Dr. Timothy Cox: Searching for Clues About Cleft Lip and Palate

Searching for Clues About Clefts

Dr. Timothy Cox is on the trail of the genetic and environmental factors that cause cleft lip and palate.

Cox and lab

Dr. Timothy Cox (right) and members of his lab are working to understand how genetic and environmental factors interact to cause cleft lip and palate. Graduate student Monica Parada (left) is studying the role played by IRF6, one of three major genes studied by the lab that are associated with cleft lip and palate.

When a child is born with cleft lip and palate, it’s the end of a biological process gone awry, and the beginning of a difficult journey to survive and thrive.

Dr. Timothy Cox, a researcher with Seattle Children’s Craniofacial Center, is studying why the normal progression of prenatal development veers off course to cause cleft lip and palate. His work is breaking new ground and could someday spare thousands of children from the condition’s punishing consequences.

“We know cleft lip and palate is likely caused by a combination of genetic and environmental factors, but we don’t understand how it all fits together,” Cox says. “If we can solve that puzzle, we can better identify who’s at risk and prevent or minimize this devastating birth defect.”

One in 1,000 affected

Cleft lip and palate is one of the most commonly occurring birth defects, affecting one in 1,000 children.

The condition occurs when a child’s lip and/or palate (the roof of the mouth) fail to come together during prenatal development.

Understanding the connections between genetics and environment is the first step toward establishing preventive measures.

Most people perceive the condition as easily correctable by surgery. Yet surgery is not an ideal solution. Cleft lip and palate requires a long and disruptive period of ongoing care – multiple operations, extensive dental work, speech therapy – that lasts through adolescence. And the results may be less than perfect.

Surgery isn’t even an option in many parts of the world where cleft lip and palate is prevalent. Left untreated, many babies die because they struggle to eat and breathe. Many of those that survive are ostracized because of their facial disfigurement and poor speech.

Studying three genes

Cleft cell

This cell is stained to show 
one of the three proteins 
that the team studies. The 
cell's chromosomes are 
shown in blue, the 
structural components 
of the cell are in red, and 
the protein implicated in 
cleft lip and palate – 
known as midline 1 – 
is greenish-yellow.

Children can be born with just a cleft lip, just a cleft palate or both. Cox and his team are studying the interaction of three particular genes and various environmental factors – like alcohol use and vitamin A deficiency – that can influence susceptibility to cleft lip. “These genes are defective in some children with cleft lip, but it’s still not clear how they disrupt normal facial development,” he says.

They are using chick embryos and three-dimensional imaging to record how the manipulation of these three genes affects development of the lip. “Children’s is the only center in the world with the laboratory and imaging capabilities to do this research,” says Cox, who moved from Australia to join Children’s in 2006.

His latest data suggests all three genes are linked to a single molecular pathway that controls a key step in the formation of the lip. The million dollar question is what tips the balance to result in cleft lip.

“Many children can have the same genetic abnormality associated with cleft lip but not all will be born with a cleft,” Cox says. “We think the children who are born with a cleft had a less favorable environment within the womb, and we think it may be due to nutritional deficiencies or specific chemical or drug exposures, such as alcohol.”

The challenge is to tease out the connections between genetics and environment and translate them into preventive measures.

Possible intervention identified

Cox recently completed a pilot study showing that increasing the presence of vitamin A during gestation prevented nearly all of the facial defects that normally develop when chick embryos are exposed to alcohol. The study suggests that women could reduce the risk of their babies being born with cleft lip by ensuring their diets meet the recommended daily requirements of vitamin A.

This is important because even moderate alcohol use early in pregnancy – when a woman often doesn’t know she’s pregnant – is a risk factor. Sufficient vitamin A also addresses another risk factor — vitamin A deficiency due to poor diet, which is common in many countries, including the U.S.

“Having a simple and effective preventive approach akin to using folic acid to guard against spina bifida could have a huge impact on the incidence of cleft lip,” Cox says. “I don’t think we can prevent every cleft but we can lessen the risk, avoid some surgeries and ease the burden for many children and their families.”