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Diagnosing a Rare, Genetic Disease

Five years ago, a one-year-old boy named Connor was brought in for a second opinion. He had gone to a fine pediatrician on the Main Line who knew that something was very wrong, but did not know exactly what.

by Gary Emmett, M.D.

Five years ago, a one-year-old boy named Connor was brought into my office for a second opinion. He had gone to a fine pediatrician on the Main Line who knew that something was very wrong, but did not know exactly what. As a baby, Connor had seemed healthy and normal until about 4 months when instead of growing new skills, he started losing old ones. He had rolled over by 4 months, but then he stopped turning over. He no longer paid attention to people or smiled for his mother. Connor had seen a developmental specialist who took a sample of his chromosomes and performed an imaging study of his brain, but couldn't make a diagnosis.

Connor's mother was determined to find out what was wrong. She is a very bright woman who knows that names give us power. We might find a treatment if we knew the name of Connor's condition. We might find the origin of his developmental delay if we had a name. We would know if it could happen again in his family. (Fortunately, it did not. Connor has a younger, perfectly healthy sister and an older, equally healthy brother.)

I did not know the name of Connor's problem either, but I had an intuition that a single gene was not working properly. He was (and is) a beautiful, fair child with very large eyes and always a smile. He had a very wide mouth, Cupid's bow lips -- and poor muscle tone. When I first met him he was very weak; he "performed" developmentally at the level of kids less than half his age. But, I could tell he was really not so much losing skills as trying to move with muscles too weak to work well. This was good news, because babies who are really losing developmental milestones have deteriorating brains. They will always get much worse. Also on his side: His mom's powerful determination, which meant we were going to get a name for what he had or bust.

Finding that name took time. We didn't wait. Long before he was finally diagnosed, Connor was in an early intervention program and attended an Easter Seals daycare plus physical therapy. His parents took him to see orthopedic and developmental doctors. The result: Now he can interact, though talking is still a challenge. He can move with braces. He can take care of himself a little. And he continually gets better, though he has a long way to go.

What about his diagnosis? That was a long road. TV and the media give us the impression that you just put a patient's blood sample into a machine and it spits out a diagnosis. But it's not that easy. When diagnosing a suspected genetic disease, a physician can ask a lab whether a patient has one or more specific conditions. Then the lab answers with a definitive "Yes" or "No" (if you are lucky), and a "Maybe" if you are not very lucky. Parents know that their new babies have blood drawn at birth and tested for many genetic diseases, but there are several thousand named genetic diseases out there (and more yet to be named). We test for less than 40 in Pennsylvania; some states test for only 6. So finding answers can take a long time.

Other clues can help point to the right name. The doctor can look for "stigmata" — physical signs of a condition. In this case, Connor's handsome but unusual facial features helped. So did his brain-imaging study, which was abnormal but didn't give us enough information to make a diagnosis. General chromosome checks came back normal, but a check of a specific gene uncovered the answer. Connor has a single gene mutation called Pitt-Hopkins Syndrome - PTHS.

According to a support group called the Pitt Hopkins Syndrome International Network, PTHS is a rare genetic disorder affecting a specific gene in chromosome 18, called TCF4. This gene affects development of the nervous system and the brain. Until recently, the group says, even getting PTHS diagnosis was impossible; the condition's genetic causes, and a test for it, were only found in 2007. When the support group formed a year later, parents discovered that they weren't alone – and that many kids with PTHS can, like Connor, improve their skills. These kids, the group says, "are creative, vibrant, and joyful people continuing to learn over time, and who seem to bring happiness to everyone who knows them."

Naming this condition is powerful not just for individual families. Once the gene was discovered, and with it a test that gave families around the world a diagnosis at last, parents and researchers could pool information on treatments, support each other, and learn more about daily life with a child with PTHS.

Connor's family belongs to an on-line support group of parents of children diagnosed with PTHS and now a research scientist is trying to figure out if anything can treat the symptoms and stop some of the damage. There are only a few hundred people formally diagnosed with PTHS but experts estimate that several thousand people actually have it – far more than the 60 originally believed to have PTHS! We call such rare diseases "orphan diseases" because there are not enough people ill with them to encourage scientist and drug companies to find treatments. But as genetic testing becomes less expensive and more widely available, there's hope that science will search for ways to fix it.

What helped Connor? It was the combination of hard, continual repetitive therapy to overcome his physical limitations and the fight by his parents to find the unique name for their child's condition. Together, they're making this special boy's future look much brighter.