Tragedy and a DNA puzzle

Transforming unspeakable loss, a couple help fund research into a rare disorder that took three of his children.

Posted: February 17, 2008

Like any thriving newborn, Lincoln Snyder was a wiggly bundle of hunger when he woke up in the morning.

So on Aug. 23, NiCole Robinson and Craig Snyder noticed the difference in their 34-day-old son. He was listless. His breathing was rapid and shallow.

The changes seemed innocuous, but Snyder's mind raced: It can't be. It must be. God, I hope it's not.

Doctors had told the couple that they could safely have children, even though Snyder and his first wife had lost two newborns to an incredibly rare, untreatable congenital lung disorder.

But here was Lincoln, struggling for breath. Rushing him to the hospital, Snyder felt an excruciating sense of helplessness. Thirteen days later, Lincoln was taken off life support. An autopsy confirmed that he, too, had the disorder, alveolar capillary dysplasia.

ACD, first described in the medical literature only 27 years ago, has defied study. The fact that it is so rare and so lethal has masked its hereditary forms, stymied gene-hunting techniques, and discouraged research funding. Why spend money on a disease known to have killed 114 newborns - ever?

When ACD killed Lincoln Snyder, however, it created an even rarer phenomenon - an unspeakable loss that opened the door to great gain.

Craig Snyder, 46, a lawyer and former chief of staff to Sen. Arlen Specter, is a lobbyist whose clients include hospitals and leading disease-advocacy groups such as Autism Speaks. Robinson, 35, is an actress perhaps best known for her role as Margaret on the TV show The West Wing. The couple have homes or offices (or both) in New York, Philadelphia and Washington.

Soon after Lincoln's death, they created the 3 Angels Memorial Fund for ACD Research to try to find the genetic cause.

"We're definitely draftees. We did not volunteer for this cause," Snyder said in the couple's Center City condo, a 36th-floor aerie with a sweeping view. "But if this tragedy was going to happen to anyone, NiCole and I are the best equipped to make something positive come out of it. We have the money, the network, the experience."

Snyder and Robinson fervently believe that finding the ACD gene is doable within a year. That could lead to a prenatal test, important for couples in their extraordinary situation. But it could also have farther-reaching benefits. It might reveal secrets of lung formation in the womb, shed light on common disease mechanisms, perhaps even explain some cases of sudden infant death syndrome.

At least, that's the hope.

A disease discovered

At a scientific conference in 1990, Claire Langston presented the first detailed analysis of a case of alveolar capillary dysplasia.

Langston, a pediatric pathologist at the Baylor College of Medicine in Houston, had autopsied the corpse of a full-term, deceptively healthy-looking newborn. In the lungs, she found some veins distorted and "misaligned." But the real problem was microscopic.

The tiniest pulmonary blood vessels - capillaries four-millionths of an inch thick, finer than human hair - were mostly missing, apparently never formed. Normally, beginning in the 16th week of fetal development, these capillaries wrap like a vine around the lung's air sacs, called alveoli. With an infant's first gulp of air at birth, oxygen seeps through the alveoli into the capillaries, then rushes into the bloodstream.

No capillaries meant no respiration. No survival.

To Langston's surprise, her paper was "a smash hit." It turned her into the preeminent - if not only - expert on ACD. Case reports from around the world began trickling in to her.

Because none of these known cases were siblings, ACD was believed to involve a spontaneous, out-of-the-blue gene mutation in the baby. Such "sporadic" mutations were impossible to predict or prevent, but at least the one that caused ACD was so uncommon it couldn't arise twice in one family.

That's what doctors told Snyder and his then-wife, Lois, after their firstborn, Rebecca, died in 1991 despite heroic measures to save her at St. Christopher's Hospital for Children in Philadelphia. They were assured that ACD - diagnosed on autopsy by a savvy coroner - could not strike again.

The next year, the Snyders welcomed the birth of Jonathan.

He died on his 42d day - as had his sister - but unlike her, he had become gravely ill within hours of birth.

Day after day, he was kept barely alive only because Children's Hospital of Philadelphia had new technology to bypass the heart and lungs, a machine called extracorporeal membrane oxygenation, or ECMO. When even that did no good, Jonathan was scheduled for what would have been the first infant heart-lung transplant.

"He never got that far," Snyder said. "His other organs failed."

Soon after the autopsy confirmed Jonathan had ACD, one of his doctors, Elaine Zackai, contacted Langston. Jonathan's death showed ACD could run in families, suggesting a hereditary form.

Langston and Zackai subsequently published a paper on the first known ACD siblings.

And scientists began rethinking what they had believed.

Another baby lost

Snyder met Robinson in 2002 when they were doing advocacy work for an autism organization.

"The truth: Bradley Whitford couldn't go," Robinson said, referring to her West Wing cast mate, who went to college with the founder of Cure Autism Now.

Snyder was immediately smitten by the vivacious redhead, who was incongruously funny and porcelain-doll pretty. (Not unlike Margaret, the quirky secretary to the president's chief of staff.)

By their second date - in Las Vegas, where she was doing stand-up comedy - the Idaho-born Mormon who became a Hollywood actress and the Jewish lawyer from Philly were headed for marriage.

Naturally, they anguished about having children. When Robinson got pregnant in 2004, Snyder wrote a six-page backgrounder for the pediatrician.

