Top poker players know that the face mirrors the brain. Specialists in embryonic development wouldn’t disagree. In fact, because the same clumps of primordial cells mold the final features of both, a close look at a child’s face can often yield clues about less visible problems within the skull: a cleft lip or other abnormal facial features can read like a map of brain development gone awry.
Now for the first time, researchers at the Stanford University School of Medicine and the University of California-San Francisco have provided a powerful example of how one genetic pathway can wend its way through an emerging “city” of brain structures and facial features, influencing each phase of development in slightly different ways. Like an architect overseeing a complicated building process, a key protein required early in development for embryonic survival exerts a waning but vital influence throughout the sequential construction of the brain and face. Blocking this protein’s action at varying developmental stages yields very different anatomical results – including one in which only the exterior, or the face, is affected while the scaffolding, or the brain, is left unscathed.
The results not only shed light on a common cause of miscarriage in humans, they also help to untangle a medical mystery: why children born with the same genetic disorder can have vastly different symptoms.
“Everybody recognizes that in some genetic diseases, one person can be much more severely affected than another, and we’ve all wondered ‘Why is that?’” said Jill Helms, DDS, PhD. “We thought that uncovering the gene or genes responsible for the condition might answer the question, but in many cases that has only added more confusion.”
Helms, an associate professor in plastic and reconstructive surgery, recently came to Stanford from UCSF, where the current work was conducted. She is the senior author of the research, which appears in the Aug. 16 issue of The Journal of Clinical Investigation. Helms is supported by the Lucile Packard Foundation for Children’s Health.
Helms, along with former UCSF researcher Dwight Cordero, MD, who is now a perinatologist at Albert Einstein Medical School, and their colleagues studied a birth defect called holoprosencephaly, or HPE, that results when the embryonic brain fails to properly divide into two hemispheres. Although the disorder affects only about one in every 10,000 infants in this country, it’s believed that the initial rates are much higher, occurring about once in every 250 conceptions. Most fetuses are so severely affected that they are miscarried early in pregnancy.
Symptoms range from death within days to severe mental retardation, seizures and an inability to speak. Others, however, suffer only mild learning disabilities. Facial defects can include a cleft lip, a single central incisor or “front tooth,” close-set eyes or even a single eye in the center of the child’s forehead.
Although it’s not known exactly what causes HPE, overexposure to alcohol or other chemicals during early development has been implicated. There’s also a genetic component: children with HPE routinely crop up in some families, although the severity of symptoms within a family can vary widely. This mishmash of possible causes and symptoms has made it difficult for doctors to prevent and treat the disorder.