Background: Germline mutations in several members of RAS/RAF/MEK/ERK pathway cause clinically similar genetic disorders, including Noonan syndrome (NS), Costello syndrome (CS) and cardio-facio-cutaneous syndrome (CFC). Each of these syndromes has a wide spectrum of molecular etiology. The aim of the present study was to conduct a comprehensive genetic analysis of RAS/RAF/MEK/ERK pathway in these syndromes.
Methods: Three patients with NS and two patients with CS/CFC were examined. Peripheral blood samples were collected from all patients as well as from 100 healthy Japanese volunteers. The protein phosphatase, non-receptor type II (PTPN11), KRAS, HRAS, NRAS, BRAF, RAF1, Son of Sevenless (SOS1) and MEK1genes were analyzed.
Results: In a patient with a severe Noonan phenotype, a rare PTPN11 mutation was detected: A to G transition at position 172, causing an N58D substitution within the N-SH2 domain. In a CS/CFC patient no HRAS mutations were found, but a novel SOS1 missense mutation was found: A to G transition at position 473, causing a T158A substitution within domain of histone-like fold (HF).
Conclusions: A case mimicking CS with SOS1 T158A substitution, which has not been reported previously in CS, revealed the complex relationship between the genotype and phenotype of overlapping syndromes of the RAS/RAF/MEK/ERK pathway.
© 2010 Japan Pediatric Society.