Cardiofaciocutaneous syndrome (ORPHA:1340)
A rare, multiple congenital anomalies syndrome characterized by craniofacial dysmorphology, congenital heart disease, dermatological abnormalities (most commonly hyperkeratotic skin and sparse, curly hair), neurological manifestations (hypotonia, seizures), failure to thrive and intellectual disability.
Epidemiology
Around 300 cases have been published in the literature to date. Prevalence has been estimated at 1/810,000 people in Japan. However prevalence is believed to be higher.
Clinical description
Cardiofaciocutaneous (CFC) syndrome displays wide phenotypic variability. Polyhydramnios is often reported. Neonates present at birth with relative macrocephaly, short webbed neck and distinctive dysmorphic craniofacial features (i.e. coarse facial appearance, large forehead, low-set ears, ptosis, downslanting of eyes, epicanthal folds, short nose with depressed nasal bridge, prominent philtrum, high arched palate, thick lower lip). Cardiac abnormalities, if present, may not be diagnosed until later, and include valvular pulmonary stenosis, interauricular communication and hypertrophic cardiomyopathy. Feeding difficulties, leading to failure to thrive, gastroesophageal reflux (GER), vomiting and constipation often appear in infancy but improve in childhood. Growth failure leading to short stature is sometimes due to a growth hormone deficiency. Dermatological manifestations include sparse, thin, and curly hair; dry, hyperkeratotic and hyperelastic skin (on arms, legs and face); general hyperpigmentation; progressively forming nevi; ichthyosis; palmoplantar keratoderma; café au lait spots; lymphedema; and hemangiomas. Severe eczematous lesions are frequently seen. Hypertelorism, strabismus, nystagmus, optic nerve hypoplasia and astigmatism can lead to decreased vision and acuity. Recurrent otitis media has also been reported. Neurological abnormalities (hypotonia, learning difficulties and developmental delay (motor and speech, mainly)) are seen in all children. In 50% of cases, seizures can also be present.
Etiology
CFC syndrome is considered a RASopathy and is due to mutations in one of the 4 genes: BRAF (7q34) (in 75% of CFC cases), MAP2K1 (15q22.1-q22.33), MAP2K2 (19p13.3), and KRAS (12p12.1), which encode proteins of the sarcoma/mitogen-activated protein kinase (RAS/MAPK) signaling pathway. This signaling pathway participates in the regulation of cell differentiation, proliferation, migration, and apoptosis.
Diagnostic methods
Clinical diagnosis is based mainly on the presence and frequency of the characteristic clinical traits and the sporadic occurrence of the disease. Molecular genetic testing, preferably multigene panel testing, including all known RASopathy genes, is preferable. If unavailable, sequential gene testing is recommended, starting from BRAF, exons 6, 12 and 11 being the most commonly mutated.
Differential diagnosis
Differential diagnoses include Costello Syndrome (CS) and Noonan Syndrome, which have overlapping phenotypes with CFC syndrome. CFC syndrome, unlike CS, does not appear to have an increased risk of malignancies.
Antenatal diagnosis
Prenatal testing is possible in families with a known mutation.
Genetic counseling
All bona fide cases reported to date are due to de novo dominant mutations. Due to sporadic nature of the disease, the sibling recurrence risk is very small.
Management and treatment
Management requires a multidisciplinary team. Infants may require nasogastric or gastrostomy feeding or a Nissen fundoplication when severe GER is present. Monitoring by a cardiologist is necessary and heart surgery may be required to repair specific defects. Monitoring by a neurologist is needed for the patients presenting seizures. Regular ophthalmology exams as well as corrective lenses or surgery can improve vision. Standard treatment of skin conditions is recommended. Referral to an endocrinologist may also be needed. Early occupational, physical and/or speech therapy promotes motor and speech development.
Prognosis
Prognosis is highly variable and is dependent on clinical manifestations. Life-expectancy can be close to normal or reduced (if severe heart and/or neurological manifestations are present).

                            Last update: 
                            October 2020


                            - Expert reviewer(s): 
                            Pr Maria Ines KAVAMURA