Conquering Cloacal Exstrophy

gearhart and sponseller

Surgeons John Gearhart, left, and Paul Sponseller have restored urinary continence—the gold standard for success in CE repair—in 90 percent of their patients.

On May 5, 2010 — their five-year-wedding anniversary — Meagan Cline, a nurse, and Brandon Cline, a science teacher, went for a routine prenatal ultrasound. The Mississippi couple, who’d been struggling with infertility, was expecting a child and eager to find out if they were having a boy or a girl. Instead of the baby’s gender, the ultrasound brought a far less welcome revelation: the baby had cloacal exstrophy (CE), a rare birth defect. Children with CE are born with a constellation of gastro-intestinal and urinary tract anomalies, including non-fused pelvic bones and open abdominal wall that leave the bladder, intestines, spleen and liver outside the body. Babies with CE can also have short colon, an anus with a missing or blocked opening and, in some 70 percent of the cases, a non-fused spinal column or other spinal defects. In addition to forming outside the abdomen, the bladder is typically split in half.

CE is considered one of the most severe birth defects compatible with life— a mere few decades ago, most babies with CE didn’t survive. Today, the majority of them do, but face years of com-plex reconstructive surgery—with often uncertain outcomes—to build normal anatomy and restore healthy organ function. The news shook the Clines to the core. “It felt like a punch to the stomach that knocks the wind out of you,” says the child's father, Brandon.

“Knowing that the child you wanted, hoped for and prayed for so much was going to be born with this condition, not knowing whether he was going to survive and that there’s nothing you could do about it is one of the most helpless feelings,” Meagan says.

After the initial shock wore off, the Clines got to work. They did research relentlessly, devouring articles from medical journals and brushing up on anatomy and physiology. Then something struck them. Every time they typed in “cloacal exstrophy” one name popped up over and over again: John Gearhart.

Advancing Surgical Repair
At the crack of dawn on a sweltering morning last June, John Gearhart, the director of pediatric urology at the Johns Hopkins Children’s Center, breezed through the hallway of the pediatric surgery prep area and was promptly swallowed by a set of double doors leading into the operating rooms. On his to-do list for the day: a surgery to relieve kidney obstruction, a hernia repair, two bladder cystoscopies, and an orchiopexy, a procedure to bring down an undescended testis. All of them routine urologic procedures, all of them before noon. It was one of Gearhart’s light OR days. Then it was clinic time.

Gearhart’s first visitors that afternoon were the Clines. A month earlier, their son, Carter, had undergone pelvic reconstruction and bladder closure—back-to-back procedures to repair two of CE’s hallmark defects. During the first surgery, pediatric orthopedic surgeon Paul Sponseller cut Carter’s pelvic bones and inserted metal pins that would slowly pull his separated hip bones closely together over several weeks. A few weeks after his pelvic repair, Gearhart positioned Carter’s bladder deep inside the child’s abdomen, where it should have been in the first place.

A tall Southerner with a larger-than-life personality and contagious laughter, Gearhart is disarmingly casual in his interactions with the Clines. Brandon describes his very first Gearhart encounter as instant doctor-patient chemistry.

“I am sitting in the room waiting to meet this prestigious doctor and in walks Dr. Gearhart and starts asking me if I knew this person or that person,” Brandon says. “Turns out our families are from the same small town in Kentucky. “He talked to me like one of my hunting-and-fishing buddies, and immediately I felt ‘OK, we’re going to be all right here,’” Brandon says.

Gearhart’s folksy, relaxed manner and straight talk can quickly melt the suffocating anxiety experienced by parents of children with exstrophy facing one of the most complex and rarest conditions in medicine.

“Everyone else we’d seen up to that point was so tentative,” Brandon says. “Dr. Gearhart told us ‘This is what we’ll do, and this is what’s going to happen,’ and we really needed to hear that.”

In the exam room with the Clines that afternoon, Gearhart examined Carter carefully, pressing here, prodding there, firing question after question about his appetite, energy level, fevers. Pleased with Carter’s progress, Gearhart predicted that come Independence Day, the boy would be playing in the pool.

