Mc Cune-Albright is a genetic syndrome caused by mutations in the GNAS1 gene. It is characterized by deformities and fractures of the bones, endocrine abnormalities including early puberty, skin hyperpigmentation.
Epidemiology
The exact incidence of MAS in the United States and internationally is unknown, but its prevalence is probably between 1 case in 100,000 population and 1 case in 1 million population, rendering it a very rare, sporadically occurring disorder. In a review of radiographs from 82,000 patients, only 23 cases of PFD were found. Polyostotic variants of FD are uncommon, and MAS is even less common. The relative incidence of monostotic FD is 70%, whereas that of PFD is 30% and that of MAS is less than 3%.
Severe cases of MAS involving multiple endocrine tissues may be recognized shortly after birth. Cases of infantile Cushing syndrome and hyperthyroidism have also been reported in the neonatal period. Additionally, FD, café-au-lait pigmentation, liver disease, and hypophosphatemia can initially be seen in infancy.
Less severe findings of MAS can occur at almost any time during childhood. Most commonly, the onset of MAS occurs in early childhood (mean age, 4.9 years; range, 0.3-9 years), typically earlier in girls than in boys. Precocious puberty in girls can be seen in infants as young as 4 months, though it more frequently occurs in girls older than 1 year. Café-au-lait pigmentation is more likely to become apparent later in the progression of the syndrome.
GH-producing pituitary tumors and functional-thyroid adenomas secondary to activating GNAS1 mutations can occur in individuals at any age. Disease with a later onset (in the early to late teenage years) tends to be associated with clinically attenuated phenotypes.
Both sexes are affected by MAS, but the syndrome has been reported to be about twice as common in females as in males. That girls develop precocious puberty far more frequently than boys (9:1 female-to-male ratio) probably explains why this autosomal mutation is recognized more frequently in girls than in boys. Other manifestations of MAS probably occur with approximately equal frequency in females and males.
MAS has no ethnic predilection.
Symptoms
People with McCune-Albright syndrome develop areas of fibrous tissue in their bones, a condition called polyostotic fibrous dysplasia. Polyostotic means the lesion may occur in many bones; often they are confined to one side of the body. Replacement of bone with fibrous tissue may lead to fractures, uneven growth, and deformity. When lesions occur in the bones of the skull and jaw it can result in asymmetric growth of the face. Asymmetry may also occur in the long bones; uneven growth of leg bones may cause limping. Scoliosis may also occur. Bone lesions may become cancerous, but this happens in fewer than 1 percent of people with McCune-Albright syndrome. In addition to bone abnormalities, affected individuals usually have light brown patches of skin called café-au-lait spots, which may be present from birth. The irregular borders of the café-au-lait spots in McCune-Albright syndrome are often compared to a map of the coast of Maine. By contrast, café-au-lait spots in other disorders have smooth borders, which are compared to the coast of California. Like the bone lesions, the café-au-lait spots in McCune-Albright syndrome often appear on only one side of the body. Girls with McCune-Albright syndrome usually reach puberty early. These girls usually have menstrual bleeding by age two, many years before secondary sex characteristics such as breast enlargement and pubic hair are evident. This early onset of menstruation is believed to be caused by excess estrogen, produced by cysts that develop in one of the ovaries. Less commonly, boys with McCune-Albright syndrome may also experience early puberty. Other endocrine problems may also occur in people with McCune-Albright syndrome. The thyroid gland, may become enlarged (goiter) or develop nodules. About 50 percent of affected individuals produce excessive amounts of thyroid hormone, resulting in a fast heart rate, high blood pressure, weight loss, tremors, sweating, and other symptoms. The pituitary gland may produce too much growth hormone. Excess growth hormone can result in acromegaly, a condition characterized by large hands and feet, arthritis, and distinctive facial features that are often described as "coarse." Rarely, affected individuals develop Cushing's syndrome, which causes weight gain in the face and upper body, slowed growth in children, fragile skin, fatigue, and other health problems.
