The Potential is Unlimited - Glennon Magazine

Genetic Discoveries Shape the Future
of Pediatric Medicine

At the beginning of the 20th Century, infectious diseases were responsible for most admissions to childrens’ hospitals. By the end of the century, serious infections were no longer a common part of childhood. Genetic diseases were responsible for roughly half of pediatric hospital admissions.

At the beginning of the 21st Century, the expanding knowledge of genetics makes textbooks outdated as quickly as they are printed. New genetic diseases are identified in nearly every monthly medical journal. There are treatments for illnesses that were not identifiable a few years ago. Current research could bring revolutionary treatments for genetic diseases within the lifetimes of today’s newborns.

“Things are happening so quickly in genetics. Information is expanding exponentially,” said Gary S. Gottesman, M.D., director of the division of medical genetics at SSM Cardinal Glennon Children’s Hospital.

The hospital’s three geneticists and three genetic counselors work with every other pediatric subspecialty, assisting in the diagnosis and treatment of children with genetic diseases. A dietitian assists patients with metabolic disorders who must strictly adhere to special diets.

“Our role is to provide education as much as to provide clinical care,” Gottesman said. “Each clinician cannot keep up with the ever-mushrooming amount of information. We help in explaining new genetic tests that are available and arranging for studies to be done.”

Congenital defects are identified in about two percent of newborns in the U.S., he said. Defects resulting in developmental delay may not become apparent until the pre-school years. By the time they start school, five percent of all children have an identifiable genetic problem.

Diagnosing Diara
Diara Wilburn is a bright, pretty energetic girl. But earlier this year the seven-year-old arrived at the Cardinal Glennon emergency room in a coma.

She had become sleepy at school and her teachers could barely keep her awake. Her mother was called, picked her up and took her directly to the hospital. “By the time we got here she wasn’t responding to anything,” said her mother, Christeen.

Diara had a blood ammonia level over 350. “That is more than ten times normal, enough to destroy the cells in your brain,” said Gottesman, an associate professor of pediatrics at Saint Louis University School of Medicine.

Biochemical tests confirmed that Diara has ornithine transcarbamylase deficiency, the lack of an enzyme that helps the body break down protein and excrete nitrogen, which is a by-product of protein metabolism. The disease occurs in about one of every 80,000 births.

“There are only a few hundred kids in the country with this disorder,” Gottesman said. “Without treatment she would have died of liver failure and elevated ammonium levels.”

Diara spent nine days in the hospital, the first three in intensive care. “They even had her hooked up to a breathing machine,” her mother said. “After she got better they were amazed that she was still able to do the things she can do.”

Two medications and a special low-protein diet have enabled Diara to return to school, and should allow her to lead a normal life. “Her long-term outlook is quite good if she follows her therapy and doesn’t have recurrent episodes of hyperammonemia,” Gottesman said.

One of Medicine’s Most Rapidly Changing Fields
It has been just 50 years since the double helical structure of deoxyribonucleic acid, or DNA, was first described by scientists as the recipe of life. DNA molecules in the cells of all living organisms provide the blueprint for every new cell.

Three years after the discovery of DNA, scientists determined that human cells contain 46 chromosomes, 23 inherited from each parent. These chromosomes are packages of varying sizes that carry the estimated three billion “base pairs” of coding DNA in 35,000 to 40,000 genes. The genes produce specific structural proteins and enzymes that determine whether we have normal organs and limbs, grow short or tall and see through eyes that are brown or blue.

“We tell parents the chromosomes carry the recipe that makes a human being,” Gottesman said. “When there is an altered gene, one of the ingredients is changed. If you try to bake a cake and alter one of the ingredients, you don’t get the expected result. When a gene is altered it may cause a problem in one of the developmental or metabolic pathways, resulting in a baby with a genetic problem.”

More than 14,000 genetic diseases have been identified, Gottesman said. “Eventually we will probably know of 20,000 to 25,000.”

Genetic disorders fall into three basic categories, chromosomal abnormalities, single-gene disorders and multifactorial conditions.

