My daughter’s mutation is MAP2k1. Quite often, when I see pictures of the pathway, that only comes under CFC Syndrome and Noonan’s isn’t mentioned on that mutation—I just wondered why?

There is a definite overlap between Noonan Syndrome and CFC Syndrome and where the lines are drawn is not clear at all. Often, it’s relatively historical about in which group of patients the gene changes were identified first, and so for MAP2k1, that was one of the original genes described as being a cause of CFC Syndrome and that then got its label as a CFC gene. As testing has been extended, there are more and more people with what looks clinically like a Noonan Syndrome phenotype who pop up as having a change in a previously CFC described gene. There has always been a few people known to have MAP2k1 gene changes in a fairly mild phenotype and they are in the literature here and there, and this degree of overlap is sufficient such that the way some labs now report their testing is “This result is consistent with a Rasopathy” which is fine as long as all of you guys who have Noonan Syndrome as part of your family know that Noonan Syndrome is the archetypical Rasopathy. We’ve had issues where paediatricians have sent for genetic testing and the result says “consistent with a Rasopathy” but the paediatrician nor the family have never heard of a Rasopathy and things become very difficult until we’ve been able to catch up with them and explain that it all makes sense. So, there are people with mild patterns of difference who have MAP2k1 mutations that were more characteristically described in people with a more severe CFC phenotype. The dilemma is do you define diagnosis by the gene or do you define it by the clinical features? I think probably we’re defining it by the clinical features first and then looking at the gene, but it’s an ongoing discussion. The best known and most widely used diagnostic criteria for Noonan Syndrome were done nearly 20 years ago before we had much gene testing at all. At the meeting in Milan we’re having a session on what should be the diagnostic criteria for Noonan Syndrome. Originally it was about the face, your stature, and whether or not you had congenital heart disease or a relative affected. I think they’ll be very different now and they will somehow have to incorporate a gene change.