroidism does not always occur in infancy. Case reports describe hyperthyroidism occurring abruptly in later childhood, including one case of thyroid storm after surgery for fibrous dysplasia.

Rarely, severe hypophosphatemia can occur in McCune-Albright syndrome. If untreated, severe rickets and short stature can result. Typical findings in hypophosphatemic rickets include bowing of legs, widening of wrists, and thickening of the costochondral junction (rachitic rosary).

Cushing syndrome is also rare in McCune-Albright syndrome. Patients with Cushing syndrome have profound growth failure in infancy. Although both weight and length percentiles decrease, linear growth failure is more pronounced. Frequently, these infants have round cushingoid faces and may have markedly decreased muscle tone and soft doughy skin. Hypertension also may be present.

Infants with McCune-Albright syndrome may have persistent jaundice and mild hepatomegaly but generally lack other symptoms of liver failure.

Growth hormone producing somatotroph adenomas can occur in McCune-Albright syndrome. In children, growth hormone (GH) excess results in a marked increase in linear growth velocity. If untreated, features of acromegaly can develop later in life, including enlargement of the hands and feet and coarsening of the facial features. Individuals with GH excess may also have hypertension and mild decreases in muscle tone.

McCune-Albright syndrome is the result of a postzygotic somatic mutation in the gene that codes for Gsa. G proteins couple cell surface receptors to intracellular proteins to activate or inactivate signaling cascades (see the image below).

The stimulatory G protein is normally activated when a hormone or other ligand binds to the cell surface receptor. The activated Gsa subunit subsequently disassociates from the receptor, binds to adenylyl cyclase, and stimulates an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. The Gsa subunit then is inactivated, reassociates with the receptor, and is again available for hormone-mediated reactivation.

The specific mutations that cause McCune-Albright syndrome occur at a site in the protein that mediates the inactivation of the Gsa subunit (see the image below).

Once activated, the mutated Gs alpha subunit remains activated for a prolonged period despite the absence of hormone stimulation of the receptor. The result is constitutive activation of the Gsa subunit, constant stimulation of adenylyl cyclase, and persistently high levels of intracellular cAMP. In various tissues, increased cAMP levels can mediate mitogenesis and increased cell function. The specific phenotype depends on the cell type containing the mutation.

The classic triad of features in McCune-Albright syndrome, polyostotic fibrous dysplasia, autonomous endocrine function, and café au lait skin pigmentation, can all be explained by activation of the Gsa subunit and increased intracellular cAMP.

Eumelanogenesis (formation of brown/black pigment) is normally stimulated by melanocyte-stimulating hormone (MSH) binding to the MSH receptor, a classic G protein receptor coupled to Gsa. Constitutive activation of the Gsa subunit in melanocytes results in the increase in brown pigmentation characteristic of the café au lait spots seen in the syndrome. Likewise, both the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) receptors are Gsa coupled receptors.

Constitutive activation of the postreceptor cAMP signaling cascade in ovarian follicular cells results in cyst formation, estrogen production, and gonadotropin independent precocious puberty. Similar mechanisms of increased intracellular cAMP likely explain essentially all of the other endocrine and nonendocrine features of McCune-Albright syndrome.

Because McCune-Albright syndrome results from a postzygotic somatic mutation, all the daughter cells of the embryonic cell in which the initial mutation occurred also contain the mutation. The earlier the mutation occurs in embryogenesis, the more widespread the tissue involvement. Mutations late in embryogenesis are more focused and account for the mild cases with only 2 or 3 of the classic phenotypic features of the syndrome. If the mutation occurs very late in tissue development after differentiation into a specific cell line, then a single adenoma may result. Gsa activating mutations have been reported in isolated hyperfunctioning thyroid nodules and in somatotroph adenomas.

Although Gsa mutations could occur in germ cells (either the oocyte or spermatocyte), the resulting zygote and all daughter cells then would contain the mutation. Activating Gsa mutations are likely lethal if they occur very early in embryogenesis. This accounts for the lack of autosomal dominant transmission of this syndrome.