Chromosomal abnormalities such as Down syndrome result from a child having extra or missing chromosomal material, or both.

Single-gene disorders include conditions such as cystic fibrosis, which is caused by the presence of two altered “recessive” genes, one inherited from each parent. Other single-gene disorders, such as Huntington disease, are caused by the presence of only a single altered “dominant” gene.

Many conditions, including diabetes, psychiatric disorders and heart disease, are inherited in a multifactorial manner in which the complex interaction of genes predisposes to the illness and environmental conditions.

“Most genetic disease originates when the egg and sperm combine, and every subsequent cell that is generated carries the alteration,” Gottesman said.

Each of us carries five to ten abnormal genes, Gottesman said. If a defective gene is “recessive,” it will remain unexpressed as long as the same gene received from the other parent is normal.

“As long as we don’t find a partner who also has a defect in the same gene, it doesn’t become evident. Most people never express these alterations.”

Genetic defects also can arise later in life. Most of the billions of cells in the body routinely die and are replaced with new cells. “Our cells constantly make mistakes in copying our DNA,” Gottesman said. “There are mutations in about one in every million base pairs of DNA as the code is copied. We have a system of DNA repair that corrects those changes as they are made. Sometimes a mutation will get through and be copied into subsequent cells and cause problems.”

Exploring the Human Genome
The Human Genome Project has identified nearly all of the base pairs in our DNA. While the genes responsible for many defects and diseases have been found, it still is not technically or economically feasible to obtain a battery of laboratory tests that can survey all the genes to identify an unsuspected alteration or mutation.

In most cases, geneticists first must put together pieces of a puzzle drawn from a patient’s history of present illness, family history and physical examination. When a specific diagnosis is identified, there may be a genetic test that can confirm the presence of the suspected altered gene.

“Most of the things we do still require us to observe and lay our hands on the patient,” Gottesman said. “We do many things that other physicians don’t do, like measure the distance between the eyes, the length of the ears, the distance between the nose and the mouth, the length of the fingers and a whole host of other physical features.

“I usually have a pretty good idea when what I am looking at is not normal. Then I have to determine how abnormal it is, and whether the clinical finding is a feature of a specific disorder.”

Computerized databases help geneticists diagnose rare conditions. They often consult with colleagues across the country or around the world who have experience with a rare disorder.

“Because there are more than 14,000 different disorders, we only see a small number of them during our careers,” Gottesman said. “There will be things we will see once and never again.”

Many patients present their geneticist with a new learning opportunity, said Verna Rose, M.D., of the Cardinal Glennon genetics staff.

“Some of the disorders are more common, so they are easier to recognize,” she said. “Maybe a quarter of the time we cannot come up with an answer. People come up with unusual birth defects or combinations of defects all the time.”

She once saw a patient whose family asked about finding a support group, but there was only one other child in North America who had the same disorder.

Children may visit a geneticist for years in search of diagnosis. “As they grow into their diagnosis their appearance may give us new clues. There may not be a gene test for the disorder today, but maybe in two years when we see them again there will be a new test,” said Rose, an assistant professor of pediatrics at Saint Louis University.

Adults often visit the hospital in hopes that new information or laboratory studies will finally explain their genetic problems. A mentally handicapped woman came to Glennon and received a long-awaited definitive diagnosis, Rose said. “No matter how bad the news is, most people just want to know why this happened and if it can happen again.”

Serving Many Patients
One day each week the division’s doctors see patients in a general medical genetics clinic. Another half-day is devoted to metabolic disorders. On alternating weeks a multi-disciplinary clinic is held for patients with neurofibromatosis, a disorder that affects the insulation around the nerves. That clinic is shared with Glennon’s orthopedics, neurology and ophthalmology staffs. Three times each month a geneticist and genetic counselor see patients with the cleft lip/palate and craniofacial deformities team. Medical genetics services also are provided at outreach clinics in Wood River in Illinois and Cape Girardeau and Sikeston in Missouri. A new site will soon be opened in Mt. Vernon, Illinois.

