Interesting article on hypochondroplasia and seizures

Because Fi is settling in creche so well and the other two are at gymnastics, I have an hour to catch up on work, tidy the house, cook... OK to share this article abstract I saw a while back. Here is the link

Dr Antonio Romeo asks the question:

Does the Co-occurrence of FGFR3 Gene Mutation in Hypochondroplasia, Medial Temporal Lobe Dysgenesis, and Focal Epilepsy Suggest a Syndrome?

And I think the answer is probably: no, it doesn't indicate a syndrome, unfortunately we know of too many families where children with HCH had temporal lobe dysgenesis and seizures. 

If anyone can get the full article, I would be grateful.

- Update- I got the article. If anyone is interested, message me. 

From the Finnish researcher

There was a small but relevant study I shared a while back, you can read the post here.

I wrote to the researcher and asked a few questions and she has kindly replied. SO it's my duty not to forget and share. I did tell her that I would share with others.

- Based on my discussion with dozens of parents, it appears that most children with HCH wouldn't have an MRI done unless indicated. We were wondering if any of the findings (temporal lobe dysgenesis, peritrigonal white matter reduction, and abnormally shaped lateral ventricles) would show up on a CT, which they seem to be more likely to have? I am thinking the abnormally shaped ventricles would, but I am not sure of the other two? You´re right, on a CT you can only note the shape and size of ventricles, but not temporal dysgenesis. 

- I presume it didn't make any statistical difference which of the 2 common mutations the children had? Right. Both common mutations (c.1620 C>A and c.1630 C>G result to the same amino acid substitution and consequences are similar. We did not have children with other rare mutations. 

- When you use the term mild intellectual disability, I presume the IQ range meant is 50-69, is that correct?  That is correct. 

- Is there a significant difference in the verbal/non-verbal IQ that would have been noted? In most cases verbal IQ was lower than non-verbal, but there were a few exceptions. 

- In terms of the expressive language issues, is there a diagnosis provided by the speech pathologists, such as specific language impairment or any particular pattern in which way their speech seems to be impacted. - Speech delay seems to be the most common problem, so any light you could shed on this, based on your research, would be most appreciated, I realize this is not about neurology. In children with language problems: both speech production and understanding language were impaired, but in most cases expression (speech production) was more delayed/impaired than understanding. These children had benefit from augmentative and alternative communication, like using pictures and signs to aid communication.  

- Do you know if any of the children had hearing problems? - Up to 75% of kids with HCH seem to have recurrent otitis media and need multiple sets of grommets, etc.  Only one child had hearing impairment, but that was not caused by recurrent otitis media (it was sensorineural).

New research on hypochondroplasia and epilepsy

I just came across this research abstract yesterday as I was working on my HCH - GH project.

It is a retrospective, small and quite bias study, in the sense that they didn't do MRIs for all their 13 patients, but used the MRIs from their archives (for 8 kids). Now, of course kids with HCH don't typically get MRIs done, unless they have seizures or accelerating head growth and the authors correctly point this out. Nevertheless their neuroimaging findings are pretty uniform.

If you have 4 USD you can buy read-only access on Deep-dive for 7 days. I think it's money well spent. I am also trying to see if I can get a pdf from the publishing journal through their parent access program, in which case I will be happy to e-mail the file to any parent who will ask me.

It reinforces the points about the kind of seizures that children with HCH have as well as the cognitive/learning disorders and speech issues that Dr Pauli has documented before.

I have also tried to contact the authors to get some clarifications on a few points. See if we get anywhere with that. In addition with the selection bias, I have 2 main questions: it doesn't define what is meant by mild intellectual disability, I will try and get an IQ range and it would be great to see a verbal versus non-verbal results. It would be good to get a range on the speech delay as well.
Secondly, it was done by neurologists; when listing the specialists children attended ENT was not mentioned, I would be quite interested in understanding that aspect as well.

I truly hope that if I get accepted to do my PhD, all of you will participate in my research project, so that we can get a study on the way with larger numbers and get some answers for future parents and our children's generation.

Epilepsy 2

Hypochondroplasia - epilepsy 1 - is the post on my blog which gets the most hits every month hands down. Which tells me 2 things that I already know...

1. It is extremely under-researched, under-published, not even geneticist who deal with skeletal dysplasia patients seem to know a lot of the time based on parental reports.

2. It could be more common than the 8-10% which has been quoted previously. This number was not based on any research, just observations by medical professionals who see kids with HCH.


When we met with the 3 lovely WI/MN families in October whose children have HCH, Fi was the only one who didn't have seizures as an infant. They all had the common mutation...

