Costello syndrome is a rare genetic condition that impacts multiple parts of the body, including the heart, muscles, bones, and skin. With an estimated birth prevalence ranging from 1 in 300,000 to 1 in 1.25 million, it is an exceptionally uncommon disorder. The condition presents a complex clinical picture that evolves throughout an individual’s life, requiring ongoing medical attention.
Genetic Origins of Costello Syndrome
Costello syndrome arises from specific mutations in the HRAS gene, located on chromosome 11. This gene provides instructions for making the H-Ras protein, which is part of a communication network known as the RAS/MAPK pathway. This pathway directs cellular functions, most notably cell growth and division. The mutations result in an H-Ras protein that is constantly active, leading to uncontrolled cell proliferation.
The genetic changes are almost always new, or de novo, occurrences, meaning the mutation appears for the first time in the affected individual and is not inherited. These are random, spontaneous events. If an individual with Costello syndrome has children, there is a 50% chance of passing the condition to each child because it is an autosomal dominant disorder.
Key Characteristics and Health Concerns
The effects of Costello syndrome become apparent at different life stages, often starting with challenges in infancy. Many individuals are born with a higher-than-average birth weight but experience severe feeding difficulties and a failure to thrive. This may necessitate a feeding tube to ensure adequate nutrition during the early years.
Physical Features
Individuals with Costello syndrome often share facial characteristics that include a large head (macrocephaly), full lips, a large mouth, and wide nostrils. The skin is frequently affected, appearing unusually loose and soft with deep creases on the hands and feet. Some develop dry, hardened skin on the palms and soles, a condition known as palmoplantar hyperkeratosis.
Hair is often curly or sparse and fine. Another common feature is the appearance of small, noncancerous growths called papillomas. These tend to form around the nose, mouth, or anus.
Growth and Development
After birth, individuals show slow growth, leading to short stature in adulthood. Developmental delays are common, with milestones like smiling, walking, and talking occurring later. Most people with the condition have some level of intellectual disability, which generally ranges from mild to moderate. Musculoskeletal issues are also prevalent, including weak muscle tone (hypotonia), highly flexible joints, and tight Achilles tendons that can cause toe-walking.
Major Health Issues
Cardiovascular problems are present in a majority of individuals, with hypertrophic cardiomyopathy (HCM) being a frequent finding. HCM involves a thickening of the heart muscle that can impair its function, and heart rhythm abnormalities (arrhythmias) are also common.
There is a recognized predisposition to developing certain types of tumors, both benign and malignant. The constant signal for cells to grow increases this risk to an estimated 15% over a lifetime. The most common childhood cancers are rhabdomyosarcoma, a cancer of muscle tissue, and neuroblastoma, which arises from nerve cells. In adolescence and adulthood, there is an increased risk for transitional cell carcinoma of the bladder.
The Diagnostic Process
The diagnostic process begins when a physician recognizes the characteristic signs and symptoms of Costello syndrome. A healthcare provider may suspect the condition based on features like the distinctive facial appearance, feeding difficulties, and developmental delays.
Because symptoms overlap with other RASopathies like cardiofaciocutaneous (CFC) syndrome and Noonan syndrome, a physical evaluation alone is not sufficient. These conditions share similar underlying mechanisms in the RAS/MAPK pathway, which accounts for their similar presentations and makes differentiation based on physical traits challenging.
A conclusive diagnosis is made through molecular genetic testing. A blood sample is analyzed to detect a pathogenic variant in the HRAS gene. Identifying this mutation confirms the diagnosis of Costello syndrome and is important for guiding medical management and surveillance for known health risks.
Management and Therapeutic Approaches
There is no cure for Costello syndrome, so treatment focuses on managing symptoms and providing supportive care. This requires a coordinated, multidisciplinary team of specialists to address the various ways the condition affects the body. This team often includes cardiologists, oncologists, geneticists, orthopedic surgeons, gastroenterologists, and developmental pediatricians.
Regular monitoring is a core part of management. Due to the high incidence of heart problems, routine cardiac evaluations with electrocardiograms and echocardiograms are performed to monitor for hypertrophic cardiomyopathy and arrhythmias. Regular screenings are also recommended to watch for tumors, often including abdominal and pelvic ultrasounds to screen for rhabdomyosarcoma and neuroblastoma during childhood.
A variety of therapies address functional and developmental challenges. Physical therapy helps with weak muscle tone and orthopedic issues, while occupational therapy can improve fine motor skills. Speech therapy assists with communication delays, and for infants with severe feeding problems, interventions may include a feeding tube. Educational plans are tailored to accommodate learning disabilities.
Living with Costello Syndrome
Costello syndrome is a lifelong condition, and the long-term outlook varies depending on the severity of health issues, especially cardiac complications. Strong support systems are invaluable for both individuals and their families. Living with a rare and complex condition presents unique challenges, so access to resources, support groups, and counseling can help families cope. Despite the medical path, many children with Costello syndrome are described as having friendly and outgoing personalities.