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Aug 18, 2017 2:00 PM

An Almost Four-Decade Odyssey to Find the Cause of a Rare Muscle Disease

Janice and Cody Hanson. Credit: Hanson Family

Sitting in a comfortable, plush green chair, Janice Hanson is a poised woman with an elegant, short haircut. Her calm, dignified demeanor belies the turbulent decades of raising two children with a rare genetic disorder. Little could she imagine that this journey, which began with the birth of her first child 57 years earlier, would culminate with the discovery of a rare genetic mutation responsible for the constellation of symptoms that restricted, but never stopped her children from seeking the most out of life.

“My mom is strong-willed, one might say hard-headed,” admits Cody Hanson, Janice’s youngest son who along with her oldest daughter Tonya helped define a new disease, christened with the name Carey-Fineman-Ziter syndrome (CFZS).

Without a culprit to point to, the researchers gave their names to the mysterious collection of symptoms. It would take another 37 years for technology to catch up with the medical community to identify the cause of the disease.

Tonya at 29 years old and Cody at 11 years old. Credit: Hanson Family

Diminutive in stature, Tonya and Cody exemplify all of the physical characteristics of CFZS. At birth, a cleft palate and weakened muscles limited their ability to swallow and get proper nourishment. They struggled with severe respiratory distress for the first nine years of life. Their facial muscles were so weak that they required extensive speech therapy to communicate. As they grew older, aggressive scoliosis contorted their small bodies, which affected their mobility and lung capacity. The siblings endured numerous medical interventions and painful surgeries over the years, but the overlying mystery remained. What was causing all of this?

On New Year’s Eve in 2014, Cody received an unexpected phone call. Cody’s doctor, John C. Carey, MD, believed CFZS might be caused by a recently identified gene mutation. His suspicions were confirmed in an article published on July 6, 2017 in Nature Communications.

“It was a surreal moment,” explained Cody. Janice sat up straight in her chair with a huge grin on her face. “I was always hoping we could find the gene.”

If She Is Breathing, There Is Hope

In 1960, Janice stood vigil outside the neonatal room where her small, fragile daughter clung to life in an incubator. For the first three months, she was restricted to two visits a day—one hour in the early afternoon and one in the evening. During their limited interactions, she wasn’t even allowed to caress her daughter.

Tonya at six days old in the incubator. Credit: Hanson Family

“It was shear torture,” she said. “I could only stand next to the isolette and look at her.”

For Janice, every day was steeped in uncertainty, as Tonya’s doctors treated each new medical crisis as it unfolded. Despite her daughter’s extremely fragile state, Janice was adamant. She was going to take her baby home.

“I just did what I had to do to keep her alive,” she said.

Tonya’s health continued to waver. For her first three years, Janice suctioned her daughter’s mouth every 15 minutes to prevent her from choking on excess phlegm. She routinely laced a feeding tube through Tonya’s nose, bypassing her cleft palate, to her stomach to ensure her daughter had nourishment. Despite these interventions, Tonya was constantly plagued by strep throat and pneumonia, prompting daily doses of antibiotics to protect her body against disease.

The medical community reassured the Hansons that future children would be spared Tonya’s condition. Over the next 17 years, the family grew to include four more children. It was her youngest son, Cody, who proved the medical community wrong.

Shortly after Cody’s birth, he was whisked away by the doctors. The family was told that something was terribly wrong. Janice was frozen with fear and worry in her hospital bed, imagining the worst-case scenario and wondering how she could handle it. When the doctors returned, they informed Janice and her husband Dennis that Cody was a duplicate of Tonya. They were surprised by her reaction.

“I was so relieved,” she said. “My greatest fear with Tonya was wondering if she would survive, but she was OK, and I knew Cody would be OK too.”

Just as important, Janice knew that two children with an extremely rare and un-named condition could not be a fluke. She realized that if she ever wanted to get to the bottom of her children’s disease, she had to see a geneticist.

A Needle in a Haystack

Today, identifying the gene mutation responsible for a rare syndrome is difficult. In the early 1980s when the field of medical genetics was still in its infancy, it was next to impossible. Nevertheless, Janice remained undeterred and began seeing specialists at the U of U Health where she found the perfect partner in her fight.