So if you are reading this and you have questions or comments about this, feel free to e-mail at tiny.hypo at gmail. com

Cognitive problems 3

Those of you who have been following my ramblings for a while know, this topic is one of my hobby horses. The lack of certainty of proper research findings frustrates me and the careless way of some authors really annoys me...
I just got a fail and really bad criticism about my academic writing skills last week, but even I would know not to say things like "10-50 % may have mild/moderate cognitive problems/learning difficulties"... OK, rant over.
I had 2 specific questions to Dr Pauli about this subject during our visit in October this year. He has one of the largest HCH patient base and I know that he has a few patients with moderate intellectual problems.

1. Have you had any patients with mild/moderate cognitive problems who did not have epilepsy which is almost always linked with temporal lobe dysgenesis. - He took a second to think through his patients and discussed with Peggy and then said no, all of them had seizures. Of course not all kids with HCH and  seizures have cognitive/learning problems, that is clear.
To be honest this was exactly the answer I expected as this has been my finding talking to dozens of families over the last year and a half. Of course we don't have any research on this, so hence I asked my second question.

2. Has there been any progress about trying to get a hold of the data held but not analyzed by big pharma of about 300+ HCH patients, read more here. And apparently yes... if I understood correctly, the main skeletal dysplasia experts met and this topic was identified as a priority and there was a person named to head the research up. I think someone at Cedar Sinai. I think she was going on maternity leave. Anyway, this is great news and it is certainly something I will keep asking and posting about.

Cognitive problems

I have been avoiding writing about this topic, although it is something that I think about almost every day. I avoid writing about it, because it makes me very upset and by some stupid superstitious belief, I almost feel like not writing about it is the right thing to do, but it's not really. It is a HUGE, controversial and totally under-researched topic.
Whenever you read about HCH, you will run into this extremely annoying, idiotic sentence which will go like this: about 10% of patients with hypochondroplasia seem to have learning difficulties and/or mental retardation (some will add mild/moderate, others will say moderate/severe).

There is one, really thorough, albeit very small study which had 27 people of which none had any intellectual problems...
Then there is the infamous Bellus-Francomano study, I stand open to correction, but here is what I understand happened... These 2 geneticists undertook to conduct the largest ever study on patients with hypochondroplasia,  about 300 patients were included. I think some big pharmaceutical was involved and they were going to test for HGH effectivity as well. When the HGH part fell through, the big pharma pulled the funding and the good doctors or the big pharma are now sitting on the data which has never been evaluated. My understanding is that this study wasn't an objective study as in participants didn't take IQ tests (and don't get me started about the objectivity of those...), but it was more a retrospective study where patients/parents were asked about learning difficulties, developmental delays etc. According to one source about half have claimed to have had speech/other developmental delay in both the N540K and other kind of mutation groups, which of course is significantly higher than in other populations.
The fact that the results have never been published hasn't stopped Dr. Francomano from referring to the study on the NCBI write-up about hypochondroplasia, here is what she had to say: "The authors' preliminary studies [Bellus & Francomano, unpublished results] suggest that individuals with FGFR3 N540K mutations may have an increased incidence of mild-to-moderate intellectual disability or learning disabilities."
I have written to Dr. Francomano several times and unsurprisingly never got a response, I realize she is a very busy person. I am not sure how ethical or smart it is to start referring to an unpublished study without giving any further detail and making such a vague statement. It sure is not very helpful to all parents in the zone...
I have specifically asked Dr. Pauli about what he thinks based on his 30+ years of experience and relatively large patient numbers. This is what he said:
- He does have few patients who have severe mental disability, this should be visible very early in infancy.
- He thinks that up to 50% may have some kind of an isolated learning disability, most often verbal, like speech delay or later dyslexia like - these children may need extra help to overcome this, but do well in school.
- He thinks the mental disability% is about 10%
- He also noted that most often in the literature patients with mental disability have "temporal lobe dysgenesis"
This is actually the very same phrase that is being used by most HCH patients who have seizures, you can read more about that here.
I think over the last year I have connected with at least 50 families whose children (and some parents) have hypochondroplasia. 6 have had epilepsy.
The only children I know of who have cognitive problems all have epilepsy - 3 out of the 6.
2 of them are non-verbal, 1 is attending mainstream school and is doing well with support.
Many seem to have some speech delay, which could also be attributed to the high incidence of otis media, whether that is the case or not, I guess noone knows...
When we are seeing Dr. Pauli next I will specifically ask him if in his practice there have been any children with cognitive problems and no epilepsy.
I wish we could just come up with a list of questions and ask all parents and then analyze the data, but I know that's the idealist statistical nerd in me...

