One of these conditions, Costello syndrome (CS), is typically caused by an activating de novo germline mutation in HRAS and is characterized by a wide range of cardiac, musculoskeletal, dermatological and developmental abnormalities.
Here, we report on a novel heterozygous HRAS germline mutation (c.187_207dup, p.E63_D69dup) in a girl presenting with a phenotype at the milder end of the Costello syndrome spectrum.
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.
Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified.
Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation.
We report a patient with typical Costello syndrome and a novel heterozygous missense mutation in codon 117 (c.350A>G, p.Lys117Arg) of the HRAS gene, resulting in constitutive activation of the RAS/MAPK pathway similar to the typical p.Gly12Ser and p.Gly12Ala mutations.