McCune-Albright syndrome in its classic form consists of at least 2 of the following triad of features:
Polyostotic fibrous dysplasia
Café-au-lait skin pigmentation
Autonomous endocrine hyperfunction. The most common form of autonomous endocrine hyperfunction in this syndrome is precocious puberty, which is typically gonadotropin-independent
Other endocrine syndromes described in association with MAS include:
Hyperthyroidism
Acromegaly or gigantism (due to GH-producing pituitary adenoma)
Gonadotropinomas
Hyperprolactinemia
Cushing syndrome
Hyperparathyroidism
Gynecomastia
Hypophosphatemic rickets
Some severely affected patients may present with associated hepatic, cardiac, and gastrointestinal dysfunction (for example, elevated hepatic transaminases, polyposis, and cardiomyopathy).
The clinical presentation of MAS is highly variable, depending on which of the various potential components of the syndrome predominate.
Diagnosis
Diagnosis of MAS depends on finding at least 2 of the phenotypic features associated with activating GNAS1 mutations.
Early recognition is vital. In typical cases, the diagnosis of MAS is not in doubt. However, in atypical cases, the combination of cutaneous pigmentation, bony lesions, and soft-tissue masses may suggest other conditions (eg, systemic mastocytosis and neurofibromatosis).
Full endocrine studies should be performed under the care of an endocrinologist. Testicular or ovarian hyperfunction is the most common abnormality. Diagnostic imaging modalities that may be considered include plain radiography, ultrasonography; CT, MRI, and radionuclide bone scanning (as clinically indicated)
In MAS, plain bone radiographs typically show multiple patchy areas of bony lysis (see the first image below) and sclerosis. The findings are consistent with bone dystrophy: areas of hypertrophy and geodes bounded by fine sclerotic rims. Mixed radiopaque and radiolucent areas with thin or hypertrophic cortices are present.
In general, monostotic FD is more common than polyostotic FD; however, MFD is not associated with other findings that are typical of MAS. PFD can be detected by means of a skeletal survey. Total radiation exposure can be decreased if the skeletal survey is preceded by a bone scan. The laboratory can reduce the number of radiographs needed by focusing only on positive sites indicated by bone scanning.
Virtually any bone in the body may be affected. Commonly affected bones include the femur, tibia, ribs, and facial bones. Involvement of the small bones of the hands and feet accounts for 50% of cases. Long-bone lesions are more frequent in the metaphyseal and diaphyseal regions. The individual lesions may be trabeculated, with thin cortices and ground-glass appearance. Formal bone-age estimations may be higher in patients with sexual precocity.
Sclerosis of the basilar or temporal skull is seen, with possible involvement of the ossicles or impingement on the temporal nerve. Evidence of past or current pathologic fractures is seen. Findings of hypophosphatemic rickets may be present. Osteosarcoma is rare (2%) and is found most often in patients who have received radiation treatment to affected bone lesions.
Ultrasonography may be a useful diagnostic adjunct for evaluating patients with historical or physical evidence of soft-tissue swelling. Myxomas in the context of MS can be seen as sharply defined hypoechoic masses with a few central, fluid-filled cavities. However, an abdominal ultrasonogram that reveals multiple hypoechoic cystic lesions within the uterus and upper vaginal vault is characteristic of embryonal rhabdomyosarcoma.
Ultrasonographic examination of the pelvis is helpful in identifying ovarian cysts. Typically, ovarian size is not uniform in MAS: Cysts tend to be larger in one ovary. Often, cysts are unilateral, whereas cysts in central precocious puberty are small and bilateral. Furthermore, ultrasonography can help detect or rule out ovarian tumors or the presence of vaginal tumors or foreign bodies as a cause of isolated vaginal bleeding.
CT of the skull may show pituitary adenoma..