But all the doctors they consulted reassured them. By then, Langston's team at Baylor had pedigrees for more than 30 ACD families. Some had found her through the Alveolar Capillary Dysplasia Association, an Internet support group created by bereaved parents. Among the 30 families were six with affected siblings, and four in which parents had divorced, remarried and had more children.

All of these families fit the theory that the inherited form of ACD was caused by a recessive gene mutation - meaning both parents had to carry the defect and both had to pass it on for their child to have the disease.

Given how rare the mutation was, it was unimaginable that Snyder would wind up with a genetically star-crossed mate - not just once, but twice.

In 2005, Robinson gave birth to Shirley. As she grew into an adorable, assertive toddler, she seemed to be proof that the doctors were right.

And then came Lincoln - 20 inches long and not quite 7 pounds, with thick dark hair and piercing brown eyes.

Hours after his birth on July 20, he developed a grayish pallor - possibly a sign of oxygen deprivation - but it went away, and doctors chalked it up to a transient heart-duct problem that occurs in some newborns.

"He looked fine," Robinson said. "He was eating, sleeping, growing."

Sitting in their living room, with Floyd the German shepherd hovering protectively, Robinson pulled out a stack of snapshots: Linc snuggling in bed with Shirley. Linc in his stroller. Linc's hand wrapped around his mother's finger. Shirley "reading" to Linc and her stuffed animals.

"These are what I like to call 'the Hemingway shots,' " Robinson said of Linc furrowing his brow in apparent deep contemplation.

When his breathing became labored on Aug. 23 - two days after his birth announcement went in the mail - the family was in New York City. Snyder and Robinson rushed him to the Weill Cornell Medical Center, where he was intubated, connected to a ventilator, and treated with the usual desperate medical arsenal. Antibiotics. Nitric oxide. Surfactant.

Naomi Bishop, a pediatric critical-care physician with decades of experience, had never seen a case of ACD.

"Craig pulled us aside and said, 'This is painfully familiar to me,' " Bishop recalled. "I deal with tragedy on a regular basis, but this was almost unthinkable. The horror of it still has not left me."

Snyder refused the heart-lung bypass machine, determined not to submit his son to a futile ordeal. Still, the baby hung on.

His parents could not hold him because any stress, even the touch of a hand, was enough to depress his vital signs. Robinson played a recording of household noises and voices each morning, watching brief improvements in Lincoln's heart rate signaling his awareness.

Definitive diagnosis of ACD requires a lung biopsy - not advisable in a fragile infant. Because the doctors could not rule out that Lincoln had a survivable illness, they didn't want to say what his parents already knew: There was no hope.

On Sept. 5, Snyder and Robinson asked Bishop to help them withdraw life support, an arduous process that involves notification of hospital officials and reams of consent forms. The couple also wanted to donate their son's organs and carefully preserve tissue samples for research.

Bishop called their courage "remarkable."

"NiCole said, 'I want to be holding Lincoln when we disconnect the ventilator because I want his last memory to be my voice and touch.' "

A dominant gene

Lincoln's death complicated the genetic puzzle of ACD even as it simplified the technological search for the mutation. The obvious inference was that Lincoln, Jonathan and Rebecca all had inherited ACD from the parent they had in common - their father. That meant Snyder's gene had to be dominant: Only one copy would be needed to produce the disease.

"The fact that his nickname was Linc - he is the link," Robinson said.

The Center for Applied Genomics at Children's Hospital of Philadelphia, which has one of the world's most advanced genotyping programs, has made rapid headway toward finding the gene.

Lincoln's DNA sample was the key to homing in on areas of three chromosomes where the mutation may exist, center director Hakon Hakonarson said.

That's still a vast expanse of DNA to comb through - like looking for a single typo in the many chapters of three big books. Even so, Hakonarson said he was optimistic that the mutation could be found within a year with tissue samples from a few more ACD families. Toward that end, he hopes to collaborate with researchers at Baylor - something that Langston said she was open to, and that Snyder is eager to arrange.

Even if they find the mutation, many questions will remain: Are there other ACD-causing gene defects that are recessive? Does the dominant form always cause disease, or is its activity sometimes masked, as it apparently is in Snyder? How much does the severity of ACD vary? Could some people with chronic pulmonary problems have mild ACD?

The 3 Angels foundation is assembling the funding, awareness campaigns, and research agenda to find answers. Snyder obtained a $250,000 congressional appropriation that the U.S. Centers for Disease Control and Prevention will use to educate neonatologists about ACD - an important step toward collecting more tissue samples and figuring out the true incidence of the disease. Robinson has lined up a friend, Tony Award-winning singer and West Wing cast mate Kristin Chenoweth, to do two fund-raising concerts.

This is not just about ACD, experts agree, but about understanding the primitive molecular origins of pulmonary vascular development.

"That could be important for other diseases and for repair mechanisms that could benefit many more people," Langston said.

Snyder and Robinson would love to have another child if research yielded a prenatal test for ACD, so speeding up the glacial pace of scientific discovery is in their interest. But like the very decision to conceive, their motivation is manifold.

"It's our way to honor these three children, and also protect our Shirley in case she carries the gene," Snyder said. "And maybe do something good for the world."


Contact staff writer Marie McCullough at 215-854-2720 or mmccullough@phillynews.com.

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