Cardiofaciocutaneous syndrome

Overview

Cardiofaciocutaneous (CFC) syndrome is a rare genetic disorder that affects multiple parts of the body, including the heart (cardio), facial features (facio), and skin (cutaneous). It is part of a group of conditions known as RASopathies, which are caused by mutations that affect the RAS/MAPK cell signaling pathway, crucial for development. CFC syndrome is characterized by distinctive facial features, congenital heart defects, developmental delays, skin abnormalities, and growth problems. Symptoms are typically present from birth and vary widely in severity among individuals.

Causes

CFC syndrome is caused by mutations in genes that are part of the RAS/MAPK signaling pathway. The most commonly affected genes include:

• BRAF – the most frequent cause

• MAP2K1 and MAP2K2

• KRAS

These gene mutations lead to abnormal cell growth and development, resulting in the features seen in CFC syndrome. The condition is inherited in an autosomal dominant manner, but in most cases, it arises as a sporadic (de novo) mutation and is not inherited from either parent.

Symptoms

The symptoms of CFC syndrome vary, but most individuals share common characteristics involving the heart, facial structure, skin, and development:

• Facial features: High forehead, widely spaced eyes (hypertelorism), downward-slanting eyelids, short nose, wide mouth with full lips, and low-set ears

• Cardiac abnormalities: Pulmonary valve stenosis, atrial septal defect (ASD), ventricular septal defect (VSD), or hypertrophic cardiomyopathy

• Skin and hair abnormalities: Dry, rough, or thickened skin; sparse, curly, or brittle hair; hyperkeratosis

• Developmental delays: Delayed milestones, intellectual disability (mild to severe), and learning difficulties

• Feeding problems: Poor sucking, reflux, or failure to thrive in infancy

• Short stature and poor growth

• Skeletal anomalies: Joint laxity, scoliosis, or chest deformities

• Neurological issues: Seizures, hypotonia (low muscle tone), and motor coordination problems

• Eye problems: Strabismus, nystagmus, or optic nerve abnormalities

Diagnosis

Diagnosing CFC syndrome involves a combination of clinical evaluation and genetic testing. The diagnostic process includes:

• Physical examination: Assessment of characteristic facial features, skin texture, and growth parameters

• Cardiac evaluation: Echocardiogram and ECG to identify congenital heart defects

• Developmental assessment: Evaluation of motor skills, speech, and cognitive development

• Genetic testing: Identification of mutations in BRAF, MAP2K1, MAP2K2, or KRAS genes confirms the diagnosis

• Imaging studies: Brain MRI to check for structural abnormalities if neurological issues are suspected

CFC syndrome can overlap clinically with other RASopathies like Noonan syndrome and Costello syndrome, making genetic testing essential for a definitive diagnosis.

Treatment

There is no cure for CFC syndrome, and treatment focuses on managing the individual’s symptoms and improving quality of life. A multidisciplinary approach is usually required, including:

• Cardiology: Monitoring and managing heart defects with medications or surgery if needed

• Dermatology: Managing skin issues with emollients, keratolytics, or other treatments

• Neurology: Seizure management and evaluation of developmental concerns

• Speech and physical therapy: To support motor development, feeding, and communication

• Endocrinology: Monitoring growth and hormonal imbalances

• Gastroenterology and nutrition: Addressing feeding problems and ensuring adequate growth

• Special education and psychological support: To assist with learning and social development

Prognosis

The prognosis for individuals with Cardiofaciocutaneous syndrome varies depending on the severity of symptoms. With early intervention and supportive care, many children make developmental progress and lead fulfilling lives. However, lifelong medical care is typically necessary due to the multisystem involvement. Some individuals may have significant physical and cognitive challenges, while others may be more mildly affected. Advances in medical and educational support have greatly improved quality of life for those with CFC syndrome.