Costello syndrome is a rare genetic condition that affects multiple body systems, causing growth delays, intellectual disability, distinctive facial features, heart problems, and an increased risk of certain cancers. It is estimated to affect somewhere between 100 and 1,500 people worldwide, with a prevalence of roughly 1 in 300,000 to 1 in 1.25 million births. Nearly all cases are new mutations, meaning the child is typically the first person in the family to have the condition.
The Genetic Cause
Costello syndrome belongs to a family of conditions called RASopathies, all caused by mutations in genes that control a specific signaling pathway inside cells. In Costello syndrome, the culprit is a mutation in the HRAS gene. This gene provides instructions for making a protein that works like an on-off switch for cell growth and division. In more than 95% of cases, the mutation hits one of two very specific spots on the gene, locking the switch in the “on” position.
When this growth-signaling switch is stuck on, cells throughout the body receive constant signals to grow and divide. That single glitch ripples outward into problems affecting the heart, skin, bones, brain, and other organs. The mutation is almost always spontaneous, appearing for the first time in the affected child rather than being inherited from a parent.
Early Signs and Feeding Challenges
Costello syndrome often shows hints before birth. Prenatal ultrasounds may reveal excess amniotic fluid (seen in over 90% of pregnancies), increased thickness at the back of the neck, short limb bones, a characteristic wrist position, and sometimes a fast or irregular fetal heart rate. Many babies with the condition are born preterm.
After birth, severe feeding difficulties are one of the first and most pressing challenges. Babies struggle with low muscle tone, poor coordination of the mouth and throat muscles, and frequent reflux. Most require tube feeding during their first years of life, either through a nasal tube or a surgically placed feeding tube directly into the stomach. The feeding tube approach is generally preferred when support is needed beyond three months, because it frees up the mouth for therapy aimed at building swallowing and oral motor skills. Weight gain typically improves around age three or four, though height and weight generally remain below average throughout life.
Physical Features
Children and adults with Costello syndrome share a recognizable set of physical traits. Facial features tend to be coarse, with a wide mouth, full lips, and a relatively large head. Hair is often curly, fine, and sparse.
Skin changes are especially distinctive. Newborns frequently have loose, soft skin. Over time, the skin darkens in patches, and deep creases develop on the palms and soles of the feet. Small wart-like growths called papillomata commonly appear on the face and around the nose during childhood, sometimes spreading and becoming more prominent with age. Thickened skin on the palms and soles, along with soft or abnormal nails, is also typical.
The hands and wrists take on a characteristic posture, with the wrists angling toward the pinky side and the fingers splayed apart with wide, padded fingertips. Tight Achilles tendons develop progressively through childhood, and other skeletal issues include hip dysplasia, curvature of the spine, and chest wall abnormalities.
Heart Problems
Cardiac involvement is the norm rather than the exception. Close to 90% of people with Costello syndrome develop at least one heart-related abnormality. The most common is hypertrophic cardiomyopathy, a thickening of the heart muscle, which affects about 61% of patients. Congenital heart defects, most often a narrowed pulmonary valve, occur in roughly 44%.
Perhaps the most distinctive cardiac feature is a specific type of irregular heart rhythm called multifocal atrial tachycardia. About half of children with Costello syndrome develop this arrhythmia during infancy or early childhood. In this rhythm disturbance, electrical signals fire from multiple abnormal spots in the upper chambers of the heart, causing a rapid and chaotic heartbeat. This arrhythmia is notably resistant to treatment and is rarely seen in other RASopathies, making it something of a hallmark of Costello syndrome.
Development and Learning
Developmental delays are universal, though the degree varies. Motor milestones like sitting, crawling, and walking come later than typical. Low muscle tone and joint looseness contribute to these delays. Speech development is also affected, partly because of the oral motor difficulties that begin in infancy.
Intellectual disability ranges from mild to moderate in most individuals. Interestingly, some features suggestive of autism spectrum disorder may appear in early infancy but often improve significantly by around age four. People with Costello syndrome are frequently described as having warm, sociable, and outgoing personalities, though anxiety can be a significant challenge. Neurological complications such as a Chiari malformation (where brain tissue extends into the spinal canal), tethered spinal cord, or seizures can also occur and require monitoring.
Cancer Risk
One of the most serious aspects of Costello syndrome is an estimated 15% lifetime risk of developing cancer. This is directly tied to the overactive growth signaling caused by the HRAS mutation. Three types of cancer account for the greatest concern:
- Rhabdomyosarcoma: a cancer of muscle tissue, carrying a cumulative risk of about 7%. It is most common in young children.
- Neuroblastoma: a cancer of nerve tissue, with a cumulative risk of about 2%, also occurring primarily in early childhood.
- Bladder cancer: specifically transitional cell carcinoma, with a cumulative risk of about 2.2%, typically emerging in adolescence or young adulthood.
Because of these risks, cancer screening begins as soon as the diagnosis is confirmed. Abdominal and pelvic ultrasounds are recommended every three months until age 14 to check for rhabdomyosarcoma, and every six to twelve months until age 10 for neuroblastoma. Starting at age 10, annual urine testing screens for early signs of bladder cancer, with more invasive examinations considered on a case-by-case basis.
How It Differs From Similar Conditions
Costello syndrome can be difficult to distinguish from two closely related RASopathies: Noonan syndrome and cardio-facio-cutaneous (CFC) syndrome. All three share coarse facial features, heart involvement, and developmental delays. Several features help set Costello syndrome apart.
Loose skin at birth, diffuse skin darkening, wart-like papillomata, the characteristic wrist and hand posture, and nail abnormalities are hallmarks of Costello syndrome that are uncommon in the other two conditions. CFC syndrome is more associated with sparse eyebrows and a particular type of skin roughness called follicular hyperkeratosis. Noonan syndrome generally involves milder developmental delays. Severe cardiac arrhythmias, particularly multifocal atrial tachycardia, occur in about a third of Costello syndrome cases but are rare in both Noonan and CFC syndromes. The significantly elevated cancer risk is also largely unique to Costello syndrome among the RASopathies. Genetic testing for the HRAS mutation provides definitive confirmation.
Ongoing Management
There is no cure for Costello syndrome, so management focuses on addressing each system affected and optimizing quality of life through coordinated care. A multidisciplinary team typically includes cardiologists, orthopedic specialists, neurologists, endocrinologists, oncologists, and vision specialists, since nystagmus and refractive errors are common.
Physical therapy, often several times per week, plays a central role from early childhood through adulthood. Ankle-foot orthoses (braces) introduced at walking age can help prevent the progressive tightening of heel cords that many children experience, and may improve outcomes if surgical tendon release is eventually needed. Occupational therapy supports fine motor skills and daily living tasks, while speech therapy targets both communication and swallowing.
Orthopedic issues tend to worsen over time, making ongoing care from orthopedic surgeons and physical therapists important well into adulthood. The most common surgical interventions include tendon releases, hip surgery, and spinal fusion for progressive curvature. Bone health monitoring is also part of long-term care, as bone metabolism can be affected.
Many individuals with Costello syndrome reach adulthood, though they require ongoing medical surveillance and support. The combination of cardiac monitoring, cancer screening, and proactive management of musculoskeletal and neurological issues forms the backbone of lifelong care.