From Difficult Case to New Syndrome (2015)
Mo Neville interviews the Phelps family and Keith Choate, MD, PhD
When Keith Choate, MD, PhD speaks about his research program to identify and understand new genetic causes of ichthyosis, he always begins by discussing the importance of genetics to medicine. He notes that it has the power to provide genetic diagnoses, to identify new genes for novel disorders, and to identify pathways which could be therapeutically relevant. Behind all this, though, he says is a motivation “to do something meaningful” for families with ichthyosis. I interviewed Dr. Choate and one family particularly touched by his research to learn more about the scientific and personal impact behind finding new genetic causes of ichthyosis.
The story begins when Suzanne and Eric Phelps welcomed a beautiful baby boy to their family on December 21, 2004. His name was Dane Christian Phelps, and by all accounts he was as healthy as can be. “He was such a joyful child, right from the beginning. Such a happy baby, ” said Suzanne. At that time, worries were scarce for the Phelpses, a kind and loving family of five from San Jose, California. They took Dane home with great anticipation of watching their young boy grow.
“It wasn’t until Dane was about four to six weeks old that he started showing any symptoms,“ said Suzanne.
A seemingly healthy baby, Dane began to present with a relentless skin condition. His skin grew extremely red, dry and flaky. His feet became thickened with skin and burdened with deep cracks. He was constantly shedding and his skin was becoming more and more fragile. The slightest touch from a fingernail or ring would leave a cut, making his bath time all the more uncomfortable. He had issues with overheating and on days when he was itching more than usual, he required additional baths, additional skincare products, and oral antihistamines and medications. He’d wake in the early morning hours thrashing terribly due to the intense itching and discomfort.
“Even with all he had to go through, this little child was always smiling. He had such an easy spirit about him. And he was empathetic to others who were hurt or suffering. He was such an old soul,” said Suzanne. To this day, friends and family still remember Dane for his love and enthusiasm for life.
“His gracious spirit and attitude were truly inspiring,” she said.
Although he was a joyous child, there was no mistake that his health was continuing to suffer, and the Phelps family grew more and more desperate to find the cause. “We had many types of medical and genetic testing done and they all came up negative and/or inconclusive,” said Suzanne.
“When Dane was 2 years old,” she continued, “my aunt found FIRST online and also contacted one of their members. It was becoming clearer that the descriptions of those with ichthyosis were matching many of Dane’s symptoms. But, at the time I was in a real state of denial, and I myself didn’t contact FIRST at that point. I was still in a ‘fairytale land.’ Since there was not a diagnosis, I did not believe nor was I ready to accept that it was a chronic condition as rare as any of the disorders that fell into the ichthyosis category.”
After two more years of genetic testing, it became apparent that, despite their best efforts, the medical community could not offer any answers about what was causing Dane’s condition.
As the Phelps family continued on this journey, their desperation worsened and their frustrations grew. “Nothing is more frustrating than having people ask you if you have tried using sunscreen for your child when they saw how red Dane was. As if I would never have thought of that! And it was even more frustrating to not be able to explain his condition, because we didn’t know what it was. I think the human spirit can prevail, no matter what situation it is given. The problem was, though, that we didn’t know what we were dealing with.”
With no other options, the Phelpses continued to bring Dane for many more tests and visits to the doctors, especially as he started to lose his hair and it became clear that he was not growing properly.
“It was so hard to make the decisions to keep bringing him, to keep causing him discomfort and sometimes pain with all the testing and biopsies. If we had known what the condition was, even if it was a life-threatening diagnosis, he could have just been living his life, just being a kid going to the beach like he loved, but we were so desperate for an answer. This was the burden, the decision to keep searching. A heavy burden for so long.”
Months later, Suzanne finally contacted FIRST herself in 2007 when Dane was a little over 2 years old. “I contacted Jean Pickford regarding a medical grant from a foundation associated with my family that FIRST might have the opportunity to receive. I thought, if we’re not going to have an answer, at least we can DO something.”
It was around this time that Dane was diagnosed with a heart murmur. “We didn’t know that he had heart issues other than the murmur, which we were told was normal for someone with a chronic skin condition.”
Suzanne could see a change in what would be the last month of Dane’s life, as he became more tired and lethargic. “He was a little edgy, which was not like him,” Suzanne said. After his death, they would come to know that these were the beginning signs of heart failure. “Again, not knowing about the heart condition, not having an accurate diagnosis, and not being informed of what to expect, there was nothing we could have done.”
