Cardiofaciocutaneous (CFC) syndrome is a rare genetic condition that impacts several body systems, including the heart, face, and skin. It is recognized as one of the RASopathies, a group of genetic disorders that stem from issues within the RAS/MAPK pathway, which governs cell communication. The condition’s effects on growth and development are evident from infancy or early childhood.
Genetic Basis
CFC syndrome arises from mutations in specific genes, primarily BRAF, MAP2K1, MAP2K2, and KRAS. These genes provide instructions for proteins within the RAS/MAPK pathway, a complex signaling network in cells. This pathway plays a role in regulating cell growth, division, and maturation processes.
In CFC syndrome, these mutations can lead to an overactive protein within the RAS/MAPK pathway, disrupting the normal signaling required for development. Most CFC syndrome cases (75-80%) are linked to BRAF gene mutations. Mutations in MAP2K1 and MAP2K2 account for another 10-15% of cases, with KRAS mutations affecting under 5% of individuals.
CFC syndrome is an autosomal dominant condition, meaning only one altered copy of a gene is sufficient to cause the disorder. Most reported cases result from a de novo gene mutation rather than being inherited from parents. However, in rare instances, parental mosaicism, where a parent carries the mutation in some but not all of their cells, can lead to familial recurrence.
Recognizing the Signs
Individuals with CFC syndrome have characteristic physical features affecting the face, skin, and hair. Facial features include a high forehead, widely spaced, downward-slanting eyes, drooping eyelids (ptosis), and a short nose with a broad base. Also common are sparse or absent eyebrows and eyelashes, a long or broad face, and a small chin.
Skin abnormalities are common. They include dry, rough skin (xerosis), thickened patches (hyperkeratosis), and small, bumpy rashes, particularly on the arms, legs, and face (keratosis pilaris). Other skin issues include fish-scale-like skin (ichthyosis), eczema, or an increased number of pigmented moles. Hair is frequently sparse, brittle, or curly.
Heart defects are a common feature, often congenital. The most frequently observed cardiac issue is pulmonary stenosis, which is a narrowing of the valve that carries blood from the heart to the lungs. Other defects include atrial septal defects (holes between the heart’s upper chambers), ventricular septal defects (holes between the lower chambers), and hypertrophic cardiomyopathy, where the heart muscle thickens.
Neurological involvement is also common. Developmental delays impact motor milestones and cognitive abilities. Intellectual disability, varying from mild to severe, is common in nearly all individuals with CFC syndrome. Some individuals may experience seizures, which can sometimes be difficult to manage with therapy. Low muscle tone, known as hypotonia, is also frequently reported, especially in infants.
Gastrointestinal issues are common. Feeding difficulties often contribute to poor growth and weight gain. Some individuals may experience gastroesophageal reflux, where stomach contents flow back into the esophagus. These feeding challenges may require supportive measures like nasogastric or gastrostomy tube feeding.
Diagnosis and Ongoing Care
Diagnosing CFC syndrome begins with a thorough clinical evaluation, where healthcare providers assess characteristic physical signs and review medical and family history. Due to overlapping features with other RASopathies like Noonan and Costello syndromes, genetic testing is used to confirm the diagnosis by analyzing an individual’s DNA to identify specific mutations in genes such as BRAF, MAP2K1, MAP2K2, or KRAS.
Once a diagnosis is established, ongoing care for CFC syndrome adopts a multidisciplinary approach involving a team of specialists to address diverse needs. Cardiologists monitor and manage heart defects, while neurologists address developmental delays, intellectual disability, and seizures.
Dermatologists provide care for skin and hair abnormalities, and gastroenterologists manage feeding difficulties and other digestive issues. Developmental pediatricians oversee overall growth and development, coordinating care among various specialists. Therapists, including physical, occupational, and speech therapists, help individuals achieve developmental milestones and improve functional skills. The primary goal of management is to provide symptomatic treatment and supportive care tailored to the individual’s specific needs.
Living with CFC Syndrome
Living with CFC syndrome is a lifelong condition, and the long-term outlook can vary among individuals. While the condition presents ongoing challenges, early intervention and consistent supportive care can significantly improve outcomes and quality of life. Many individuals with CFC syndrome can make developmental progress at their own pace with appropriate therapies and interventions.
Congenital heart defects are a primary factor influencing life expectancy. Family support and community resources play a role in assisting individuals and their families. Organizations like CFC International offer support groups and information exchange. These groups provide a space for families to connect, share experiences, and access guidance on various aspects of care, including feeding challenges and transitions into adulthood.
Research efforts continue to advance the understanding of CFC syndrome and related RASopathies. Scientists are exploring potential therapies, including studies on MEK inhibitors in model systems like zebrafish, which could offer targeted treatments for progressive phenotypes. Participation in research studies helps expand knowledge about the syndrome and contributes to the development of new interventions.