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At a Glance
McCune-Albright syndrome is characterized by multiple fibrous bone lesions (fibrous dysplasia), cafe au lait spots, and a variety of endocrine disorders, including gonadotropin-independent precocious puberty. Although the syndrome is rare, the underlying defect is an activating mutation in the GNAS gene, which leads to constitutive activation of cAMP-based intracellular signaling. Such mutations may arise at different points during early development, and the location and timing of the mutation in any given patient accounts for the varied, mosaic distribution of clinical manifestations.
cAMP signaling is important as a downstream second messenger for a large number of endocrine receptors, including PTH receptor, MSH receptor, FSH receptor, TSH receptor, ACTH receptor, and GHRH receptor. Thus, activating mutations can cause a clinical phenotype consistent with an excess of one or more of these hormones without an actual increase in circulating levels. Based on the receptors that are activated, McCune-Albright can cause the clinical signs and symptoms of hyperthyroidism, Cushing’s syndrome, acromegaly, hyperprolactinemia, and hyperparathyroidism.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
If the patient presents with precocious puberty, a typical workup might measure FSH, LH, estradiol, testosterone, hCG, and thyroid hormones (TSH, T4). If estradiol or testosterone is high but FSH and LH are low, this indicates a peripheral cause of the pubertal phenotype. In the case of McCune-Albright, this is due to intracellular signaling that mimics the effect of FSH or LH in target cell types. If painful bone lesions or fractures are the presenting symptom and radiologic imaging suggests fibrous dysplasia, then PTH, calcium, phosophate, and vitamin D (25-OH and 1,25-OH) levels should be obtained.
Since the fibrous dysplasia of McCune-Albright is due to autonomous activation downstream of the PTH receptor, circulating PTH and calcium levels should be normal. Other clinical endocrine disturbances should be investigated just as if they were the primary presenting symptom (e.g., TSH and T4 for symptoms of hyperthyroidism, ACTH and free urine cortisol for Cushing’s). In each case, low or normal levels of the stimulating hormone (TSH, ACTH, LH, etc.) in the presence of elevated downstream mediators (T4, cortisol, testosterone) or appropriate signs and symptoms are consistent with a diagnosis of McCune-Albright. Cafe au lait spots are due to activation of the melanocyte-stimulating hormone (MSH) receptor, and no further testing is needed.(Table 1)
Table I.
| Stimulating hormone (e.g., FSH, TSH, PTH, ACTH, GHRH) | Effector hormone (e.g., estradiol, testosterone, free T4, free urine cortisol) | Downstream syndrome (e.g., fibrous dysplasia, Cushing’s, precocious puberty) |
| No elevation that would explain clinical phenotype | Elevated | Presence of clinical syndrome |
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
Immunoassays for testosterone are unreliable in low ranges and, therefore, are not appropriate for measuring children or women. In such cases, testosterone should be measured by LC-MS/MS.
Free T4 may be affected by heparin, free fatty acids, and phenytoin.
Plasma TSH may be increased by St. John’s Wort.
Plasma PTH may be transiently decreased by alcohol consumption.
Urine cortisol may be lowered by kidney disease and increased by pregnancy.
If a patient is taking glucocorticoids, this may cross-react with some cortisol immunoassays, while suppressing ACTH. This would give a false picture of peripheral activation (low ACTH, high cortisol), which could be misinterpreted as being consistent with McCune-Albright.
All immunoassays may have falsely elevated values because of endogenous interfering antibodies.
What Lab Results Are Absolutely Confirmatory?
McCune-Albright syndrome is diagnosed on the presence of the clinical triad of fibrous dysplasia, cafe au lait spots, and autonomous endocrine disorders. Although the gold standard would be demonstrating an activating mutation in the GNAS gene, there is no current clinical rationale for doing so. Thus, laboratory diagnosis is best accomplished by demonstrating peripheral, autonomous endocrine function as previously described.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Markers of bone turnover, including bone alkaline phosphatase and N-telopeptide, may also be elevated as a reflection of ongoing fibrous dysplasia.
Note that, because it is not clear when during development any patient may have acquired the activating mutation in the GNAS gene, it is not possible to precisely predict how the mosaic expression will manifest in symptoms of McCune-Albright. For example, a given patient may have one, two, or more endocrine disorders. Female precocious puberty is the most common manifestation; however, the presence of fibrous dysplasia and cafe au lait spots is consistent with a diagnosis of McCune-Albright, even in the absence of overt endocrine disorders.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
Very high levels of liver alkaline phosphatase may show some cross-reactivity with bone alkaline phosphatase values.
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