'You know, this is really not normal': Serendipitous encounter leads to girl's rare diagnosis

Lucy Wiese, who just turned 10, was diagnosed at age 3 with a very rare disorder called Jobs syndrome, which can result from a spontaneous genetic mutation. Photo / Wiese family

The pediatrician was blunt but not unkind. Even so, her unequivocal message made Jan Wiese bristle.

"You know, this is really not normal," the doctor told Wiese after seeing 2-year-old Lucy Wiese for the first time. Struck by the little girl's medical history, especially her repeated skin infections, the suburban Washington doctor recommended that Lucy see a paediatric immunologist in Baltimore.

"I was kind of offended," Wiese recalled of the encounter. It had not occurred to her or her physician husband that their daughter's infections might signal something more serious than a toddler's normal — if acute — susceptibility to unfamiliar germs.

Years later, Wiese ruefully recalled how indignant she felt. "Of course she was right," Wiese conceded.

In the months following that routine 2010 appointment, it would become clear just how extraordinary Lucy's medical situation was. Timing and luck proved to be crucial: A serendipitous encounter with a specialist expedited a diagnosis that can take decades. And proximity eased Lucy's access to one of the world's preeminent treatment centres.

Over the past eight years, Lucy's odyssey has consumed her family, who have marvelled at her ability to survive repeated setbacks and endure some of medicine's most arduous treatments. Her precarious health, which had been spiraling downward, appears to have rebounded in recent months.

"She's just a really spunky kid," her mother said. "It's really a miracle that she's here."

Lucy's birth in June 2008 at a hospital in Richmond, Virginia, followed an uneventful pregnancy. Doctors noted what they characterised as a benign newborn rash that blanketed her body. To Wiese, the rash looked like little freckles, which scabbed over and then fell off. Lucy also had a mild case of jaundice — common in newborns — which required a week of light-exposure therapy at home.

At nine months she developed an infection near her toenail. The area grew swollen and pus-filled, but it wasn't painful. The pediatrician drained it and the toe healed.

Three months later, something similar happened to two of Lucy's fingers, which she habitually sucked.

"It really looks like she's been burned," one doctor told Wiese, who assured him that this was not the case.

"Luckily, they believed me," Wiese recalled. Lucy was given antibiotics, and the doctor advised that she be prevented from sucking her fingers — easier said than done, her mother observed.

Lucy had also developed periodic patchy outbreaks on her face and torso that resembled a heat rash and puzzled her doctors.

Wiese and her husband, Scott, then a fourth-year medical student, thought Lucy might simply be vulnerable to the germs he was bringing home from the hospital.

Around the time of her first birthday, the family moved to Charlottesville, Virginia, where a new pediatrician noted the large size and unusual shape of her head, which was somewhat long and narrow.

"We have kind of big heads in our family," Wiese told the new pediatrician. After a CT scan revealed sagittal craniosynostosis, a birth defect that results in premature closure of the bones in a baby's head, Lucy was referred to a pediatric neurosurgeon at the University of Virginia. He deemed her case mild and recommended against surgery, which can be risky.

Five months later, Lucy developed an abscess behind her left ear. More serious than the previous infections, it needed to be surgically drained and required that she be hospitalised for IV antibiotics. This infection, unlike the previous ones, healed more slowly and required a round of oral antibiotics as well as corticosteroids.

Around the time of Lucy's second birthday, the family moved again, temporarily settling in the Washington suburb of Reston, Virginia. A few months later, she saw the pediatrician who recommended an immunology work-up in Baltimore.

Lucy's parents agreed, and she was placed on a waiting list at Johns Hopkins.

But weeks before her third birthday, the little girl developed a severe case of oral thrush, a fungal infection that causes white patches inside the mouth and esophagus.

"It was so painful she couldn't swallow her own saliva," Wiese recalled. Lucy was admitted to MedStar Georgetown University Hospital in Washington, where her father was an anesthesiology resident.

An infectious-disease specialist noted that thrush, one of the opportunistic infections that can affect patients with HIV, was extremely unusual in a patient Lucy's age and strongly suggested a malfunctioning immune system.

