ID #1067

Can Costello syndrome be diagnosed by physical examination alone?

A clinicaldiagnosis of Costello syndrome is based on a thorough evaluation of the pastmedical history, current health, and examination by a geneticist and othermedical specialists. Sometimes the clinicaldiagnosis is clear, while other times it can be difficult to tell Costellosyndrome from some of the closely related Ras/MAPK pathway syndromes,especially CFC syndrome, and, less often, Noonan syndrome. 

A molecular diagnosis of Costello syndromeis made when a disease-causing mutation in the HRAS gene is identified. HRASis the only gene associated with Costello syndrome. A molecular diagnosis confirms a clinical suspicion ofCostello syndrome. In other words, if an individual is thought to have a clinical diagnosis of Costello syndrome,molecular (genetic) testing is important because it helps either confirm thatCostello is the correct diagnosis, or tells the doctors that they shouldconsider the possibility of another closely related disorder that sharesCostello syndrome's features.

Genetictesting is an important part of a completeevaluation. Here?s an example: A person with a broken leg has tenderness,swelling, and inability to bear weight, but the x-ray confirms the break.

Every individual with Costello syndrome hasa mutation in HRAS.  If a person with a clinical diagnosis of "Costellosyndrome" has a normal HRAS genetictest, their doctor should consider other closely related syndromes. Because ofthe striking similarities in physical appearance and types of medical problemsto CFC and NS, a number of individuals with a clinical diagnosis of CS havelater had their diagnosis changed based on the result of their moleculargenetic test results.

Thegenetic test for Costello syndrome looks at the entire length of DNA within theHRAS gene to try to identify a change("mutation").  This is like trying tofind a spelling error of a word on the page of a book. 

InCostello syndrome, most of the mutations so far have been found in one areawithin the HRAS gene called codon12.  The most common mutation is called G12S. "G" is the code for an amino acid called glycine, and "S" is the code for theamino acid serine. The "12" refers to the location of the mutation (codon 12).  So, at codon 12, there is a "spelling error" changefrom glycine to serine. This change causes the formation of an abnormal HRAS protein.


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