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Pediatric Update

 
Summer 2005

Advances in Genetics Bring New Possibilities to Pediatric Practices

"The 13-year effort to sequence the 3.2 billion base pairs of DNA in the human genome was indeed a scientific tour de force. The true challenge of genetics and genomics will be to understand the potential impact of the science on us as individuals and as members of social groups." -Edward R.B. McCabe, M.D., Ph.D, co-director, UCLA Center for Society and Genetics, executive chair, UCLA Department of Pediatrics and physician-in-chief of Mattel Children's Hospital at UCLA

The sequencing of the human genome and the wealth of information yielded about the hereditary material in our cells opens up new possibilities in pediatric practices—some clear and some controversial. When is genetic testing appropriate? Do treatments exist for detected diseases? Is the cost of a DNA test fiscally responsible?

While those and other questions will continue in medical debates, some genetic advances are already clearly impacting pediatric and family medicine practices.

Newborn Screening

California joins ranks this summer with the majority of states by mandating expanded newborn screening for 30 genetic diseases using a simple blood test. The test helps identify the one child in roughly 5,000 who may have some inherited metabolic disorder.

 “With proper diagnosis, parents and physician can often put these children on special diets or otherwise treat the condition,” notes Stephen Cederbaum, M.D., UCLA professor of psychiatry, pediatrics and human genetics, who was legislative sponsor for California’s pilot program. Undetected and untreated, these diseases can quickly prove fatal or lead to mental retardation.

Babies born in California have routinely been tested for PKU, galactosemia, primary congenital hypothyroidism and sickle cell anemia. Using tandem mass spectrometry technology on the heel-stick blood sample, scientists can now detect up to 30 more inherited conditions.

Cystic fibrosis, a recessive disease with completely normal carriers, can also be detected at the DNA level. Wayne Grody, M.D., Ph.D., director of UCLA’s Molecular Diagnostic Laboratories, has led the way in developing a nationwide screening program to identify cystic fibrosis carriers. “Some states are proposing this screen for all newborns, and I think California will soon be one of those,” Dr. Grody notes. “Currently, obstetricians and family medicine physicians should offer the test to all pregnant couples to identify those at risk; if two parents carry the mutant gene, a one in four chance exists that their child will inherit cystic fibrosis.”

Although early treatment for cystic fibrosis is not as dramatic as for metabolic diseases—and therefore screening for the condition is still controversial—Dr. Grody notes that some newborns with the disease fail to thrive and these children can be put on special diets and enzyme supplements. The current testing guidelines are similar to those used to identify Tay-Sachs carriers in pregnant couples, the only difference is that Tay-Sachs testing is aimed at a specific ethnic group (Ashkenazi Jews), while cystic fibrosis carrier screening applies universally.

“Preferably this screening—now considered standard of care—should be offered at the first prenatal visit, so that if the parents elect to have prenatal diagnosis it can be done early enough to still offer options, such as pregnancy termination, or to allow time to plan for postnatal care,” Dr. Grody explains.

UCLA is also participating in a National Institutes of Health (NIH) study to test DNA in newborns and toddlers for the most common genetic cause of hearing loss: the gene connexin 26 (cx26), which causes approximately 50 percent of nonsyndromic autosomal recessive sensorineural deafness. The presence or absence of cx26 mutations will play an important role in determining the medical follow-up for children with hearing loss, notes Dr. Grody. He is working with Christina Palmer, Ph.D., medical geneticist and assistant professor in the UCLA Center for Neurobehavioral Genetics, to study the feasibility of a DNA test to back up the current mandated newborn hearing screening in California.

Current California guidelines dictate that a newborn needs to fail the hearing screening three consecutive times before being referred to an audiologist for diagnostic hearing tests. Ideally, these follow-up tests occur within a month, but compliance by parents is not always ideal. In the NIH pilot program, newborns and toddlers are eligible to be tested for cx26 anytime between failing the hearing screening the first time while in the hospital and being diagnosed with hearing loss. “So far about one-third of the infants have tested positive for cx26,” Dr. Grody observes.

Testing for fragile X syndrome, a mental retardation syndrome that mostly affects males, has been proposed for all pregnant women, or even school-aged children, so that special stimulation programs can be initiated early. “This screening is a bit complicated since ‘premutations’ can be detected,” Dr. Grody notes. “The accepted application currently is to test for fragile X to make a diagnosis of a symptomatic child, or test a pregnant woman if there is a family history of the disorder.”

Predictive Genetic Testing

Dominant diseases in which a 50 percent chance exists that a mutant gene will be transmitted from parent to child can be detected through DNA testing years or even decades before the first symptoms appear. “Huntington’s disease, a degenerative neurologic disorder, usually becomes evident in middle age, and rarely affects children. In general, this would be a disease for which we would not offer predictive testing to a child because of ethical considerations,” Dr. Grody says. Testing for a familial breast cancer caused by a mutation in the BRCA 1 and 2 genes would also not be offered to girls of mothers with this disease until they are 18 years old. “Just because a test is available does not mean it is the best thing to do,” he says.

However, some dominant disorders do start in childhood and prophylactic therapies can be offered, including familial adenomatis polyposis (FAP) and multiple endocrine neoplasia (MEN2). In both these cases, children can be tested early to see if they carry the gene and then watched carefully or have a prophylactic colonectomy (to prevent colon cancer) or thyroidectomy (to prevent thyroid cancer), if necessary. Conversely, if the mutant gene is not present, the child can be spared unnecessary colonoscopies and surgery.  

Prenatal Diagnosis

Choices for prenatal diagnoses are expanding. Down’s syndrome can be picked up in the first trimester by routine ultrasound examination based on nuchal skin fold thickness, Dr. Cederbaum notes.

Prenatal testing for cystic fibrosis should be offered to couples at risk since amniocentesis or CVS can test DNA for inherited mutations. Offering prenatal diagnosis for adult-onset genetic diseases becomes more controversial, since many of these diseases may not show up for decades, and cures may actuallybe found in the meantime.

“Right now these are personal choices best left to the discretion of the patient, physician and DNA lab director,” Dr. Grody notes.

Genetic Counselors

“The most powerful tool available to any physician is the family history,” stresses Michelle Fox, M.S., C.G.C., UCLA genetics counselor. “By asking specific questions about your patient’s family history, valuable information can be gathered and specific testing recommendations can be made. If the physician does uncover a pattern of retinal disease, heart disease, cancer or developmental problems, a primary physician may discuss options for testing, refer to a geneticist, or suggest speaking to a genetic counselor.”





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