Dane passed away in the early morning hours of June 25, 2008.
“My prayer from that day since has been, please God, in our lifetime, could we find out what it was.”
The Phelpses had become convinced that it had to be some form of ichthyosis as the similarities were uncanny.
“We decided to go to the next FIRST conference after Dane’s death and as soon as I walked in the room I felt like I was surrounded by him. There was such a similarity in their spirits and their skin presentation. It really felt like he was all around me. It was meant to be for us to have this experience, this ’confirmation.‘“
The Phelps family would have the opportunity to share information about Dane with the ichthyosis medical experts at the conference, who also agreed it might have been some form of ichthyosis, perhaps so rare that he was the only one with the mutation.
In 2015, seven years after Dane’s passing, the Phelpses received a message from Dr. Choate, who they’d met at FIRST family conferences. He told them that that he’d been studying other families who had children who looked like Dane, and who had heart problems. He asked if they were interested in participating in his team’s research efforts, and had a very specific request – he needed to find something that had Dane’s DNA. He specifically asked if Dane had ever had a skin biopsy.
It turns out that shortly before Dane’s death, Sheilagh Maguinness, MD, a dermatology fellow/resident at University of California, San Francisco suggested that they do a skin biopsy. After all Dane had been through, this was an anguishing thing consider, but the Phelps family agreed, hoping for an answer. Dr. Choate was able to request this biopsy tissue from UCSF, and within days had an answer.
Dr. Choate’s team discovered that Dane had a mutation which had arisen spontaneously in his cells very early in development in the gene which encodes a protein called desmoplakin, which is essential for normal heart and skin function. He and his team would name Dane’s disorder erythrokeratodermia-cardiomyopathy syndrome and had identified two other children with the disorder, one who had an undetected cardiomyopathy. Suzanne recalled that when Dr. Choate called with the news, he said “I want you to know Dane’s story doesn’t stop here. His story is going to change how we think about children with ichthyosis, and now we know that others with his condition will need cardiac evaluation. We know this because of Dane.”
“It was an overwhelming sense of relief,” said Suzanne. “I cannot express the gratitude I feel toward Dr. Choate. If I had to lose my own son, I could at least now know that maybe I could help someone else’s child. Maybe that’s what Dane’s life was about. Maybe this diagnosis would save another life, maybe even many.”
When asked about her thoughts on genetic testing and diagnosis in general, Suzanne said, “An answer gives you a game plan, so your mind doesn’t go crazy. So you don’t have to waste so much energy constantly searching. I cannot emphasize enough, whether the condition is chronic or life-threatening, or not, having peace of mind about what the condition is, and being able to just cope with it…and just live… is truly a gift.”
Dr. Choate says that the Phelps family is not alone – up to 20 percent of ichthyosis cases do not have mutations in currently known genes. He has partnered with FIRST and physicians across the country and around the world to identify families with ichthyosis who are seeking answers about their diagnosis. He told me “behind every new discovery are families who are willing to continue to engage in our common goal of finding answers. We are deeply grateful to families like the Phelpses and many others who have been so generous in sharing their stories and participating in research.” Dr. Choate’s team has recently discovered three new genes which cause ichthyosis and tells us that more are on the way. He says he hopes “that no child will go undiagnosed, and that we can make discoveries that are ultimately relevant to cures.”
The Phelps family has supported the mission of FIRST each and every year since first connecting with the organization. Since Dane’s passing, over $800,000 has been raised for FIRST in his memory. We share their story in loving memory of Dane, in gratitude to their family and community, and with hope for a better future for all those with ichthyosis and related skin types.
The article about Dane’s condition,erythrokeratodermia-cardiomyopathy syndrome, appeared in the January 16, 2016 issue of Human Molecular Genetics. FIRST Medical and Scientific Advisory Board members Brittany Craiglow, Erin Mathes, Mary Williams, and Peter Elias were contributors. Reference: Boyden LM, Kam CY, Hernández-Martín A, Zhou J, Craiglow BG, Sidbury R, Mathes EF, Maguiness SM, Crumrine DA, Williams ML, Hu R, Lifton RP, Elias PM, Green KJ, Choate KA. Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome. Hum Mol Genet. 25(2):348-57.
If you would like to participate in Dr. Choate’s research on the genetic causes of ichthyosis, please email Jessica Magro at firstname.lastname@example.org with your contact information to learn more.