The bones most frequently affected in MAS are the femur, tibia, ribs, and facial skeleton. A specific change involving the fibula is the presence of pseudocystic areas. This change is referred to as the shepherd’s crook deformation; it is due to the weight put on a less resistant bone, and the occurrence of many secondary cortical microfractures is not uncommon. Ground glass–like areas occur in the femur. Asymptomatic sites of FD can be detected with radionuclide (technetium-99) bone scans. On bone scanning, PFD appears as areas of increased activity. This is helpful in defining the extent of disease activity after the diagnosis is made. Finding these sites when gonadotropin-independent precocious puberty is also present can confirm the diagnosis of MAS. The poor specificity of increased patchy bone activity on bone scans precludes their use for screening or exact diagnosis
Abdominal CT can help evaluate infantile Cushing syndrome. Bilateral enlargement of the adrenal glands is consistent with the adrenal hyperplasia seen in infantile Cushing syndrome secondary to MAS. Unilateral enlargement is more consistent with an adrenal adenoma or adrenocortical carcinoma.
In the setting of myxomas, MRI identifies hypointense or isointense areas on T1-weighted imaging with gadolinium enhancement or on T2-weighted imaging. Like bone scanning, MRI may be useful for defining the extent of bony disease.
Arterial blood gas determination can be performed to evaluate for acidosis, if suspected. ECG can be performed to evaluate for arrhythmia.. Endoscopy can be performed to evaluate for gastrointestinal polyposis.
Bone biopsy may be necessary to rule out malignancy in a patient with a rapidly expanding lesion. It can be used clinically to aid in the diagnosis of osteomalacia and has been used for research purposes in an academic setting. Similarly, a rapidly expanding myxoma may call for muscle or soft-tissue biopsy. Enlarging thyroid nodules or hypofunctioning solitary thyroid nodules warrant a fine-needle aspiration biopsy to establish a definitive diagnosis and to exclude thyroid cancer.
Histopathology
The café-au-lait spots seen in MAS are large, melanotic macules. Except for hyperpigmentation of the basal layer, no abnormal pathology is apparent. The melanocytes are normal in both number and size. Some specimens show giant melanosomes, but this finding is by no means diagnostic. Giant melanosomes can also be found in CALMs of patients with neurofibromatosis and in healthy patients.
That MAS is a disease of excess abnormal and imperfect bone formation helps elucidate its mechanisms.The bone affected by PFD has areas of fibrous metaplasia within flat and tubular bones. The basic anomaly in FD lesions is a progressively expanding fibrous lesion of bone-forming mesenchyme. The lesions typically expand concentrically from the medullary cavity outwards. The bony lesions are well defined, though invariably, they are not encapsulated.
The bony lesions are rich in spindle-shaped fibroblasts, with a swirled appearance within the marrow space and erratically arranged “tongues” of woven bone. Islands of cartilaginous tissue also may be interspersed within the lesions. Some parts of the affected bones may have cystic lesions lined by multinucleated giant cells, akin to osteitis fibrosa cystica (of severe hyperparathyroidism) but with a paucity of osteoblasts.
Thyroid findings in individuals with hyperthyroidism secondary to MAS can range from a single adenoma to a goiter. The histologic appearance has been reported to range from multinodular hyperplasia to colloid goiter. Single nodules have the appearance of follicular adenomas.
Cushing syndrome in MAS is associated with bilateral nonpigmented adrenocortical hyperplasia with nodular elements. Multiple micronodules can be found in the adrenal cortex surrounded by normal tissue. Only the nodules contain DNA coding for the activating Gs alpha mutation; the surrounding normal tissue does not contain the activating mutation, a finding that supports the mosaic nature of this genetic disorder.
Somatotroph adenomas take on the character of typical pituitary adenomas. Somatotroph tumors lack true capsules, with the margins of the adenoma containing normal cells interspersed with adenomatous cells. These adenomatous cells can be confirmed as somatotrophs by means of immunostaining. Although technically not malignant, somatotroph adenomas may be locally invasive into the surrounding bony architecture and vasculature.
Liver histology in individuals with elevated hepatic enzymes can range from the presence of normal hepatocytes with some fatty infiltration to focal nodular hyperplasia with bridging fibrosis and chronic cholestasis. Detailed study of liver biopsy specimens has detected mild biliary abnormalities in many of the specimens, with extramedullary hematopoiesis in a few.
Examination of the ovary in MAS generally reveals large unilateral ovarian cysts, which are follicular.