Hypochondroplasia -epilepsy

OK, as promised, I will start adding bits and pieces for the medical section of this blog as part of my new year's resolution.

Please remember that all of this is my opinion and I am not medically trained.

I would welcome all comments and guest posts, so we can gather and share what we know. 

To start off, let me just say that hypochondroplasia and related seizures is a really interesting and very under-researched subject... Apart from a few studies, not much seems to have been done to explore this area.

Apart from a few experts no one really seems to make the connection, I have personally spoken to 2 parents whose kids have had seizures and were told that it wasn't related.

Even if you read the official gene mutation review: http://www.ncbi.nlm.nih.gov/books/NBK1477/, epilepsy is not mentioned. 


I think one of the reasons why the connection is often not made, is that hypochondroplasia is quite rare; the best estimates say it impacts 1:350,000 live births (so 3-4 in 1 million). But  it is also not typically diagnosed until toddler age and in some cases a lot later. At the same time the vast majority of seizure symptoms seem to occur in the first year of life. So by the time HCH is diagnosed, the epilepsy is either under control with medication or even gone. So no wonder, the connection is not made.


If you do a search on google which I am sure you would have all done, if you are reading this,
you will find that the same few cases are cited over and over again, most often the one about one family where 2 of the children had medial temporal lobe dysgenesis and seizures: http://www.ashg.org/genetics/ashg07s/f20570.htm

Temporal lobe dysgenesis seems to feature in all cases that I could find. The reasoning says that because the FGFR3 also expresses in the brain, it could be causing this structural abnormality.

In terms of frequency I have seen 5-10% and 10% quoted by different authors.

Children with hypochondroplasia also have macrocephaly (and I will write about this soon) so that could also increase the risk of developing neurological symptoms, including seizures.

All kids whose parents I have spoken to had the the infancy onset seizure-precipitated apnea that appears to be the most common one based on Dr. Pauli's study as well. 



Here is the google docs link to the wonderful Dr. Pauli's study summary:

https://docs.google.com/viewer?a=v&pid=explorer&chrome=true&srcid=0B23x_OlN3FTNNzA1MDVmZGMtOTUxNS00OWEyLWFiNGEtNjMxYmM2YjllMGQ2&hl=en_US

So what should you do if you worry that your child has seizures, do exactly what you would do with any other child, except when you meet with the doctors, you may want to print out the study and take it with you.

If your child has apneic episodes or seizure-like events, they should have an EEG and and MRI of the brain, but I think this is standard practice anyhow. 

Should you do anything if your child doesn't have seizures? Our pediatrician was really pushing for an MRI and I refused, I didn't want to have Fi sedated and examined for something that she just has a higher risk for.

There will be no MRI...

Before we had a diagnosis, when there was doubt whether  Fi had achondroplasia or hypo I asked our pead to get a CT scan done, based on Dr. Pauli's instructions. For achon it's important to get a baseline to see the amount of fluid and the foramen magnum. A CT is better than an MRI because although it involves radiation, it is quicker, they can do it without sedation and there is a chart about foramen magnum size, this doesn't exist when the imaging is done using an MRI.

 When we found that that she has hypo, these instructions changed: no need to do a CT unless HC is off the average chart, which isn't the case for now anyhow.

Our pead nevertheless referred us to an MRI last month, needless to say up to today we didn't even get an appointment and I have decided that unless her HC is off the chart there will be no MRI. I will not starve this child for 8 hours and have her put under general anesthesia for something she doesn't need. I think she will have plenty of procedures in her lifetime, so we will hold off this one.

Also, if they find some brain abnormality I would just worry myself to death about what that implies in terms of learning difficulties, cognitive issues, etc. And if they told me that everything is fine, I wouldn't believe completely anyhow, since the same doctors told us that the X-rays were all clear... So I guess it's not even about not wanting to know, it is about not wanting to do something that will tell us nothing for sure...

Hypochondroplasia and cognitive problems 2

This topic is my hobby horse for a number of reasons which I will write about very-very soon. For now I will publish this very informative link, I hope it will stay active for a long-long time.

http://books.google.ie/books?id=hxsZ-KeyZCQC&pg=PA120&lpg=PA120&dq=N540K+mental&source=bl&ots=T5Fqkq6sX6&sig=nLsuctTCRoZI16Qhko9ojrlI7vM&hl=en&ei=3awhTrH8BcyChQfm77HlBQ&sa=X&oi=book_result&ct=result&resnum=6&ved=0CEIQ6AEwBQ#v=onepage&q=N540K%20mental&f=true