When Joseph Fairweather was born in 1999, he had abnormally lax skin, a hiatal hernia, swollen eyelids and multiple defects on his bladder. Doctors were puzzled about Joseph’s condition and thought it might be cutis laxa, an inherited connective tissue disorder that causes skin to hang loosely from the body. They gave Joseph one year to live.
Urban
But his parents, Evelyn and Lee Fairweather, didn’t give up on him. Joseph was an active, happy baby. His parents vowed to do what they could to help him to get better.
The Fairweathers visited many physicians to find one who could help their firstborn. Despite care from 10 specialists, Joseph died at 15 months.
Since Joseph’s death, the Fairweathers have followed research on cutis laxa and related disorders. In searching for information on the condition, they became acquainted with Zsolt Urban, Ph.D., assistant professor of pediatrics, of genetics and of medicine at the School of Medicine.
Now, Urban and fellow researchers have found an answer to the mystery of Joseph’s disease. Urban and colleagues at McGill University in Montreal, New York University and collaborating institutions have found a recessive genetic mutation in four children born with similar abnormalities as Joseph.
The children were born with abnormally developed lungs, gastrointestinal and urinary systems, skin, skull, bones and muscles. In addition, all had cutis laxa. Three of the children died from respiratory failure before age 2.
Details about the discovery of the mutation were published in the Oct. 15 online edition of the American Journal of Human Genetics.
Elaine C. Davis, Ph.D., senior author and associate professor of anatomy and cell biology at McGill University, compared various tissues from a mouse genetically engineered to be missing a form of the LTBP4 gene with skin tissue samples from one of the children. She found remarkable similarities. The mouse, provided by Daniel Rifkin, M.D., the Charles Aden Poindexter Professor of Medicine and professor of cell biology at NYU Langone Medical Center, showed similar connective tissue alterations as the patient, who had cutis laxa, lethal pulmonary complications and gastrointestinal and urinary disease.
Based on these observations, researchers in Urban’s lab sequenced the LTBP4 gene in the four children and confirmed they had mutations. They determined that the patients were the first described to show severe symptoms of a novel syndrome, which the researchers have named Urban-Rifkin-Davis Syndrome.
The findings have potential implications for newborns with underdeveloped lungs as well as older patients with severe lung diseases, including chronic obstructive pulmonary disorder (COPD), said Urban, first author of the paper.
“Many newborns commonly have breathing difficulties,” Urban said. “Part of the problem is that the lung is not developed properly, especially the alveoli, the tiny sacs at the end of the smallest airways that serve as a place for oxygen uptake and gas exchange. This finding helped us identify a gene essential for the development of alveoli and potentially provide a target for intervention in premature babies.”
The researchers now are broadening their research into the new syndrome among other patients with cutis laxa. Urban heads the International Center for the Study of Cutis Laxa at St. Louis Children’s Hospital.
Urban and colleagues also are testing samples collected from patients with COPD for LTBP4 mutations. When lungs are damaged with COPD, alveoli lose their elastic quality, and the walls between them are destroyed as they become thick and inflamed.
“Patients who may have a slightly reduced activity of LTBP4 might be more susceptible to chronic lung diseases later in life,” Urban said. “Identifying genes that are central for the formation of alveoli may help us devise ways to regenerate alveoli in patients with COPD.”