Nicholas Volker (1/3): A baffling illness

Desperate for clues to a 4-year-old’s gut-destroying disease, doctors wonder whether a pioneering DNA technique could help.

One in a Billion

A boy’s life, a medical mystery: Read the full series and view videos, photo galleries and interactive graphics.

On a Saturday morning in June, when his children are at piano lessons and the Whitefish Bay house is quiet, pediatrician Alan Mayer composes the e-mail he hopes will persuade a colleague to try a costly new technology. He has been shaping the argument in his mind – the chance to take the first steps into the future of medicine and maybe save the life of a very sick little boy.

“Dear Howard – I hope you are well,” he writes, addressing Howard Jacob, director of the Medical College of Wisconsin’s Human and Molecular Genetics Center. “I’m writing to get your thoughts on a patient of mine . . . ”

Nicholas Volker is a short, blue-eyed 4-year-old who loves Batman and squirt gun fights and steak – on the rare occasions when he’s not restricted to a feeding tube.

Food has become his dream – and his curse. Severely underweight, he arrived at Children’s Hospital of Wisconsin in 2007 with the bony arms and distended belly of a famine victim. Yet when he ate, unusual holes would open between his intestine and skin, causing feces to leak into a large wound in his abdomen.

For two years he has suffered from this mysterious illness. He has survived more than 100 trips to the operating room. He has endured gut pains so severe he asked his mother to pray for him. Surgeons have removed his colon, its pink hue discolored by an enormous yellow ulcer.

The disease is relentless. Mayer and the other doctors have never seen anything like it. They have been unable to find another doctor anywhere who has observed the boy’s affliction. Nor have they found the disease among millions of entries in the medical literature.

The case churns through Mayer’s brain at night. He dreams of being lost in the woods and wakes with a tightness in his throat that comes from feeling responsible for another life.

A 44-year-old father of two with a background in genetics, Mayer has now arrived at what may be Nicholas’ last hope.

“I am writing to ask if there is some way we can get his genome sequenced,” he tells Jacob. “There is a good chance Nicholas has a genetic defect, and it is likely to be a new disease. Furthermore, a diagnosis soon could save his life and truly showcase personalized genomic medicine.”

As he types that morning, June 27, 2009, Mayer realizes he is proposing a high-tech fishing expedition – the search for some mutation in a gene that explains the vicious disease he sees in the boy. They could spend months and tens of thousands of dollars only to find not one culprit, but a multitude among Nicholas’ 21,000 or so genes. Even if they are lucky enough to find a single mutation, it is only a first step. They could discover the cause of the disease and learn they are helpless to treat it.

Mayer understands the uncertainties. They are outweighed by his responsibility to the boy and his faith that he’ll know the right mutation when he sees it. The doctor rereads and polishes the e-mail until he is certain he has made his best case.

Then he hits “send.”

Mayer’s plea goes beyond one sick child. Reading Nicholas Volker’s genes could change the way doctors treat patients, especially those whose symptoms don’t match any known disease.

Even if the boy’s illness affects just a handful of people around the world, the technique might be used to diagnose other rare, hereditary illnesses. Taken together, rare diseases, most of them hereditary, afflict 25 million to 30 million Americans, roughly one in 10.

The sequencing question also goes beyond standard medical research with its anonymous participants and far-off benefits. This time scientists would be trying to help a single child with a name and a desperate need.

Seldom has there been such urgency connected to the sequencing of one person’s DNA. To this point, the technology has been used for research, or as a crystal ball to tell us whether we have a mutation that will lead later to a devastating disease such as Huntington’s.

What Mayer needs is not a forecast, but an explanation for the disease Nicholas has today. Without it, he can only respond to symptoms.

The doctor has come to view the unknown illness as a dragon. All his skill has only lulled it into a temporary sleep.

“You want this dragon gone,” he says.

From his office window at the Medical College, Howard Jacob can see Flight for Life helicopters land on the roof of nearby Froedtert Hospital. Urgency is something he understands.

For almost two decades Jacob has pushed to take our genetic code from the laboratory to the health care system. He imagines a day when doctors will read our DNA, review health risks, and devise ways of countering the defects and vulnerabilities each one of us has inherited.

But this is only a vision on the morning he reads Mayer’s e-mail. His target for sequencing patients at the hospital is 2014, still an ambitious timetable. As of June 2009, there have been no published reports of patients diagnosed using this technology.

If sequencing enters the clinic in 2014, a new era in medicine will begin 61 years after James Watson and Francis Crick discovered DNA’s structure, the spiraling strands, or double helix, that Crick called “the secret of life.”