Etiology
The GNAS gene provides instructions for making one component, the stimulatory alpha subunit, of a protein complex called a guanine nucleotide-binding protein (G protein). Each G protein is composed of three proteins called the alpha, beta, and gamma subunits.
In a process called signal transduction, G proteins trigger a complex network of signaling pathways that ultimately influence many cell functions by regulating the activity of hormones. The protein produced from the GNAS gene helps stimulate the activity of an enzyme called adenylate cyclase. This enzyme is involved in controlling the production of several hormones that help regulate the activity of endocrine glands such as the thyroid, pituitary gland, ovaries and testes and adrenal glands. Adenylate cyclase is also believed to play a key role in signaling pathways that help regulate the osteogenesis. In this way, the enzyme helps prevent the body from producing ectoping bone.
Mc Cune-Albright syndrome is caused by a sporadic, early postzygotic somatic mutation in the GNAS1 gene at locus 20q13.1-13.2, (more precisely, the GNAS gene is located from base pair 57,414,794 to base pair 57,486,249). coding for the G protein subunit Gs alpha
GNAS gene mutations that cause McCune-Albright syndrome result in an abnormal version of the G protein that causes the adenylate cyclase enzyme to be constitutively activated. Constitutive activation of the adenylate cyclase enzyme leads to over-production of several hormones, resulting in the abnormal bone growth, unusual skin pigmentation, and endocrine problems that occur in McCune-Albright syndrome.
McCune-Albright syndrome is not inherited. Instead, it is caused by a random mutation in the GNAS gene that occurs very early in development. As a result, some of the body's cells have a normal version of the GNAS gene, while other cells have the mutated version. This phenomenon is called mosaicism. The severity of this disorder and its specific features depend on the number and location of cells that have the mutated GNAS gene.
Treatments
McCune-Albright syndrome is a multisystemic condition with a host of variable presentations. Diagnosis and treatment of this syndrome require a high index of suspicion in any patient with characteristic café-au-lait spots and endocrine dysfunction or pathologic fractures. No measures are available to prevent MAS; however, appropriate care must be taken for fracture prevention in patients with severe polyostotic fibrous dysplasia.
For most physicians who are not endocrinologists, the crucial treatment aims are recognition of MAS and prompt referral of the patient to an endocrinologist who is experienced in its management. The endocrinologist, in turn, offers other referrals (eg, to an orthopedic surgeon or neurosurgeon) as indicated. An astute primary care physician (a pediatrician or an internist, depending on the age of the patient) who will coordinate the various aspects of the patient’s care is also necessary.
No specific medications are available to treat the bone manifestations of MAS. Antiresorptive agents; like bisphosphonates, are being evaluated for this indication and have great palliative value owing to their pain-controlling attributes in this disease. Transsphenoidal surgery remains difficult secondary to massive thickening of the skull base. Irradiation of the bone should be avoided unless the treatment is absolutely necessary, because irradiation may increase the risk for sarcomatous degeneration.
The precocious puberty of MAS generally does not respond to GnRH agonists, and short-acting aromatase inhibitors have had limited effectiveness. Inconsistent results have been reported with bromocriptine, cabergoline, octreotide, or a combination of these. Pegvisomant, a GH receptor antagonist, is a possibility, though it has not been specifically evaluated for treatment of MAS with GH pathology.
