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Pursuing Genetic Insights – and Clinical Solutions – For Prune Belly Syndrome
20 percent of babies with prune belly syndrome (PBS) are stillborn and 30 percent die of renal failure or urosepsis by age two — but Linda Baker, M.D., a pediatric urologist at Children's Health℠ and a Professor of Urology at UT Southwestern, is working toward treatments that could improve outcomes for this rare genetic disorder. She’s leading a National Institutes of Health study to uncover the genetic changes that drive PBS, while pursuing clinical solutions to improve the quality of life for patients and their families.
“Finding the deranged genes behind PBS would be a step toward prevention or cures, but that could be a long way off, and we want to help patients as soon as possible,” says Dr. Baker. “That’s why our research has both a genetic and a clinical arm.”
NIH-Funded Genetic Research
Dr. Baker is one of just seven pediatric urologists with NIH-funded investigator-initiated research, and her five-year PBS study has three goals:
- Identify new gene changes (mutations or variants) that cause PBS
- Study PBS-affected organs at the molecular level
- Characterize the role of a recently-identified PBS candidate gene
An Intriguing Hypothesis
Dr. Baker is using her NIH grant to pursue an intriguing hypothesis: Since about 95 percent of PBS patients are male, she believes the condition could be sex-linked autosomal recessive or of X-linked inheritance.
Dr. Baker is taking an especially close look at the genetic profiles of males who have PBS and are under age 18. In partnership with the Prune Belly Syndrome Network (PBSN), Dr. Baker’s team has recruited ~140 PBS cases from the US and internationally.
The PBSN is a support group that has national conventions and family “meet-ups” around the U.S. Dr. Baker’s research team attends these meetings to recruit study participants and provide educational lectures.
“We’re incredibly lucky to have access to such a large pool of patients, and that families are so eager to join our research,” Dr. Baker says. “They know we are working hard to find the cause and to help those with PBS.”
Identifying New Mutations
Using whole-exome sequencing, Dr. Baker’s lab at UT Southwestern has identified candidate PBS genes. Studying “multiplex” PBS families – families with more than one child with PBS – has been particularly helpful.
Dr. Baker’s team identified an especially interesting mutation in two half-brothers with PBS-affected muscle cells. Now the researchers are taking a closer look at the mutation to unravel its potential role in PBS.
Eventually, understanding these mutations could lead to gene therapies that treat or even cure the disease.
“I hope we can start exploring gene therapies for PBS in my lifetime,” Dr. Baker says. “At the very least, I want to lay a solid foundation for the next generation of scientists to build on.”
Goal: Improve Treatment Today
Dr. Baker’s pursuit of better PBS therapies extends to the clinic, where she has assembled a team of pediatric pulmonologists, gastroenterologists, nephrologists and physical therapists to investigate PBS from multiple angles. Their goals include:
- Reducing kidney damage, dialysis and kidney transplants. Many children with PBS suffer from recurrent urinary tract infections (UTIs) and can’t empty their bladder well. This leads to back up of urine in the ureters and kidneys, and to recurrent urinary tract infections (UTIs).
Some PBS babies are born with kidneys that don’t work, and require dialysis as infants. Others have normal kidneys that slowly go into kidney failure from recurrent UTIs and incomplete bladder emptying. Many need bladder and ureteral reimplantation surgery.
Dr. Baker and her colleagues are exploring ways to prevent UTIs and improve bladder emptying.
- Making physical therapy more effective. Children with PBS do not have normally-formed muscle in their belly. This muscle weakness means they can’t cough well or push down forcefully to pass urine or stool.
In some cases, patients need a surgery called abdominoplasty to improve the belly’s appearance and function. Children’s Health physical therapists are working to develop an evidence-based physical therapy protocol for PBS, and to measure and define abdominal muscular weakness in kids with PBS.
“This could improve physical therapy for PBS and also inform surgeons during abdominoplasty procedures, because knowing which specific muscles are affected will inform which ones should be preserved or removed,” Dr. Baker says.
- Pinpointing which patients can benefit from pediatric urological surgery. Children with PBS often need additional surgeries, including surgery to reposition the testicles in the scrotum instead of in the belly. At Children’s Health, we often perform this surgery laparoscopically. We also work hard to combine surgeries to reduce hospitalizations and anesthesia exposure.
Transforming Treatment for Pediatric Urological Disorders
Dr. Baker hopes her work sets the stage for transforming PBS treatment — and it’s just the latest step in Children’s Health’s push to improve care for a wide variety of pediatric urological disorders.
For example, our surgeons are renowned leaders in all types of pediatric urological robotic surgeries and have pioneered the use of buccal mucosa to construct or reconstruct females born with severe birth defects of the vagina, or scarring from past vaginal surgeries.
With 10-disease specific programs, Children’s Health treats a broad range of urologic conditions, from incontinence to ureteropelvic junction obstruction. We offer the full spectrum of urological care, from before birth, through childhood, and sometimes even into adulthood. We’re also experts in the latest technology – every physician on our team is certified on the da Vinci Robotic Surgical System. This comprehensive care, combined with our recent expansion into four neighboring cities, helps explain why U.S. News & World Report placed Children’s Health among the top urology programs in 2018-19.
Learn more about the urology program at Children's Health