What is Costello Syndrome?

Costello syndrome is a genetic disorder which causes developmental delay, intellectual disability, and physical characteristics such as heart abnormalities. Children born with the syndrome are also more likely to develop certain types of cancer. The syndrome is extremely rare, and there have been only a few hundred reported cases worldwide.

Costello syndrome is caused by a mutation in a gene called HRAS. This gene codes for a protein which is involved in the control of cell division and growth. In children with the disorder, the HRAS gene is permanently switched on. This causes cells to grow and divide constantly, instead of doing so only in response to extracellular cues. The genetic mutation is autosomal dominant, meaning that a child needs only one copy of the defective gene to develop the disorder. Nearly all cases have resulted from spontaneous mutations.

One of the most noticeable characteristics of children born with Costello syndrome is simply failure to thrive. Other characteristics of the disorder include intellectual disability, developmental delay, and congenital heart defects such as valvular pulmonic stenosis or arrhythmia. Common physical characteristics include large mouth and full lips, loose skin, papilloma of the face or anus, and tight Achilles tendons. Children also have an increased risk of developing certain types of cancer. Around 15% develop tumors such as rhabdomyosarcoma, neuroblastoma, or bladder cancer as children or adolescents.

Diagnosis of the syndrome is based on documentation of the above characteristics and genetic testing to confirm the presence of HRAS mutation. There are no treatments that can cure the disorder or prevent symptoms from occurring. Most Costello syndrome treatments are based on preventing or treating secondary complications, and some are carried out to try and correct certain symptoms.

One of the most challenging problems to treat is failure to thrive, which is the result of postnatal feeding issues. Children who cannot feed without assistance are fed via nasogastric tubes or gastrostomy. Cardiac problems and cancers cannot be prevented, but are regularly screened for and treated as they arise. Symptoms such as Achilles tightening are treated via surgery, while papillomas are routinely removed with dry ice treatment.

Children are also vulnerable to secondary complications. Hypertrophic cardiomyopathy, a thickening of the heart muscle, is a common cardiac symptom which makes children vulnerable to anesthesia complications. Children with valvular pulmonic stenosis have reduced blood flow to the lungs, and are at risk of subacute bacterial endocarditis. These children must usually take prophylactic antibiotics to prevent endocarditis, an infection of the inner layer of the heart.

Research on treatment for Costello syndrome has been slow to develop, partly because there are so few people with the disorder. This makes testing treatments very difficult, because clinical trials require a statistically significant number of individuals. Many researchers believe that only one medication can be tested at a time, meaning the choice must be made as to which to try first. With little information about how effective the drugs might be, this is a difficult choice to make.

A recent development that may solve this problem is the creation of a Zebrafish animal model for the disorder. In this animal model, the Zebrafish has been genetically engineered so that it has the mutation that causes Costello syndrome in humans. The Zebrafish animal model can then be used to carry out preliminary tests on medications. This means the researchers can make more educated choices about medications to trial in children with the syndrome.