ESPE Abstracts

Background: Cardiofaciocutaneous syndrome (CFCS) is a rare autosomal dominant (AD) condition characterized by cardiac abnormalities, a distinctive craniofacial appearance and short stature. Endocrine manifestations include GH deficiency and precocious puberty. CFCS is part of the RASopathy group including Noonan, LEOPARD, and Costello syndromes. The four associated genes are BRAF (~75%), MAP2K1 and MAP2K2 (~25%), and KRAS (<2%). Most individuals represent new sporadic mutations. To date one family with transmission of an AD germline mutation (MAP2K2) through multiple generations has been reported.

Objective and hypotheses: To describe a sibling pair with CFCS due to gonadal mosaicism.

Method: Two brothers presented for paediatric management of failure to thrive (FTT) and developmental delay. The parents are healthy, unrelated with one unaffected daughter.

The first boy was born at term with a normal birth weight (50th centile). There was polyhydramnios, intrauterine growth restriction and right sided hydronephrosis on antenatal scans. He had FTT and gastro-oesophageal reflux disease in the neonatal period. A phenotype suggestive of Noonan syndrome with short stature, pulmonary stenosis, global developmental delay, and sensorineural hearing loss became apparent. Fifteen months later his brother was born at term with a normal birth weight (50th centile). Echocardiogram showed concentric left ventricular hypertrophy. He has a similar phenotype to his brother.

Results: Mutation analysis of the PTPN11, MEK1, and MEK2 genes were normal. Mutation analysis of the BRAF gene showed heterozygosity for a pathogenic mutation in BRAF c.770A>G (p.Gln257Arg) in both brothers. Neither healthy parent had the BRAF mutation in their blood DNA.

Conclusion: The likely explanation for these findings is that one or other parent has mosaicism for the BRAF mutation at least in their gonadal tissue. There could be up to a 50% chance of the parents having another affected child. This is the first reported family with CFCS due to gonadal mosaicism for a pathogenic BRAF mutation.