In its classic form, McCune Albright syndrome (MAS) comprises of at least 2 of the following three characteristics: polyostotic fibrous dysplasia (FD), “café au lait” skin pigmentation marks and hyper-functional endocrinopathy (1, 2). Although precocious puberty is the most frequently observed abnormality, patients can also present more rarely with other endocrine pathologies, the main ones being hyperthyroidism, ACTH-independent Cushing’s syndrome, and acromegaly. Nevertheless, non-endocrine abnormalities are also observed with this syndrome (chronic hepatopathy and cardiac rhythm problems). MAS is a rare disease, the exact incidence of which is unknown. The age the syndrome is identified can vary. Patients suffering from multiple and/or severe cell hyper-functionalities are generally noticed in the 1st month / 1st year of their life. In less severe cases, with few or no endocrine or non-endocrine abnormalities, diagnosis can occur at any age during childhood. The varying degree of clinical severity is related to the site and the moment the mutation takes place during embryogenesis. A late mutation will give more focused tissue effects, and lead to a more moderated phenotype with only 2 or 3 manifestations of cellular hyper-functionality.
Clinical presentation of MAS
MAS classically presents with wide clinical heterogeneity. Above all there is a sexual dimorphism, with the vast majority of cases found in girls.
FD is by far the most frequently found component in the diagnosis of MAS. It is typically polyostotic, and is described in the previous section entitled “Fibrous Dysplasia”. Hypophosphatemia often presents with MAS and must be systematically investigated as it may be a risk factor in reduced height and/or rickets in children if left untreated.
“CAFÉ-AU-LAIT” SKIN PIGMENTATION MARKS
Apart from the potential aesthetic problems, this hyper pigmentation does not present any pathological characteristics. In the majority of cases the marks are present at birth, but can become more apparent as the syndrome progresses.
- Precocious puberty
Precocious puberty is defined as the appearance of the signs of puberty before the age of 8 in girls and before the age of 9 in boys. In MAS, it is typically LH/FSH-independent and is more readily observed in girls (9 girls for every 1 boy). In girls, the symptoms (menstrual bleeding, breast development, reoccurring ovarian cysts) can be observed very early, from a few months old, and develop very irregularly. As a fairly specific example, vaginal bleeding can be observed before the start of any breast development. In boys, autonomous testicular function can also be accompanied by the presence of swelling from hyperplasia of the Leydig or Sertoli cells (3).
- ACTH-independent Cushing’s syndrome
Development of hypercortisolism is most often observed in the first year of life, sometimes with no other sign associated with MAS initially (4). An increase in volume of the adrenal glands is observed in CT scans, containing one or more autonomous bilateral secreting nodules.
This is seen generally later in childhood, also with the presence of one or more nodules. The presence of a goitre is possible. In cases of tachycardia, the risk of cardiac rhythm problems may be increased (see below).
MAS is probably one of the primary causes of acromegaly in young children. Nevertheless, the development of a GH secreting pituitary adenoma can be observed at any age. They are generally always associated with a hyper-secretion of prolactin. GH hyper-secretion leads to a risk of aggravating cranio-facial FD and could encourage the more frequent appearance of breast (5), and thyroid (6) cancer.
OTHER NON-ENDOCRINE ABNORMALITIES
- Disruption of hepatic function
The abnormalities observed in certain cases are varied: relatively moderate rise in transaminase, neonatal jaundice, chronic cholestasis and steatosis.
- Cardiac rhythm problems
The G protein is involved in the transduction of the adrenergic signal (see the following paragraph). The existence of a persistent b-receptor tachycardia roughly associated with cardiomelgaly has been described in MAS. Many cases of sudden death, including paediatric observations, have been reported. Even if it was not possible to clearly establish the cause of death, a cardiac arrhythmia (often in the context of general anaesthetic) is often proposed. The patients concerned are often affected by multiple endocrine and non-endocrine problems associated with the disease.
PATHOPHYSIOLOGY OF MAS
The classical triad for MAS, polyostotic FD, autonomous endocrinopathy and skin pigmentation, can be explained by the activation of the alpha subunit of the Gs protein, and the intracellular increase in cAMP (7). On an endocrine level, the Gs protein is usually activated when a hormone fixes on to the specific receptor of the cellular membrane (classically a 7 transmembrane domain receptor is coupled to the Gs protein). The alpha subunit dissociates from the receptor and stimulates the increase in cAMP, which leads to the necessary signal cascade. This subunit is subsequently deactivated and reassociates with the receptor to become reactive again and respond to another hormonal signal. The specific mutation seen in MAS (see section entitled “Fibrous Dysplasia”) occurs in the area of the protein that controls the deactivation of the alpha subunit. After activation the mutated subunit remains activated, despite the absence of any hormonal receptor stimulation. This results in a consecutive and persistent increase in high levels of intracellular cAMP that can lead to a hyper-functionality of endocrine cells. Similar mechanisms explain practically all endocrine and non-endocrine abnormalities in MAS (activation of the G protein coupled to the LH receptor and to the FSH receptor in the gonads in precocious puberty, activation of the G protein coupled to the MSH receptor in the melanocytes in hyper-pigmentation etc.). Precocious puberty is consequently the result of autonomous activation and gonadotropin-independent ovarian function (far more rarely testicular) in childhood. Ovarian autonomy accompanies the formation of follicular cysts that secrete oestradiol. This steroid hormone is responsible not only for early sexual maturity, but also acceleration in the rate of growth by the advanced maturing of the growth plates, with a common consequence of reduced height in adulthood.