Carter’s pelvic bone reconstruction and bladder closure—considered the pivotal and most complex part of the multi-stage CE repair—were a turning point for the Clines, but his case also marked an important milestone for the Johns Hopkins Children’s Center. That spring, Carter became the 100th patient to undergo CE repair at Johns Hopkins—the highest number of such surgeries performed by any hospital.

Gearhart and Sponseller perform five to seven CE repairs a year. The number may seem misleadingly small until one factors the astonishing rarity of the condition. Estimates vary, but the general agreement is that fewer than one in 200,000 to one in 400,000 babies with CE are born every year in the United States.

“The largest CE repair series ever reported in the medical literature from a single hospital is just about 50. We’ve doubled that!” says Gearhart.

CE repair involves a multi-stage reconstruction over several years and remains one of the most challenging surgeries in modern medicine. The first repair, typically done within a few weeks of birth, involves putting any exposed abdominal organs, such as spleen, liver or intestines inside the abdomen, closing the abdominal hole and sewing the split bladder halves together. Any spinal cord defects, if present, are also repaired at this age. The second step, performed around age 1 or 2, involves cutting and realigning the split sides of the pelvic bone, followed by putting the bladder deep inside the abdomen. Finally, around age 6 or 7, patients undergo a continence procedure, during which surgeons build an internal urinary reservoir from intestinal tissue that allows children to hold urine, rendering them catheter-free.

Many of the surgical and non-surgical advances in exstrophy repair over the last several decades were spawned at Hopkins, starting in the 1970s with Robert Jeffs, the founding father of pediatric urology at Johns Hopkins, and continuing today under the leadership of Gearhart, one of Jeffs’s disciples. These advances include the development and perfection of the staged approach to exstrophy repair, the introduction of several orthopedic innovations to treat the bony malformations of exstrophy, creation of new imaging modalities and redefining the way pain is managed.

The staged surgical repair, known as the “Jeffs approach,” emerged in the 1970s and was considered experimental well into the 1990s. Today, it is the standard of care for most children with cloacal exstrophy, as well as those with bladder exstrophy—the less-severe form of the condition in which the bladder is the only organ formed outside the body. The beauty of the gradual repair is that it reduces the tension on the abdominal wall muscles caused by abrupt pel-vic bone fusion, says Gearhart, allowing the muscles of the pelvic floor to stretch slowly, over several weeks, as the bones are gradually brought closer together.

“Jeffs took a major birth defect which consigned children to a dismal life and devised a three-step technique to repair it, basically altering the lives of thousands of children throughout the world,” Gearhart says.

The Perfectionists
Historically, the rarity of CE and paucity of patients have meant fewer opportunities to study the condition, fewer surgeries and, consequently, more sluggish progress, at least when compared to the pace of advances made in more prevalent conditions such as congenital malformations of the heart, one of the most common birth defects.

As recently as the 1950s and well into the 1960s, physicians considered CE repair medically futile, sending newborns home for end-of-life care. Those who made it through the first year of life were relegated to a reclusive existence. Their bladders were excised, urine and stool-collection bags patched up to their bodies, requiring round-the-clock nursing care. The first cloacal repair leading to long-term survival was performed in 1959 by Peter Rickham, a British physician and pioneer in pediatric surgery who founded the first neonatal surgical unit in the world. Working alongside him was James Herbert Johnston, one of the founding fathers of pediatric urology. In his 1959 address to the British Paediatric Association, Rickham stated that CE was either completely absent from urology textbooks, or, when mentioned, dismissed as untreatable. Rickham made it his mission to change that.

Although a giant leap forward at the time, early CE repairs were primitive by today’s standards, but the technique improved steadily over the next 20 years. By the mid-1980s long-term survival after CE repair was hovering around 85 percent. Today, nearly every child who undergoes CE surgery survives. Most of those who undergo proper and timely repairs at the handful of institutions in the world with advanced exstrophy expertise, can also lead normal lives.

Today, the name of the game is perfection, Gearhart says.

“Today we no longer ask ourselves whether we could or should operate on these children. It’s all about how to do it in a manner that gives them a normal or near-normal physiological function and a healthy life,” Gearhart says.