Pharmacotherapeutic
Precocious puberty: Therapy for precocious puberty is available and should be tried; however, it is still largely experimental. Precocious puberty in MAS is gonadotropin-independent and therefore does not respond to the gonadotropin-releasing hormone (GnRH) agonist therapy that is so successful with gonadotropin-dependent central precocious puberty, though one study did find GnRH analogue therapy for children to have some success in girls with MAS. For female patients, the central aim is to block estrogen effects. To this end, the aromatase inhibitors have been the mainstay of therapy in girls with persistent estradiol elevation. Patients who respond to treatment should continue therapy until the age of normal puberty or until a bone age of 15-16 years. A GnRH analogue may be added to aromatase inhibitors as an adjunct in the treatment of precocious puberty to suppress pituitary gonadotropin production. Depot leuprolide acetate at a dosage of 7.5 mg (300-500 µg/kg) every 28 days is a typical regimen; the dosage can be adjusted upward or downward on the basis of clinical and laboratory findings. Preliminary trials of other aromatase inhibitors have been initiated with the aim of achieving better management of precocious puberty. In one clinical trial, fadrozole, a more potent aromatase inhibitor, was ineffective in preventing progression of precocious puberty; however, anastrozole, a highly selective aromatase inhibitor, significantly slowed precocious puberty in one case and offered the added benefit of once-daily dosing. The third-generation aromatase inhibitor letrozole has had some success. Ketoconazole was used in 1 study as an alternative therapy in 2 girls, who also showed significant improvement in signs of precocious puberty. Unfortunately, ketoconazole’s dosing frequency is 3 times daily, which is a drawback in comparison with the once-daily dosing of anastrozole or tamoxifen. Estrogen receptor antagonists, such as tamoxifen, may have a therapeutic role but have not yet been systematically investigated. Tamoxifen has shown some evidence of efficacy for treating precocious puberty in girls with MAS. In a multicenter study that used a regimen of 20 mg of tamoxifen once daily, the investigators reported significant improvement in growth velocity and rate of skeletal maturation.Other pilot clinical trials have been performed, in which the antiandrogen cyproterone acetate was used to block pubertal development in young female patients, while ketoconazole was used in males. Adequate response to these therapies can be assessed by administering serial GnRH stimulation tests after 3-6 months of therapy.Additional treatment options include medroxyprogesterone acetate, which is particularly useful for controlling menstrual bleeding. The preferred agent is Depo-Provera in intramuscular doses of 4-15 mg/kg monthly. No definitive clinical trials have determined the efficacy of this medication in the setting of MAS. In males, adequate medical therapy for precocious puberty consists of the use of antiandrogen and antiestrogen preparations, typically a combination of spironolactone and aromatase inhibitors. Alternative antiandrogens (ketoconazole) may also be used, in a dosage range of 600-800 mg/day. In one report, combined treatment with ketoconazole and cyproterone acetate was used in a boy with MAS and peripheral precocious puberty, with some positive effect.
Polyostotic fibrous dysplasia: PFD is very difficult to treat. Currently, no clinically proven medical therapies are available. Studies of oral and intravenous bisphosphonates (particularly pamidronate, alendronate, and zoledronate) suggest that these agents may have beneficial effects on the bony disease, with regard to reducing both bone pain and the frequency of pathologic fractures, as well as to slowing the evolution of the bony disease. However, data on the ability of bisphosphonates to heal fibrous dysplasia are conflicting. One study found that long-term bisphosphonate treatment had beneficial effects on bone health in MAS; fracture rate and bone pain were reduced, and radiologic evidence of long-bone pathology resolution was observed. Another suggested that bisphosphonate may be helpful. A 2011 case report found continuous low-dose oral alendronate to be helpful in a 79-year-old woman with PFD. However, another study found that bisphosphonate treatment of PFD in children with MAS did not arrest progressive bone pathology
Hyperthyroidism: As a rule, hyperthyroidism in the setting of MAS is treated with the same medication options as regular hyperthyroidism, including propylthiouracil and methimazole. Hyperthyroidism due to functional thyroid follicular adenomas can be treated medically. Antithyroid medications can be used to decrease thyroid hormone production. Unlike Graves disease, hyperthyroidism secondary to a GNAS1 mutation is unlikely to go into remission. Therefore, patients probably should use antithyroid drugs indefinitely. A more permanent treatment of the hyperthyroidism, including radioiodine therapy or thyroidectomy, should be considered if a diagnosis of MAS is confirmed. Hyperthyroidism usually occurs in the context of toxic multinodular goiter. Notably, hyperthyroidism secondary to toxic multinodular goiter is the second most common endocrinopathy in MAS, after precocious puberty. Although radioiodine can be effective in controlling hyperthyroidism, it is a less popular option, because high doses or repeated administration may be necessary. Obvious issues arise with regard to the safety of radioiodine in children, especially in view of the potential for benign and malignant thyroid nodules to develop after radioiodine therapy.
