Costello syndrome

Costello syndrome is a disorder that affects many parts of the body. This condition is characterized by delayed development and intellectual disability, distinctive facial features, loose folds of extra skin (especially on the hands and feet), and unusually flexible joints. Heart abnormalities are common, including an unusually fast heartbeat (tachycardia), structural heart defects, and a form of heart disease that enlarges and weakens the heart muscle (hypertrophic cardiomyopathy). Although infants with Costello syndrome may be larger than average at birth, they have difficulty feeding and grow more slowly than other children. People with this condition have relatively short stature and may have reduced growth hormone levels.

Beginning in early childhood, people with Costello syndrome are at an increased risk of developing certain cancerous and noncancerous tumors. The most common noncancerous tumors seen with this condition are papillomas, which are small, wart-like growths that usually develop around the nose and mouth or near the anus. The most frequent cancerous tumor associated with Costello syndrome is a cancer of muscle tissue called a rhabdomyosarcoma. Neuroblastoma, a tumor that arises in developing nerve cells, also has been reported in children and adolescents with this disorder. In addition, some teenagers with Costello syndrome have developed transitional cell carcinoma, a form of bladder cancer that is usually seen in older adults.

The signs and symptoms of Costello syndrome overlap significantly with those of two other genetic conditions, cardiofaciocutaneous (CFC) syndrome and Noonan syndrome. The three conditions are distinguished by their genetic cause and specific patterns of signs and symptoms; however, it can be difficult to tell these conditions apart in infancy.

This condition is very rare; it is estimated to affect 200 to 300 people worldwide.

Mutations in the HRAS gene cause Costello syndrome. This gene provides instructions for making a protein called H-Ras that helps control cell growth and division. Mutations that cause Costello syndrome lead to the production of an H-Ras protein that is continuously active. Instead of triggering cell growth in response to signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This unchecked cell division can cause cancerous and noncancerous tumors to develop. It is unclear how mutations in the HRAS gene cause the other features of Costello syndrome, but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division.

Some people with the characteristic signs and symptoms of Costello syndrome do not have an identified mutation in the HRAS gene. In these cases, affected individuals may actually have cardiofaciocutaneous syndrome or Noonan syndrome, which are caused by mutations in related genes. The proteins produced from these genes interact with one another and with the H-Ras protein. These interactions help explain why mutations in different genes can cause conditions with overlapping signs and symptoms.

In at least one reported case, an individual with features of Costello syndrome had an HRAS mutation in only some of the body's cells. This situation is known as mosaicism. Researchers suggest that mosaicism may account for some cases of Costello syndrome where no HRAS mutation is identified. Because the mutation does not occur in all cells, it may not be present in the sample of cells that are tested.

Costello syndrome is considered to be an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Almost all reported cases have resulted from new gene mutations and have occurred in people with no history of the disorder in their family.