Rose has a special interest in children with abnormal mental development and dysmorphic features — defects such as missing or extra body parts or other alterations of physical appearance.

“A lot of children with learning or developmental problems still can be quite functional in life. They can eventually hold jobs and have families,” she said. “Some of the most difficult children to work with are the ones who have disfiguring syndromes but average intelligence so they know they look different.”

Providing Information and Support
Genetics counselors help parents detail their family tree and medical history, which in turn can narrow the search for an inherited defect.

“Once a diagnosis is made we’ll talk to the family about what the condition will mean for their child,” said counselor Laura Waldman, M.S. “They will want to know how other children cope with the condition, what are the medical issues and the chances for future children to have a similar problem.”

When a defect may be inherited, counselors provide guidance on testing that may benefit other family members.

Glennon’s genetic counselors each have more than 20 years of experience and have seen enormous changes in their field. “We used to think there were just single-gene and chromosomal conditions. Now we know there are other factors that can complicate the way something is inherited,” Waldman said.

Explaining the complexities of genetics to parents can be difficult, Waldman said. “Some of it is counter-intuitive and very abstract.”

Prenatal Counseling
Two counselors are based at SSM St. Mary’s Health Center in St. Louis to assist obstetricians in providing pre-pregnancy and pre-natal care.

Special screening is recommended for mothers who are older than 35 years or have been exposed to medications or chemicals that have been linked to birth defects, said counselor Kathy Morris, M.S.S.W. Testing also is suggested if there is a family history of genetic disorders or if a pre-natal blood test or ultrasound detects a possible problem. Women are referred for testing and counseling if their pregnancies are considered “high-risk” or if routine screenings during pregnancy detect a fetal abnormality.

“There are some things that are just suspicious and by themselves don’t mean anything bad for the baby,” Morris said.

“About 80 percent of the people we see are at risk but after testing it turns out there is not a problem,” said Meg Hefner, M.S.

Routine ultrasounds conducted during pregnancy can detect abnormal growth and unusual anatomy within the skull, heart, spine, kidneys and abdominal wall, Hefner said.

Early diagnoses permit parents to be referred to specialists at Glennon before their baby is born. Expectant parents often tour the hospital’s neonatal intensive care unit and meet their child’s future doctors to discuss surgeries and other treatments.

Parents often visit genetic counselors several times. “Parents can’t really take in much of the information when they’ve just heard for the first time that their baby has a serious birth defect,” Morris said. “We give them some initial information, hand them something to read and make sure they know they can come back to see us again as they come up with questions.”

Parents also are referred to support groups so they can meet other parents who are facing similar challenges. Even after a diagnosis has been made, geneticists and their counselors cannot answer all the questions parents pose because there can be a wide range of outcomes.

“We can’t tell them exactly what their baby will be like. Even when the baby has an extra chromosome 21 and therefore has Down syndrome, we know there will be mental retardation but we don’t know whether it will be mild, moderate or severe,” Hefner said. “We also don’t know whether there will be heart problems or other defects.”

Promise for Treatments in Cancer
Geneticists participate in the treatment of cancer, which may also have an underlying genetic origin.

“Genetic alterations within a cell lead to cancer,” said Maulik Shah, M.D., Ph.D., a member of the Glennon division of medical genetics and an instructor in pediatrics at Saint Louis University. He sees patients at Glennon and also conducts cancer research. A small portion of cancer cases are believed to have a hereditary component. Most result from spontaneous cellular mutations.

“When one cell replicates, three billion base pairs are being copied. If a mutation occurs in one in every ten billion or a hundred billion cells and you have trillions of cells, the odds are likely that there will be cells that develop problematic mutations,” he said.

“If the mutation is in a critical gene, the cell is not going to be viable and will just die. If the mutation happens to be in a tumor-suppressor gene or a gene that promotes cell growth, you develop cancer.”

Geneticists occasionally assist doctors in the division of hematology and oncology in diagnosing patients because some cancers can appear similar yet have different genetic causes. Knowing the specific gene defect involved enables doctors to choose the most effective treatments.

