Researchers Identify a Genetic Link to Growth and Development
A study in the December 2003 issue of the New England Journal of Medicine describes a boy who was perfectly healthy at birth, but weighed only four pounds and was 15.8 inches long, as compared to the average newborn who weighs about six pounds and is 20 inches long.
In 90 percent of cases, infants born small for gestational age catch up, but in this case, the boy did not catch up, says Steven Chernausek,MD, of the Division of Endocrinology at Cincinnati Children's and corresponding author of the study.
Dr. Chernausek, M. Jennifer Abuzzahab, MD (the first author of the study who is now with Children's Hospitals and Clinics in Minneapolis/St. Paul, Minnesota), and colleagues traced the root of the boy's small size before and after birth to mutations in the gene for the insulin-like growth factor I (IGF-I) receptor. They also found the same mutation in a girl, who, like the boy, was small for gestational age.
While this work had been previously conducted in mouse models, this is the first time researchers have linked mutations in the IGF-I receptor gene to gestational and postnatal growth in humans.
"Our observation in humans illustrates how important the IGF-I receptor pathway is. Now that we know which pathways are involved in growth, this can lead to new hypotheses about growth and eventually, new treatments during and after gestation. Still, gene-based treatments are years away from use in the clinical setting," Dr. Chernausek says.
Ongoing Debate
The genetic and environmental factors that influence growth before and after birth have been discussed and debated by physicians and researchers for years. It is known that smoking, alcohol consumption, drug use, high blood pressure and diabetes during pregnancy can lead to having low birth weight babies.While there has been a large body of circumstantial evidence implicating the IGF system in the control of human fetal growth, there had been no conclusive evidence of such a link – until this study.
"The significance of the study is not that this genetic abnormality explains the majority of cases of small fetal growth in humans, but rather it clearly establishes the IGF pathway as extremely important in the control of human growth as previously suggested in mouse studies.The broader implication is that there are other problems that are not necessarily genetic, such as smoking, alcohol consumption and drug use, that cause poor fetal growth and are possibly doing so by having an effect on the IGF pathway," he says.
Researchers suspected that diminished intrauterine and postnatal growth were linked to mutations in the gene for the insulin-like growth factor I (IGFI) receptor. IGF-I and II genes have been known to be associated with growth and are known to act through a common receptor. The study conclusively determined that mutations in the IGF-I receptor gene interfered with the function of the IGF-I receptors and in doing so, affected growth before and after birth.
Both of the children in the Cincinnati Children's study were small for gestational age and have since grown at far below average rates.
Patients React Differently
The defects in the receptor gene affected the boy and girl differently. The boy's health condition was marked microcephaly, and mild retardation of motor development and speech. His mother and sibling carried the same gene mutation and his mother was far below the mean average height.The boy, who is in elementary school, remains far below the mean height for his age.
The girl was born weighing 3 pounds. Despite having been fed high-calorie formula, her growth rate remained significantly below average.At age 14, she reached her full height of 4.40 feet, as compared to her target height of 5 feet.
The girl was not mentally impaired, but she did suffer from mild psychiatric problems, such as excessive fantasy role playing and social phobias.
Why and how the defects in the receptor gene occur and why patients react differently to these mutations remains under study.According to Dr. Chernausek, identifying the receptor gene and describing its role in determining growth before and after birth is an important step in understanding the growth process in humans.
"Identifying the mutations raises the possibility," he says,"that even small changes in the function of the receptor might have a biological meaning.
Dr. Chernausek is a professor of pediatrics and associate director of the Division of Endocrinology at Cincinnati Children's. His study was published in New England Journal of Medicine (349[23]:2211- 2222, 2003 December 4).