The new era would dawn some 40 years after Americans Walter Gilbert and Allan Maxam and Englishman Fred Sanger discovered different methods of reading the information on the double helix. They translated our genetic makeup into chains of chemical bases, a language of sentences and paragraphs written in a four-letter code: A for the base adenine; G for guanine; T for thymine and C for cytosine.

The new era would begin a little more than a decade after the Human Genome Project took the Gilbert-Maxam-Sanger discoveries to their logical extension by stringing together those sentences and paragraphs to produce the finished book, the first complete blueprint of a human being.

Jacob had played a major role in the 2004 sequencing of the first rat genome, significant because the vast majority of medicines are developed and tested using rats. He has seen the field move rapidly, especially in the last few years.

At presentations, he shows a slide of the machines that sequenced the first human genome. It took hundreds of machines seven years to accomplish the feat at a cost of $600 million. Today, a single machine at the Medical College accomplishes the job of 200 of the original human genome workhorses.

Sequencing a genome now takes a few months and costs tens of thousands, or hundreds of thousands of dollars, depending on the level of analysis.

Mayer’s e-mail challenges Jacob and the Medical College to go beyond what can be done in theory or in several years.

If Nicholas Volker’s disease continues, if doctors cannot discover the cause, he may not live to see 2014 and the grand plans Jacob has envisioned.

At the end of the e-mail is a link to the online journal kept by Amylynne Santiago Volker, Nicholas’ mother. Read it, Mayer says, “and you will get a good flavor for the desperation of this situation.”

Jacob has two children of his own. He clicks on the journal and reads.

The story begins October 26, 2004. The birth of a boy with a name as unique as his genes: Nicholas Zane Fernando Santiago Volker.

Amylynne, a homeschooling mom, and her husband, Sean, an electrician, choose “Nicholas” after the patron saint of children. The parents are Christians, regulars at their church in Madison. A silver cross dangles from Amylynne’s neck.

Sean, a quiet, pickup truck and blue jeans kind of guy, has wanted a boy so badly – they have three girls – that before the birth, he would not allow Amylynne to pick female names. He sees himself tossing a football to his son, a Wisconsin boy through and through.

For almost two years, Nicholas appears healthy, the only sign of trouble, a certain pickiness about food. While he consumes breast milk, other foods repulse him. He lags on the growth charts.

Just before Nicholas’ second birthday Amylynne discovers an abscess at the opening of his rectum. Doctors at the University of Wisconsin Children’s Hospital in Madison give him antibiotics and the abscess bursts.

In its place, two holes appear. It does not seem to Amylynne that the doctors are worried initially, but she is sure something is wrong. She has grown up with doctors: her father, stepmother, two brothers and their wives, a sister and her husband.

Her fears are borne out. The two holes merge into a larger opening, and stool leaks through it.

But tests only tell the doctors what Nicholas does not have.

Eight months of visits to UW Children’s Hospital bring a succession of medications.

No diagnosis.

The disease is relentless.

In early 2007, Amylynne takes Nicholas to a gastroenterologist at Children’s Hospital of Wisconsin near Milwaukee for a second opinion. Subra Kugathasan has seen hundreds of patients with inflammatory bowel disease, but none like Nicholas.

The boy is much younger than most patients with such an illness. His symptoms resemble Crohn’s disease, a type of inflammatory bowel disease. But Crohn’s can be treated. Nicholas’ disease cannot.

“He basically failed every single medical, surgical and nutritional approach,” Kugathasan would say.

Amylynne likes Kugathasan for his gentleness. She forms a particular bond with Marjorie Arca, the pediatric surgeon who examines Nicholas’ large intestine.

Arca fell in love with pediatrics years ago, the evening a sick 4-year-old gave her a Christmas ornament he’d made. Amylynne trusts her. Both women are Filipino. Both wear crosses. Most of all, Arca is thorough.

In her initial examination, the surgeon discovers that Nicholas now has four holes, pencil pricks drilled through the skin all the way into his intestine. That’s why stool is leaking. Arca says the holes are called fistulas. Weeks earlier another doctor had found no fistulas.

Arca performs a colostomy, diverting waste from his damaged intestine to a bag outside his stomach.

Less than a month after the surgery, Nicholas has more fistulas. The skin surrounding the holes grows purple. By late June, Nicholas seems to be fading fast.

Doctors give him blood transfusions and a medication that spurs the production of infection-fighting white blood cells. Gradually his energy returns. He is playing with his trains again. His cheeks grow chubby. The fistulas heal.

On Sept. 1, 2007, he tells his mom he’s not sick anymore.

Two days later, the Volkers race along I-94 from Madison, bound for the emergency room at Children’s Hospital. In the back seat, Nicholas is hallucinating. He sees spiders on the ceiling.

