From the infant's first moments, his mother thought something seemed off. And she soon learned that the newborn's doctors thought so, too.
"The doctors immediately took him away," said Ms. O. Although the newborn boy was born four days overdue, he weighed a mere 5 pounds and 4 ounces. More striking, though, was how his scalp was missing a patch of skin.
"They took off his little hat and it looked like his head was bleeding, but when you touched it, there was no blood on your hand," Ms. O said. Doctors were puzzled, and at only 1 week old, the boy was the guest of honor at the hospital's medical grand rounds, a tiny baby at the center of a crowd of dermatologists.
And that was only the beginning of the O family's saga. From his birth in 2009 until his diagnosis almost eight years later, he and his family endured an onslaught of symptoms in a search for answers where there were none for far too long.
A diagnosis that didn't quite fit
The boy was just a few weeks old when he began making strange noises in his sleep; the sound was something between a scream and a grunt. Ms. O knew in her gut that something was wrong, and she paid a visit to his pediatrician.
"They said I was just a new mom, and that babies make noise," she said. But Ms. O felt the unnerving noise was a sign of something more, and she learned online that it could indicate reflux - the backwash of stomach acid that causes heartburn. His doctor prescribed an acid-blocking medicine, and the nocturnal noise came to a halt.
But other symptoms popped up. A specialist took a peek down the baby's nose and throat, revealing an abnormal floppiness of the windpipe known as laryngomalacia. Then the boy started losing weight. He'd put on the pounds normally at first, growing into a healthy, chubby baby. Yet around age 9 months, his weight gain plateaued, then began to backpedal. At a year old, he weighed a mere 17 pounds - almost 5 pounds less than the average for that age.
"He kept going lower and lower on the growth chart until he was on the absolute bottom," said Ms. O. Supplemental formula provided extra calories on top of his already significant milk intake, but his weight kept falling, despite his hearty appetite.
"He would eat anything I'd give him. Why wasn't he healthy?" Ms. O asked herself.
The baby's constellation of symptoms - the skin problems, the weight loss, the reflux - seemed like they might be related. After all, what were the chances they would've all arisen separately? So in November 2012, when he was about 2 years old, the pediatrician recommended seeing a geneticist, who sequenced the boy's genome. The test pointed to a possible problem with a gene called EVC2, which can cause short stature, nail and tooth problems, and serious heart issues; thankfully, the boy's heart tests were normal. But although the diagnosis of EVC2 would account for his short stature, it wouldn't explain his scalp and windpipe problems - and the fact that his heart was normal was also unusual for this rare disorder. Ms. O couldn't get away from the nagging feeling that the diagnosis didn't quite fit.
Still, the family was eager for a diagnosis, however imperfect. And they focused on the fact that none of his symptoms had been life-threatening.
"We thought, let's count our blessings," Ms. O said. "It's superficial." Still, because the root of the symptoms remained unknown, they couldn't help but wonder if more serious problems might lie just beyond the horizon.
When chapped lips are a lot more
During the winter when the boy was 4 years old, something strange started to happen to his upper lip. He'd been born with a scar snaking from his left upper lip to his left nostril, "as though he'd had a cleft lip repair in the womb," Ms. O said.
That winter, his upper lip began to split at the scar, working its way up towards his nose. So the O family saw a cleft lip surgeon at Texas Children's Hospital, who recommended an operation to repair the split.
The surgery went well, but the Os and the surgeon were flabbergasted to find that the boy's lip just wouldn't heal.
"It looked about like it did before" the surgery, Ms. O said.
Perhaps he was allergic to the sutures, the surgeon supposed. She performed the procedure again and once more was stunned by the snail-like pace at which his lip healed. Nobody seemed to know why this had happened, or whether it might portend something more serious down the road.
Finally, an answer
The O family got a fresh set of eyes to examine the case when Dr. Bret Bostwick, a geneticist at Baylor College of Medicine, took over the boy's care.
"One of the first things [Bostwick] said was, 'this doesn't look like EVC2,'" Ms. O said. She was relieved to hear that, and confessed that she'd felt the same way.
"His clinical presentation was immediately intriguing to me," Bostwick said.
The child - by now 8 years old - had a collection of facial features the doctor had never seen before. His nose was remarkably narrow, with thin nostrils, and his small cone-shaped teeth were covered in incompletely formed enamel. His fingers were bent, and his hair was sparse, coarse, and dry. But although Bostwick was convinced that a genetic syndrome was at play, he wasn't sure what it was - and the possibilities were myriad.
So he made a list of the boy's symptoms and physical features, then searched a database to create a list of diagnoses that might explain. Because the child's parents didn't share any of these physical features, it was possible that whatever genetic disease had caused the symptoms had arisen from a new mutation in his genetic code - a so-called de novo mutation.
But finding the exact mutation was like searching for a needle-sized genetic sequence in a haystack full of genes.
"Usually in any exome, there are one or two variants that are de novo," Bostwick said. "To find those, you have to know where you're looking, and it can be difficult to find."
So Bostwick sequenced the genes of the boy's mom and dad, then compared them to their son's to see what was different. That pointed to genetic changes known to cause a disorder called oculodentodigital dysplasia, or ODDD - a diagnosis that had been on Bostwick's list of possibilities.
ODDD is extremely rare; fewer than 1,000 cases have ever been diagnosed. The disorder is caused by a defective version of the GJA1 gene, which tells the body how to manufacture connexin43, a protein vital for communication between the body's cells.
Those affected frequently have a thin nose, sparse hair, and curved fingers. Problems with the windpipe and tooth enamel also are common. And healing from surgery or accidents can take much longer. That explained why the boy's lip had been so slow to heal.
Bostwick had found what seemed like a perfect fit. And the Os were relieved to learn ODDD's effects ran only skin deep. Though the disorder put the boy at risk of slower healing in the future, it didn't portend life-threatening health problems, a possibility that had always hung over their heads.
"Because all of his symptoms were superficial, we didn't really worry about them, per se, but we never knew what was around the corner," Ms. O said. "What if we were missing something?"
Now they can focus on helping their son - an extremely bright, social, and happy child - thrive.
He "is not raised as if something is wrong with him," Ms. O said. "We tell him that we are trying to make sure that he is the best he can be."
Allison Bond is a hospitalist at Massachusetts General Hospital. If you have dealt with a diagnostic puzzle that has been solved, either as a caregiver or a patient, please email Allison at email@example.com.