Infantile Cushing syndrome: no effective medical treatment for ACTH-independent Cushing syndrome is available, and the currently recommended treatment is bilateral adrenalectomy. During the procedure and afterwards, the patient needs replacement of both glucocorticoids and mineralocorticoids in appropriate amounts. Stress doses of glucocorticoid (approximately 10 times maintenance) should be administered perioperatively and slowly reduced to maintenance levels. Mineralocorticoid replacement should be started soon after surgery as the hydrocortisone dose is weaned toward maintenance levels.
Gigantism and acromegaly: Management of GH excess in the setting of MAS should be achieved by using pharmacotherapeutic agents because such excess is invariably the result of diffuse nodular pituitary hyperplasia rather than of a single definitive adenoma. Surgical removal of adenomas, even if they appear to be present on radiologic testing, may be complicated by coexisting fibrous dysplasia involving the skull bones that distorts anatomic planes and increases the potential for torrential intraoperative bleeding. Irradiation of the pituitary is also not ideal, given the potential risk of inducing sarcomatous degeneration in bones affected by FD. No systemic investigation into the use of focused gamma knife–based pituitary irradiation has been done, because this condition is so uncommon. Most patients with GH excess in MAS are treated with octreotide in dosages similar to those used in regular acromegaly. Octreotide successfully lowers GH levels in many cases but rarely normalizes GH secretion. Long-acting somatostatin analogues have also been used on a case-by-case basis. The dopamine agonists bromocriptine and cabergoline have also been used to decrease GH secretion. These agents appear to have particular utility in the setting of prolactin and growth hormone co-hypersecretory states suggestive of somatomammotropinomas. Dopamine agonists have been used as monotherapy but are typically used in conjunction with octreotide. A study showed that cabergoline was able to decrease GH secretion but was unsuccessful in bringing GH secretion down to normal. Combined octreotide-cabergoline therapy has yielded additional improvement in GH secretion in comparison with monotherapy, but in general, it has not been successful in bringing levels down to normal.
Surgical interventions
Precocious puberty: the need for excision of hyperfunctioning endocrine tissue is directed by the severity of the patient’s endocrine imbalance and the efficacy of medical treatment. When medical therapy fails, oophorectomy or ovarian cystectomy has been used as a last resort for the control of precocious puberty. Despite this approach, most female patients with MAS who have had this surgery have retained normal fertility. Historically, wedge resection of the ovary was performed if a single large follicular cyst was found. Unfortunately, this approach was often only temporarily successful in treating the estrogen hypersecretion, and other large follicular cysts subsequently formed. Accordingly, many advise against surgical treatment of precocious puberty in MAS. Laparoscopy minimizes surgical aggression and allows the acquisition of tissue biopsy specimens for molecular analysis. Additionally, hyperestrogenism can be arrested with the excision of hyperactive ovarian tissue.
Polyostotic fibrous dysplasia: fracture is the primary indication for surgical treatment of dysplastic lesions. Most fractures are treated with traction. However, proximal fractures of the femur may have to be treated with surgically placed fixation devices. Rarely, severe and progressive malformation of the femur can occur. These lesions are usually painful (because of the multiple small fractures associated with them) and may have to be removed surgically. For most PFD lesions, routine removal is not warranted; after removal, the lesion may recur at the same site.
Hyperthyroidism: ablative therapy (either radioiodine treatment or thyroidectomy) is warranted for the treatment of hyperthyroidism due to MAS. Any cells left behind that contain GNAS1 mutations may result in adenoma formation and recurrence of hyperthyroidism. Thyroidectomy or hemithyroidectomy is the treatment of choice for hyperthyroidism associated with a goiter in patients with MAS. Partial or total/near-total thyroidectomy may be necessary for the control of thyrotoxicosis or the removal of multiple benign thyroid adenomas (even when they are not hyperfunctioning), progressively increasing goiter, and, of course, the very rare cases of coexisting thyroid carcinoma.
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