CD40LG Duplication-associated Autoimmune Disease: Elijah’s story

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Elijah’s family was running out of hope. After years of mysterious and painful symptoms, examinations by dozens of specialists at four hospitals, they were still no closer to knowing what was wrong with Elijah.

Elijah smiling outside That changed when they received a surprise phone call from a doctor they’d never met before.

“I’ll never forget that call,” says Elijah’s dad, Rich Patino. “It was a voicemail saying, “Hello Mr. Patino. My name is Neil Romberg and I’m a doctor at Children’s Hospital of Philadelphia. I came across Elijah’s file and I think I can help.”

The family was in the car and immediately pulled over to call Dr. Romberg, an immunologist and Jeffrey Modell Endowed Chair in Pediatric Immunology Research at Children’s Hospital of Philadelphia (CHOP).

That day, Dr. Romberg and the team at CHOP began a diagnostic odyssey to pinpoint the genetic and molecular cause of Elijah’s illness, leading to the discovery of a new, never-before-seen autoimmune disease, and ultimately to creating a treatment designed specifically for Elijah.

Today, Elijah is a happy, healthy and active 7-year-old who plays baseball, loves Legos®, and dreams of being an engineer.

“After five straight years of being in and out of the hospital, to see Elijah so active for the past year and a half has been wonderful,” says Elijah’s mom, Noami.

First sign of trouble: an enlarged spleen

When Elijah was born on Nov. 30, 2010, he was a healthy 5 pounds, 11 ounces. He was a little fussy as a newborn, but appeared to gain weight and quickly became a chubby baby.

The first sign of trouble came at Elijah’s 5-month well visit when his pediatrician noticed the baby’s belly was “super extended,” Noami says. After measuring Elijah’s waist, the doctor sent the family to the emergency department of a nearby hospital to get an ultrasound.

After the imaging test, doctors told Noami and Rich that their son’s spleen was about three times larger than normal. For the next week, Elijah underwent a battery of tests. Eventually, doctors diagnosed him with hemolytic anemia, a disorder in which red blood cells are destroyed faster than the bone marrow can produce them. Elijah was prescribed prednisone to suppress his immune system and lessen the inflammation. For a while, that worked. But because long-term use of prednisone has significant side effects, doctors repeatedly tried to wean Elijah off the medication.

“Every time the dosage went down, Elijah would get sick again, and then they’d increase the dose and he’d begin to get better,” Rich says. “That happened over and over again for two years.”

When Elijah wasn’t feeling well, he was lethargic and irritable, his huge belly protruded, and his enlarged spleen pushed against other organs making it painful to eat and play. When the medication was working, Elijah’s sweet personality emerged. Noami says he was an alert and curious baby who loved to explore the world around him.

Symptoms mimicked leukemia

In 2013, when Elijah was 2 ½ years old, his condition took a turn for the worse during a family vacation to Disney World. “Elijah just wasn’t acting like himself,” Rich says. “He got a fever at 2:30 p.m. every afternoon, was very lethargic, and his skin was yellow.”

“His belly was so big, he looked pregnant,” adds Elijah’s sister Mya, who’s now 12.

Back at home, Elijah was admitted to a New Jersey hospital where more tests were conducted. Again, doctors suspected leukemia or another cancer, and also considered hemophagocytic lymphohistiocytosis (HLH), which could lead to severe organ damage or death if not treated quickly enough.

“At this point, Elijah’s lungs and liver were showing major signs of infection,” Noami says. That’s when the family decided they needed a second opinion elsewhere.

The family traveled to Ohio and New York to see new specialists and undergo more tests. Both medical teams suspected Elijah had some type of autoimmune disorder but couldn’t diagnose it.

To help manage his many symptoms, Elijah began receiving intravenous gamma globulin (IVIG), an IV therapy used to fight off infections. At the time, he was under the care of a local immunologist in New Jersey.

Along with the new treatment, the Patinos decided to take a new approach to Elijah’s medical care. Instead of looking for one hospital to diagnose his overall condition, they sought help from a myriad of specialists that treat the many body systems affected by his disorder — hematology, nephrology, pulmonology, immunology — as well as an infectious disease specialist.

And this time, they came to Children’s Hospital of Philadelphia.

Advanced genetic testing

One of the doctors the family saw at CHOP, Immunologist Soma Jyonouchi, MD, ordered a new type of test for Elijah — whole exome sequencing. The genomic technique allows rapid sequencing of large amounts of DNA and catalogs all of the protein-coding genes in a person’s genome.

Dr. Jyonouchi was puzzled by the results and discussed Elijah’s case with his immunology colleagues at CHOP. Neil D. Romberg, MD, who was then new to the team, volunteered to investigate the genetic results further.

“We suspected Elijah had an inherited autoimmune disorder, but quickly realized his condition wasn’t in any of our medical books,” Dr. Romberg says.

