Costello syndrome is characterized by severe failure-to-thrive, short stature, 
cardiac abnormalities (heart defects, tachyarrhythmia, and hypertrophic 
cardiomyopathy (HCM)), distinctive facial features, a predisposition to 
papillomata and malignant tumors, postnatal cerebellar overgrowth resulting in 
Chiari 1 malformation, and cognitive disabilities. De novo germline mutations in 
the proto-oncogene HRAS cause Costello syndrome. Most mutations affect the 
glycine residues in position 12 or 13, and more than 80% of patients share 
p.G12S. To test the hypothesis that subtle genotype-phenotype differences exist, 
we report the first cohort comparison between 12 Costello syndrome individuals 
with p.G13C and individuals with p.G12S. The individuals with p.G13C had many 
typical findings including polyhydramnios, failure-to-thrive, HCM, macrocephaly 
with posterior fossa crowding, and developmental delay. Subjectively, their 
facial features were less coarse. Statistically significant differences included 
the absence of multifocal atrial tachycardia (P-value = 0.033), ulnar deviation 
of the wrist (P < 0.001) and papillomata (P = 0.003), and fewer neurosurgical 
procedures (P = 0.024). Fewer individuals with p.G13C had short stature (height 
below -2 SD) without use of growth hormone (P < 0.001). The noteworthy absence 
of malignant tumors did not reach statistical significance. Novel ectodermal 
findings were noted in individuals with p.G13C, including loose anagen hair 
resulting in easily pluckable hair with a matted appearance, different from the 
tight curls typical for most Costello syndrome individuals. Unusually long eye 
lashes requiring trimming are a novel finding we termed dolichocilia. These 
distinctive ectodermal findings suggest a cell type specific effect of this 
particular mutation. Additional patients are needed to validate these findings.