History
A complete medical history is important in the evaluation of apparent endocrine hyperfunction such as that seen in McCune-Albright syndrome (MAS), though it is often more important for ruling out other causes of such hyperfunction than for diagnosing MAS itself. Patients generally do not have a family history of MAS. The clinical presentation of MAS is highly variable, depending on which of the various potential components of the syndrome predominate.
Precocious puberty
Precocious puberty can result from either central gonadotropin-dependent causes or peripheral gonadotropin-independent causes (see Etiology). [5] Symptoms of an intracranial process (eg, 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 MAS. Previous brain injury due to infection or trauma is also associated more often with central precocious puberty.
Although the following pattern is not universal, the [peripheral gonadotropin-independent puberty in MAS tends to be seen more frequently with vaginal bleeding 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.
In patients with precocious vaginal bleeding or breast development, other possible causes of estrogen excess must be considered. Accidental ingestion of estrogen supplements can cause breast development, increased height velocity, and maturation of the endometrial lining. As estrogen levels decrease, withdrawal bleeding can occur. If vaginal bleeding occurs in the absence of other signs of estrogen excess (eg, breast development or increased height velocity), a careful history mindful of possible trauma or sexual abuse should be obtained.
Forms of sexual precocity are observed in more than 50% of women with MAS. [30] Sexual precocity also occurs in male patients but is less common. Some MAS patients may have normal onset of puberty at a normal age.
Café-au-lait pigmentation
Evaluation of café-au-lait pigmentation requires a detailed family history because neurofibromatosis (NF) also produces multiple café-au-lait spots. Unlike MAS, which occurs sporadically, NF is an autosomal dominant condition. A diagnosis of NF should be considered if a family history of café-au-lait pigmentation is noted, and the possibility should not be discounted even when precocious puberty occurs with café-au-lait spots. Hypothalamic optic gliomas with NF can lead to gonadotropin-dependent precocious puberty.
Polyostotic fibrous dysplasia
In cases where polyostotic fibrous dysplasia (PFD) is marked, multiple pathologic fractures are prominent early in the history (usually in childhood). [31] In many cases, bony involvement predominates clinically on 1 side.
The potential presenting features include gait anomalies (eg, a limp), visible bony deformities, bone pain, and joint stiffness with pain, most often the result of secondary osteoarthrosis. Symptoms begin during childhood, though in some cases, the disease is clinically silent and is discovered on routine radiographs obtained for an unrelated reason. In other cases, the phenotypic affectation is mild, and the onset of symptoms is considerably delayed; subtle findings can include mild facial asymmetry, dysmorphism, and a small difference in limb length.
Spontaneous improvement or resolution of the bony lesions does not occur. Existing bony lesions may slowly worsen or remain static, or new lesions may develop. Bony lesions have been noted to worsen during pregnancy and other settings of estrogen excess. This worsening may be due to the trophic effects of estrogen on fibrous dysplastic bone, which does possess estrogen receptors.
Patients with myxomas often present with a history of palpable masses in the limbs, anterior abdominal wall, or back. These often are otherwise asymptomatic and may be painful.
Other manifestations
Hyperthyroidism rarely occurs in MAS without several other features of the syndrome also being present. A family history of autoimmune thyroid disorders supports a diagnosis of Graves disease, though Graves disease can occur in the absence of a family history. If no other features of MAS are present, autoimmune thyroid disease is far more likely. In cases of unexplained hyperthyroidism, surreptitious administration of thyroid hormone should be considered; again, this explanation would be more likely in the absence of physical findings of MAS.
Infantile Cushing syndrome may initially be seen without other signs of MAS. 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.
In the absence of other signs of MAS, exogenously administered steroids should be considered before excess cortisol is attributed to an activating mutation of the alpha subunit of the stimulatory G protein (Gs alpha; GNAS1 gene). Injections of steroids can be long-lasting; triamcinolone acetonide has caused Cushing syndrome for well over 1 year after the final injection, presumably as a result of an inability to metabolize and excrete the steroid.
Growth hormone (GH) excess coexisting with MAS is uncommon and generally is not found until early adulthood or mid-adulthood. Patients with MAS and GH excess present with the same paradoxic responses as regular patients with acromegaly upon thyrotropin-releasing hormone stimulation and upon oral glucose tolerance tests.
Associated hypogonadotropic hypogonadism may be present, particularly in the setting of hyperprolactinemia. Hyperprolactinemia in the absence of acromegaly has not been described in patients with MAS.
Rarely, MAS has been associated with high-output congestive heart failure similar to that seen in Paget disease.
Physical Examination
Like the findings from the clinical history, the physical findings may vary, depending on the particular manifestations of MAS in a given patient. Diagnosis of MAS depends on finding at least 2 of the phenotypic features associated with activating GNAS1 mutations.
