Costello Syndrome is a rare, multisystem genetic condition affecting approximately one in 300,000 to 1.25 million people globally. It is classified as a developmental disorder and a RASopathy, meaning it results from a malfunction in the body’s RAS/MAPK cell signaling pathway. This pathway regulates cell growth and division, and its disruption leads to a variety of physical, developmental, and medical challenges.
Genetic Origin of Costello Syndrome
Costello Syndrome (CS) is caused by a change in the HRAS gene, which is located on chromosome 11. The HRAS gene provides instructions for making the HRas protein, a component of the RAS/MAPK signaling cascade that governs cellular communication, growth, and survival. The genetic changes that lead to CS are typically specific missense point mutations that result in a “gain-of-function” for the HRas protein.
This gain-of-function mutation means the HRas protein is constantly “turned on,” signaling cells to grow and divide aggressively. The most common mutation, p. Gly12Ser, is found in about 80% of cases, replacing glycine with serine at position 12. Because the HRAS gene is expressed throughout the body, its malfunction impacts multiple organ systems.
The condition is inherited in an autosomal dominant pattern, but in the vast majority of cases, the mutation is de novo. This means it arises spontaneously in the affected individual and is not inherited from either parent. In these sporadic cases, the parents do not carry the gene change and the risk of having another child with CS is low, though rare instances of parental carriage make inheritance possible.
Key Physical and Developmental Characteristics
Infants with Costello Syndrome often present with a higher-than-average birth weight but subsequently experience severe feeding difficulties and failure to thrive. This leads to poor weight gain and short stature, often necessitating the use of a feeding tube for nutritional support. The condition is also characterized by distinctive facial features, including a large head (macrocephaly), a prominent forehead, full cheeks, and a large mouth with thick lips.
Cardiac abnormalities are a significant concern, with a high incidence of structural heart defects and issues with heart function. The most frequent cardiac issue is hypertrophic cardiomyopathy, which involves a thickening of the heart muscle that impairs its pumping ability. Individuals may also experience arrhythmias, or irregular heart rhythms, and other structural problems like pulmonic stenosis.
The skin and musculoskeletal systems are also visibly affected by the syndrome. Individuals often have soft, loose skin with deep creases on the palms and soles. Small, wart-like growths called papillomata frequently develop, especially around the nose, mouth, and anus. Musculoskeletal features include joint laxity, particularly in the wrists and fingers, which can lead to ulnar deviation.
Developmental delays are nearly universal in CS, with most individuals experiencing mild to moderate intellectual disability. Children often reach milestones such as walking and speaking later than their peers. Other neurological and physical issues include weak muscle tone (hypotonia), seizures, Chiari I malformation, and tight Achilles tendons that may cause toe-walking.
Diagnosis and Specialized Health Monitoring
The diagnosis of Costello Syndrome begins with clinical suspicion based on characteristic features, such as the distinctive facial appearance, heart issues, and developmental delay. Definitive diagnosis is confirmed through molecular genetic testing, which involves sequencing the HRAS gene to detect an activating germline mutation. The presence of a known pathogenic variant in HRAS is sufficient to confirm the condition.
A major consideration in the management of CS is the significantly increased lifetime risk of developing certain cancers. Individuals with CS have an estimated 10-15% lifetime risk of developing a malignant tumor, a risk substantially higher than in the general population. The cancers of concern are typically solid tumors that arise in early childhood.
The most common malignant tumors include embryonal rhabdomyosarcoma and neuroblastoma. There is also an increased risk of transitional cell carcinoma of the bladder in adolescence and young adulthood. Specialized cancer surveillance protocols are recommended due to this heightened risk. These protocols typically involve regular abdominal ultrasounds and specific tumor marker tests until the age of 8-10 years to screen for these early-onset tumors.
Management and Multidisciplinary Supportive Care
The management of Costello Syndrome is lifelong and requires a comprehensive, multidisciplinary approach to address its wide range of symptoms and complications. A team of specialists, including cardiologists, gastroenterologists, neurologists, geneticists, and oncologists, provides coordinated care from infancy through adulthood. The goal of treatment is to manage symptoms, maximize developmental potential, and implement preventative health measures.
Specific interventions are tailored to the individual’s needs, starting with aggressive support for feeding difficulties, which may include special diets or the placement of a gastrostomy tube. Cardiac issues, particularly hypertrophic cardiomyopathy and arrhythmias, require regular monitoring and may be treated with medication or other cardiac interventions. Developmental support is crucial, utilizing early intervention services, physical therapy, speech therapy, and occupational therapy to address motor and cognitive delays.
The ongoing care also involves monitoring for orthopedic issues such as scoliosis and tight tendons, which may require surgical correction or bracing. Given the predisposition to cancer, adherence to the recommended cancer surveillance schedule is a fundamental component of the long-term management plan. This proactive, coordinated management aims to improve the overall quality of life for individuals with Costello Syndrome.