The whole exome sequencing test identified an extra copy of a gene called CD40LG. Too much CD40LG caused Elijah’s white blood cells to inappropriately attack his own organs, causing his illness.

While doctors have known for years about hyper IgM syndrome, a condition caused by a missing CD40LG, this was the first case of the gene being duplicated. Dr. Romberg named the disorder CD40LG duplication-associated autoimmune disease.

Identifying an unknown disorder

Once Dr. Romberg identified the genetic anomaly, he wanted to understand what caused it, if anyone else in Elijah’s family had the mutation, and the best way to treat it. That’s when Dr. Romberg — who had never met the Patinos — called them out of the blue to offer them something they sorely needed: hope.

Within days, the family was back at CHOP for an appointment with Dr. Romberg. He explained he’d found a duplication of the CD40LG gene and requested that Rich, Noami and Mya donate blood to be tested.

When the family’s blood was analyzed, doctors discovered Noami shared the same genetic mutation as her son, an extra copy of CD40LG, but learned her symptoms were much different. She had experienced periodic joint pain and had sluggish blood flow to her fingertips (Raynaud’s), but medicine made the problems manageable. When she got pregnant with Elijah, her symptoms resolved.

“This disease presents differently in females and males,” says Dr. Romberg. The CD40LG gene is X-linked (located on the X chromosome). In women, who have two X chromosomes, the body compensates by silencing the abnormal, duplicated chromosome and using only the normal one. During times of stress, sickness or inflammation, that silencing may be compromised, resulting in temporary, rather than lifelong, autoimmune symptoms.

In males, there is only one X chromosome (and one Y chromosome to determine their sex). If it’s abnormal, there’s no backup X chromosome to use instead.

Noami’s parents, brother and sister were also tested. None had a duplicated CD40LG gene, leading doctors to believe Noami’s condition was caused by an accidental doubling of a small part of the X chromosome that occurred in either her parents’ eggs or sperm. Then Elijah inherited that genetic difference from his mother. At this time, Elijah and Noami are the only two people in the world diagnosed with CD40LG duplication-associated autoimmune disease.

Rare disorder — personalized treatment

Elijah with Dr Romberg After identifying the cause of Elijah’s symptoms, the hard work of developing a customized treatment began. Dr. Romberg and his colleagues needed to find a way to control Elijah’s overactive immune system while minimizing treatment side effects.

Elijah underwent two rounds of rituximab, a powerful medication used to stop his immune system from fighting itself. It wasn’t a long-term solution but it did improve his health long enough for Dr. Romberg and his team to investigate more permanent solutions.

The team determined cyclosporine A, a potent immunosuppressant medication commonly used to prevent organ rejection after transplant, could be the key to controlling Elijah’s symptoms.

Before giving the drug to Elijah however, Carole Le Coz, PhD, a researcher in Dr. Romberg’s laboratory, tested the medication on Elijah’s cells in laboratory studies to determine the appropriate dosage. Too little of the medication wouldn’t halt Elijah’s overactive immune system. Too much could cause side effects such as headache, nausea, upset stomach and high blood pressure.

Once Le Coz determined his ideal cyclosporine dose in the laboratory, Elijah began taking the customized therapy. “Within a week or two, we started noticing a difference,” Noami said. “His spleen was getting smaller, his belly less distended. He wasn’t falling asleep right after school anymore and wasn’t as lethargic. And for the first time in a long time, he began to grow — he’s grown a good six inches in the past year.”

Immunosuppressive treatment offers hope for the future

For the past year, Elijah has flourished. Along with the cyclosporine A, he also takes a daily antibiotic to help prevent infections and receives weekly injections of Hizentra® immunoglobulin therapy. He no longer needs prednisone or IVIG, and he only returns to CHOP for checkups every six months. His blood levels are monitored regularly and medication adjusted as he grows.

Now 7 years old, Elijah is an active first grader. He loves math, sports, building with Legos, and playing with Zoe, the family’s boxer.

“We still hope for a cure, but today Elijah is being successfully treated. For the most part, he can just be a normal kid,” Noami says. And Elijah has more than a few ideas for his future: “I want to be a mechanic and an engineer and a soccer star.” His sister Mya says he’d make a great engineer or electrician, “because he’s always interested in knowing how things work.”

This spring, Elijah was finally able to play baseball and soccer. Dr. Romberg prescribed a custom-made, hard-plastic guard to protect Elijah’s still-recovering spleen against any wayward balls. Contact sports like football and karate remain off-limits for Elijah.

“Words can’t capture what it means to see Elijah doing so well. To have a hospital like CHOP go above and beyond for one child — our child — is so special,” Rich says. “There are a lot of special people at CHOP. Dr. Romberg doesn’t feel like a doctor to us; he feels like a friend. And we will be forever grateful for what he’s given us.”

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