Costello Syndrome is a rare genetic condition that impacts several body systems, affecting development and overall health.
Defining Costello Syndrome
Costello Syndrome is a rare, multisystem disorder characterized by a range of physical and developmental features. Individuals with this condition often present with distinctive facial characteristics, developmental delays, and a predisposition to certain medical issues. While it affects various parts of the body, the specific manifestations and their severity can vary among individuals. It is part of a broader group of conditions known as RASopathies, which stem from issues within the RAS-mitogen activated protein kinase (MAPK) pathway.
The Genetic Cause
Costello Syndrome arises from specific mutations in the HRAS gene. This gene plays a role in cell growth and division, forming part of the RAS/MAPK signaling pathway. The mutations in the HRAS gene lead to an overactive H-Ras protein, which continuously signals cells to grow and divide. Most cases result from de novo mutations, meaning the genetic change occurs spontaneously and is not inherited from either parent. In such instances, the recurrence risk for future pregnancies is very low.
Key Physical and Developmental Features
Distinctive facial characteristics often include coarse facial features, a large mouth with full lips, wide nostrils, and low-set, prominent ears. Many individuals also have curly or sparse hair and a large head size. Skin abnormalities are common, such as loose, soft skin, particularly noticeable on the hands and feet, with deep palmar and plantar creases. Papillomas, which are small, wart-like growths, frequently appear around the nose, mouth, or anal region, especially during childhood.
Musculoskeletal issues include generalized joint laxity, ulnar deviation of the wrists and fingers, and tight Achilles tendons, which may lead to toe walking. Short stature is common, and some individuals may experience hip dysplasia or spinal curvature like scoliosis or kyphosis. Developmentally, most individuals experience delays in milestones such as walking and speaking, and many have mild to moderate intellectual disability. Feeding difficulties are frequently present from infancy, sometimes requiring tube feeding due to weak suck and swallow.
Associated Health Challenges
Cardiac abnormalities are common, with hypertrophic cardiomyopathy being a frequent finding, where the heart muscle thickens and can impair its function. Other heart issues include arrhythmias, particularly multifocal atrial tachycardia, and valvular pulmonic stenosis. These cardiac concerns often necessitate close monitoring and can influence long-term health.
Individuals also have an increased lifetime risk of developing certain tumors, with an approximate 10-15% risk for solid malignant tumors. These can include rhabdomyosarcoma, a childhood cancer of muscle tissue, and neuroblastoma, which forms in nerve cells, typically in early childhood. In adolescence and adulthood, there is an elevated risk for transitional cell carcinoma of the bladder. Regular surveillance for these malignancies is an important part of ongoing care.
Gastrointestinal issues are frequently encountered, including severe feeding difficulties in infancy, which can lead to poor weight gain and require feeding tube placement. Gastroesophageal reflux disease (GERD) and constipation are also common. Neurological complications can arise, such as seizures and a structural abnormality of the brain known as Chiari I malformation, which involves brain tissue extending into the spinal canal.
Diagnosis and Ongoing Care
Diagnosing Costello Syndrome typically begins with a clinical evaluation based on characteristic physical and developmental features. Confirmation is achieved through molecular genetic testing, specifically identifying a mutation in the HRAS gene. This genetic test can differentiate Costello Syndrome from other conditions with similar symptoms, such as Noonan syndrome and cardiofaciocutaneous syndrome, which are also RASopathies but involve different genetic mutations.
Managing Costello Syndrome requires a comprehensive, multidisciplinary approach focused on addressing specific symptoms and providing supportive therapies. Regular screenings are important for potential complications, including ongoing cardiac monitoring with echocardiograms to detect and track hypertrophic cardiomyopathy and arrhythmias. Tumor surveillance, often involving abdominal and pelvic ultrasounds, is recommended, particularly in early childhood, to screen for rhabdomyosarcoma and neuroblastoma.
Early intervention therapies are instrumental in supporting development, including physical therapy for musculoskeletal issues and hypotonia, occupational therapy for fine motor skills, and speech therapy for communication and feeding difficulties. Educational support is also important to address intellectual disabilities.