Yale School of Medicine professors Scott Rivkees and Jeffrey Gruen are changing the future of genetic disorders diagnoses.
Over the past five years, Rivkees, Gruen, and a team of Yale-based researchers have developed a new diagnostic test to detect the genetic disorder Turner’s Syndrome in young girls aged 2 and 3 years old. The study will be published for the first time in the March 2011 issue of the Journal of Clinical Endocrinology and Metabolism, and has important implications for helping girls affected by Turner’s Syndrome, which affects the height of those afflicted, achieve normal height.
Turner’s Syndrome, a disorder characterized by short stature, sterility and health issues such as inherited heart disease, is caused by an abnormality in the female sex chromosomes. Rather than having two X sex chromosomes, girls with Turner’s syndrome only have one. The syndrome often goes unnoticed until a girl in her early teens is still unusually short and fails to begin menstruating, said Rivkees, a professor of pediatrics and a practicing pediatric endocrinologist.
But by her teenage years, it is too late to help a girl with Turner’s Syndrome reach normal height with hormone therapy, said Rivkees.
“If you see a girl who is short, she has a 1 in 50 to 1 in 100 chance of having Turner’s Syndrome,” he said. “Four or five years ago, in the course of a week, I saw about three girls who came in, quite short, we weren’t previously thought to have the syndrome. This really disturbed me, because if these girls could have been helped earlier they may have grown to be 5’2” instead of 4’6”.”
On one of their afternoon jogs in 2005, Rivkees asked Gruen, a clinical neonatologist who conducts research in pediatric genetics, if he had ever heard of newborns being diagnosed with the disorder. Gruen responded that a diagnosis this early was rare because signs of the disorder do not show up until around puberty.
In the course of their conversations, the two doctors said they realized that a test was needed to diagnose the disorder at a very early age — around 2 or 3 years old — so the girls could be given 10 years of consistent hormone therapy to achieve normal height before the end of their teens.
The answer, the doctors said, was a DNA sequencing-based test. If they could use a single nucleotide polymorphism, a part of a DNA sequence, to identify when a female has only one X sex chromosome instead of the normal two, they could diagnose for the disorder, Gruen said.
But Turner’s Syndrome exists in two forms. If a girl has classic Turner’s syndrome, then all of her cells lack one X chromosome, but if she exhibits a characteristic called mosaicism, some cells are normal while some are missing a chromosome.
To account for mosaicism in the diagnostic test, Gruen and Rivkees used a process called qualitative genotyping, in which they test DNA by examining specific markers along the sequence, said Gruen. Analyzing the results of this test shows a clear difference between a normal genetic makeup and one with Turner’s syndrome, he said.
By using skin cells from a cheek swab, doctors will be able to test a large number of girls, he said.
Paul Saenger, a New York-based pediatric endocrinologist, said the test looks promising because it is cheaper and allows for the early diagnosis that is key to dealing with the syndrome.
“The current paradigm is watchful waiting,” Gruen said. “We’d like to turn this paradigm around with these tests.”
Turner’s Syndrome was named after Dr. Henry Turner, who first identified symptoms of the disorder.