SNP Shot: Genomic Insights

McCune-Albright syndrome (MAS) is a rare condition affecting the skeleton, skin pigmentation, and hormone-producing (endocrine) glands.

A hallmark of MAS is polyostotic fibrous dysplasia, where abnormal, scar-like tissue replaces normal bone. "Polyostotic" indicates that multiple bones can be affected, often predominantly on one side of the body. This replacement of bone can cause fractures, uneven bone growth, and skeletal deformities. When the skull or jaw bones are involved, it can lead to facial asymmetry. Uneven growth in leg bones can cause a limp. Scoliosis, or abnormal curvature of the spine, may also occur. While rare (less than 1% of cases), these bone lesions can become cancerous.

Individuals with MAS typically have light brown skin patches called café-au-lait spots, sometimes present at birth. These spots are characterized by irregular borders, often compared to the coastline of Maine. This distinguishes them from café-au-lait spots associated with other conditions, which have smoother borders resembling the California coast. Like the bone lesions, these spots may appear predominantly on one side of the body.

Premature puberty is common in girls with MAS, often starting as early as age 2 with menstrual bleeding. This is thought to be caused by excessive estrogen production from ovarian cysts. Boys with MAS may also experience early puberty, though less frequently.

MAS can also lead to other endocrine problems. The thyroid gland may enlarge (goiter) or develop nodules. Hyperthyroidism, or overproduction of thyroid hormone, affects approximately 50% of individuals, causing symptoms like rapid heartbeat, high blood pressure, weight loss, tremors, and sweating. The pituitary gland may produce excess growth hormone, leading to acromegaly, characterized by enlarged hands and feet, arthritis, and "coarse" facial features. Excessive growth hormone can also exacerbate fibrous dysplasia in the bones, particularly in the skull. In rare cases, individuals develop Cushing syndrome before age 2, caused by excessive cortisol production from the adrenal glands. Cushing syndrome manifests as weight gain in the face and upper body, slowed growth in children, fragile skin, and fatigue.

Additional problems, such as non-cancerous gastrointestinal polyps and other abnormalities, can occur in various organs and systems in individuals with McCune-Albright syndrome.

Inheritance:

McCune-Albright syndrome is not inherited. It arises from a spontaneous, random mutation in the GNAS gene during early embryonic development. This results in mosaicism, where some cells carry the normal GNAS gene, while others carry the mutated version. The severity and specific features of MAS depend on the number and location of cells with the mutated gene. While affected individuals may have mutated reproductive cells (eggs or sperm), an embryo with the mutation in every cell is unlikely to survive. Therefore, MAS is generally not passed down to subsequent generations.