Cardio-facio-cutaneous syndrome

Cardio-facio-cutaneous syndrome is a rare genetic disorder. It is genetically heterogeneous and usually results from a de novo pathogenic variant, although inherited cases can occur. The phenotype overlaps with Noonan syndrome and Costello syndrome, but CFC syndrome is particularly characterized by its combination of cardiac disease, distinctive facial features, prominent skin and hair abnormalities, and neurodevelopmental impairment. A distinctive presentation may include the combination of frontal bossing, characteristic skin abnormalities, and congenital heart disease.

It can present with psychiatric features such as anxiety, ADHD or attention difficulties, obsessive or perseverative behaviors, aggression, irritability, and behavioral dysregulation. Autism spectrum disorder (ASD) may also occur. Sleep disturbance may be present. Cognitive impairment, developmental delay, and speech and language impairment are common, with severity ranging from mild to profound. Motor development is also frequently delayed, reflecting hypotonia and muscle weakness. These manifestations generally emerge during childhood or development, although behavioral and neuropsychiatric difficulties may persist into adulthood and require ongoing assessment and support.

From a morphologic lens perspective, other features include (but are not limited to):

• Macrocephaly

• Prominent forehead

• Underdeveloped supraorbital ridges

• Neck webbing

• Widely spaced eyes

• Epicanthus

• Downslanted palpebral fissures

• Proptosis

• Ptosis

• Increased posterior angulation of ears

• Short nose

• Deep philtrum

• Deep palmar creases

Other characteristic features include hypotonia, poor growth, severe feeding difficulties, and cutaneous and hair abnormalities, including xerosis, hyperkeratosis, keratosis pilaris, eczema, sparse or woolly hair, and dystrophic nails. Cardiovascular manifestations are particularly important and include pulmonic stenosis, hypertrophic cardiomyopathy, septal defects, other valve abnormalities, and cardiac rhythm disturbances. Neurologic manifestations may include seizures/epilepsy and structural brain abnormalities, including Chiari I malformation, hydrocephalus, and abnormalities of myelination. Ophthalmologic manifestations may include strabismus, nystagmus, refractive errors, and optic nerve hypoplasia. Additional reported features include lymphedema or chylothorax, gastroesophageal reflux, constipation and other gastrointestinal abnormalities, musculoskeletal abnormalities, hearing impairment, cryptorchidism in males, renal abnormalities, and bleeding or platelet abnormalities.

Early diagnosis is important to identify and monitor potentially serious cardiac, neurologic, gastrointestinal, ophthalmologic, lymphatic, hematologic, renal, and developmental complications, recognize neuropsychiatric needs early, and institute tailored multidisciplinary surveillance and treatment. Lifelong surveillance is recommended, including ongoing cardiac monitoring because hypertrophic cardiomyopathy and rhythm disturbances can develop later in life.