Ten and a half years ago Matt and I sat bewildered when our OB told us that our prenatal ultrasound showed our little baby girl had unusually bright kidneys. We began our search for answers ten and a half years ago, but all we found were more questions, that is, until last Thursday.
Naomi was born with club feet, a distended abdomen, and kidneys that functioned poorly. She grew into an intense, demanding, and draining baby, and then toddler. Then her eyes crossed. Then we were told she had a heart murmur. When our third daughter, Emma, was born with a similar condition both girls were given the diagnosis of Autosomal Recessive Polycystic Kidney Disease and Congenital Hepatic Fibrosis, called ARPKD/CHF for short, and we added the concerns of liver disease to our list of diagnoses.
We learned everything we could about ARPKD/CHF, but were still left with questions. Children with ARPKD/CHF have kidney and liver disease, but do not normally have crossed eyes, heart murmurs, and general developmental delays (unless it is delays from long hospitalizations due to illness). My girls had multiple neurological problems including: difficulties with balance and coordination, severe stuttering, severe speech apraxia, slowed mental processing times, eyes that were overly sensitive to light, nearsightedness, and decreased white matter volume on brain MRI. These problems, the experts told us, were not a part of ARPKD/CHF and must be purely coincidental.
We were told we knew for certain that the girls had a "ciliopathy," meaning a defect to a gene important for the proper functioning of the cilia (or tail-like structure) on many cells of the body, and that ARPKD/CHF was the one ciliopathy they shared the most features with. When Naomi began to struggle with obesity that no doctor could explain to me I had had enough. I researched every ciliopathy that had been documented so far in human history, looking for clues. What I found both shocked and scared me. I found Bardet-Biedl Syndrome (BBS).
BBS is also a ciliopathy that can cause polycystic kidneys and liver fibrosis, but can also cause a host of other conditions in children, including problems in almost every system of the body. It can cause neurological and developmental delays, it is often associated with severe speech problems, it can cause heart murmurs, crossed eyes, social communication issues, sensory-processing problems, and autistic-like traits. It can also cause morbid obesity. These findings were almost a relief to me: we had these issues already so finding a cause would have been a cause for celebration if it weren't for the main symptom of BBS: retinal degeneration inevitably leading to blindness.
I brought my findings up to several doctors who told me with certainty that my daughters did not have BBS. These doctors thought you had to be born with extra fingers and toes to have BBS (in actuality only 80% of patients with BBS have extra fingers and toes). They told me my girls weren't obese enough to have BBS, (but they wouldn't take into account that Naomi had had celiac disease for the first six years of her life and I had worked very hard to control the obesity after that). They told me that my girls would be mentally retarded if they had BBS (a very common and unfortunate misconception made by doctors who didn't understand that slow mental processing time is not the same as being stupid). And so I let the idea rest for awhile.
Last January, with Naomi's kidney function worsening, we saw a new nephrologist (kidney doctor). She told me with in no uncertain terms that my girls did NOT have ARPKD/CHF. Their kidneys were small instead of enlarged, and their blood pressure was not elevated as you would see in ARPKD. She believed their kidney condition was either Cystic Dysplastic Kidneys or Nephronopthisis, two kidney conditions that can be seen on their own, or as a feature of BBS. She didn't want to jump to the conclusion that the girls had BBS, but it was enough evidence for me.
I came home and joined the Families of Bardet-Biedl Syndrome Facebook group, where I found that there was an upcoming BBS convention in Iowa and that I could send in my children's blood samples for free genetic testing ahead of the conference if a doctor suspected they might have BBS. We sent our samples off in March and waited and tried not to think too much about it in the meantime.
Last Thursday Matt and I met with a researcher from the Wynn Institute for Vision Research at the University of Iowa and she told us that Naomi and Emma do, in fact, have Bardet-Biedl Syndrome. After ten and a half years the genetic mutation has been found and we have a concrete diagnosis. She handed us papers that I wanted to just stare at stating:
A homozygous ATG>AGG nucleotide substitution resulting in an amino acid change of Met390Arg is present in the coding sequence of the BBS1 gene of this patient. This finding is consistent with the diagnosis of Bardet-Biedl Syndrome (BBS).
I read it over and over in the following days, because with that finding, everything changes.