The presence of 2 distinct physical findings consistent with autonomous hyperfunction increases the likelihood that the single underlying cause is an activating GNAS1 mutation rather than activating mutations in genes (ie, receptors) specific to a tissue type. Although an activating GNAS1 mutation can be isolated in only 1 tissue type, confirmation requires molecular analysis of that specific tissue. Additionally, certain physical findings should lead away from the diagnosis of MAS.
Precocious puberty
Patients with precocious puberty invariably are taller as children. However, as a result of a combination of precocious puberty, recurrent fractures, and hypophosphatemic rickets, the majority of patients with MAS have a final height below that of their peers and below their projected midparental height. An important scenario in which a patient with MAS attains normal height is that in which there is a coexisting GH excess (a clinical pearl that aids in diagnosis in these particular cases). [5]
Precocious puberty in girls with MAS is indicated by the appearance of signs of excess estrogen 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 examining 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 the 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.
Testicular enlargement (macroorchidism) occurs in males with MAS. Although it is usually bilateral and occurs against a context of sexual precocity, this is not always the case. A 4.6-year-old boy with unilateral macroorchidism without sexual precocity or other MAS pathology has been described. [32]
Café-au-lait pigmentation
Café-au-lait spots, ranging from light brown to dark brown in color, are the classic symptom of MAS. They may not be apparent in very young patients but may become more prominent with age. A Wood lamp can help detect subtle lesions. Pigmented areas are often few but can be quite large (see the first image below). These lesions often display a segmental distribution and frequently predominate on one side of the body (the side with more bony fractures and deformity). Individual lesions generally do not cross the midline (see the second image below).
Large café-au-lait patches around shoulder in child with McCune-Albright syndrome.
McCune-Albright syndrome case showing café-au-lait pigmentation. Lesion does not cross midline, which is typical of pigmented lesions in this syndrome.
If precocious puberty and café-au-lait pigmentation are the only features noted, NF cannot be ruled out. Generally, the café-au-lait spots in MAS are characterized by an irregular outline (“coast of Maine”; see the image below), whereas the spots in NF tend to be smaller and have a smooth outline (“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 is suggestive of NF.
Café au lait spot. This is a fairly large, irregular-edged ("coast-of-Maine" variety) lesion. It presents as a brownish, otherwise-asymptomatic macule/patch. The degree of pigmentation is fairly uniform.
The lesions are arranged in a segmental fashion that coincides with the developmental lines of Blaschko. They are located most commonly on the buttocks and the lumbosacral back. Common areas to look for subtle café-au-lait spots include the nape of the neck and the nasal clefts. However, these pigmented lesions are absent in 10-20% of patients and can be detected (by a formal dermatologic assessment) in as many as 10% of healthy subjects; accordingly, their diagnostic utility is limited when they are not associated with other features of MAS. However, it was reported that irregular congenital café-au-lait macules in a blaschkoid pattern on a patient's back were used to diagnose MAS (later confirmed by genetic evaluation) even though other signs of the disorder were not present at the time. [33]
A few cases have been described in which MAS has been associated with either patchy or diffuse alopecia (first described by Shelley and Wood).
Polyostotic fibrous dysplasia
Fibrous dysplasia (FD) in MAS ranges from asymptomatic lesions to markedly disfiguring involvement of the skull, spine, [34] and long bones. Involvement of the skull can be particularly problematic, with lesions of the orbit resulting in visual loss or proptosis and lesions of the ear resulting in deafness and vertigo. Like the cutaneous lesions, the bony lesions are not uniformly distributed and tend to be unilateral.
Other manifestations
Hyperthyroidism is uncommon in MAS, commonly appearing as a hypermetabolic state. Findings may include tachycardia, supraventricular arrhythmias, hypertension, hyperthermia, tremor, sleeplessness, and involuntary weight loss. Infants with hyperthyroidism often exhibit failure to thrive. Hyperthyroidism does not always occur in infancy: There are case reports describing hyperthyroidism occurring abruptly in later childhood, including 1 report of thyroid storm after surgery for FD.
Cushing syndrome is also rare in MAS. 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.
GH-producing somatotroph adenomas can occur in McCune-Albright syndrome. In children, GH excess results in a marked increase in linear growth velocity. If it goes 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.
Rarely, severe hypophosphatemia can occur in MAS. If it is not treated, 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).
Infants with MAS may have persistent jaundice and mild hepatomegaly but generally lack other manifestation of liver failure.
Complications
Complications of MAS depend on the degree of involvement and tissue distribution of GNAS1 mutations.
In precocious puberty, increased estrogen secretion can result in an initial increase in height velocity (as well as early breast development and vaginal bleeding). 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.
Lesions in FD range from relatively benign and asymptomatic to serious and debilitating, depending on the location. Lesions in weight-bearing bones can cause pathologic fractures. Depending on the specific bone involved and the specific location, potential complications of fractures include secondary osteomyelitis, compressive neuropathy, Volkmann contractures, sympathetic algodystrophy (reflex sympathetic dystrophy), myositis, ligamentous ossifications, and pseudoarthrosis.
