On Tuesday, I challenged readers to figure out the cause of a girl’s jaw swelling and pain. Over 130 people read the story, and seven people submitted their responses on this website. You can read the original case here. Read below for the complete case, in addition to comments about the correct diagnosis.
Details regarding the patient’s history and exam have been changed to protect the patient’s confidentiality.
Imagine you’re a 13 year-old girl. Your main worries in life are classes, boys, and your soccer team. Over the course of a few days you develop pain and swelling in your jaw. You think it may be related to a toothache, or you vaguely remember being hit by a soccer ball during practice, so you take Tylenol for pain. The pain and swelling go away after a few days, and you get back to your life.
A few weeks later, the pain and swelling return. This time you’re annoyed. You don’t remember any soccer balls landing anywhere near your head. You show your mom the jaw swelling, and she takes you to your pediatrician. He thinks it may be a tooth infection and prescribes you antibiotics for a week. Within a few days, you’re back to business as usual.
A week before your class trip to Washington DC, the pain and swelling in you jaw returns, in exactly the same location. Medications don’t help much. You visit your doctor, who is concerned about a serious infection, and he orders an MRI of your jaw. The results are frightening: there seems to be something chewing up your bone. Could this be cancer? An antibiotic-resistant bacteria? The only way to find out is to have surgery to remove a small piece of the bone and examine it in the laboratory. Thoughts of dying before ever having your first kiss enter your mind.
You miss your trip to DC, and instead spend several days in the hospital after your surgery. Looking at the bone through a microscope reveals a lot of white blood cells (neutrophils, monocytes, macrophages), but no evidence of cancer. What are all those cells doing there? Nobody knows. They suspect an infection, but bacteria are not seen under the microscope. A piece of bone is sent to the microbiology lab, where it’s given a warm environment with plenty of food for bacteria. Days go by, but no bacteria is ever found.
“Maybe the bacteria didn’t like the food we gave it” a doctor says. “Maybe the bacteria is difficult to grow in the lab,” another wonders. In any case, you get treated for a presumed infection (what else could it be?) with several weeks of intravenous antibiotics. You improve.
Several months go by, and you’re fine. “The antibiotics must have done the trick,” you think to yourself. But just before you leave for summer camp, the pain and swelling return.
Over the next few years, you continue to have episodes of jaw pain and swelling. Nobody knows why. Over time, your jaw becomes disfigured, and you begin wearing your hair over the right side of your face, to cover up the asymmetry. Every time you have an episode, your doctor prescribes you more antibiotics. You have a second bone biopsy, just in case, which again reveals a lot of inflammatory cells, but no evidence of cancer or infection.
You are 18 years old when you finally see a rheumatologist. You have had five years of episodes of jaw swelling and pain, which nobody has been able to diagnose. You have seen many doctors, had many tests, but received no answers. The rheumatologist listens to your story closely, examines your jaw, notes the increased growth over your right mandible, and looks at the results of your bone biopsy. The rheumatologist diagnoses you with chronic recurrent multifocal osteomyelitis (CRMO), also known as chronic nonbacterial osteomyelitis (CNO), and starts appropriate treatment.
This was the story of a patient I recently saw in clinic. Like many patients with CRMO, her diagnosis was delayed because the disease is not well known and is poorly understood. It also closely mimics the more common infectious osteomyelitis, except that cultures from the bone fail to grow any organisms. As a result, CRMO is likely underdiagnosed. Increased awareness of this entity may lead to earlier recognition and better patient outcomes.
CRMO most commonly presents in children at around age 10. It can affect almost any bone in the body, most commonly the bones of the leg. Like my patient, children complain of pain and swelling at the sites affected. Some children have low-grade fevers as well. Even though most children have “multifocal” disease (inflammation affecting several bones at the same time), about 30% of children have inflammation in only one bone. Interestingly, up to 25% of children with CRMO have evidence of inflammation of other organs such as the skin ( psoriasis or palmar plantar pustulosis) or intestines (inflammatory bowel disease such as Crohn’s or ulcerative colitis).
In adults, patients with a similar presentation are usually diagnosed as having SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis). It is likely that CRMO and SAPHO are the same disease, the only difference being the age of diagnosis.