For just over a decade scientists have been looking for means to cure genetic diseases by correcting defects deep within the genes. Current approaches involve the development of harmless viruses that carry desired genetic coding into affected cells.

The most promising genetic therapies involve cancer, Shah said. “There are probably more than 250 gene therapy trials being conducted, and about 60 percent of them involve cancer.”

Corrective gene therapy for diseases such as muscular dystrophy, metabolic disorders or immune deficiencies has proven to be much more difficult than originally imagined. Curing these diseases will require the precise insertion of a normal gene into each of the trillions of cells in the body.

A cancerous tumor offers a much smaller target for gene treatment. Shah is working on viruses that would work in brain, breast, colon and prostate cancers. The viruses would replicate only in the malignant tissues, avoiding side effects, and secondarily boost the cellular immune system to help it fight the cancer.

Other treatments, such as surgery, radiation and chemotherapy, still will be needed in conjunction with cancer gene therapy, he said. “There is no way you could inject a virus in the tumor and get 100 percent of the malignant cells. We are hoping that once we get rid of 80 or 90 percent of the cancer, the immune system could take care of what is left.”

Cancer gene therapies could gain broad use over the next five to ten years, he said. Genetic therapies for other diseases may be one to two decades into the future.

A Regional Resource
The molecular cytogenetics laboratory at Cardinal Glennon conducts specialized tests for hospitals across eastern Missouri and southern Illinois. Blood, bone marrow, amniotic fluid and solid tumor tissues are cultured and examined using a number of very precise and complex procedures. The Glennon lab often is the first in the region to offer a new test.

The lab employs nine people who perform approximately 2,200 genetic tests each year, said laboratory director Jacqueline R. Batanian, Ph.D., a professor of pediatrics and pathology at Saint Louis University. The lab’s case load has tripled in the past decade. “These tests are very specialized and very expensive,” Batanian said.

Her research seeks to develop more detailed means of analyzing chromosomes and genes. She also is trying to find better diagnostic tools for the chromosomal defects that cause mental retardation. “We don’t yet know the reason for mental retardation in 50 percent of affected patients,” she said.

Problems with Metabolism
Clinical researchers have made much progress in treating children born with metabolic disorders that make it difficult or impossible for them to process certain nutrients, such as protein, fat or sugars, Gottesman said. If untreated, such disorders can cause seizures, heart or brain disease or even death.

“There are hundreds of metabolic disorders. Depending on the disorder, we may be able to do a lot for affected patients. We can put them on special diets or give them vitamin supplements. We can’t cure them, but we can treat them.”

Diara’s mother must closely monitor her diet to limit the protein she eats. “She has to stay away from meat and milk products,” Christeen said. “I make her lunch for school every day and have to write down everything she eats. It is something she will be faced with every day of her life, but she seems healthy right now.”

Hope for the Future
In the not-distant future, medicine will be able to offer even better means of diagnosing and treating genetic illnesses, Gottesman said. “The technology is getting better every day. We are still in the primordial stages of gene therapy, but I think the potential is unlimited in terms of what we can do. We are learning more about multifactorial diseases that have a genetic component, from high blood pressure and diabetes to headaches. There will be treatments that can be done prenatally, so the kids won’t be born with diseases.”

In the meantime, there is satisfaction in deploying a rapidly improving array of tools on behalf of patients.

“The number of things we can offer patients is surprising,” Rose said. “When we don’t have a lot to offer as treatment, we do what we can to maximize the child’s potential.”

“I love working with families and seeing how kids do over time,” Waldman said. “We get a lot of surprises as far as how well some of them do.”

Diara’s quick diagnosis and treatment gave her the potential for a long and healthy life.

“Diara is doing well in school,” her mother said. “She bounced right back and pulled her grades up, despite the fact that she missed 20 days. It’s been a pleasure seeing the people who have helped us here. I saw this as a miracle from God. I had faith and believed she could pull through anything. I just have to take all the necessary precautions to insure that she remains like she is now.”