Medical mystery: The pain gripped his left ankle. Within months, it was spreading.

When he turned 42, Ram Gajavelli made himself a promise: He would take better care of his health.

But in August 2017, a few months after the software engineer began exercising regularly, his left ankle grew swollen and painful, even though he didn’t remember injuring it.

He continued walking regularly for exercise and experimented with home remedies, including stretching and heat, for relief. But in October, after a short hike with his son caused his ankle to swell, he saw an orthopedist. An X-ray revealed nothing, but an MRI showed a possible stress fracture.

The doctor suggested Gajavelli wear a walking boot. Eight weeks later, his ankle still hurt.

Gajavelli, who lives near Philadelphia, waited two months, then consulted a second orthopedist who is an ankle specialist. “He didn’t see anything and had no explanation other than ‘Maybe you’re just one of those where it is taking time to heal,’” Gajavelli recalled. After a blood test showed that the level of bone-building vitamin D was normal, he was given an order for physical therapy.

The PT sessions relieved his ankle pain, but only temporarily. By May, the pain had migrated to his right knee and lower back. A month later his metatarsals — long bones in the feet that maintain balance and distribute body weight — began to hurt. The pain then moved to his shoulders.

Soon, he found it painful to lie flat or get up from a seated position.

His internist suspected Lyme disease, but a test was negative. Blood tests ordered by a rheumatologist found nothing amiss. A neurologist ordered electromyography (EMG), a test that can identify neuromuscular problems. It, too, was normal.

The podiatrist Gajavelli consulted could find nothing wrong with his feet. He suggested Gajavelli wear a different brand of shoes with padding, which helped temporarily.

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By November 2018, walking on tiptoes or standing on a hardwood floor was exquisitely painful. The ribs on his right side hurt so much that Gajavelli was sleeping in a recliner. He relied on prescription-strength ibuprofen to get through the days — and nights.

During a routine appointment in December, his dentist was surprised to discover significant decay in two wisdom teeth; one was literally crumbling. Six months earlier his teeth had looked normal. He sent Gajavelli to an oral surgeon for an extraction. Like the other symptoms, the cause of his sudden dental deterioration was unexplained.

“I was frustrated,” Gajavelli remembered. “But doctors couldn’t find anything, so I was relieved by that.”

In January 2019,

Gajavelli was planning a brief trip to see relatives in southern India. After consulting with a cousin who is a physician in Atlantic City, he made an appointment with a rheumatologist and an orthopedist at a hospital in Hyderabad. He would have to pay out of pocket — the cost of tests and treatment would total about $1,000 — but he hoped one of them might be able to figure out what was wrong.

The orthopedist quizzed Gajavelli about his symptoms, then ordered several tests, including a bone scan, his first. The nuclear medicine test uses a small amount of radioactive tracer that can help pinpoint the cause of bone pain.

The result was terrifying. It revealed multiple stress fractures that started at Gajavelli’s metatarsals and extended to his jaw. The orthopedist told Gajavelli that he most likely had a widely metastasized cancer or some sort of metabolic bone disease. He advised Gajavelli to consult an endocrinologist as well as an oncologist when he returned to Philadelphia.

“I was so upset I couldn’t talk,” Gajavelli recalled.

His physician-cousin suggested calling a specialist both men knew socially: Ravi K. Amaravadi, one of the leaders of the Cancer Therapeutics Program at Penn Medicine’s Abramson Cancer Center.

Amaravadi ordered scans for cancer along with blood tests, including one to check the level of phosphorus, a mineral that is essential to the formation of bones and teeth. Gajavelli’s level was low — a key clue to what might be wrong.

After ruling out cancer, Amaravadi sent Gajavelli’s records to Mona Al Mukaddam, an assistant professor of clinical medicine and orthopedic surgery who directs the Penn Bone Center. The most likely culprit appeared to be a rare bone disease.

Al Mukaddam told Gajavelli she thought he was suffering from tumor-induced osteomalacia (TIO), a bone-weakening disease caused by one or more typically benign, slow-growing tumors. These tumors produce high levels of a protein called fibroblast growth factor 23 (FGF23), which limits the ability of the kidneys to absorb phosphate. The first signs of the disease, also known as oncogenic osteomalacia, include fractures, bone pain and muscle weakness — all symptoms Gajavelli had reported.

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Although it is almost certainly underdiagnosed, TIO is very rare: Fewer than 1,000 cases have been reported worldwide.

“One of the most challenging components associated with TIO is thinking of the diagnosis and checking phosphorus,” Al Mukaddam said. Subsequent tests confirmed that Gajavelli’s FGF23 level was elevated and that he was losing phosphorus in his urine.

Diagnosing the problem was only the first challenge. Doctors then needed to find the tumor — a painstaking process because it is often tiny and can be anywhere in the body. Surgery to remove the tumor is usually the preferred treatment because it can cure the disease and prevent a recurrence, which is common.

Using a sophisticated gallium scan, a nuclear medicine test that can detect tumors, doctors found a pea-sized mass tucked behind Gajavelli’s left hip joint. The next challenge for the orthopedic surgeon was to figure out the best way to remove all of it without having to perform a total hip replacement on a young patient.

For three months before surgery, Gajavelli took supplements to boost his phosphorus level and reduce muscle weakness. “They made me feel much better” almost immediately, he recalled.

In August 2019, he underwent a tricky, nine-hour operation performed by Robert J. Wilson II at the Hospital of the University of Pennsylvania. The orthopedic surgeon was able to remove the tumor in its entirety without replacing Gajavelli’s hip.

A day after surgery, Gajavelli’s FGF23 was normal. A week later, his phosphorus level was, too. Recovery took several months. On Christmas, he walked a mile without pain for the first time in more than two years.

His case, Al Mukaddam said, underscores the importance that doctors “not just go with what they know” but also think about what they “could be missing.”

“It’s OK if we don’t know the answers to refer to someone” who might know, she said. “We’re all humbled every day in medicine by learning new things.”