A Lump on the Skull and the Misdiagnosis of a Rare Bone Disease

11/30/22 • 11 min

In 1964, Nancy, a 5-year-old, is having her evening bath when her parents discover she has a lump on the skull the size of a grapefruit. This would mark the onset of a mysterious and debilitating disease that researchers are still struggling to understand.

Over the next 40 days, medical professionals struggled to discover what was causing the lump on the skull. Each test seemed to exacerbate the swelling in Nancy's neck. In hindsight, that was a big clue, but it took doctors a while to recognize it.

Instead, what happened next was a common mistake when it comes to patients with this disease. Nancy was diagnosed with terminal cancer. Doctors said she had less than a year.

Yet, over the next few months, Nancy's condition didn't progress. She actually seemed to get better. Over the next few months, she was taken to a series of specialists. It was finally an oncologist who noticed something that was pivotal to her diagnosis ... her toes. Misshapen big toes — generally short and bending inward — are a hallmark of Nancy's disease.

While Nancy had several telltale signs of the disease, diagnosing rare diseases is difficult in part because they’re exactly that: rare.

“I can see how a practicing physician may feel a rare disease, ‘I'm never going to see it.’ But [this disease] is so striking that I think once you see someone with the disease ... the image stays in your mind and even if someone, as a general internist or a pediatrician, never expects to see the case, you never know,” shares Dr. Eileen Shore, a medical researcher and geneticist specializing in musculoskeletal disorders at the University of Pennsylvania School of Medicine.

And early diagnosis of this — and other rare diseases — is crucial, not only for treatment but to avoid diagnostic tests that can harm patients. While Nancy did finally receive a definitive diagnosis, many of the earlier diagnostic tests were actually causing more harm than good.

“If you just have that in the back of your mind, that you have a vague image of what [it] is and see a patient who you think might have it,” says Dr. Shore, “to send a referral and get it confirmed, just think of the difference it would make in that family's life.”

Instead, what happened next was a common mistake when it comes to patients with this disease. Nancy was diagnosed with terminal cancer. Doctors said she had less than a year.

While Nancy had several telltale signs of the disease, diagnosing rare diseases is difficult in part because they’re exactly that: rare.

Previous Episode

Metatarsal Bone Fractures and a Rare Bone Disease Hiding in Plain Site

A patient in her mid-50s complains of foot and leg pain. She's post-menopausal with low bone density. A classic case of post-menopausal osteoporosis.

Not exactly.

And it won’t start to become clear until it gets to the point of her having repeated metatarsal bone fractures.

Let’s go back a little. It’s 2005. Our patient visits her family doctor complaining of pain in her legs and feet. But the discomfort she's experiencing isn't your typical aches and pains associated with aging.

“She develops a lot of [foot and leg] pain ... So much so that she required pain management for this pain and her gate started to become affected,” shares Dr. Katherine Dahir, a professor of medicine at Vanderbilt University, who specializes in metabolic bone disease.

Her gait becomes wobbly and she’s experiencing an acceleration of degenerative changes in her spine. An osteoporosis screening reveals she has low bone density. She’s diagnosed with post-menopausal osteoporosis and is treated with bisphosphonates, the standard of care for patients with osteoporosis.

And this is when things get much more complicated.

Although all signs show an improvement in bone density, she begins to experience metatarsal bone fractures, which is highly unusual with osteoporosis. And not only does she have these unusual fractures, the fractures will not heal.

“And so that's when you need to put your thinking cap on and try and figure out, why is this patient a treatment failure?” says Dr. Dahir.

To solve the case, the patient’s team studies her labs and finds a missing flag. “... It was called alkaline phosphatase, which is seen in a routine chemistry panel. Back at that time, it was only flagged if it was above the normal reference range because that usually indicates liver disease, but it wasn't flagged if it was below the normal reference range because that was considered to be non-significant.”

But this finding would prove to be very significant. Combined with new research at the time, it helped identify a diagnosis for this patient — showing the importance of medical research that leads to more treatment options and more hope for patients.

Next Episode

Non-Specific Symptoms Lead to Complicated Diagnosis

It starts small. A slight pain in the foot, followed by an achy shoulder. There's some fatigue. The type of non-specific symptoms that often go ignored ... until they can’t be anymore.

A 37-year-old visits the family doctor, complaining of foot, shoulder and chest pain that progresses over weeks. And she's really tired. Otherwise, there’s nothing notable.

She's just a busy parent. Being tired is normal, right?

Sometimes that’s true, but in this case, this would prove to be a dangerous assumption.

She visits her primary care provider who decides to run X-rays. There’s nothing to note other than an expanded area of cartilage at the end of the sixth rib. The doctor doesn’t think much of it at the time, but this would prove pivotal to solving the case.

The patient is prescribed physical therapy, but it doesn’t help. It actually makes things worse.

“She's getting very fatigued to the point where she's having to lay down in the afternoons. She can't really do her full family activities,” shares Dr. Suzanne Jan De Beur, an endocrinologist with a specialty in metabolic bone disorders at Johns Hopkins University School of Medicine in Baltimore, Maryland. “She gets terrible pain ... And then eventually she was found to have a left hip fracture and needed surgery to repair the hip fracture.”

This incredible progression — a hip fracture with no trauma at 39 years old — leads to more tests. She’s diagnosed with celiac disease, a wheat allergy that can cause weak bones from not absorbing vitamin D and other nutrients into the bones. This explains the fractures, but not the muscle weakness.

She’s compliant with her celiac therapy, but it keeps getting worse — to the point of needing a walker. This is when the patient sees Dr. Jan De Beur.

It’s at this time that a very small discovery leads to a very big diagnosis.

It also leads to many lessons — one being to not only zoom in on one specific symptom, but to zoom out on a case over time so you can put the puzzle pieces of non-specific symptoms together and find your diagnosis.