Victoria Gomez fixes her enormous eyes on her parents, gazing at them through long lashes. She’s wearing a blue dress with a matching bow in her silky brown hair.
Victoria is tiny for a 3-year-old, weighing just 27 pounds, but her skin is clear and her eyes bright as she sits contentedly on her mother Darlyn’s lap. It’s an enormous improvement for a little girl who has been ill and in pain for most of her life.
“To see her now, people wouldn’t believe it,” says her father, Ariel Esquea Capellan.
Victoria has a severe case of very early onset inflammatory bowel disease — defined as inflammatory bowel disease that appears before age 6. When she was admitted to the Johns Hopkins Children’s Center on Dec. 3, 2022, she was just 16 pounds, frail and unhappy looking, with a perianal fistula, very little hair and skin pocked with lesions.
She stayed for six months as Tony Guerrerio, director of the Very Early Onset Inflammatory Bowel Disease Clinic, along with a team of other Johns Hopkins experts, fine-tuned her diagnosis and treatment, landing on a regimen of inflammation blockers that are keeping her symptoms at bay while she gains strength for a potential bone marrow transplant.
Victoria’s condition is different from irritable bowel syndrome, a chronic condition experienced by about 15% of the U.S. population and characterized by gastrointestinal discomfort. Inflammatory bowel disease is an autoimmune disorder that causes inflammation in the intestines and is often accompanied by other inflammatory diseases.
Even though the “bowel” component is emphasized in the name, inflammatory bowel disease (IBD) is typically a systemic disease, involving the gastrointestinal system but also many other organs and tissues. Like every other disease, it is caused by a combination of genetic and environmental factors, but in children, the genetic component is generally more influential, says Guerrerio, who earned both his M.D. and his Ph.D. from the Johns Hopkins University School of Medicine.
“It’s something different for everybody,” says Guerrerio. “The challenge is that every patient needs an individualized investigation and an individualized treatment plan.”
Guerrerio has been studying this debilitating condition since 2006, when he began his fellowship working with legendary Johns Hopkins geneticist and pediatrician Hal Dietz.
When the Very Early Onset (VEO)-IBD Clinic was created about five years ago, Guerrerio says, it formalized the work he was already doing and his relationship with colleagues in other divisions, including immunology, rheumatology and genetics.
The team follows about 100 patients with VEO-IBD, from diagnosis at age 6 or younger and through their teenage years.
“Establishing the clinic solidified a team of doctors and providers to create personalized plans for these very complex patients,” he says.
So far, mutations in over 90 genes encompassing diverse biological processes have been definitively linked to a clinical diagnosis of VEO-IBD, but gastrointestinal complications are known for virtually every genetically driven immune condition. Though cases of VEO-IBD appear to be on the rise, there is still much to learn before clinicians can confidently match mutations with treatments.
For Victoria, the turning point was a genetic analysis revealing that she had a rare deficiency in her RIPK1 gene, says Guerrerio. “Patients with deficits in the protein encoded by this gene can have quite widespread inflammation in their bodies.”
A Desperate Search for Answers
Ariel had moved from the Dominican Republic to Puerto Rico in 1994, when he was 12 years old, and to Maryland in 2001. A few years ago, he traveled back to the Dominican Republic for the first time to celebrate his mother’s retirement. He wasn’t planning to fall in love, but when he met Darlyn, it seemed inevitable.
The two married and eagerly awaited the day that Darlyn’s immigrant visa petition would be approved so she could move to the United States. Their happiness grew when Victoria was born on Aug. 3, 2020, weighing a healthy 7 ¾ pounds.
However, it soon became clear that their beautiful daughter was not thriving.
“Starting when she was a week old, she was getting sick, she had reflux, she was vomiting and she had a fever,” says Darlyn, who speaks Spanish, through a medical translator during a recent visit to the Children’s Center. “She was not taking breast milk or formula.”
The terrified mother went from doctor to doctor, seeking answers. First, Victoria was diagnosed as lactose intolerant, but changing her formula didn’t help. She suffered from lesions and other skin conditions, and developed a perianal fistula — a hole near her anus that is a particularly painful and dangerous IBD complication.
“I was a first-time mom, always spending time in hospitals,” says Darlyn. “All the time I was crying. I could see that she was very sick, and I was afraid she was going to die in my arms. It’s something I don’t wish for anyone.”
Doctors in the Dominican Republic eventually diagnosed Victoria with severe combined immunodeficiency (SCID), a serious genetic disorder characterized by a lack of white blood cells and therefore an inability to fight infections. The only way to cure it is by replenishing white blood cells through a bone marrow transplant.
Darlyn and Ariel knew their only hope was to get Victoria to the United States. “I was planning to bring Victoria here for medical care. And this is the hospital I had in mind to bring her to,” says Ariel, speaking with assistance from the same medical interpreter, although his English is quite strong.
