NF1 Gene Deletion vs. Mutation

My 2 yr old daughter had her initial appointment with the genetics clinic at Seattle Children's hospital this Thursday. It went well and the drs there were so nice. So our daughter has her official diagnosis of NF1 due to CALs, freckling, Nuerofibromas and motor skill delays and other things. They were pretty sure also that it was spontanious, by clinical diagnosis alone. One thing casually mentioned by the head Dr. was that she suspected her of having NF1 gene deletion vs. gene mutation. I asked if that meant she might be more prone to a severe case of NF1. But she said that hasn't been confirmed by studies, but so far it doesn't appear to play a role in severity or being more prone to Cancer, etc. They also stated that they don't generally due genetic testing unless the parents of the child want to have prenatal testing done for future children, which we personally won't have done. Or for the patient's own concern for bearing children/ genetic counseling etc. Which they typically do around age 18. So for now there's no test planned. Though I'd really like to maybe know one way or the other about possible gene deletion. So I'm looking into it a little and I was wondering what people here have heard as far as this issue (gene deletion vs. mutation) and if anyone has been diagnosed with one vs. the other or what Dr.s have told you. I also would like to ask how common it is for diagnosis to be made without genetic testing? I know that for my daughter it's not needed because she has more than the needed criteria for NF1. But just thought I'd ask around for other people's experiences and thoughts.
There's not a whole lot on the web to read about gene deletion in the NF1 gene. Although I'm only just now part way into a search on it. Thank you!

By steph1of9
Posted October 31, 2009 at 3:51 pm
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Well, leave it to me to think this would be an easy answer. Ha ha. So "gene deletion" is a lot more complex than I thought. I was reading online here:
http://jmg.bmj.com/cgi/content/full/44/12/800
It looks like there are two major "gene deletion" types and then there are deletions in different areas, things called single and multi-exon deletions, 3-bp deletion in NF1 exon 17, and others. And severity can be related to complete gene deletion ... but I'm still reading about in what types of cases and how they map these deletions and such. So ... I might direct my question to the genetics department as they invited me to ask anything that might come up; via e-mail or phone or during a visit. All are still invited to still post their answers though! =)

By sweetiecat
Posted October 31, 2009 at 5:20 pm
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I've never heard of gene deletion. I learn something new here everyday. Is tht where the 17th chromosone is missing? How do they determine that vs. mutation? Are there different symptoms?

By steph1of9
Posted October 31, 2009 at 7:53 pm
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About whether there are different symptoms or not, that's what I'm trying to figure out ... and I think the medical community is too. And yes, I believe gene deletion is when the whole gene is missing vs. being mutated. It's quite complex ... way more than I even guessed. I guess they have to look at the section of chromosomes (not to mention there are a pair of them, not just one to look at) and look at the genes within.
Thanks for commenting! I wish I was more knowledgable to explain what gene deletion is ... but I myself have only just begun to learn about it too. =)

By CindyLouWho
Posted November 1, 2009 at 4:25 pm
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Whole gene deletions do often appear to represent a more severe case of NF, at least according to most of the research. This type of mutation may represent somewhere between 5-10% of NF cases. It is one of the few times in NF where there is an increased frequency of a certain mutation being correlated to specific symptoms. Not sure what signs they were reviewing specifically in your case. Doctors may suspect a whole gene deletion where there is global delay, early onset of neurofibromas, higher tumor load, and dysmorphic features. However, like everything else NF related while these things are often seen with this type of mutation there are still exceptions and some variability. Let me repeat that....NOT ALL WHOLE GENE DELETION PATIENTS WILL HAVE THE SEVEREST FORMS OF NF. Furthermore, many NF children who appear to show this phenotype do not end up having a whole gene deletion. Studies have found that clinical observation may NOT be a good predictor of who actually has the whole gene deletion. For example, speech and delayed walking are common in NF children and are not always reflective of IQ. Also some children just do have dysmorphic features and some may have another NF phenotype called NF Noonan's syndrome. My point is that there are many factors to be considered and that NF is a very complex disorder. One study found that out of 26 NF children who were suspected of having a whole gene deletion, only 4 actually did as confirmed by genetic testing. The genetic testing is the only way to know with any certainty.

Does your doctor have much NF experience...I am just a bit surprised that he would bring that up before having confirmation. As I said, many NF experts will routinely see patients with these features who do not actually have whole gene deletions. The decision to do the testing is up to you but sometimes it may be more beneficial to go ahead with the testing than to research and worry about something your daughter may not have. Also some doctors feel that in cases where there is a whole gene deletion extra vigilant medical supervision may be wise so knowing may help to determine what type of follow up your daughter requires.

