Individualized Medical Genetics: Connor’s Story

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Connor suffered from an unusual series of infections as a young child, then developed osteoporosis. His parents brought him from Texas to Philadelphia to find a cause for his symptoms. Genetic testing found a mutation in the STAT3 gene, which led to a tailored treatment plan that is allowing him to live life to the fullest.

Connor playing basketball When Connor was 8, he started to have terrible back pain after jumping on a trampoline. Doctors in Texas, where the family lives, found that he had compression fractures in the thoracic and lumbar regions of his spine. A bone density test revealed significant osteoporosis. But scans and blood tests didn’t reveal a cause for the weakness in Connor’s bones. He was fitted with a back brace and prescribed rest, causing him to miss several weeks of school.

Coming back to CHOP

“They suggested we wait it out,” recalls Connor’s parents, Sharon and Gil. “But we knew that a healthy child does not get osteoporosis.” The family had experienced the medical expertise at Children’s Hospital of Philadelphia (CHOP) many years before, where Connor’s older brother had been treated for leukemia. They reached out to specialists there, and started the process of getting insurance approval for a second opinion and additional testing.

The family flew to Philadelphia to meet with Edward Behrens, MD, Chief of the Division of Rheumatology at CHOP. He reviewed Connor’s history, which, in addition to his osteoporosis, included numerous childhood infections. Connor had pneumonia four times as a toddler and had undergone multiple sinus surgeries. Treatment with antibiotics had often been unsuccessful. He’d spent weeks with sicknesses that other children would have recovered from quickly.

Dr. Behrens thought the combination of health problems might be linked in some way, and suggested the family meet with genetic experts at CHOP’s Roberts Individualized Medical Genetics Center (IMGC). The Center facilitates access to genetic testing, and its experts explain the tests to patients and families. Dr. Behrens also recommended that Connor start treatment with bisphosphonate medication to slow down or prevent bone loss, and he made a referral to a doctor in Texas.

Using exome sequencing

The next day, Connor and Sharon met with Livija Medne, MS, LCGC, a senior genetic counselor, and Cara Skraban, MD, an attending physician in the Division of Genetics. Livija and Dr. Skraban agreed with Dr. Behrens that Connor’s medical problems might be connected and might have a genetic cause. They recommended exome sequencing, a comprehensive test that reads the genetic code of about 20,000 genes, and SNP-based chromosomal microarray analysis, a test that looks for extra or missing portions of chromosomes.

Connor’s parents agreed to the tests. “We were flying back to Texas in two days,” Sharon says, “So they expedited the process, knowing our time at CHOP was limited. We agreed to have our blood drawn and DNA saved while the Roberts IMGC team worked to obtain insurance authorization.”

The authorization and subsequent analysis of the samples took several months. A conference call was scheduled with Sharon and Gil, the Roberts IMGC team, Dr. Behrens and Kathleen Sullivan, MD, Chief of the Division of Allergy and Immunology.

The medical team explained that Connor has a novel mutation in the STAT3 gene, known to cause a form of an immune disorder called hyper-IgE syndrome. At the time of the call, the team suspected this gene change played a role in Connor’s findings, but could not definitively say if the gene change fully explained his symptoms.

Connor and Sharon returned to CHOP in July 2016 to see Dr. Sullivan for an Immunology evaluation. After examining Connor and reviewing his medical history, she felt that Connor’s clinical course and findings were consistent with a mild form of hyper-IgE syndrome.

Developing a medical plan

“This explained a lot!” Sharon says. She knew that IgG levels are key to the body’s ability to fight infections. Connor’s IgG levels had tended to run a little low, but the connection had never been made to his multiple bouts with illness.

Dr. Sullivan devised a medical plan for Connor. Additional research-based testing done in collaboration with her colleagues at the National Institutes of Health showed that the protein product coded from STAT3 gene in Connor had some atypical function. This finding added another layer of evidence that the STAT3 gene change was playing a role in Connor’s symptoms. Dr. Sullivan also reached out to his doctors in Texas and explained the findings.

Connor continued with bisphosphonate medication for a year and a half, which restored his bone density to near normal levels. The compression fractures in his spine healed, and he was able to retire the back brace. With the genetic diagnosis, treatment for infections is handled differently now. When he gets sick, a culture is started, and when the source of the infection is identified, a specifically targeted course of antibiotics is prescribed. The goal is to maintain the effectiveness of each antibiotic instead of giving him a broad-based antibiotic that his body could become immune to.

Connor today

Connor playing in the sand at the beach At 10, Connor enjoys swimming, golf and riding his bike. He’s a good-natured, caring kid who goes out of his way to help others. And he loves his dog, Harlow.

“Without the help of the Roberts IMGC team, Dr. Behrens and Dr. Sullivan, we would not have found a diagnosis for Connor, which led to starting the appropriate treatment,” says Sharon.

We are thankful to these specialists and the Roberts IMGC team as they went above and beyond to help our son. We are truly grateful”.

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