LABORATORY TESTS AND IMAGING FOR MAS
The non-endocrine laboratory work-up comprises systematically of measuring blood calcium, phosphorus, transaminase and bilirubin levels.
Endocrine work-up is carried out to indentify or confirm potential biological hyper-functionality symptoms.
Within the scope of precocious puberty, oestrogen secretion (or more rarely testosterone) is the most often episodic investigation, and iterative analyses of oestradiol levels are necessary. Furthermore, a test of stimulation by GnRH allows better documentation of gonadotropin-independent characteristics and gives evidence of lowered or undetectable plasmatic LH and FSH levels. Investigation into other hyper-functional enocrinopathies relies on the analysis of the average level of base plasmatic hormones (T4, TSH, ACTH, cortisol, IGF-1, prolactin, AMH and inhibin B), of plasmatic cycles over 24 hours (cortisol and ACTH), urinary secretion over 24 hours (free cortisol), and if required dynamic tests (dexamethasone suppression test). Routine molecular analysis of the GNAS1 gene is possible, notably from leukocyte DNA, which is easily obtainable. However, a negative result does not exclude the presence of the mutation, which may only be present in tissues presenting with hyper-functionality (bone and follicular fluid are amongst the more easily obtainable). If the clinical diagnosis is established, the analysis is not of interest for treatment, as there is no genotype/phenotype correlation.
Pelvic ultrasound is invaluable for documenting the possible presence of ovarian cysts, which are more likely to be unilateral and large in size.
The existence of other hyper-functional endocrinopathies warrants the need for targeted adenoma investigation (thyroid and testicular ultrasound; computerized tomography of the adrenal glands; MRI of the pituitary gland).
The assessment of bone age allows the potential excessive maturity of growth plates to be tracked in cases of precocious puberty.
The complete bone work-up is detailed in the section entitled “Fibrous Dysplasia”.
THERAPEUTIC MANAGEMENT OF MAS
Therapeutic methods for bone problems and hypophosphatemia are detailed in the section entitled “Fibrous Dysplasia”.
In MAS, precocious puberty is gonadotropin-independent and consequently does not respond to treatment by GnRH agonists (Triptorelin, Decapeptyl®; Leuprorelin, Enantone®), that are generally very effective in the treatment of the more common gonadotropin-dependant form of precocious puberty. However, these treatments are often considered when there is an advance in bone maturity caused by excessive secretion of secondary sexual steroids from autonomous ovaries (or more rarely testicles) complicating a secondary veritable central precocious puberty by the advanced maturity of the hypothalamic-pituitary-gonadal axis. Aromatase inhibitors, which block the conversion of testosterone to oestradiol, are currently the most widely used treatment, more particularly in the form of Testolactone (Fludestrin®, 50 mg capsule) (8). Although moderate to constant efficacy is seen at a dosage of 20 to 40 mg/kg/day taken every 4 to 6 hours to achieve the reduction in circulating oestrogens, the use of this 1st generation inhibitor means that large quantities of capsules need to be taken many times per day, and even at night, which poses compliance issues. Apart from Fadrozole, which was reported as being ineffective (9), 3rd generation inhibitors (Letrozol, Femara®; Anastrazol, Arimidex®, to be taken once daily, orally) have shown a certain degree of efficacy against the progress of puberty in clinical trials, with a limited series of patients (10). Anti-oestrogens (Tamoxifen, Nolvadex®, taken once daily, orally) have also shown to be effective, but from fewer reported patients (11), other clinical trials with new products are in progress.
In boys, if aromatase inhibitors can also be used to prevent diminished height, Spironalactone (Aldactone®) can be beneficial in treating the symptoms linked to an excess of androgens if required. Ketoconazole (Nizoral®, 200 mg tablets, average dosage 400 mg/day taken over 2 to 3 times) is an alternative treatment for both sexes, due to its ability, in high doses, of inhibiting steroidogenesis (12). To date, none of these drugs for treating precocious puberty have a MAA. In cases of large ovarian cysts, surgical or laparoscopic resection or ultrasound guided draining can sometimes be necessary.
There are no management or surgical modes specific to MAS.
The treatment of ACTH-independent Cushing’s syndrome is classically a bilateral adrenalectomy. Nevertheless, the use of ketocortizone (see above) or mitotane (Lysodren®) may be proposed initially.
Medical treatment is the most effective route to be proposed initially: somatostatin analogues (Octreotide, Sandostatine®; Lanreotide, Somatuline®) or a GH receptor antagonist (Pegvisomant, Somavert®) (13) often in association with a dopamine agonist (Cabergoline, Dostinex®). Radiotherapy or surgery to the adenoma is rarely indicated due to problems linked to the very frequent dysplasic regrowth to the area at the base of the skull.
PROGRESS – MONITORING
Clinical monitoring of patients is reliant on the knowledge of the many abnormalities that can be apparent in MAS. The consequences of the spontaneous onset of precocious puberty are multiple: rapid progress of bone aging leading to a long term potential loss in height as an adult, maturity of the hypothalamic- pituitary-gonadal axis with the development of central precocious puberty and negative physiological and social effects. In cases where drug therapy is being used (aromatase inhibitors, ketocortizone and anti-oestrogens), hepatic tolerance must be assessed regularly. For ovarian cysts, ultrasound monitoring is implemented to prevent the risk of torsion from a significant increase in volume. The prognosis may be compromised under certain circumstances: sudden death complicated by cardiac rhythm, severe fibrous dysplasia leading to chronic respiratory failure +/- heart failure from the ribs and the chest being affected and acute adrenal gland failure following an adrenalectomy.
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Created: 09 june 2010