Healthcare Professionals

  • The Long Road to Solving a Cancer Mystery

    Watch the family tell their story about the rare gene mutation.
  • Medical Mystery Reveals Lethal Legacy

    Rare Gene Mutation Gives Researchers a Puzzling Opportunity

    After a chilly overnight rain, sunrise in the mountains of Southeast Kentucky reveals halos of mist that drape the coal-country ridges around Pikeville.

    Down the road and up a long hollow lives a family of proud, hardworking people. They have forged their lives from these mountains – mining coal, rearing children and embracing their faith as they care for each other more than anything else.

    Now those lives are shrouded by a baffling and potentially deadly medical mystery.

    It started with Cincinnati Children’s physicians trying to unravel the complicated case of three-year-old Dalson Cable. They discovered his family is prone to a rare mutation involving a gene called RUNX1. It puts family members at high risk for a rare blood disorder and an aggressive form of acute myeloid leukemia (AML), according to Ashish Kumar, MD, PhD, a hematologist in the Cancer and Blood Diseases Institute at Cincinnati Children’s.

    “The type of mutation is so unique it has previously been described in only one other family in the world,” Kumar explains. “In fact, the mutation is not picked up by gene sequencing tests and at first we missed it.”

    Dalson was first referred to Kumar for what appeared to be a mild case of idiopathic thrombocytopenic purpura (ITP) – a bleeding disorder in which the immune system destroys platelets necessary for normal blood clotting. Dalson had low blood platelets as a baby and suffered from skin rashes and infections.

    Diagnostic Dead Ends

    While examining Dalson, Kumar learned other family members – including the boy’s mother, Toni Cable – also have low blood platelets and skin rashes. What puzzled Kumar is that ITP is not known to be hereditary, so he had other family members screened for gene mutations associated with familial thrombocytopenia. The tests were negative - no mutations.

    “In mild cases of ITP, health is not seriously affected,” Kumar says. “At first I was not that concerned. Everyone appeared to be pretty healthy, but things started to not add up.”

    When Dalson had to be examined for an apparent eye infection, his ophthalmologist and pediatrician were concerned about certain aspects of the boy’s appearance. They referred him to rheumatologists at Cincinnati Children’s, who recommended additional genetic tests. Geneticists from the medical center probed more deeply into the family’s medical history, revealing that at least two of Dalson’s great maternal uncles and a distant cousin had died from leukemia.

    “The geneticists here then made a connection between thrombocytopenia and familial leukemia,” Kumar says.

    They also saw potential for a rare condition called familial platelet disorder with propensity to AML (FPD-AML), where the RUNX1 gene is mutated. They ran RUNX1 sequence tests on family members, and those also came back normal.

    For Kumar and his colleagues, it appeared to be another diagnostic dead end.

    Birth of a Clue

    A major break in the case came by happenstance, when a premature baby boy was born to a family cousin. The child had low blood platelets. Doctors in Southeastern Kentucky decided to screen the infant for possible genetic disorders, but they ordered a different kind of genetic test.

    Rather than analyze gene sequence, the test looked at the number of copies of genes at the chromosomal level. It detected an abnormality in chromosome 21 - part of the chromosome was duplicated. The affected segment of chromosome 21 included RUNX1. High-resolution testing revealed part of the RUNX1 gene was duplicated, likely making it non-functional.

    The baby’s test was reviewed by the same Cincinnati Children’s geneticist who had looked at Dalson’s genetic screen. Doctors at Cincinnati Children’s then ran the same test on Dalson and his mother, Toni. Those results were positive, confirming a rare genetic diagnosis and hereditary FPD-AML.

    The diagnosis came full circle when Toni’s father, a disabled coalminer with black lung disease, had an accident requiring medical treatment. Tests revealed Homer Tackett has advanced AML. His brothers were the great uncles who had died from leukemia.

    Chemotherapy followed by bone marrow transplant is the only treatment that might help Tackett. With mounting family financial problems and his black lung, Tackett says he is an unsuitable candidate for further treatment. He prefers to focus his remaining time on enjoying his family.

    “Maybe they can do some research to help,” Tackett says. “My hope is for the younger ones.”

    Family Pushes Testing, Research

    As Toni helps Kumar locate family members willing to be tested, the details of everyday life weigh on her, like painful blisters that break out on her hands and keep her from bathing Dalson. “It’s just been one thing after another,” she says.

    Kumar has come to know the family well, describing them as “very good and humble people.” He is moved, although not surprised, that many members of the extended Tackett family are agreeing to be tested and participate in research.

    “This is not a simple thing for them to do, but they have agreed to do it,” he says.

    Kumar now maintains an ever-expanding chart that resembles a handwritten family tree. It denotes which family members have been tested and results. Of the just less than half testing positive for the mutation so far – including Dalson and Toni Cable – current knowledge suggests about 35 percent will develop AML.

    Cincinnati Children’s scientists are eager to begin studying blood samples to look for answers. The research opportunity is both challenging and somewhat unprecedented, Kumar says. Right now he wants to make sure willing family members get tested and channeled into appropriate medical care, if needed.

    “The case involving this family gives us an excellent opportunity to study the biology of a potentially large repository of human cells, some in people who have the mutation but have not developed leukemia,” Kumar says.

 
  • Dr. Ashish Kumar.

    Dr. Ashish Kumar.

    Dr. Ashish Kumar.

    Dr. Ashish Kumar says this rare family case allows scientists to gather and study important genetic information about familial platelet disorder and the risks of developing leukemia. 

  • Dalson Cable.

    Dalson Cable

    Dalson Cable.

    The baffling case of 3-year-old Dalson Cable helped scientists at Cincinnati Children's discover a rare gene mutation among Dalson's family that puts them at risk of developing leukemia.