Gearhart entered medicine just when pediatric urology was coming out of its “dark ages.” As a medical student at the University of Louisville, he became fascinated with embryology and abnormalities of fetal development. He felt that surgery offered a chance to correct nature’s errors: “It became clear to me that all major birth defects happen in the first 12-14 weeks of pregnancy, and that there isn’t much we can do to prevent that, but I felt surgery offered a stage to fix these defects.”

By the time Gearhart was out of medical school and entering specialty training, the field was on the cusp of a boom—an “Enlightenment” era of sorts. Gearhart went on to train in England under the exstrophy pioneer Johnston and became one of his last residents. In 1984, Gearhart joined Johns Hopkins as a fellow under Jeffs, whom he eventually succeeded as director of pediatric urology. Gearhart performed his first CE repair in 1987, and has led 60 of the more than 100 CE surgeries performed at Hopkins.

Gearhart and Sponseller have re-stored urinary continence—the definitive marker of normal urinary function and the gold standard for success in CE repair—in some 90 percent of the patients they have treated, an astounding feat given the complexity of the defect and the significant portion of corrective surgeries the two perform. About half of all CE repairs done at Hopkins are corrections of failed surgeries done elsewhere.

Reconstructing the anomalies of CE into a normal anatomy is not unlike piecing a jigsaw puzzle. The various organs and systems affected require a multidisciplinary team of specialists and years to complete. There are few other disorders that demand the breadth and depth of expertise that CE does—urology, general surgery, orthopedic surgery, neurosurgery, gastroenterology, radiology, pain management and nutrition. No two children with CE are alike. The organs involved and the severity of malformations vary greatly from patient to patient. For example, in addition to non-joined pelvic bones, some children also have club feet, tethered spinal cords or hip dislocations. This variance demands surgical timing and technique tailored to each patient’s specific anatomy and overall health. In that sense, CE surgery is not unlike performing a symphony, except each time the piece is slightly different with fewer or more elements, un-expected twists that require additional instruments or performers and, above all, a highly improvisational approach.

“We never really ‘play’ the same piece twice in the exact same way,” Gearhart says.

If Gearhart is the orchestra conductor, then Paul Sponseller, the director of pediatric orthopedics at Johns Hopkins Children’s Center, is the concert master. Sponseller repairs the bone malformations of exstrophy and his work lays the foundation for all subsequent soft-tissue and muscle corrections.

Gearhart and Sponseller cut a curious pair. Gearhart is tall, gregarious and voluble. He cracks jokes. Sponseller is a slim, gentle-eyed man of few words and quiet intensity. Over the last 30 years, Sponseller and Gearhart have operated side by side on hundreds of bladder and cloacal exstrophy patients. Their work in the OR brings to mind a beautifully synchronized duet, but their partnership goes beyond the OR. The two frequently travel abroad to perform pro-bono surgeries and train colleagues in the latest techniques of exstrophy repair.

Children with CE are born with separated and asymmetric pelvic bone due to a missing pubic symphysis, the cartilage that joins the two sides of the pelvic bone in the front. This absent joint leaves the pelvis open, split in half with a gap that can vary from 2 to 6 inches. To close the opening and realign the pelvis, surgeons cut both sides of the pelvic bone in several places, insert surgical pins and slowly pull the two sides together over several weeks. In the late 1980s, Sponseller, working with Jeffs and Gearhart, developed a novel technique that involves cutting the pelvic bone closer to the front rather than in the back. This frontal osteotomy, Sponseller says, allows the pelvic bones to rotate more naturally and eliminates the need to flip patients on their abdomen during surgery. The approach, now standard of care at Hopkins, is catching on elsewhere.

Another one of Sponseller’s innovations is the use of a metal implant to hold the hip bones together in place of the missing joint. Sponseller introduced the metal bar in the 1990s as an alternative to suturing, which, he says, was never strong enough to resist the natural tendency of the pelvic bones to pull back apart after reconstruction. And while surgical steel is decidedly better than sutures, it is less than perfect, Sponseller says. He and his colleagues are on a quest to find a more malleable material that would respond more naturally to changes in a child’s pelvis as it grows. Even though the metal bar works great in holding the pelvic bones together, it doesn’t have the flexibility of normal cartilage, which allows the pelvic bones to shift gently and separate ever so slightly during movement.

