[Molecular genetic diagnostics in syndromes associated with the RAS/MAPK signalling pathway].
BACKGROUND
Mutations in genes of the mitogen-activated protein kinase (MAPK) cascade have recently been shown to cause several syndromes characterized by dysmorphic facial features, growth retardation, cognitive impairment, heart disease and cutaneous abnormalities. This signalling pathway involves RAS and RAF proteins, and is central in the regulation of normal growth and the development of cancer.


METHODS
We have studied 23 Norwegian patients for whom there was a clinical suspicion of Costello, Noonan or cardio-facio-cutaneous syndrome. Patients suspected of having Noonan syndrome had previously tested negative for mutations in the tyrosine phosphatase gene PTPN11. The material was examined for mutations in the HRAS, KRAS, RAF1 and BRAF genes. Two patients are described to illustrate diagnostic challenges and the usefulness of genetic testing.


RESULTS
Ten of 23 patients (43 %) had mutations affecting the RAS/MAPK signalling pathway. Mutations in HRAS were most common (five cases), while three patients had mutations in KRAS and two in RAF1. Spontaneous mutations were demonstrated in eight cases. Our data indicate an annual incidence of 1-2 new cases of congenital RAS/RAF mutations in Norway.


CONCLUSIONS
Upon clinical suspicion of syndromes of the RAS/MAPK signalling pathway, molecular genetic analyses may be essential for a correct diagnosis. Certain mutations are associated with an increased cancer risk, exemplifying that results of genetic laboratory testing may influence medical management.
Molven
Anders
A
Gades institutt, Universitetet i Bergen og Avdeling for patologi Haukeland universitetssykehus 5021 Bergen, Norway. anders.molven@gades.uib.no
Søvik
Oddmund
O
von der Lippe
Charlotte
C
Steine
Solrun J
SJ
Njølstad
Pål R
PR
Houge
Gunnar
G
Prescott
Trine E
TE
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D056685:Costello Syndrome / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics; D005821:Genetic Techniques; D006801:Humans; D007223:Infant; D044542:LEOPARD Syndrome / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics*; D009634:Noonan Syndrome / Q000235:genetics; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013577:Syndrome; D018631:ras Proteins / Q000235:genetics*
D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins