Some positive news has come out of the Queen Mary University of London this month. Scientists have discovered the underlying genetic cause of Dyskeratosis Congenita (DKC).
Published in the Journal of Clinical Investigation, the researchers used the latest genetic sequencing methods to study 31 children with the disease and discovered a defect in the biological process known as deadenylation. This is the routine breakdown and recycling of the body’s messenger ribonucleic acid (mRNA) – the molecules which transcribe instructions from DNA to make proteins.
This is the first time a defect in the deadenylation process, controlled by the poly(A)-specific ribonuclease (PARN) gene, has been found to cause a genetic disease. Until now, scientists have believed that DC is caused by defective telomere maintenance (the caps of chromosomes that shorten with age). However, this research has shown that in some of these cases it’s the deadenylation deficiency which impacts the telomere maintenance, thereby causing the condition.
The bottom line, is that these new finding should lead us very quickly to identifying the condition “definitively” in patients. Up until now, they have had several indicators, along with a broad set of symptoms, that has led them to be “fairly confident” that someone might have DKC. With these new findings, testing will be more direct, and will lead to a definitive yes or no answer as to whether a patient has DKC or not.
To Beth and I, this isn’t hugely impactful – today. But it is our hope that knowing the underlying condition with precision, will allow researchers to focus there efforts on curing this underlying condition. And to us, that represents the best hope so far in finding a cure.
As a side note, for those of you eager to share the excitement directly with the authors, they have put together this short video of their findings and their methodology. Needless to say, it requires a lot of understanding of the underlying medical conditions and terminology to fully comprehend – but I think you can pick up on the giddy excitement and joy of the findings regardless.
We haven’t gone into much detail on Clark’s eyes yet. But, considering it is believed to be related to his Dyskeratosis (DKC), I think this is relevant to the blog.
Shortly before Clark turned 1, Patrick notices that Clark’s left eye was looking ever so slightly outwards. Unfortunately we couldn’t just see an eye specialist when ever we feel necessary, we need to “follow protocol”. Thankfully our pediatrician referred us to an optometrist, even though he saw no such eye wandering. He actually said that the bridge of Clark’s nose was wide, making the wandering look like an illusion.
One optometrist, a pediatric optometrist, an ophthalmologist, a pediatric ophthalmologist and 2 pediatric retina specialists later…. And we find out that Clark has a torn retina. And within the time it took to move up the ladder of “specialists”, Clark went blind in his left eye. We were told that it might have been prevented if caught sooner. Unfortunately we acted as quickly as possible, but the “system” didn’t react with the same intensity.
I’m still learning about Clark’s eye. And for some reason, learning about blood conditions and Clark’s BMT seem to make more sense to me than understanding the eye. So, please bear with me as I try to explain.
From what the specialists could see, Clark has Exudative Retinopathy. He has many fibrous vessels in his eye (more than normal). They believe that a vessel burst, and caused a bruise. Normally a bruise would stop bleeding, and slowly dissipate. In Clark’s case, the bruise didn’t stop bleeding (possibly due to hemophilia OR low platelets). It caused a slight tear in his retina, and the blood pushed it inward. Unfortunately the retina detached right at Clark’s optic nerve, causing the blindness. If it has been anywhere else, it might have been easier to treat.
Exudative Retinopathy is a possible symptom for Clark’s specific Dyskeratosis, Called Rêves Syndrome found on the TINF2 gene. It is common to have it on just one eye. We are closely watching Clark’s right eye for wandering, to help prevent total blindness.
This brings us to Clark’s appointment! Clark finally met his new Ophthalmologist last week. He wanted to meet Clark, and make sure he wasn’t having any new vision problems. We were also assured that Clark is taking the correct eye drops daily. The good news is that Clark will be seeing a Pediatric Retina Specialist! These are hard to come by. We are scheduled to see him in 3 months, once the doctor’s paperwork is in order (he is moving here from London).
Clark now has glasses. Not prescription glasses, but safety glasses to protect his right eye. We were pretty hesitant at first, but after looking at MANY different styles, we finally found a pair that we think look adorable on him.
As the parents of a child with a weak immune system, I would like to share my thoughts on vaccinations. You’ve probably heard both sides of the argument, but here is my 2 cents.
tl;dr, Please seriously consider vaccinating your child.
Clark is currently out of “isolation”. Meaning, that it is now safe for him to come with me to the grocery store, play at the playground, and dig in the dirt. It is even now safe for Clark to catch a common cold, or even the flu. His immune system should be strong enough to fight these off (it is still a gamble, to some degree).
But to our chagrin, our post-isolation elation was short lived. As soon as we got the good news, measles started to spread in our area. Unfortunately close to 7% of the children in Marin are not vaccinated. That is a lot considering the national average is 2.5%.
Now you might ask – with only 7% risk in a small county next door, why panic? Frankly, at first we didn’t panic, until we learned a little more about the measles. Surprisingly, measles are extremely contagious. How contagious you ask? Try this on for size: if a person with the measles is in a room, breathing, and leaves the room – you can still catch the measles up to 2 hours after they have left the room. I know what you are thinking, “holy sh*t“… right?!? Don’t believe us? Here’s the quote from the CDC themselves:
Measles spreads when a person infected with the measles virus breathes, coughs, or sneezes. It is very contagious. You can catch measles just by being in a room where a person with measles has been, up to 2 hours after that person is gone. And you can catch measles from an infected person even before they have a measles rash. Almost everyone who has not had the MMR shot will get measles if they are exposed to the measles virus. Link: http://www.cdc.gov/vaccines/vpd-vac/measles/fs-parents.html
There is a very high likelihood that Clark would not survive getting the measles. Because of this, we decided to continue to keep Clark in a “semi-isolation”. His immune system is not strong enough to fight off major diseases like the measles, chicken pox, etc.
My husband, myself, and our oldest child are all up-to-date with our vaccines. Clark’s vaccination schedule starts in late March, and I can’t wait. Not only does this prevent our family from catching deadly diseases, it also prevents us from spreading it to others.
About 3 months ago, Clark’s big toenail looked like it was breaking off. Almost like the skin underneath was pushing upwards and cracking the nail.
Since Clark’s immune system was so weak at the time, we needed to see the dermatologist immediately. The fear was that a nail fungus could go into his blood stream, causing an infection. Or that this could be some sort of cancerous growth. Either way, this would in-case turn into a hospital stay with extra antibiotics, fungicides, or possibly surgery.
Thankfully this isn’t the case. He hasn’t had a fever (from this), and we found out it is not a fungus. Unfortunately we can’t seem to determine what is causing the problem! He has had 2 samples taken, and watched for over 5 weeks each. There was no sign of fungus, or any other growth.
Another possibility is that this could be related to his Dyskeratosis. It is common for DKC patients to have nail dystrophy. This usually occurs on more than one toenail though, and looks slightly different.
We have tried anti-fungal cream (2x/ day for 3 weeks), and it looked like it was getting worse. Since then we were told it is not growing into a fungal infection, so I decided to stop completely. This has almost helped it clear up. But not completely. The only thing that seems to help it out is regular baths. But so far, no results. We will have another follow up appointment in 3-6 months to see if anything has changed.
Why all the nasty pictures?
We’ve included detailed pictures as a reference for other parents dealing with DKC. In our experience, there isn’t much visual documentation on how the nails of children with DKC are affected by nail dysplasia. We’re hoping this might provide some guidance for other parents dealing with the disease in their own children.
While Clark had his Broviac (Central Line), we needed supplies for it’s upkeep. This included a number of bandages, biopatch, Heparin, Saline, gloves, caps, masks etc….
Since his Broviac was unexpectedly taken out, I had a FULL box of supplies left! The pharmacy would not take them back, since they can’t re-sell a product that might have been tampered with, or has expired. And I didn’t want to throw out such valuable and expensive materials. Thankfully, I was still able to put them to good use. There are many organizations that take donations of medical supplies. Some are for local non-profit clinics, while other organizations send the supplies overseas to 3rd world countries. I was lucky enough to find a local organization close to us called MedShare. You can read about them here http://medshare.org/
If you have any extra medical supplies that are no longer needed, please consider donating. There are many organizations throughout the country.
Clark’s results came back from his Lymphocyte test. The key indicator is the reading of his “T-cells”. If (when) these are high enough, Clark will be able to be set free from isolation! So we are watching this number very closely. As of today, his T cells are still too low for him to get out of isolation. This isn’t a huge surprise, considering we are still very early in the game.
Apparently there are multiple types of T cells (news to me!). Clark’s CD4 T-cells are at 98 (17%). They need to reach 200 or greater. And his CD3 T-cells are 128 (13%) which the doctors would like to see at 400 or greater before Clark is clear to get out of house arrest… Oops, I meant isolation. Orange is the new black, girlfriend.
As for the lymphocyte functionality test…. well, they can’t do it when the T cells are too low, so we didn’t get any results for it. However, I was just informed that they will re-test Clark at his next check-up in December. So, everyone cross their fingers!
You might be led to believe that we are sad or upset that Clark’s numbers weren’t high enough to be released from isolation. Surprisingly, it really doesn’t bother us. We feel that Clark is doing great at home, and we are glad we have control over his routine and his isolation protocol. We feel his recovery has been great to date because of this. And… his T cells ARE increasing. I think that is a fantastic sign. This race is a marathon, not a sprint. A sure but steady recovery will equal a long and healthy recovery.
There has been one outstanding mystery we’ve been puzzled by. Why did Clark’s retina detach, and why did it go so bad, so quickly? Was it caused by DKC specifically, or was it an accident and DKC was the reason it didn’t heal? Was it totally unrelated? We really weren’t sure up until about a week ago.
On August 29th, UCSF had a visiting scholar give a speech on Dyskeratosis Congenita (DKC), Dr. Tony Xiao. Dr. Xiao was a visiting dermatologist who was studying the skin and nail abnormalities with BMT patients. After spending a month with the BMT team at UCSF, he wanted to speak on a topic that covered both dermatology and bone marrow transplants. DKC was the perfect topic. Some of the early signs of DKC are fingernail and toenail dysplasia, leukoplakia of the mouth, and pigmentation abnormalities of the skin.
Dr. Xiao came by to take a look at Clark and talk to us. My first question to him was whether he thought Clark’s detached retina in his left eye was due to his DKC? He responded by saying, “…typically no. Eye problems are not usually associated with DKC, unless there are brain calcification as well… ”
To which I answered, shocked, “actually, he has brain calcifications…” According to a CT scan we had 8 months ago as well as an MRI 3 months ago, Clark has scattered spots of calcification throughout his brain. So I was instantly curious… “what does that mean??”
Dr. Xiao then said, “Oh… Then that means that Clark has Revesz Syndrome.”
And there it was… an exact diagnosis (or at least as exact as we can expect with this relatively unknown condition). Clark has Revesz Syndrome. We finally know exactly what we are dealing with.
Features that distinguish Revesz syndrome from general types of dyskeratosis congenita include:
excess fluid in the retina of the eye (exudative retinopathy)
brain abnormalities such as cerebellar hypoplasia
cerebral calcifications that lead to unsteadiness and balance problems
Growth retardation both in utero and after birth
Cognitive impairment is greater as well
Up until this point, we really didn’t have any correlation between the DKC and his eye problems. But finally bringing it all together, we can better know what to expect in the years to come.
Why did it take so long to get here? From what we understand, DKC is a very new disease. Every doctor we spoke with about DKC had to run into a darkly lit library and read up on it before answering any of our questions. So most of the answers we received were just paraphrasing of medical journals, rather than speaking from experience. It was nice to have a team with enough practical experience to finally put the two together.
Clark’s white blood count (WBC) continues to approach zero, as expected. The drop is a result of the conditioning (chemo) from Day -10 to 0. Once it bottoms out, and the new marrow starts to engraft, we will slowly see his counts rise again.
With his low, or absent WBC, Clark is prone to illness. This includes viral, bacterial and fungal infections. Right now, Clark is in the “danger zone”. His body is unable to fight off a mild cold, let alone anything more serious.
Clark has received an allogenic transplant. Meaning he is using marrow from someone other than himself. Patients undergoing allogeneic transplantation are at a greater risk of infection because of a longer time to achieve engraftment (prolonged neutropenia) and the added risk of GvHD.
Engraftment is the process in which the transplanted stem cells find their way to the bone marrow spaces in the centre of the large bones of the body. Only then can the transplanted stem cells begin to produce new blood cells. Engraftment happens in stages:
The first sign of engraftment is the gradual rise of Neutrophil (WBC). This can occur as early as 10 days after transplant but is more common around 14-20 days.
Shortly after Clark’s WBC starts to show signs of engraftment, his platelet counts will start to rise. A platelet count of 20,000 to 50,000 is a sign of platelet engraftment.
Lastly, we have red blood cells (RBC). The engraftment of RBC’s Usually occurs a couple of weeks after everything else. There is no “exact” time frame for engraftment to occur. Many things play a roll in how Clark’s body reacts, such as his specific disease, his age, and the quality of his old blood cells.
While there are many risks involved in Clark having a bone marrow transplant, the hope is the benefits outweigh the risks. In Clark’s case, without a BMT, he would most definitely die at a very young age. But thankfully, with a successful transplant, Clark can at least live a life without the need of regular blood transfusions.
After Clark ate a full breakfast, we had a “surprise” visitor… Let’s call him “The Book Fairy”. The book fairy came and read stories to Clark! Only moments after story time was over, the “Music Man” arrived. Clark was serenaded, and given musical instruments of his own to play along. And that’s not the end of it…
Next was Physical Therapy. This may sound like work, but for a child who is not in physical pain, this is actually closer to “playtime”. They walked around the room, climbed on my bed, and basically just played around! All the excitement of the day made for an easy transition to nap time. This was probably the most “full” day Clark has had since he came into the hospital.
About 2 weeks before Clark came to UCSF, he had a mandatory dental exam. The purpose, was to identify potential sources of oral infection that can lead to bacteremia (bacteria in the blood). It is important to prevent or eliminate dental infection before chemotherapy or other medications that lower the ability of the body to fight infections. Severe gum disease, tooth decay, tooth abscesses and poor oral hygiene can lead to pain and/or bacteremia before, during and after chemotherapy. Thankfully Clark had a clean (dental) bill of health.
It is extremely important to keep the mouth clean and healthy during the bone marrow transplant procedure to help reduce the risk of infection and bleeding. Research has shown that mouth sores are less severe in people with excellent oral hygiene. Some of the preventative medications Clark is on are usually very effective in lowering the risk of viral and fungal (thrush) infections in the mouth as well as in other areas of the body. Fewer infections in the mouth results in less pain and better nutrition.
Clark being silly while Mom brushes his teeth.
With that in mind, one of Clark’s daily rituals, is brushing his teeth! Unlike big brother, Clark actually loves brushing his teeth. This is wonderful, since we have to brush them 4 times a day! He uses a new disposable sponge brush each time he brushes, and instead of toothpaste, Clark uses Sodium Bicarbonate (basically a liquid baking soda)….which, oddly, he likes the taste. Flossing and the use of a normal toothbrush are not recommended when the platelet count is lower than 50,000. To date, Clark has had no signs of mouth sores!
This marks Clark’s official second birthday. Coincidentally, it is also Patrick’s birthday! Happy Birthday Patrick!
Clark celebrating his second birthday after the transplant.
The actual transplant was pretty straightforward. They gave him some pre-meds (Benadryl, cortisone and Tylenol) to help manage any allergic reactions, and then intravenously pushed in the donated bone marrow over a 2 hour period. Clark did amazingly well. The Benadryl made him drowsy, so he was asleep the entire time. The really good news was that he didn’t get a fever or show any signs of an allergic reaction.
Clark sleeping through the transplant process. If you look closely, you can see the red line containing marrow.
I won’t say the process was stress free, as we were told that the bone marrow donor was a different blood type (ABO) and a different RH (-/+). These two together represented a small (but higher) risk of allergic reaction. So the nurses and doctors were in the room the entire 2 hours, taking temperature, heart rate, and blood pressure every 5 minutes. Yes, every 5 minutes.
During the 2 hours of the transplant, we had time to talk to the doctor about what the process to extract and deliver the bone marrow is like. It is a pretty amazing story.
There are several steps leading up to the donation of bone marrow where they check, and then double check they have a good candidate. But we were really interested in hearing what happens from the extraction to when it arrived in the syringe for implant. Especially since we were aware this donation came all the way from Europe!
Each pull gets 10ml of liquid. For Clark, 500ml was required.
The extraction process starts 14 hours before Clark’s transplant, where the patient is admitted to the hospital and prepped for surgery. After prep, they are then taken into surgery and put under general anesthesia. This is because the process of extraction is somewhat intrusive. A needle is pushed into the lower back (if you have back dimples, this is exactly where they enter) and about 10ml of liquid is extracted. Then the needle is pulled out, and re-inserted into the same place, but at a different angle. They repeat this until they get enough liquid. The amount depends on the size of the recipient, but in Clark’s case, they extracted about 500ml. this means the donor had approximately 50 insertions. Most likely 25 on each side of the pelvic bone.
After the liquid is pulled, some quick tests are done to ensure they have pulled enough stem cells, and then all of the extracted liquid is thrown into a cooler. There are cases where the liquid has to travel longer, in which case a preservative is added and the liquid is frozen. In our case, because Europe is only 10 hours away, no freezing is required. They just need to keep it at room temperature the entire way.
The cooler is then handed to a volunteer delivery person, who immediately jumps in a cab and goes to the airport. The “courier” will have 2 tickets for flights to the destination city via 2 different airlines. This is done just in case a flight is delayed or cancelled. The bone marrow is carried by the courier the entire way, and they are not allowed to store it in checked baggage nor do they allow it to go through scanners. This can be very stressful for the person charged with carrying the marrow. The upside is that the volunteer gets a free flight to the destination city, and usually books some extra days of vacation before they return.
When they arrive in San Francisco, they immediately jump in a cab and drive to UCSF. The UCSF lab receives the marrow and starts to process it further. In our case, the bone marrow donor had a different blood type than Clark, and the lab needed to remove red blood cells before transplanting. Due to time constraints, they can only do one pass of this process, which did leave a small risk of allergic reaction because of the residual blood cells.
Finally, the remaining liquid is loaded into an oversized syringe, and brought up to Clark’s room for transplant. It is then placed into a drip line on his broviac, and administered.
A wild ride, all timed out and executed perfectly.
Another interesting fact we learned today, is that Clark will actually have 2 blood types. More likely than not, the donor marrow will only constitute 80-90% of Clark’s bone marrow. The other 10-20% will be his original marrow. Both marrows will continue to produce their respective blood types. This is actually considered a good thing, and will greatly help reduce the chance of Graft-vs-Host-Disease. If the bone marrow were completely empty, and then the donor marrow took root (and was 100% of Clark’s bone marrow), this would almost guarantee GvHD. Having a tiny bit of the original marrow acts as a cushion, dramatically reducing the chance of GvHD. Now, why not aim for 50-50% of old and new marrow? Because the body will most likely just reject the new marrow. It is a balancing game that is almost all science, but also a little art.
We are both blown away by the process, and in awe of the donor who went through this with us. Thank you again to our generous and kind donor who gave their marrow for Clark. We are very, very grateful for your donation. Thank you!!