He had been doing so well. Home from the hospital for the weekend. Blood counts good.

But Sunday his breathing had turned rapid and shallow. He had no energy. Amylynne felt his forehead; he was burning up.

She knew what was wrong. Nicholas had classic symptoms of sepsis, an often deadly blood infection.

As Sean drives, Amylynne sits in back comforting Nicholas. The boy is sweating, his pulse galloping. He mumbles and Amylynne prays aloud, the words flowing almost mechanically because there have been so many emergencies.

Oh Heavenly Father, I ask that you please protect Nic.

Children’s Hospital confirms her fear. Nicholas has sepsis. For several weeks, her journal fills with worry. Sometimes others write the entries. While Sean works and cares for the girls, Amylynne seldom leaves her son’s bedside. Although she is not supposed to, some nights she curls up beside him.

Nurses marvel at the way she pulls herself together each morning, applying makeup, dressing in business suits. She does not give up on anything, not even her appearance. No matter how grave the news.

Sept. 4.

“Nicky is in dire straits . . . He is at risk for all organs being damaged or failing now. His temp is now at 106 . . . ”

Sept. 6.

“The doctors are asking her to make decisions about whether or not to resuscitate him if he would go into cardiac arrest . . . ”

Sept. 13.

“Nicholas had a couple of breathing scares because of his collapsed lung . . . ”

Sept. 20.

“Nicky is in day 5 of a very high fever which has reached as high as 105.6. He has tested positive for E. coli which has come from his breathing tube.”

At times the situation is so serious that relatives talk to Amylynne about visiting a funeral home; she refuses. Her father encourages her to give a “do not resuscitate” order. Absolutely not, she says. I will not give up hope.

There is a word she won’t write in her journal. She calls it “the D word.”

In the end, there is no need for the word. After receiving powerful antibiotics and numerous transfusions of blood, plasma and platelets, the boy Amylynne calls her “little warrior” pulls through. A month after the crisis began, he is well enough to eat scrambled eggs, the first food in all that time that has not come through a tube. In late October, seven weeks after the sprint to the emergency room, Nicholas goes home.

Early in 2008, the inflammation and fistulas return.

The longer Nicholas’ illness defies diagnosis, the more specialists weigh in. Half a dozen doctors now form the core of the boy’s expanding medical team. They take home questions and hunches about him. At night, they search the medical literature. At conferences across the country, they tell colleagues about Patient X, the anonymous child with the mysterious disease.

“I thought he was going to be one of those kids who dies without us knowing the answer,” Kugathasan would say.

Doctors run tests on individual genes and more tests on the immune system. One theory holds that Nicholas’ immune system has turned against his body, killing healthy cells. Bill Grossman, an immunologist at Children’s and the Medical College, spends hour after hour dissecting complex genetic pathways, hoping to understand what is happening inside the child’s body.

“We did pretty much any test you can think of on him,” Grossman says. “The more we got back, the more confusing the picture was. . . . He really was a one in a billion kind of case.”

In August 2008, the Volkers seek another opinion, this time at Cincinnati Children’s Hospital Medical Center, which has expertise in illnesses that resemble Nicholas’.

“He’s certainly one of the sickest children we’ve seen,” says Ted Denson, who is medical director of the hospital’s center specializing in inflammatory bowel disease. “You needed to give him about twice as much nutrition as you’d normally give a child to get any weight gain at all.”

The doctors in Cincinnati conduct numerous blood and genetic tests. They find no specific genetic cause. The best they can tell, Nicholas has an immune disorder. For some reason, white blood cells called lymphocytes have kicked into overdrive, destroying cells that line the intestinal wall. The Cincinnati hospital concludes that Nicholas must receive more nutrition until he is well enough to have his diseased colon removed.

By January 2009, Nicholas is back at Children’s Hospital of Wisconsin. He is now 4 years old. He has been poked, prodded and jabbed with needles so often that sometimes he growls at the doctors and nurses.

He weighs less than 20 pounds, well below the 35 pounds of a typical 4-year-old.

No diagnosis.

The gaping wound in Nicholas’ abdomen from his colostomy will not heal. As the disease spreads from his bottom to his colon and small intestine, more holes form and stool drains through them into the wound, raising the threat of infection.

No article in a medical journal prepares a surgeon for such a wound. It must be cleaned and dressed so frequently that for several months Arca has a standing daily appointment with Nicholas in the operating room.

Although cleaning and dressing wounds is not usually considered surgery, in Nicholas’ case the task takes at least two hours and requires general anesthesia.

They have a routine. Nicholas’ mother carries him to the operating room, which she cannot enter without wearing scrubs. Arca meets her and carries the boy inside.

