At a Glance
McCune-Albright Syndrome (MAS) is a triad of bone lesions (polyostotic dysplasia), brown nonelevated pigmented areas of skin (cafe-au-lait spots),and endocrine dysfunction (usually precocious puberty). The disease is not inherited and is due to a post-zygotic activating mutation in the GNAS1 (alpha subunit of the G protein stimulating adenylate cyclase) gene. Since it is a post-zygotic mutation, not all cells are affected (mosaicism). The clinical manifestations are dependent on the particular distribution of affected cells. Clinical manifestations can be seen anytime from birth onwards. As a result, a broad spectrum of endocrine andnon-endocrine effects has been reported.
Typical endocrinopathies include precocious puberty, hyperthyroidism, growth hormone (GH) excess, hyperprolactinemia, and hypercortisolism. Non-endocrine manifestations include the cafe-au-lait spots, polyostotic fibrous dysplasia, and renal phosphate wasting.
Endocrinopathies Associated with MAS
Precocious puberty is more common in girls (64-79%) than in boys (15%) with MAS. Most girls show pubertal signs before 4 years of age; often menstrual bleeding is the first sign, followed by other Tanner stages of development. Precocious puberty is usually associated with short stature, but stature may be normal in the presence of GH excess.
Hyperthyroidism (2-22% of MAS) is the second most common endocrinopathy and is more frequent in girls than in boys. TSH levels are low and T3 levels are usually elevated. Patients can vary in their symptoms, from being asymptomatic to presenting in a thyrotoxic crisis. Hyperfunctioning and nonfunctioning adenomas can be present.
GH excess (4-50% of MAS) is a common manifestation of pituitary adenomas, and whether gigantism develops is presumably dependent on the results of the antagonistic effects of sex steroids (precocious puberty) and stimulatory effects of GH on the growth plate in bones.
Hyperprolactinemia (2-17% of MAS) is frequently associated with GH excess, and some patients may show galactorrhea or oligo/amenorrhea.
Hypercortisolism (Cushing’s syndrome) is seen in 2-8% of MAS, frequently within the first year of life. This is associated with severe effects on bone density with resultant fractures and nephrocalcinosis.
Non-endocrine Manifestations of MAS
Fibrous dysplasia (46-98% of MAS) is mono-ostotic in one-third of cases and polyostotic in others. These lesions cause progressive deformity, fractures, and even nerve entrapment. The axial skeleton, craniofacial bones, as well as pelvic bones can be involved. Renal phosphate wasting is seen in 50% of patients with fibrous dysplasia.
Cafe-au-lait skin lesions are seen in 53-93% of cases of MAS. These pigmented lesions have irregular borders (Coast of Maine) as compared to those in neurofibromatosis, which have smooth borders (Coast of California). These lesions are typically close to the midline, usually on the same side of the skeletal lesions and commonly on the buttocks and lumbo-sacral region.
Liver function abnormalities may be present in the form of neonatal jaundice, which shows a slow regression, but liver enzymes may remain persistently abnormal.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow up tests might be useful?
Diagnosis is based on the clinical history and physical examination. At least 2 components of the triad must be present. MRIs of the head and X-rays of bone are necessary. The biochemical tests are related to the endocrine and non-endocrine manifestations of MAS. Thus, depending on the clinical situation, tests related to endocrinopathies (i.e., precocious puberty in which estrogen is elevated, whereas FSH and LH are low in females and testosterone is high in males, hyperthyroidism (TSH, T4, T3, FT4, FT3), gigantism (GH, insulin like growth factor-1), hyperprolacitinemia (PRL), Cushing’s syndrome (Cortisol, ACTH), and hyperparathyroidism (PTH)) may be considered.
Non-endocrine disturbances can be identified using serum phosphate levels and the tubular phosphate reabsorption ratio to detect renal phosphate wasting. Hepato-biliary disturbances can be looked at using Bilirubin, AST, ALT, and gamma-GT.
What Lab Results are Absolutely Confirmatory?
Sequence analysis of the GNAS1 gene is diagnostic.
Additional Issues of Clinical Importance
Presence of cardiac disease, dysrhythmias due to mutations in cardiac tissue, is a major risk factor for long-term survival. As previously discussed, other lesions (e.g., testicular microlithiasis and Leydig cell hyperplasia, hyperparathyroidism, and ovarian cysts) may be present, depending on which cells are affected by the mosaicism.
Certain stimulatory and inhibitory tests can be used in MAS. For example, in patients with high estrogen and low FSH and LH, nonresponsiveness of FSH and LH to GnRH is consistent with MAS. In patients with GH excess, TRH and GHRH increase GH secretion and glucose administration causes a partial suppression.
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