A Novel Missense Mutation in BRAF Caused Cardio-Facio-Cutaneous Syndrome

To the Editor Cardiofaciocutaneous syndrome (CFC) is a multiple congenital anomaly syndrome characterized by craniofacial features, cardiac defects, ectodermal anomalies and neurocognitive delay[1]. CFC is caused by mutations in BRAF, MEK1, MEK2, KRAS genes encoding proteins of the RAS/MAPK signaling pathway. In more than 70% of CFC patients, BRAF mutations are detected[2]. We present here a 10-year-old boy who was referred to the department of Medical Genetics for dysmorphological evaluation because of severe developmental delay, short stature and dysmorphic features. He was the third child of healthy, non-consanguineous Turkish parents. His parents and two siblings were healthy. He was born at term after an uneventful pregnancy. His birth weight was 3000 g (10-25th centile), height 50 cm (50th centile). His developmental milestones were globally delayed. At the age of 10, his height was 87.5 cm (<3rd centile), his weight 15300 g (10-25 centile) and head circumference 49,5 cm (<3rd centile). Physical examination revealed coarse facial appearance, low-set ears, sparse eyebrows, bilateral ptosis, down-slanted palpebral fissures, epicanthal folds, bulbous nose, prominent philtrum, high-arched palate, thick lower lip, pectus excavatum, clinodactyly of fifth fingers (Fig. 1a). His hair was curly. Two cafe-au-lait spots were also noted. A hypertrophic cardiomyopathy was detected by echocardiography. On neurological examination, he had severe mental retardation (IQ below 50) with poor social interaction at the age of 10. Myopia was detected on ophthalmical examination. Fundus examination and visual evoked potentials were normal. Laboratory tests were normal. Magnetic resonance imaging showed cortical atrophy of the brain. Abdominal ultrasonography, X-ray of vertebral column and extremities were normal. A hearing test was normal. His karyotype was 46 XY. On the basis of the observed facial dysmorphisms, hypertrophic cardiomyopathy and mental retardation, he was diagnosed as CFC. Genomic DNA from blood lymphocytes of the patient was isolated. Seven coding exons (6, 1116) in BRAF were amplified by polymerase chain reaction. The polymerase chain reaction products were gel-purified and sequenced on an ABI PRISM 310 automated DNA sequencer (Applied Biosystems). A novel, missense heterozygous c.1442C>A mutation in exon 12 was identified in the proband. This mutation was not detected in both parents (Fig. 1b). The cardio-facio-cutaneous syndrome (CFC) was first reported by Reynolds et al in 1986[3]. Overlapping phenotypes of patients with CFC, Costello Syndrome (CS) and Noonan Syndrome (NS) have been recognized [4]. Digilio et al