Less than a month later, Lucy was back at Georgetown with a second, severe case of thrush. This time, she saw Charlotte Barbey-Morel, then the hospital's chief of paediatric infectious diseases. (Barbey-Morel has since retired and moved back to her native Switzerland).

Wiese recalled that the specialist told her she was fairly confident she knew what was wrong. One of Barbey-Morel's colleagues, who split her time between Georgetown and the National Institutes of Health, had treated patients with a rare diagnosis whose symptoms sounded much like Lucy's.

"Charlotte called me and said, 'You're not going to believe it, but I think I have a patient with that disease'," recalled Barbey-Morel's colleague Alexandra Freeman, now director of the primary immune deficiency clinic at the National Institute of Allergy and Infectious Diseases.

"I would talk about these kids all the time. There was a lot of serendipity that Lucy happened to go there and that I had been working there. But it was really Charlotte who figured this out."

Lucy's symptoms were consistent with a rare disorder called Job's syndrome, also known as Hyper IgE syndrome. The immunodeficiency, which is estimated to affect roughly one person in a million, is caused by a mutation in the STAT 3 gene.

This defect both overstimulates and understimulates the immune system, causing severe bacterial and fungal skin infections that result in lesions and boils. (Hence the biblical moniker.) Other features include lung infections, fractures, skeletal problems including a curved spine or craniosynostosis, hyperflexible joints and dental problems.

Some cases of Job's are inherited — a parent with the disorder has a 50 percent chance of having a child with it — while others occur as a result of a spontaneous mutation.

There is no cure. Antibiotics and antifungal drugs are commonly prescribed to prevent and treat related infections.

A definitive diagnosis requires sophisticated genetic testing. And the best place to get that, Barbey-Morel told Wiese, was NIH, home to one of the world's largest Job's treatment programmes. In 2007, two teams of scientists, one from NIH, identified the gene responsible for the disorder, which had been first reported in 1966.

In early 2012, testing revealed that Lucy had the mutation. Because her parents and younger brother do not, Lucy's case is considered not hereditary but rather one that occurred by chance.

For Wiese, Lucy's diagnosis was difficult but not unexpected. "I was starting to get a little bit desperate," she said. "I think we were just feeling like finally, we can get some answers." She enrolled her daughter in a long-term study of the disorder that Freeman is conducting.

Freeman, who has seen about 130 Job's patients, said that unlike many in her study, Lucy was diagnosed at a young age. Some of her other patients, who include multiple generations from the same family, were not diagnosed until they were in their 40s, although they had been ill virtually their entire lives.

"This disease is especially tricky because it's multi-system," Freeman said.

When she was 4, Lucy landed in Georgetown's paediatric intensive care unit with a lung infection that nearly killed her and led to a cascade of recurrent severe infections.

Three years later, in the spring of 2015, Freeman proposed an experimental treatment to Lucy's parents: a bone-marrow transplant. While unlikely to provide a cure, a transplant might reduce the severity and frequency of Lucy's lung disease, which posed a continuing threat to her life, Freeman said.

The Wieses, who had moved back to Richmond, agreed that a transplant was worth a try, and Lucy became the first of three Job's patients at NIH to undergo the gruelling procedure. "Her parents are amazing," Freeman said. "They're so upbeat."

"I knew it wasn't a cure, but it was an experimental procedure that could help her," said Jan Wiese.

Lucy and her mother spent months in the Washington suburb of Bethesda, Maryland, shuttling between NIH's Clinical Center and the Children's Inn, a free residence open to severely ill children undergoing treatment at the research hospital.

In March 2016, about three months after the transplant, Lucy suffered a serious setback when her right lung collapsed as a result of pneumonia, and she underwent surgery at Children's National Medical Center.

"I remember bursting into tears when [the surgeon] came out and told us she had done so well," Wiese recalled.

In the past year, Lucy's health has improved significantly.

"She's doing much, much better," said Freeman, who saw her in June. "Her lungs are looking really good" and she has had no skin infections since the transplant.

"We're hopeful that the transplant and lung surgery helped her turn the corner," her mother said. Although Lucy is being home-schooled for health reasons, "she's got friends" and in many ways her life is no different than that of other 10-year-olds.

"We do anticipate her going to college one day," Wiese said. "I do think and hope she'll live a normal life."