What does this mean? It means Matt and I both carried the exact same mutation in one copy of our DNA and Naomi and Emma each happened to inherit that mutated copy of the BBS1 gene from both of us. Two mutated copies of the BBS1 gene means that the instructions to make the BBS1 protein are all screwed up and that protein is made incorrectly in both girls. The major problem is that this protein is needed (as Matt and I learned at the BBS conference this weekend, following the diagnosis) in nearly every cell of the body in order to help traffic other proteins up and down the cilia of the cells in order to send and receive messages from other cells. It's like having all the taxi cab drivers in the city drunk at once, which would severely affect the traffic flow in the city and may eventually crash the city completely. In addition the BBS1 protein also seems to somehow help the "garbage man" of the cells to collect the trash. When the "city" of the cells cannot effectively move traffic or take out the trash, they at first function poorly and eventually die.
It is this mutated BBS1 protein that causes cystic kidneys, liver fibrosis, poor neurological signaling, heart defects, skeletal defects, endocrine abnormalities, obesity, and eventual retinal degeneration leading to vision loss. We were told that Naomi's extreme sensitivity to light and Emma's near-sightedness are early signs of retinal degeneration and that they need to get to a pediatric ophthalmologist who is familiar with BBS as soon as possible for further, in depth testing including Optical Coherence Tomagraphy and Electroretinograms to evaluate the condition of their retinas. Unfortunately at this point in time, there is nothing they can do to slow the degeneration. Apart from a miracle of God or modern medicine, the girls will slowly go blind, probably over the next 10-20 years of their lives.
But here is where the good news comes in: that miracle of modern medicine may not be many years away. The University of Iowa has been given an enormous sum of money by a man with a similar retinal degeneration disease for the purpose of ending genetic retinal degeneration. They have built facilities and hired researchers and have begun trials of gene therapies that have had good success with other types of genetic retinal degeneration. Multiple children with genetic retinal degeneration have been treated in these trials with gene therapy and have had some vision restored. They told us at the conference that they believe gene therapy for the retinal degeneration of BBS is only single-digit years away from being a reality. And so we are sober, yet hopeful.
We met many other families, including adults with BBS this weekend. The conference center was full of white canes and guide dogs, but also full of smiles, laughter, and friendships. We learned from the few experts in the world working on BBS everything there is to know right now, and we in turn offered our insights to them so that they can further the research. We are hopeful.
Yet we are sober. This diagnosis has been an enormous collision of emotions for us: relief at finally knowing; sadness and fear for what is ahead. But that is still not all. The University of Iowa would also like blood samples from our boys. You see, Hannah, who was tested for BBS and found to be a carrier (one bad copy of the BBS gene, and one good copy) also has small kidneys and the same heart murmur as her sisters. Toby, who does not have cystic kidneys, has one small kidney that is out of place. Carriers for BBS do not normally show symptoms of the disease, which leads the U of I researchers to believe that there may still be another mutation, perhaps in a more kidney-related gene, that may be complicating our family's health picture further. These researchers will now be sequencing the entire exomes of all of our five children (some 20,000 genes each) in an effort to see if another genetic mutation is shared by our children that would explain why four out of five of our kids have unusual kidneys. This information will help them better understand the interactions of genes in the human genome, and it will help our family better understand the health of our children. It will be several months before we get results from all of this.
This is all very difficult for us to fully digest. When we return home I will have to begin the process of connecting our girls to the correct eye doctors and low-vision resources. I will have to argue with our school system until they conceded to teach them braille while they are young instead of waiting until they are blind, because while the potential of gene therapy is thrilling, it is not yet a reality we can count on. I will be working to connect with the Foundation Fighting Blindness and other resources which can help us on this journey. I will be working to implement more stringent dietary plans for both girls to control their weight and hopefully lower their chances of developing type II diabetes (though this may develop in BBS even with proper weight control). I will be taking Emma for further evaluations to determine the proper cause of and treatment for Emma's early puberty. And I will be sending copies of the girls' genetic testing results along with information on BBS to their geneticist, pediatrician, nephrologist, cardiologist, endocrinologist, GI doctor, speech therapist, and physical therapist.
And then, in the quiet moments, I will be grieving this new challenge that has been heaped upon more challenges in two little girls' lives.