“The doctors in the Dominican Republic didn’t have the ability to deal with her disease, and they wanted us to bring her here, to the United States. I was praying to God that the petition would process faster for her. And he listened to us.”
Finally, the family was united on Maryland’s Eastern Shore on Nov. 30, 2022.
Within days, Victoria was spiking a fever, and Darlyn was once again taking her to a hospital. But this time, it was in the United States, and Ariel was by her side. At last, the Gomez family’s fortunes were turning for the better.
“They started calling [the Children’s Center] to see if they had a space, and they opened one within an hour,” says Ariel.
As Victoria was getting admitted, “we explained the symptoms,” says Darlyn. “The doctors immediately started the studies.”
A Surprise Diagnosis
The combined use of detailed immune and genetic studies is essential for children presenting with suspected immune-mediated disease, because there is no single approach that is sufficiently informative alone,” says Xiao Peng, assistant professor of genetic medicine and director of the Genetics of Blood and Immunity Clinic at Johns Hopkins.
“With Victoria, she was actually partially worked up when her parents were in the Dominican Republic,” says Peng. “Her doctors there knew she had an immune problem and diagnosed her with SCID. However, we also had to consider the other facets of what immune disease can look like beyond immunodeficiency. When I saw her, I had the impression she was pretty inflamed, and we wanted to make sure to cast a wider net in our genetic differential than causes of SCID alone.”
Genetic studies showed and immune studies confirmed that Victoria’s VEO-IBD was actually just one feature of a rare immune condition called RIPK1 deficiency. There are fewer than 10 patients in the world reported to have this condition.
It was not good news.
If Victoria had had SCID, her body would not be able to make the white blood cells she needed to fight infection, but at least a bone marrow transplant, while difficult and risky, would cure her.
However, Victoria had two problems — “not only did her body not have enough white blood cells to protect her properly from infection, but it also was inappropriately inflamed because of problems with the cell-intrinsic immunity found in all her cells, not just her professional immune cells. So we were dealing with a much more complicated disease,” says Peng. “She probably felt miserable, because her body was essentially on fire.
“My heart kind of sank when I saw what it was, but at the same time, I was really glad,” says Peng. “We immediately did everything we could to get a better understanding of her specific immune issues up front, even if it involved shipping samples to another country. No matter what happens, we will walk with Victoria and her parents through this.”
A Multipronged Approach
The challenge for Victoria’s care team shifted to building up her strength for a possible bone marrow transplant while grappling with the fact — and breaking the news to her parents — that it might not make her inflammation completely stop.
“We think a bone marrow transplant is a good idea, but I don’t know if that’s going to make everything better,” Guerrerio says. “It’s only going to fix the deficiency in the white blood cells, not the immune problems within the intestinal cells themselves. The thought process, at least right now, is it would make the disease much easier to manage, such that conventional IBD medications would be more likely to control her disease.”
Victoria’s treatment, as with others receiving Johns Hopkins care for VEO-IBD, pulls from a wealth of experts and resources.
“You need gastroenterology, you need an immunologist, you need a geneticist, you need a rheumatologist,” says Guerrerio. “Very frequently, you’re going to need a pulmonologist, you’re going to need an allergist. You’re going to need the infrastructure to handle prescribing drugs for these kids and fighting with insurance to get the appropriate treatment. We could not do this without the specialty pharmacists here.”
The immediate goal was to find medications that would heal Victoria’s intestines enough that she could absorb nutrition by eating, instead of through intravenous feeding.
With the exception of a short visit home at Christmas, Victoria’s weeks in the hospital had turned to months, and her doctors wanted her to be healthy enough to go home nearly as much as Ariel and Darlyn did.
Guerrerio, Peng and Howard Lederman, director of the Immunodeficiency Clinic and Victoria’s immunologist, eventually settled on first trying a class of medications called tumor necrosis factor inhibitors, which suppress an important inflammatory signaling process relevant to Victoria’s disease.
Eventually, Victoria “started to get better, started to smile, started to laugh,” says Guerrerio. In July, she was well enough to be discharged, though she still returns to Baltimore for an infusion every four weeks. Her mother administers her other medications, including an immunoglobin injection once a week to help Victoria fight infection.
Victoria is feeling better than she ever has in her life, but she still has a tough path ahead of her. Bone marrow transplants aren’t easy — Victoria would once again be hospitalized for several weeks. But it could dramatically improve her life.
“My goal for all of my patients with IBD, early onset or not, is to get them to where their disease does not impact them on a daily basis,” says Guerrerio. “They’re always going to need medications, they’re going to need to come for visits with me and they’re going to need periodic lab work, but I want to manage their illness so there’s no impact on what they decide to do every day.”
As for Victoria’s parents, they are starting to think about school for their daughter. “She is very curious,” says Darlyn. “We are trying for a teacher to come to our house.”