These surgical advances have not occurred in isolation. As is the case with so much of medicine, improvements in one area are often spurred by progress in other specialties and in turn fuel innovation in others. Much of the modern work in exstrophy repair would be unthinkable without advances in imaging and pain management.

Imaging has come a long way since plain X-ray films that showed nothing more than a child’s bone defects, which are only one aspect of this multi-organ condition. For example, new imaging techniques now allow for never-before-possible visualization of the layers of muscles that cover the pelvic floor and control bladder and bowel emptying.
Johns Hopkins Children’s Center radiologists have developed a system that allows for unprecedented accuracy and detail in visualizing the soft structures of the abdomen before and after surgery. One such approach combines three-dimensional and two-dimensional visualization to create an image that is greater than the sum of its parts. The 3-D image provides visualization from any angle and any plane, while the 2-D image allows for easy anatomic measurements. Combining the two is something like magic, says pediatric radiologist Aylin Tekes-Brady.

Inspired by Gearhart’s quest to perfect exstrophy imaging, Tekes-Brady recently adapted a pre-surgical navigation system used in brain surgeries to map out exstrophy repairs before surgery. Images obtained from an MR scan are uploaded into a software program that radiologists use to flag anatomic landmarks for the surgeons before they even enter the OR. “It’s like a GPS for surgical navigation,” Tekes-Brady says.

“You know where you are in three-dimensional space at all times and since so much of our surgeries involve correcting previous surgeries done elsewhere, this visualization gives us extra confidence that we’re doing the right thing in the right spot,” Gearhart says.

Cellular Cures
Advances notwithstanding, there’s much more to be done. The holy grail of understanding exstrophy—and indeed, any disorder—lies in decoding the molecular malfunction that fuels abnormal cell behavior and leads to manifest disease. That knowledge, Gearhart says, will illuminate ways to restore normal cell function. One immediate benefit of this knowledge would be to create normal bladder tissue in the lab for use in surgery.

Johns Hopkins biomedical engineer and cell biologist Larissa Shimoda, for example, is working alongside Gearhart and a cadre of pediatric urology fellows to tease out differences in behavior between the cells of normal and exstrophied bladders. A signaling protein known as transforming growth factor-beta (TGF-beta) has emerged as a potent player in the development of exstrophies. TGF-beta is already known for its role in a range of connective tissue disorders such as Marfan and Loeys-Dietz syndromes, genetic conditions marked by blood vessel laxity and dangerous stretching of the aorta, the body’s largest blood vessel. Research conducted by Shimoda and col-leagues reveals that abnormal TGF-beta signaling may also lead to anomalous cell development in the bladder.

“We’re essentially learning how cells in the bladder talk to each other,” Shimoda says. “And we’ve learned that cells in exstrophied bladders exhibit a range of abnormalities in that regard.”

Indeed, their work has revealed that cells in exstrophied bladders have low calcium levels and altered functionality, including aberrant migration and growth patterns.

Gearhart and his group recently received a green light from the National Institutes of Health to grow urinary bladder sphincters using undifferentiated cells from a patient’s own tissue. The ability to grow bladder muscle in the lab would also benefit a wider pool of patients, including those with bladder damage following traumatic injuries to the organ, male incontinence following prostate surgery and female incontinence caused by pelvic prolapse, a condition seen in older women who have given multiple births.

Gearhart’s face lights up and his already rapid-fire talk picks up pace ever so imperceptibly when he talks about the scientific advances in exstrophy repair. Yet, he says, even with all the advances in medicine and all the boundary-pushing science, one of the greatest predictors of success remains a child’s family.

“No matter how severe the birth defect, if you have a loving and supportive family, you’re already light years ahead as a surgeon,” Gearhart says.

Case in point—the Cline family and their now-thriving toddler, Carter, whose long-term prognosis is excellent.

“Carter is going to be a normal little boy,” Gearhart says. “He’s going to be able to play contact sports, and other than a few bumps on the road, his quality of life is going to be the same as any other boy’s.”