All the best,

Cindy

By steph1of9
Posted November 1, 2009 at 5:45 pm
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My daughter has slight dysmorphic features like her ears and eyes are offset along with an overall slight cranial crookedness that's hard to put your finger on until you study her face and skull. She's going to be seen this year by the craniofacial clinic. She has an early onset of neurofibromas (already has more than I can count) coupled with her motor skill delays. So that was what the Dr. was referring to when she mentioned it ... though she only said that she was suspicious that she could have it (gene deletion). It's not confirmed. The Dr she saw was Dr. Stephanie Wallace at Seattle's Children's Hospital in the Genetics clinic. I didn't ask but she seemed fairly knowledgable and there's some stuff on the web of her discussing NF, etc. plus the hospital has a really good rep. I think she was just mentioning it as something to maybe look into ... it was certainly not a diagnosis or anything. Thank you for the large amount of info you posted though. It does answer a lot of questions I was looking for. Thank you everyone for their comments. I'll keep posted if we find anything more out ... plus if we do any testing ... now or in the future. =)

By Kierstysmom
Posted November 1, 2009 at 10:51 pm
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Hello. My 2 year old daughter has a microdeletion of the NF gene (17q11.2). I have been doing tons of reading and am not finding a lot of information that is meaningful to me. We were given this diagnosis about two months ago after they did a chromosomal microarray analysis. I was surprised that she even had NF1 because most of her problems are not commonly associated with NF. She was born with a CHD called Pulmonary valve stenosis, and she has severe feeding problems. She cannot swallow solids and has to be feed via g-tube. Also, she is constantly sick with viral infections, has FTT due to the feeding issues, and is short. She does not have any obvious dysmorphic features except after comparing many photos , I think she has a flattened nasal bridge. She has enough CAL spots for a clinical dx of NF, but they are very light and not very noticeable. She has no neurofibromin yet, but an MRI revealed that she does have 2 optic gliomas. I'm sorta at a loss. The geneticist basically said she has NF1 and the other symptoms can be attributed to the chromosomal loss.
Personally, I'm leaning toward the NF-Noonan phenotype that the PP mentioned.
I wish you and your daughter the best and feel free to PM me anytime. I'd love to hear what your Dr's are telling you, and will gladly share any tid bit of info I get.

By CindyLouWho
Posted November 1, 2009 at 11:29 pm
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Many patients with NF have some Noonan's features, it isn't all that rare. Actual Noonan's is on an entirely different chromsome than NF. Some patients who meet clinical criteria for NF but who have enough features of Noonans are considered to have something called NFNS syndrome. Other patients may have dysmorphic features because that is attributed to a whole gene deletion and some just have the odd one or two mildly dysmorphic things for no known reason. The overlap in features between NF and Noonans is likely due in part to the fact that they are both implicated in a particular pathway called RAS.

Pulmonary stenosis does also occur more frequently in NF, even in patients without other Noonan's features. It has been described in microdeletion cases or just as an occasional finding in NF. Even outside NF pulmonary stenosis is one of the more common congenital heart problems. My daughter was born with pulmonary stenosis. The first few months were pretty scary. Fortunately, our daughter grew and the heart issue didn't. Today at 11 her pulmonary stenosis is considered "trivial" and in 2007 for the first time it was no longer detectable by stethascope. Today she is an active kid who runs track and joins every activity she can. She was examined by the leading expert on Noonan's features and was found not to have any other features. We do have some genetic weirdness in our family tree but nothing the geneticist could necessarily connect.

Cindy

By Kierstysmom
Posted November 2, 2009 at 9:02 am
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Thank you for the clarification Cindy. Her official dx was NF1 microdeletion syndrome, but I felt the NFNS seemed to explain her symptoms better. I guess what I'm learning what many NF sufferers already know. There is no textbook case.

By steph1of9
Posted November 2, 2009 at 5:50 pm
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Thank you all for the posts and information. It's been wonderful to hear all the collective knowledge and learn a lot more. I really appriciate this support group, thank you.

By karan
Posted November 4, 2009 at 7:05 pm
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This has been such an informational post! I've learned so much!
My daughter's test came back with a dx of a mis-sense alteration of the nf gene. Apparently, it was a new mutation that the lab had never documented. Although there is no statistical proof, the genetics doctor believes that this may be an indicator of future mild symptoms... (and right now, I'll hang on to any hope I can!) Good luck! Isn't this site wonderful- letting you know you are never alone in this?!

By steph1of9
Posted November 5, 2009 at 3:58 pm
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Yes, I couldn't agree more. This site has been absolutely awesome. I've been getting in touch with other people and learning so much. Thank you everyone!

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