Clinical characteristics: Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, and woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Affected individuals typically have some form of neurologic and/or cognitive delay (ranging from mild to severe). Most individuals have severe feeding issues, which can contribute to poor growth, and many require nasogastric or gastrostomy tube feeding. Many affected individuals have eye findings, including strabismus, nystagmus, refractive errors, and optic nerve hypoplasia. Seizures may be present and can be refractory to therapy.
Diagnosis/testing: The diagnosis of CFC syndrome is established in a proband with suggestive clinical findings by the identification of a heterozygous pathogenic variant in BRAF, MAP2K1, MAP2K2, or KRAS by molecular genetic testing.
Management: Treatment of manifestations: Consensus medical management guidelines have been published. Care by a multidisciplinary team; increased caloric intake and a nasogastric or gastrostomy tube for severe feeding issues; surgical intervention for severe gastroesophageal reflux or malrotation; management of cardiac structural defects, hypertrophic cardiomyopathy, and arrhythmias as in the general population; increased ambient humidity or hydrating lotions for xerosis and pruritus; management of seizures may require polytherapy; routine management of growth hormone deficiency; standard treatment for peripheral neuropathy, Chiari I malformation, developmental delay / intellectual disability, constipation, musculoskeletal anomalies, hypotonia, chronic/recurrent otitis media, hearing loss, cryptorchidism, hydronephrosis, bleeding disorders / thrombocytopenia, and sleep disorders.
Surveillance: At each visit: measure blood pressure; measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for GERD, constipation, generalized dysmotility; assess for new manifestations such as seizures or changes in tone; monitor developmental progress, behavior, and educational needs; monitor for signs and symptoms of thyroid and/or growth hormone deficiency. Assess for scoliosis at each visit until skeletal maturity. Monitor for signs/symptoms of precocious or delayed puberty at each visit in childhood and adolescence. Refer to endocrinologist between the ages of two to three years (or earlier if there are concerns about growth) to monitor growth velocity. Monitor for ocular issues every six to 12 months as directed by ophthalmologist. Hearing evaluation every two to three years, or as clinically indicated. Echocardiogram every two to three years up to age 20 years in those who have an initial cardiac evaluation that is normal. Echocardiogram every three to five years in individuals older than age 20 years who have no previous heart disease found. Annual dermatologic evaluation. DXA scan in early adulthood. Reassess platelet count for evidence of thrombocytopenia in those who have evidence of easy bruising or bleeding.
Agents/circumstances to avoid: Avoid overexposure to heat, strenuous activity, and dehydration. In individuals with evidence of peripheral neuropathy, avoid drugs with a neurotoxic effect.
Pregnancy management: A pregnant female suspected of having CFC syndrome warrants high-risk obstetric care from a trained maternal-fetal medicine physician due to possible polyhydramnios, maternal cardiac issues, and/or maternal hypertension.
Genetic counseling: CFC syndrome is inherited in an autosomal dominant manner. The majority of individuals with CFC syndrome reported to date have the disorder as the result of a de novo BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant. However, instances of familial recurrence of CFC have been reported. Each child of an individual with CFC syndrome has a 50% chance of inheriting the BRAF, MAP2K1, MAP2K2, or KRAS pathogenic variant. Once the CFC syndrome-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CFC are possible.
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