Clinical characteristics: Fibrous dysplasia / McCune-Albright syndrome (FD/MAS), the result of an early embryonic postzygotic somatic activating pathogenic variant in GNAS (encoding the cAMP pathway-associated G-protein, Gsα), is characterized by involvement of the skin, skeleton, and certain endocrine organs. However, because Gsα signaling is ubiquitous, additional tissues may be affected.
Café au lait skin macules are common and are usually the first manifestation of the disease, apparent at or shortly after birth. Fibrous dysplasia (FD), which can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton, can range from an isolated, asymptomatic monostotic lesion discovered incidentally to severe disabling polyostotic disease involving practically the entire skeleton and leading to progressive scoliosis, facial deformity, and loss of mobility, vision, and/or hearing. Endocrinopathies include:
Gonadotropin-independent precocious puberty resulting from recurrent ovarian cysts in girls and autonomous testosterone production in boys;
Testicular lesions with or without associated gonadotropin-independent precocious puberty;
Thyroid lesions with or without non-autoimmune hyperthyroidism;
Growth hormone excess;
FGF23-mediated phosphate wasting with or without hypophosphatemia in association with fibrous dysplasia; and
The prognosis for individuals with FD/MAS is based on disease location and severity.
Diagnosis/testing: In most individuals, the diagnosis of FD/MAS is based on the finding of two or more typical clinical features. In individuals whose only clinical finding is monostotic fibrous dysplasia, identification of a somatic activating pathogenic variant in GNAS by molecular genetic testing is required to establish the diagnosis. Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique.
Management: Treatment of manifestations: Management is most effectively accomplished by a multidisciplinary team of specialists.
FD. Management focuses on optimizing function and minimizing morbidity related to fractures and deformity (including scoliosis).
Precocious puberty. Treatment prevents bone age advancement and compromise of adult height. For girls, the aromatase inhibitor letrozole is used; for boys, treatment options are less well established.
Thyroid disease. Methimazole effectively manages hyperthyroidism; however, because hyperthyroidism is persistent, thyroidectomy is common.
Growth hormone excess. Medical therapy is the preferred first-line treatment; options include (alone or in combination) octreotide and the growth hormone receptor antagonist pegvisomant.
Hypercortisolism. Treatment varies by the presentation of neonatal Cushing syndrome.
FD/MAS. Monitor for the following:
Infants: clinical signs of hypercortisolism
All children: growth acceleration and other clinical signs of precocious puberty and/or growth hormone excess
Age <5 years: thyroid function abnormalities
With thyroid abnormalities on ultrasound examination but normal thyroid function: periodic monitoring of thyroid function
Males: testicular lesions (physical examination and testicular ultrasound)
Somatostatin analogs: signs and symptoms of gallbladder disease
Females: breast cancer (earlier than is recommended for the general population)
Periodic radiographs to monitor existing FD and development of new lesions
Periodic serum phosphorus (for development of hypophosphatemia) and 25-hydroxyvitamin D levels
Craniofacial FD: yearly vision and hearing evaluations; periodic skull CT; routine serum IGF-1 levels through young adulthood
Spine FD: close monitoring for progressive scoliosis
Agents/circumstances to avoid: Contact sports and other high-risk activities (when skeletal involvement is significant); prophylactic optic nerve decompression (in individuals with craniofacial FD); surgical removal of ovarian cysts; radiation therapy for treatment of FD; risk factors for malignancy (e.g., radiation exposure).
Genetic counseling: FD/MAS is not inherited. No parent of a child with FD/MAS has been demonstrated to have any significant, distinctive manifestations of the disorder. The risk to sibs is expected to be the same as in the general population. There are no verified instances of vertical transmission of FD/MAS.
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