The most dreaded complication of PFD is osteosarcoma, which most often occurs in the setting of irradiation of PFD-affected bones. [35] It is very uncommon; the overall incidence of sarcomatous degeneration in the setting of PFD is less than 1%. Most frequently, it involves the bones of the face and femur.
FD in the skull can be quite disfiguring and may be associated with blindness as a consequence of optic nerve compression. [36] Deafness also can occur and is associated with vestibulocochlear nerve compression. Other potential complications can result from compressive neuropathies of the cranial nerves located at the base of the skull. Rarely, compression fractures in the spine with impingement on spinal nerves have been reported.
Hyperthyroidism in MAS 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. A decreased attention span often results in poor school performance. Osteoporosis can also result from a prolonged hyperthyroid state.
Infantile Cushing syndrome is also associated with severe growth failure, though the weight-for-height percentile deviations are not as significant as those associated with 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, though some permanent effect on growth potential may occur.
GH excess associated with a somatotroph adenoma leads to gigantism or acromegaly, depending on the age of initial presentation. In addition to the characteristic tall stature and coarse facial features, individuals are at risk for 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 as a result of increased urinary phosphate losses causes severe rickets and short stature. Although phosphate replacement and calcitriol treatment improve growth and heal the rickets, overall growth potential is reduced. Additionally, select patients may develop nephrocalcinosis and loss of renal function over time (iatrogenic sequelae).
More severe presentations of MAS are clearly associated with sudden death. Although no arrhythmias have been detected in individuals with MAS, this is the presumed mechanism of sudden death. The stimulatory G protein (see Pathophysiology) 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.
Of particular concern is the possibility that the tachycardia resulting from severe hyperthyroidism may complicate or trigger a cardiac event. Hyperthyroidism could increase the risk of such events in susceptible individuals.
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Base of the skull computed tomography scan showing extensive fibrous dysplasia in McCune-Albright syndrome. Note the asymmetrical affectation, with near-total obliteration of various neural foramina at the base of the skull. This degree of fibrous dysplasia can result in multiple cranial nerve compression neuropathies, of which blindness and deafness (from involvement of cranial nerves II and VIII) are among the most disabling.
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Café au lait spot. This is a fairly large, irregular-edged ("coast-of-Maine" variety) lesion. It presents as a brownish, otherwise-asymptomatic macule/patch. The degree of pigmentation is fairly uniform.
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Fibrous dysplasia of a long bone characterized by focal bony expansion, patchy areas of sclerosis, and bony cyst formation in McCune-Albright syndrome.
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Plain skull radiograph in a typical McCune-Albright syndrome case shows marked macrocrania, frontal bossing, and markedly thickened bony table in patchy areas, particularly at base of skull and occiput. Skull also shows hair-on-end appearance, which needs to be differentiated from similar radiologic appearances in Paget disease or poorly controlled hemoglobinopathy (eg, beta-thalassemia, sickle cell disease).
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Large café-au-lait patches around shoulder in child with McCune-Albright syndrome.
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Lucency characteristic of polyostotic fibrous dysplasia in patient with McCune-Albright syndrome.
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McCune-Albright syndrome case showing café-au-lait pigmentation. Lesion does not cross midline, which is typical of pigmented lesions in this syndrome.
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Adrenal hyperplasia with nodular elements in adrenal gland isolated from infant with infantile Cushing syndrome in the context of McCune-Albright syndrome. DNA isolated from nodular tissue was determined to have activating Gs alpha mutation (GNAS1), whereas DNA isolated from surrounding tissue did not contain this mutation.
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The G protein cycle begins with ligand binding to a 7-transmembrane domain G protein-coupled receptor (GPCR). Binding of the cognate ligand forms a ligand-receptor complex, which then stimulates an exchange of guanosine triphosphate (GTP) for guanosine diphosphate (GDP) on the alpha subunit of the stimulatory G protein (Gs alpha). This activates the alpha subunit, which subsequently stimulates adenylyl cyclase (AC) to increase production of cyclic adenosine monophosphate (cAMP). The alpha subunit contains intrinsic guanosine triphosphatase (GTPase) activity, which cleaves a phosphate group from GTP, converting it to GDP, and thus inactivates the alpha subunit. The inactivated alpha subunit is now ready to be reactivated by ligand-receptor binding, so that the next cycle of signal transduction can occur.
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Mutations in McCune-Albright syndrome inactivate intrinsic guanosine triphosphatase (GTPase) activity, thus preventing inactivation of the "turned-on" Gs alpha subunit. Once activated, the mutated Gs alpha subunit is able to continuously stimulate adenylyl cyclase, even in absence of ligand binding to its cognate GPCR receptor. The result is elevation of intracellular cyclic adenosine monophosphate (cAMP) and continual stimulation of downstream cAMP signaling cascades.
