McCune–Albright syndrome

McCune–Albright syndrome, or simply Albright syndrome, described in 1937 by Donovan James McCune and Fuller Albright,  is a genetic disorder of bones, skin pigmentation and hormonal problems along with premature puberty.

Presentation
McCune–Albright syndrome is suspected when two of the three following features are present:


 * Autonomous endocrine hormone excess, such as in precocious puberty
 * Polyostotic fibrous dysplasia
 * Unilateral, i.e. one-sided Café-au-lait spots

Within the syndrome there are bone fractures and deformity of the legs, arms and skull, different pigment patches on the skin, and early puberty with increased rate of growth.

Approximately 20-30% of fibrous dysplasias are polyostotic, which means fibrous dysplasia and sclerotic bone are present in multiple sites; two thirds of patients are polyostotic before the age of ten. The disease frequently involves the skull and facial bones, pelvis, spine and shoulder girdle. The sites of involvement are the femur (91%), tibia (81%), pelvis (78%), ribs, skull and facial bones (50%), upper extremities, lumbar spine, clavicle, and cervical spine, in decreasing order of frequency. The craniofacial pattern of the disease occurs in 50% of patients with the polyostotic form of fibrous dysplasia.

Increased production of hormones by glands regulated by the G protein system is due to a mutation in the gene causing continuous activation of stimulatory G protein. This results in the so called "autonomous production" of hormones, including thyroid hormone, cortisol, estrogen and growth hormone. Therefore, hyperthyroidism, Cushing syndrome, precocious puberty in women with premature thelarche (breast growth), premature menarche (beginning of menstrual function), increased speed of growth and growth hormone excess can ensue. Increased serum estrogen concentrations correlate with large ovarian cysts. Ovarian cysts appear and disappear with changing estrogen concentrations, causing menstrual bleeding when estrogen decreases.

McCune–Albright syndrome has different levels of severity. For example, one child with McCune–Albright syndrome may be entirely healthy, with no outward evidence of bone or endocrine problems, enter puberty at close to the normal age, and have no unusual skin pigmentation. Diagnosis may be made only after decades. In other cases, children are diagnosed in early infancy, show obvious bone disease, and obvious increased endocrine secretions from several glands.

Genetics
Genetically, there is a post-zygotic mutation of the gene GNAS1, on the long (q) arm of chromosome 20 at position 13.3, which is involved in G-protein signalling. This mutation, often a mosaicism, prevents downregulation of cAMP signalling.

Polyostotic fibrous dysplasia is usually caused by mosaicism for a mutation in a gene called GNAS1 (Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide 1).

Notable cases
The disease made headlines in December, 2005 when a Haitian teen afflicted with the disease, Marlie Casseus, underwent a 17-hour emergency surgical procedure to remove a 7 kg (16 pound) tumour-like growth of bone from her face. A series of operations at Holtz Children's Hospital in Miami, Florida restored the child's face to a more normal proportion.