Often Nicholas wears his black Batman cape and mask. On his hands: Batman gloves that make the sound “Ka-pow!” He prefers to be called “Batman.”

What should we listen to? Arca usually asks. Jonas Brothers?

Nicholas likes the Jonas Brothers. His mother has heard him sing: “A little bit longer and I’ll be fine.”

He holds out the tube in his chest, used for medications, fluids and blood draws.

I would like milky Versed, he says. That’s what he calls the anesthetic propofol (it reminds him of Versed, a sedation drug).

He chooses a flavor for the oxygen he receives. Today it’s blueberry.

I’ll hold the mask, he says. If residents try, he pushes them away.

When it is over and his eyes open in the recovery area, Nicholas always asks for Mom.

By summer 2009, Nicholas has spent more than 300 days at Children’s Hospital. Time enough for Kugathasan to move to a hospital in Atlanta and Grossman to move to a pharmaceutical company. Time enough for Kugathasan to be replaced by Michael Stephens, a gastroenterologist, who is replaced by Mayer.

Time enough for one of the nurses, Tara Bell, to find she is caring for Nicholas not only at work but in her dreams.

The wound in his abdomen heals after his inflamed colon is removed. Still, the boy’s health rises and falls so often and the lack of a diagnosis persists so long that conflicts between the Volkers and their medical team become inevitable. Getting Nicholas to gain weight without sprouting new fistulas becomes a personal mission for Mayer. At times when they disagree, Amylynne reminds him: “He’s not your child. He’s my child.”

 

She has learned to care for Nicholas outside the hospital. Years ago, she had been squeamish to the point of throwing up at the sight of excrement and had declined her father’s wish that she attend nursing school. Now she changes colostomy bags and flushes and maintains intravenous lines. She considers becoming a nurse.

Nicholas’ three sisters, all teenagers, think of their brother at school when friends mention younger siblings. They miss the crazy things he says, and even the way he gets them to compete for the honor of favorite sister.

Sean endures long absences from his son for the first two years of the illness, taking all the overtime he can get to pay what health insurance will not. Then, in the early months of 2009, the construction jobs dry up and he and Amylynne swap roles. He goes to the hospital; she does clerical work for Great Wolf Resorts.

The father and son grow close, passing long hours in the hospital room playing on the floor and talking superheroes and monster trucks. When Sean returns to construction sites, he thinks back to those days, and sometimes his phone rings and it is Nicholas’ high-pitched voice: Dad, when are you coming?

The long hospital stays get to Nicholas most of all. Amylynne sees the way he grows so familiar with the different floors that the hospital becomes a de facto home, the way he longs for friends and enjoys “hospital play dates,” the way his friends always leave. They go home after a few weeks, or they die.

Months have passed since the last time Nicholas ate real food. He tells a nurse about the steak he will eat when he goes home. At night, he sleeps with a bag of Bagel Bites cradled in his arms.

There are days Nicholas asks:

Mom, is God listening?

Is He there?

Because, why would I be here then?

Sometimes Amylynne tells him: God is always with us. Sometimes the questions leave her speechless, wiping away tears.

By now she is desperate to cure Nicholas herself. After doctors suggest he may need a bone marrow transplant, Amylynne talks with Sean about having a baby to serve as the donor (no one in their blended family is a genetic match for Nicholas). Her pastor dissuades her, saying that she would be forcing a solution rather than trusting God to provide one.

So when Mayer suggests sequencing Nicholas’ DNA, she is ready.

The cost will be high. Even if insurance did pay for such things, Nicholas has exceeded his $2 million lifetime benefit. Money will have to be raised.

Reading his DNA will have implications for the family. Nicholas’ genetic information comes from his parents; examining it will reveal things about them and about their relatives. Doctors seeking the cause of Nicholas’ gut disease could find mutations for other illnesses that run in families.

None of that worries Amylynne. What matters is Nicholas.

The mother’s journal is 230 pages and growing. A book with no end in sight.

As he reads, Howard Jacob, head of the Medical College’s genetics center, wonders what it would be like to watch one of his children wheeled into the operating room.

He imagines his child disappearing behind a door where he can neither follow nor offer protection. Then he tries to imagine experiencing that moment more than 100 times, as the Volkers have.

Jacob knows the chances of finding the cause of Nicholas’ illness – perhaps one mutation hidden among thousands of minor variations in his genetic script – are slim to none. He knows, too, that without a diagnosis the boy’s long-term odds are little better.

He must weigh the two. The risk that an ambitious test of a new technology could fail. The risk that if they do not make the attempt, a young boy could die.

Jacob recalls what he tells his students. You do the experiment because you need to do it.

There is no other way to learn whether something works.


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