Costello syndrome is caused by HRAS germline mutations affecting Gly(12) or 
Gly(13) in >90% of cases and these are associated with a relatively homogeneous 
phenotype. Rarer mutations in other HRAS codons were reported in patients with 
an attenuated or mild phenotype. Disease-associated HRAS missense mutations 
result in constitutive HRAS activation and increased RAF-MEK-ERK and PI3K-AKT 
signal flow. Here we report on a novel heterozygous HRAS germline alteration, 
c.266C>G (p.S89C), in a girl presenting with severe fetal hydrops and pleural 
effusion, followed by a more benign postnatal course. A sibling with the same 
mutation and fetal polyhydramnios showed a Dandy-Walker malformation; his 
postnatal course was complicated by severe feeding difficulties. Their 
apparently asymptomatic father is heterozygous for the c.266C>G change. By 
functional analyses we identified reduced levels of active HRAS(S89C) and 
diminished MEK, ERK and AKT phosphorylation in cells overexpressing HRAS(S89C) , 
which represent novel consequences of disease-associated HRAS mutations. Given 
our patients' difficult neonatal course and presence of this change in their 
asymptomatic father, we hypothesize that its harmful consequences may be time 
limited, with the late fetal stage being most sensitive. Alternatively, the 
phenotype may develop only in the presence of an additional as-yet-unknown 
genetic modifier. While the pathogenicity of the HRAS c.266C>G change remains 
unproven, our data may illustrate wide functional and phenotypic variability of 
germline HRAS mutations.