John C. Carey, Professor, Department of Pediatrics at the U of U Health, sets anyone at ease. Carey came of age in the 60s, steeped in a feeling of social engagement, and he brought this approach to his patients.

John C. Carey, M.D. at University of Utah Health.

“My first interest was not as a researcher,” he said. “I was first interested in connecting with families. To me, that was the centerpiece of my work.”

Lured to Utah from San Francisco by the Division Chief Robert Fineman, Carey was a founding member of the university’s genetics team.

“I believed this field offered so many opportunities to better understand birth defects,” he said.

Fineman turned the curious case of the Hanson children over to Carey, and he was quickly captivated. While initially diagnosed with Moebius syndrome and Pierre Robin sequence, Carey was skeptical. Tonya and Cody had some but not all of the characteristics of these conditions. They also had characteristics that were not associated with either disorder. Fred Ziter, another U of U Health physician, conducted a muscle biopsy, which revealed abnormal muscle formation.

“We always felt that the overarching problem was muscle weakness that lead to a cascade of other symptoms, but most importantly the kids had normal cognition,” he said.

While other doctors may have given up, Carey and his colleagues dug deeper, inspired by Janice’s perseverance.

“She wasn’t intimidating, but she was determined,” he said.

Throughout the decades, the Hanson case remained ever present in Carey’s thoughts. After describing the syndrome in 1982, several other patients around the world were diagnosed with CFZS, but the severity and assemblage of symptoms varied from patient to patient. He wanted to find the gene for CFZ, but the task was impossible with so few patients.

This changed in 2013. Carey describes how a chill ran down his spine after his colleague called him to point out a paper recently published in Nature, describing the myomaker gene. The gene controls the fusion of undeveloped muscle cells to make mature, strong muscle fibers. Carey suspected that a mutation in this gene could be responsible for CFZS in humans.

He got on the phone and called Cody.

I am CFZS

Shortly after learning of the discovery, Cody and his mother boarded a plane to the National Institutes of Health in Bethesda, MD. He shared all of his and Tonya’s medical recordseach measuring several inches thickthat his mother had meticulously kept throughout the decades. He underwent numerous tests and a second muscle biopsy to help the doctors link his condition to the gene they believed responsible for CFZS.

Their efforts were worth it. The Hansons’ medical records and DNA samples from Cody and six other patients also believed to have CFZS allowed scientists to identify mutations in myomaker that caused their shared disease. Additional tests showed that the mutations weaken the activity of myomaker, which is necessary for normal muscle development and maintenance. These new insights were published in the 2017 paper.   

The Hansons and Dr. Carey at the National Institutes of Health. Credit: Hanson Family

“I never thought I would know the secret of the syndrome,” said Carey. “These findings remind me to never lose touch with the most import aspect and privilege of being a physician, the connection and relationship with patients,” said Carey.

“I am CFZ,” said Cody. “Now that we have a gene we have a plan of action and I will do whatever I can do to help others.”

Carey and the Hansons hope that the discovery of the gene mutation will help the research community to identify new patients and begin developing therapies to alleviate many of the symptoms associated with the syndrome. The results from this study could also help patients with other rare muscle diseases.

“A lot of people talk about wanting to leave a lasting legacy,” said Cody. “I have an opportunity to help so many people. I can’t pass that up.”

While a decades long mystery has been solved, Tonya was not there to share the moment with Cody and their mother.

At only 38 years of age, Tonya developed pulmonary hypertension, a life-threatening condition characterized by high blood pressure in the arteries leading to the lungs and heart. She died at home under hospice care surrounded by her family and friends.

Cody continues to hold Tonya’s memory in the forefront of his mind.

“I feel closer and closer to her as I got [nearer] the age of when she passed away,” he said. “In hard times, I often ask myself, ‘How would Tonya handle this situation?’”

The Hanson siblings inherited a rare genetic disease that weakened their muscles, but not their spirit. They share their mother’s determination and perseverance. Today, Cody continues his mother’s advocacy through his CFZS website.

“Despite some hardships, my mother made sure I was never an outcast,” concluded Cody. “I was just a normal kid.”

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