Cardio-facio-cutaneous syndrome
CFC; CFCS; one of the family of "RASopathies" (RAS-MAPK pathway disorders) alongside Noonan, LEOPARD, Costello, neurofibromatosis 1 and Legius syndrome
Cardio-facio-cutaneous (CFC) syndrome is an autosomal dominant multisystem RASopathy caused by germline activating mutations of BRAF (~75%), MAP2K1 / MAP2K2 (MEK1/2) (~25%) or โ rarely โ KRAS. The cardinal features comprise a triad of (1) congenital cardiac defects โ most commonly pulmonary valve stenosis, atrial septal defect and hypertrophic cardiomyopathy; (2) characteristic facial dysmorphism โ high forehead, bitemporal narrowing, ocular hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly-rotated ears, short broad nose and full cheeks; and (3) distinctive cutaneous features โ sparse, curly, slow-growing scalp hair (often with sparse eyebrows and eyelashes), prominent keratosis pilaris on the face / arms / trunk, ichthyosis, palmoplantar keratoderma, and (relevant to skin oncology) multiple melanocytic naevi โ sometimes hundreds โ and a modestly increased lifetime risk of cutaneous melanoma. CFC overlaps clinically with Costello syndrome (HRAS) and severe Noonan syndrome but its cutaneous phenotype is more prominent. Distinct from neurofibromatosis 1 (NF1), although both are RASopathies.
Genetics
- Autosomal dominant; usually de novo mutations (sporadic) โ most affected individuals do not have an affected parent.
- Underlying genes (RAS-MAPK pathway):
- BRAF โ ~75%; gain-of-function activating mutations.
- MAP2K1 (MEK1) / MAP2K2 (MEK2) โ ~25%.
- KRAS โ rare.
- Disease mechanism โ gain-of-function activation of the RAS-MAPK pathway, with multiple developmental and oncogenic consequences.
- Confirm by clinical features plus germline gene-panel testing (RASopathy panel).
Cardinal features
- Cardiac (~75%) โ pulmonary valve stenosis, atrial septal defect, hypertrophic cardiomyopathy, mitral valve abnormalities; arrhythmia.
- Facial dysmorphism โ high forehead with bitemporal narrowing, ocular hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly-rotated ears, short broad nose, full cheeks; "Noonan-like" but more pronounced.
- Cutaneous:
- Sparse, slow-growing, curly / wiry scalp hair; sparse / absent eyebrows and eyelashes.
- Prominent keratosis pilaris on the face (especially the cheeks โ "ulerythema ophryogenes" with eyebrow loss), arms and trunk.
- Ichthyosis-like generalised xerosis.
- Palmoplantar keratoderma.
- Multiple melanocytic naevi โ frequently dozens to hundreds; modestly increased melanoma risk.
- Multiple infantile haemangiomas.
- Cafรฉ-au-lait macules in some.
- Neurological โ global developmental delay; intellectual disability (mild to severe); seizures (~50%); hypotonia in infancy.
- Growth โ short stature; failure to thrive in infancy with feeding difficulties.
- Cancer risk — modestly increased. Reported in CFC mainly as ALL and lymphoma case reports, and melanoma related to the high naevus burden. Hepatoblastoma and paraganglioma are more characteristic of Costello syndrome (HRAS) than of CFC; absolute cancer risk in CFC is lower than in Costello.
Surveillance & management
- Multidisciplinary care โ paediatric cardiology, neurology, endocrinology, dermatology, education / developmental support, clinical genetics; lifelong (UK CFC International Foundation; specialist genetics centres).
- Cardiac โ echocardiogram at diagnosis and serially; manage cardiac defects; cardiology MDT.
- Skin:
- Annual full-skin examination from infancy.
- Photoprotection counselling.
- Biopsy any new or changing lesion โ melanoma surveillance especially relevant given multiple naevi.
- Treatment of keratosis pilaris โ emollients, urea / lactic acid keratolytics, topical retinoids.
- Ablation of cosmetically intrusive infantile haemangiomas (ฮฒ-blocker โ propranolol; pulsed dye laser).
- Cancer surveillance โ no routine hepatoblastoma AFP / abdominal ultrasound programme is established for CFC; that approach is more characteristic of Costello syndrome. Use clinical examination, low threshold to investigate symptoms, and haematology review / FBC if clinically indicated.
- Targeted therapy โ emerging interest in MEK inhibitors (trametinib, selumetinib) for symptomatic cardiac hypertrophy in CFC; clinical trials ongoing. The same MAPK-pathway-inhibitor logic that works for NF1 plexiform neurofibroma may apply to CFC.
- Genetic counselling โ usually de novo mutations; recurrence risk for parents low; recurrence risk for affected proband's offspring 50%.
References
- Roberts AE et al. Noonan syndrome and the RASopathies โ clinical and molecular review. Genet Med; 2013.
- Pierpont EI et al. Cardio-facio-cutaneous syndrome โ clinical features and natural history. Am J Med Genet A; 2014.
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