What is the pathophysiology of McCune-Albright syndrome (MAS)?

Updated: Jan 17, 2019
  • Author: Gabriel I Uwaifo, MD; Chief Editor: George T Griffing, MD  more...
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Answer

Most of the clinical features of MAS are caused by a noninherited postzygotic activating mutation of the GNAS1 gene that results in overproduction of a variety of protein products in a fashion independent from normal feedback control mechanisms (see Etiology). [8]

Precocious puberty, the most common endocrine feature of MAS, is a result of gonadotropin-independent autonomous ovarian or testicular function. [5] Precocious puberty caused by this condition is far more common in girls than in boys. In girls, it is the result of estrogen excess from ovarian follicular cysts. [17] Because the sexual precocity associated with MAS is gonadotropin-independent, it is more accurately described as pseudoprecocious puberty.

The café-au-lait spots in MAS are large melanotic macules, sometimes referred to as café-au-lait macules (CALMs). Except for hyperpigmentation of the basal layer, no abnormal pathology is seen.

Fewer than 10 cases of MAS associated with Cushing syndrome have been well documented. This syndrome is distinct, unlike all other endocrinopathies of MAS, which are slowly progressive and persistent without treatment. Several cases of Cushing syndrome in the context of MAS have regressed within the first few years following onset.

Cushing syndrome associated with MAS is predominantly due to adrenocortical hyperfunction. Most of these cases have been described in infants or children. The adrenal glands are bilaterally enlarged and contain multiple small nodules in the cortex. In some cases, Cushing syndrome is transitory. Pituitary-based (ACTH-dependent) Cushing disease in the setting of MAS is far less common.

Hyperthyroidism typically occurs later in childhood, though it can occur within the first year of life. Like Cushing syndrome and precocious puberty, hyperthyroidism associated with MAS is a result of 1 or more autonomous hyperfunctioning thyroid nodules.

Growth hormone (GH) excess from somatotroph adenomas in the pituitary can occur at any age, resulting in gigantism or acromegaly. The GH excess among patients with MAS has been noted to be as high as 21%. The basis of GH hypersecretion in MAS remains incompletely understood, but it appears to have a different basis from that of acromegaly or gigantism in non-MAS patients. [18]  A study by Yao et al suggested that growth hormone excess in MAS occurs more frequently in males than in females; the investigators determined that of 52 patients with MAS, 13 (25.0%) had growth hormone excess, including 10 males (76.9%). The study also found an association between growth hormone excess in MAS and greater severity of skeletal lesions, with more craniofacial bone involvement. [19]

Fibrous dysplasia (FD) in MAS can involve any bone but most commonly affects the long bones, ribs, and skull. It may range 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.


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