A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation

Abstract

Noonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.

Keywords: Noonan syndrome; RAF1 mutation; RAS/MAPK pathway; hypertrophic cardiomyopathy; whole exome sequencing.

Fig. 1.

Echocardiogram at the age of 5 months showing concentric HCM (a) and right ventricular outflow tract dilation (b).

Fig. 2.

Photographs of the patient at 5 months (a, b, e, f, g) and 6 months (c, d): note the dysmorphic facial features (a, b, c, d) including large forehead, frontal bossing, bitemporal narrowing, shallow orbital ridge, hypertelorism, exophthalmos, down-slanting palpebral fissures, depressed root of nose and bulbous tip, anteverted nares, low-set, posteriorly rotated ears with thickened helix (b, d), smooth long philtrum (a) becoming deeply grooved (c), small mouth, thickening of lips (c), full cheeks (c) and retrognathia (b, d) and the cutaneous abnormalities including sparse hair, eyebrows and eyelashes (a, b, c, d), redundant and loose skin on body members (e), hands and feet (f), and deep palmoplantar creases (g).

Fig. 3.

Pedigree of the family. Affected proband is denoted by filled circle, unaffected members are denoted by empty symbols. Sequence electropherograms are shown below symbols. (+) indicates the wild-type allele, the arrow indicates the position of the mutation.