Costello syndrome

Overview

Costello syndrome is a rare genetic disorder that affects multiple systems of the body, leading to distinctive facial features, developmental delays, cardiac problems, skin abnormalities, and an increased risk of certain tumors. First described in 1971 by Dr. Jack Costello, this condition is part of a group of disorders known as RASopathies, which result from mutations affecting the RAS/MAPK cell signaling pathway. Symptoms are present from infancy and vary in severity, but with proper care, many individuals can live well into adulthood.

Causes

Costello syndrome is caused by mutations in the HRAS gene. This gene provides instructions for making a protein involved in cell growth and division. When mutated, it leads to abnormal cell signaling and affects development. The condition follows an autosomal dominant inheritance pattern, but in most cases, the mutation occurs de novo (newly) and is not inherited from the parents.

Symptoms

Costello syndrome presents a wide range of symptoms that can affect physical appearance, growth, development, and internal organs. Common features include:

• Distinctive facial features: Large mouth, full lips, thick nasal bridge, low-set ears, and coarse facial features

• Skin abnormalities: Loose, soft skin with deep creases, papillomas (small wart-like growths) around the nose and mouth, and thickened palms and soles

• Feeding difficulties: In infancy, often requiring tube feeding

• Developmental delays: Especially in speech and motor skills

• Short stature and delayed growth: Common throughout childhood

• Cardiac problems: Including hypertrophic cardiomyopathy, arrhythmias, and congenital heart defects

• Musculoskeletal issues: Joint laxity, scoliosis, and ulnar deviation of the wrists and fingers

• Intellectual disability: Ranges from mild to moderate, but some individuals may have normal intelligence

• Increased cancer risk: Particularly for rhabdomyosarcoma, neuroblastoma, and bladder carcinoma

Diagnosis

Diagnosis of Costello syndrome is based on clinical signs, developmental history, and confirmed through genetic testing. Diagnostic steps include:

• Physical examination: Identifying characteristic facial and skin features, growth delays, and musculoskeletal anomalies

• Developmental assessment: To evaluate cognitive and motor function

• Cardiac evaluation: Echocardiogram and ECG to detect heart abnormalities

• Genetic testing: Molecular analysis of the HRAS gene confirms the diagnosis

• Imaging and cancer screening: For early detection of associated tumors

Treatment

There is no cure for Costello syndrome. Treatment focuses on managing symptoms, supporting development, and monitoring for complications. A multidisciplinary care team is often necessary. Treatment may include:

• Feeding support: Special feeding techniques or gastrostomy tubes in infants with poor oral intake

• Physical, occupational, and speech therapy: To improve motor skills, mobility, and communication

• Cardiac care: Regular monitoring and treatment of heart conditions

• Dermatologic treatment: Removal or management of skin papillomas if they cause irritation

• Educational support: Individualized learning programs based on developmental needs

• Cancer surveillance: Regular screenings for early detection and management of tumors

• Orthopedic interventions: For joint instability, scoliosis, or foot deformities

• Genetic counseling: For families to understand inheritance risks and implications

Prognosis

The prognosis for individuals with Costello syndrome varies depending on the severity of associated complications, particularly heart problems and cancer risk. With early intervention and comprehensive care, many individuals can live into adulthood, although they may require lifelong medical support. Ongoing research continues to improve understanding and management of this complex condition. Early diagnosis and proactive management significantly enhance quality of life and developmental outcomes.