Cardiofaciocutaneous Syndrome

Cardiofaciocutaneous syndrome is an autosomal dominant RASopathy caused by variants in BRAF (about 75%), MAP2K1, MAP2K2 or KRAS, with a characteristic face, cardiac defects, ectodermal features and intellectual disability. Variants are usually de novo.

Pathophysiology. Gain-of-function variants in the RAS-MAPK cascade lead to excess ERK signalling, altering development of the skin, hair, heart and brain.

It overlaps with Costello and Noonan syndromes, and gene testing often clarifies the diagnosis.

Epilepsy and feeding problems are major issues in childhood.

• Macrocephaly, high forehead with bitemporal narrowing, downslanting fissures, ptosis and low set posteriorly rotated ears
• Sparse, curly, brittle scalp hair with sparse eyebrows
• Skin: keratosis pilaris, ichthyosis, eczema, hyperkeratosis, haemangiomas, naevi
• Cardiac disease: pulmonary stenosis, atrial septal defect, hypertrophic cardiomyopathy
• Intellectual disability, hypotonia and speech delay
• Seizures (about half)
• Severe feeding difficulties, reflux and failure to thrive
• Short stature
• Ophthalmic problems, constipation and growth hormone deficiency
• Lymphatic anomalies and bleeding abnormalities in some

• Genetic testing: a RASopathy panel (BRAF, MAP2K1, MAP2K2, KRAS and others) or exome sequencing.
• Clinical diagnosis from facial, skin, hair and cardiac features.
• Echocardiography and ECG at diagnosis.
• Brain MRI and EEG for seizures and structural anomalies.
• Ophthalmology, audiology, growth and endocrine assessment.

Differential diagnosis.

• Costello syndrome (HRAS, coarse face, tumour risk, arrhythmia)
• Noonan syndrome and Noonan syndrome with multiple lentigines
• Neurofibromatosis type 1 and Legius syndrome
• Other syndromic ichthyoses and ectodermal dysplasias
• Foetal alcohol spectrum disorder
• Williams syndrome

• Seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, or valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily, with other drugs by seizure type. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Feeding and growth: feeding therapy, gastrostomy for unsafe feeding, omeprazole 0.7 to 1 mg/kg daily, and macrogol 0.4 to 0.8 g/kg daily for constipation.
• Cardiac care: echocardiography and ECG at diagnosis and every 1 to 2 years. Balloon valvuloplasty for pulmonary stenosis with a gradient over 50 mmHg. For hypertrophic cardiomyopathy use propranolol 1 mg/kg daily in two to three divided doses increasing to 4 mg/kg daily.
• Skin and hair: daily emollients, urea 10% cream twice daily for hyperkeratosis and ichthyosis, topical corticosteroid for eczema, and gentle hair care.
• Bleeding risk: coagulation screen before surgery, and tranexamic acid 15 to 25 mg/kg orally three times daily (maximum 1 g each dose) for bleeding.
• Growth: growth hormone for proven deficiency, with cardiology agreement given cardiomyopathy risk.
• Eye and hearing care: ophthalmology and audiology review yearly.
• Development: early intervention, speech and communication therapy, physiotherapy and special education.
• Genetic counselling: de novo variants carry very low recurrence risk.

Special groups.

• Adults: continue epilepsy and cardiac care, and plan supported living.

Monitoring. Seizures, feeding and development every 3 to 6 months in childhood. Echocardiography and ECG every 1 to 2 years, and skin review yearly.

Referral and escalation. Refer to clinical genetics, paediatric neurology, cardiology and dermatology. Emergency for prolonged seizures, heart failure or unsafe aspiration.