Finding a home in the genetic landscape

We've been a medical mystery to geneticist for a long time.  Better said, we've been a medical mystery to many specialties of doctors for a long time.  As a longtime fan of Car Talk, I like to say that Alexis has "stumped the chumps" (no disrespect to doctors).  Literally, every time we're seen by a new doctor (and even some of our existing doctors), they ask "what is her diagnosis?" We've been a person without a home.  We've looked at many options in 11 years.  

A brief reminder of her journey:

-2006:  Karyotype testing, Signature Chip (including 22q deletion and CHARGE/CHD7 deletion), Smitih-Lemli-Opitz (all testing normal) (done through Tufts/NEMC and BCH)

-2008:  Cornelia de Lange (screened for NIPBL and SMC1A deletions) - testing normal (done through Children's Hospital Philadelphia)

-2009:  Duane Radial Ray Syndrome (DRRS) / Okihiro Syndrome - testing normal (done through BCH)

-2010:  Signature Chip showed Xq13.1 deletion, which includes a gene that is associated with Glycogen Storage Disease type IXd (testing done through BCH)

-2012:  Alexis participated in Whole Genome Sequencing testing at Duke - nothing identified

-2015:  Alexis enrolled in new Undiagnosed Diseases Network program at Duke to perform additional testing.

-2017:  Alexis determined to have skewed X-inactivation in her blood (in a normal cell in girls, the cell must inactivate one of the X - since they have 2).  Alexis is found to inactivate mom's X 100%, which means it's skewed from the normal 50%-50%.

What we learned on Friday - our definitive diagnosis.  As with the typical "genetics odyssey" - it's the collection of data and information along the trip that is useful.  The true beauty is we are uncovering new understandings and the speed of sharing is saving lives.

In investigating Alexis' Whole Genome, Duke found that Alexis has a 43kb deletion on her X (at 13.1) that includes the Glycogen Storage Disease type IXd (confirmation of the 2010 testing) AND HDAC8. 

And researchers at Children's Hospital of Philadelphia have identified other gene deletions that cause Cornelia de Lange - including HDAC8. 

So, Alexis' diagnosis is Cornelia de Lange.  

      You can read more about Cornelia de Lange at http://www.cdlsusa.org/what-is-cdls/characteristics-of-cdls.htm 

       You can also read the OMIM entry:  https://www.omim.org/entry/122470?search=cornelia%20de%20lange&highlight=de%20lange%20cornelia 

Finding a home in the genetic landscape is nice:

-we have a network of families we can learn from

-they already have deep history and research efforts under way to help identify new treatments

-it gives an idea of life expectancy (no limits other than the underlying medical conditions)

-they have a national conference every 2 years (MN in June 2018, here we come!)

-they have centers of excellence through US and world (CHOP!)

-we have a name we can tell doctors, they will recognize it and be able to refer to published literature

-we get to build on what we already know and what we've learned from our providers (doctors/nurses/therapists) and networks (CHARGE Syndrome families, MA medically complex families, etc)

-read and learn a ton more!!!

In the past 48 hours, I've been reading a lot on the http://www.cdlsusa.org/ website.  I encourage the curious of you to look at that as well.

I will throw in a caveat, as with most everything Alexis is very unique.  Of the kids that present with Cornelia de Lange, only 5% of the HDAC8 deletion.  So, if you read something on the CdLS website that doesn't jive with your impression or interaction with Alexis - it may mean what is presented reflects the larger population.  It doesn't change our diagnosis, but this PDF article explains some of the biggest differences between the smaller HDAC8 deletion and the 'usual' Cornelia de Lange population.  One of the biggest differences is that they describe these kids with a happy disposition.

And lastly, Alexis still continues to challenge geneticists.  She has two X chromosomes.  If she is truly 100% X-inactivation through all cells in her body, it doesn't make sense as to why the deletion on the inactivated X is affecting her.  Skewed X-inactivation is relatively new area of research - so while we have a diagnosis that makes sense for Alexis, the science hasn't fully caught up.  They do see this X-inactivation more commonly with kids missing HDAC8, but they are still seeking to fully understand this.

Some people have asked me how I feel about the diagnosis?

Relief

-We have a home. I've read some of the articles here http://www.cdlsusa.org/what-is-cdls/cdls-publications.htm They describe very accurately interacting with Alexis.

-We have been doing all of the right things (see publications above about therapies and benefits).  We have the right doctors, we have the right specialties, we have the right concerns.  Imaging you've been on a highway "thinking you're headed the right direction" and after 11 years of driving, you have confirmation that you're on the right highway.  Relief.

Curiosity

-We have encountered a CdLS family at a Perkins Conference before and it was always a curiosity that Alexis didn't have the genetics for CdLS

-As we felt with some of the CHARGE families at our first conferences, I will wait with anticipation to 2018 in MN to join our physical home.  In the meantime, I've joined the CdLS Facebook group and I'm sure I have a lot to learn.  I especially can't wait to connect with other families.

Concern

-Alexis' path has never been easy. We have always known that she had differences.  We know someone very close who had a daughter with CdLS who passed away.  We know that with or without a diagnosis, our vigilance and care for Alexis is our top priority.

Reserved Happiness or Peace

-It's hard to say you can be happy if you read all of the list of things that are going to challenge a kid with CdLS.  But there is great peace knowing that we've been doing the right things, connecting the right dots and pushing for a diagnosis.

-I am happy that even though Cornelia de Lange is a rare disease, it's not uber rare.  It's not that we will be hunting for families across the Internet - Cornelia de Lange already has a rich and deep network. 

And most of all, I am thrilled because no matter what Alexis' genetic material has said or kept secret for all of these years, she is still fighting to live a beautiful and rich life.  She is providing joy and happiness to all.  She is still inspiring us to make the world a better place.