April 8, 2008
Gene Disorder Can Be Fatal for Babies
Tyler Smith is a beautiful 3-month-old Oklahoma City boy. He gurgles, giggles and grips his mother's thumb tightly, his bright eyes brimming with innocence and potential as he cooperates during a medical examination by his doctor, John Mulvihill, chairman of medical genetics at Children's Medical Research Institute.
On the outside, the baby seems to be developing normally. But beneath the surface, at a chromosomal level, Tyler is far from average. He has DiGeorge syndrome, a rare metabolic disorder in which the 22nd chromosome is missing a chain of genes.
"He had started jerking like crazy. His eyes started rolling in the back of his head," she said. The baby suffered a severe seizure for two minutes, and then went limp. When Smith called for an ambulance, "He was completely pale. He looked terrible."
At Children's Hospital at OU Medical Center, Smith feared the worst for her baby when a chaplain came to the family waiting room to comfort her.
"I just knew he was dead," she said. "I knew he was gone. I dropped to my knees, my dad dropped to his knees. We both just sat there and cried."
But her son wasn't dead. A few moments later, a nurse told Smith that her baby was stable and breathing on his own.
"When do you think we can take him home?" Smith asked the nurse.
"Honey, you're not taking him home anytime soon," the nurse replied.
Tyler spent the next three weeks in intensive care. After about six weeks, Smith learned that a blood test indicated her son had DiGeorge syndrome, a disorder that is not tested for at birth but is more common than many disorders that are tested for.
One out of 4,000 babies is born with DiGeorge syndrome, which means about 12 babies in Oklahoma are born with the chromosomal disorder each year.
Missing genes Chromosomes are packages of genes, some of which have nothing to do with each other's function. Humans have 23 pairs of chromosomes, and they are numbered, one being the largest and 22 the smallest. The 23rd pair of chromosomes determines gender.
In DiGeorge syndrome patients, if a chain of genes from chromosome 22 is missing, some resulting conditions can be predicted and some depend wholly on which neighboring genes are missing. More than 180 anomalies are associated with DiGeorge syndrome but none are noted with 100 percent frequency.
These anomalies include heart defects, immunological deficiencies and variant facial features, a condition known as velo-cardio-facial syndrome, or VCFS. The term VCFS often is used interchangeably with DiGeorge syndrome, as is "22q11," which references the genetic address of the missing genes.
The deletion of genes on chromosome 22 can be hereditary but often is not recognized in whichever parent carries the disorder because its manifestation can be so mild. If a parent has the deletion, there is a 50 percent chance his or her children will be born with a similar deletion.
But, according to MaxAppeal, an organization dedicated to educating the public about DiGeorge syndrome, only about 10 percent of DiGeorge patients have a parent who also is affected.
Www.maxappeal.org states: "There is nothing that either parent could have done before or during the pregnancy to have prevented the deletion from happening ... or to have caused the deletion to occur. This is a defect of the human race, not of one particular person."
Though some babies with DiGeorge syndrome are only mildly affected, many are so severely affected that drastic interventions such as heart surgery, constant medication and monitoring are required. But, as in the case of Tyler, the syndrome often is not identified until a life-threatening event creates cause for testing. Tyler's syndrome caused the absence of his parathyroid glands that regulate the production of calcium, which caused his seizure. He now takes calcium supplements twice a day along with medicines to prevent seizures and vomiting.
Dangerous anomalies Mild to serious heart defects and immune system deficiencies are among the most common and most dangerous anomalies associated with DiGeorge syndrome. A baby's immune system is controlled by the thymus gland in the chest, and this gland is often partially or completely missing in DiGeorge patients, making them more susceptible to colds and viral and fungal infections. Generally, doctors recommend that caution be taken with immunizing these babies until "T" cell and "B" cell counts are at safe levels.
Kidney problems, leg pains and behavioral and learning difficulties are also common traits in DiGeorge patients.
The most obvious physical characteristics in babies with the syndrome are craniofacial variations, Mulvihill said, but these are often missed at birth.
"They're hardly abnormalities, just variations, sometimes as much as cleft lip and palate, sometimes just nasal features. And that's sort of an outside flag of more serious internal manifestations."
Doctors also check for subtle variations in the shape of a baby's hands and ears. Since a baby's ears often are shaped much like their parents', a pointed or oddly shaped ear can be an indicator of DiGeorge syndrome.
With age, Mulvihill said, other manifestations of the syndrome can develop, including learning disabilities and mental disabilities.
"I think one of the big points is that the disorder is very widespread. It can be very, very mild," he said. "But it can have complications in many of the organ systems."
Babies with DiGeorge syndrome need to be monitored by many doctors, but the syndrome is not a death sentence, Mulvihill said. The oldest patient he said he has seen with the syndrome was 54 years old, he said.
Tyler's prognosis is good, Mulvihill said. Though no doctor can predict exactly how DiGeorge syndrome will affect him in the future, presently, he is considered stable. As long as he continues to receive proper medicine for his calcium deficiency and seizures, Mulvihill said Tyler's future looks promising.
"If someone hears the word syndrome, they automatically think mental retardation, but that's not so as illustrated by this case," Mulvihill said. "And, too, they think that it causes early death, and that's not true. We just have to monitor for what we can and treat him as a normal kid except for the issues that have to be addressed."
No tests for syndrome No state routinely tests newborn babies for DiGeorge syndrome; however, many states, including Oklahoma, are dramatically increasing the number of metabolic disorders for which newborns are routinely tested. Currently, a drop of blood from every baby born in Oklahoma is tested for 14 metabolic disorders at the state health department's Public Health Laboratory. But by the end of the year, the department aims to increase that number to 54, in accordance with recommendations from the American College of Medical Genetics and the March of Dimes.
"We're more than doubling the number of disorders we're reporting now," said John Corpolongo, service chief of screening, special services and SoonerStart for the state Health Department. The department estimates the lives of between six and 10 babies will be saved every year once the additional tests are implemented. "We're behind other states in terms of this expansion, but by the end of the year, we'll be up with them," he said.
But even then, DiGeorge syndrome will not be tested for. A national debate exists over whether DiGeorge is common and dangerous enough to be included in the panel of tests routinely performed on newborns, Mulvihill said.
"It's frequent enough that maybe it should be, and its complications in the newborn period can be serious," Mulvihill said. "Some people would say, 'Why screen 3,999 babies unnecessarily to find one?' Other people say it's worth it."
Genetic disorders such as DiGeorge syndrome also can be detected in utero by amniocentesis, but according to The March of Dimes, between one in 200 to one in 400 pregnant women will have a miscarriage after an amniocentesis, so the test is generally only recommended for women whose babies are at higher than normal risk for genetic disorders and birth defects.
And parents can elect to have their newborns tested for DiGeorge, but the test is expensive compared to the standard tests required in Oklahoma. The battery of tests now performed on newborns costs about $100, but that figure undoubtedly will rise when the panel of tests expands to 54, so part of the debate revolves around the financial viability of testing for disorders that may not be imminently life threatening.
"As usual, it's the cost-benefit ratio," Mulvihill said. "One troubled kid is good enough reason to spend that money."