CRMO appears to be an autoinflammatory disease, caused by abnormalities in one part of the immune system called the innate immune system. Unlike in autoimmune diseases such as lupus, autoinflammatory diseases do not have disease-specific antibodies, and B and T cells are not thought to play a large role in development of the disease. In patients with CRMO, it appears that the cells of the innate system (neutrophils, macrophages, monocytes) produce too many pro-inflammatory molecules, such as IL-6 and TNF, and fail to produce anti-inflammatory molecules such as IL-10. This abundance of pro-inflammatory molecules are thought to trigger unprovoked inflammation in the bone, causing the signs and symptoms of CRMO.
No specific genes have been identified that cause CRMO. However, half of the patients with CRMO have a family member with psoriasis or inflammatory bowel disease, suggesting that there may be a genetic component for the disease. We are also learning more about CRMO by studying the genetics of other rare autoinflammatory diseases that cause similar bone inflammation, such as PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome, DIRA (deficiency of IL-1 receptor antagonist), and Majeed.
Treatment for CRMO usually involves non-steroidal anti-inflammatory medications such as ibuprofen or naproxen. If that is not sufficient, other options include methotrexate, steroids, anti-TNF agents, or bisphosphonates (the same type of medication used in older adults with osteoporosis). Unfortunately, large clinical trials have not been done to determine the best medication, and trial-and-error is often needed to find the medication that works for a particular patient.
As the name suggests, some children with CRMO will have “recurrent” episodes of the disease when medications are discontinued. Even if symptoms have resolved, there may be evidence of bone inflammation when an MRI is performed, but it is unknown if treatment would still be needed at this time. Most children are able to discontinue medications as they get older without permanent damage from the disease.
Fortunately, our understanding of CRMO continues to improve. The discovery of new medications that are effective for CRMO has allowed us to effectively manage the disease in most patients.
For my patient, I gave her a short course of steroids, and started her on methotrexate. The steroids quickly reduced the acute swelling and pain, and methotrexate proved to be effective in preventing additional flares. If you look closely at her face, you can still see a slight asymmetry, with prominence of the right mandible. However, she no longer covers up her face with her hair, and now appears more confident, perhaps because she understands her diagnosis, or perhaps because her .
-CRMO is an autoinflammatory disease that causes inflammation of the bone, thought to be due to an excess of pro-inflammatory molecules.
-It usually presents in children with lesions in several bones that cause swelling and pain, although 30% can have single lesions
-Many patients, or their families, have a history of psoriasis or inflammatory bowel disease
-Treatment can include NSAIDs, steroids, methotrexate, TNF blockers, or bisphosphonates
Mystery Case Comments
There were two main diagnoses that readers provided: juvenile idiopathic arthritis affecting the jaw (temporomandibular joint), and chronic recurrent multifocal osteomyelitis (CRMO). Although both JIA and CRMO affect the jaw, the MRI in this case showed bony destruction, which is seen in CRMO. In contrast, an MRI of the jaw in JIA would show inflammation (synovitis) and swelling around the temporomandibular joint. The pathology of the bone showed inflammation, whereas the bone in JIA is generally healthy. Finally, patients with JIA affecting the jaw may complain of chronic stiffness or pain with chewing, and may note decreased ability to open the mouth wide. In contrast, CRMO presents with episodes of swelling and pain at the site of inflammation, as in this case. Read below for more information about CRMO.
Ringo was the first person to submit the correct diagnosis. He also correctly identified the appropriate treatments for this patient. He will receive a $5 Starbucks card. Subscribe to this website if you would like to be notified when future mystery cases are published.
Borzutzky, A., Stern, S., Reiff, A., Zurakowski, D., Steinberg, E. A., Dedeoglu, F., & Sundel, R. P. (2012). Pediatric Chronic Nonbacterial Osteomyelitis. Pediatrics, 130(5), e1190–e1197. doi:10.1542/peds.2011-3788.
Ferguson, P. J., & Sandu, M. (2012). Current Understanding of the Pathogenesis and Management of Chronic Recurrent Multifocal Osteomyelitis. Current Rheumatology Reports, 14(2), 130–141. doi:10.1007/s11926-012-0239-5.
Hedrich, C. M., Hofmann, S. R., Pablik, J., Morbach, H., & Girschick, H. J. (2013). Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO). Pediatric Rheumatology, 11(1), 47. doi:10.1186/1546-0096-11-47.