When I learned my 8-year-old granddaughter was diagnosed with osteomyelitis (confirmed by MRI), I was alarmed. My experience as an internist was that this was a serious, hard to treat disease. Needless to say, I was alarmed. My husband and I immediately booked a flight to be with the family while our granddaughter was getting treated.
Our granddaughter had previously been completely healthy until she started complaining about a sore ankle. It was painful, red, warm, and swollen. She had not had an injury or skin infection in the area, so it was a bit of a puzzle to her family. Because it didn’t get better, they took her to the pediatrician who got x-rays that showed what looked like osteomyelitis, so she was sent to an infectious disease (ID) doctor who confirmed the diagnosis.
The initial treatment was oral Clindamycin capsules that she simply could not swallow. They were huge, turquoise blue, and very foul tasting pills. The ID doc switched her to oral Keflex, a cephalosporin (easier to swallow and better tasting) the next day.
Since oral treatment, instead of IV therapy, had been prescribed by the University Pediatric Infectious Disease specialist and since I am not a pediatrician, I thought perhaps there was something different, more benign about pediatric osteomyelitis than what I recalled about the severity of adult osteomyelitis.
However, after a few days on the pills, our granddaughter started having high fevers in the 102-104 range. She had difficulty getting out of bed to go to the bathroom and complained of weakness and back pain. After many phone calls and texts with doctors, her parents took her to the ER where she was admitted to Pediatric Inpatient Service at the University Hospital.
Her fevers continued despite IV Clindamycin, later changed to IV Ancef. She was briefly switched to Vancomycin (because of a concern about MRSA) and then back to IV Clindamycin (on which she developed a rash on her face and trunk). Finally, she ended up on IV Linezolid. Her fevers were remarkable for occurring only at night.
Diagnoses were tossed out and discarded as test results came in and the course became atypical. Finally, one of the pediatricians taking care of our granddaughter in the hospital consulted with Dr. Polly Ferguson, a renowned pediatric rheumatologist, who raised the possibility of Chronic Recurrent Multifocal Osteomyelitis (CRMO) for the first time. Neither my husband (an internist and immunologist) nor myself had ever heard of it. It turns out that Dr. Ferguson is one of the world’s experts on CRMO.
What is chronic recurrent multifocal osteomyelitis?
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, inherited, auto-inflammatory (not auto-immune) condition that primarily between the ages of 4 and 14, however, it can occur in both younger and older individuals, including adults. It affects girls more than boys by a ratio of 5:1. The hallmark of the disorder is recurring bouts of multi-site sterile osteomyelitis. It is a pediatric osteomyelitis not due to infection.
CRMO causes chronic waxing/waning pain, often in more than one site. It can be associated with fevers and the ESR and CRP and other markers of inflammation are usually elevated, making it difficult initially to distinguish from infectious osteomyelitis. The blood cultures are sterile as are bone cultures (if obtained). The biopsy of bony lesions reveals inflammatory cells, including polymorphonuclear leukocytes and multinucleated giant cells. In the later course of the disease, there is an increased predominance of histiocytes, plasma cells, and lymphocytes.
Common sites of involvement include long tubular bones and clavicle, but lesions have been described throughout the skeleton, including the mandible, ribs, sternum, scapula, spine, pelvis, hands, and feet. The tibia is the most commonly involved bone. (Our granddaughter’s index lesion was her distal tibia, her other lesion was in the distal femur). The lesions often occur in the metaphyses of these bones, near the growth plate (also known as the epiphyseal plate). This is also a common site for the hematogenous spread of infectious osteomyelitis because of the rich blood supply.
Initial imaging findings include lytic lesions that progressively become thin and sclerotic (hard, indurated) in approximately 1–2 weeks. There is subsequent sclerosis and hyperostosis over time as the inflammation extends to the cortex bone for both unilateral and bilateral disease. In 75% of cases, the process involves a metaphysis or metaphysis equivalent. The lesions are symmetrical in approximately 25% of cases. The clavicle is rarely involved in hematogenous staphylococcal (staph) osteomyelitis but is commonly involved in CRMO. Except for trauma, CRMO is the most common non-neoplastic (non-cancerous) process involving the clavicle in patients younger than 20 years old, and it is the most common disease to involve the medial third of the clavicle in all age groups.
CRMO is thought to be auto-inflammatory in nature because of the sterile cultures and inflammatory cells seen on histopathologic evaluation. However, there are no readily available laboratory tests that can rule in/out CRMO. Findings that steer one to the diagnosis include sterile multifocal osteo, family history of inflammatory disorders of the skin and GI tract (such as psoriasis, ulcerative colitis, and Crohn’s Disease), and multiple sites of bone involvement seen on bone scan or MRI. CMRO is considered a diagnosis of exclusion.
Some related conditions
A related condition is known as SAPHO syndrome, which involves synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis. The most commonly involved bones in SAPHO are the chest wall and pelvis. The usual age of onset for CRMO is within the first decade of life, whereas the mean age of onset for SAPHO is 28 years.
Recently, a mutation in the LPIN2 gen, located on chromosome 18, has been associated with a related condition known as Majeed syndrome. Majeed syndrome is a triad of CRMO, congenital dyserythropoietic anemia, and neutrophilic dermatosis (sometimes referred to as Sweet syndrome). This syndrome differs from classic CRMO because of the anemia and the nature of the dermatosis but, like classic CRMO, begins in the first decade and involves long bones.
Treatment and prognosis
Treatment for CRMO usually involves anti-inflammatory and/or immunosuppressive therapy, including NSAIDS, such as Indocin or glucocorticoids. Although the clinical course is highly variable, with symptoms waxing and waning over time, CRMO is usually self-limited and has a good prognosis, with most lesions resolving without long-term complications.
So, our granddaughter’s illness was a wild (and sometimes worrisome) ride. But, all’s well that ends well. She left the hospital pain free, afebrile, and excited to go home. She received the requisite 28 days of antibiotics covering the possibility of bacterial osteomyelitis. And she was discharged on Indocin and omeprazole with a follow-up next week in Dr. Ferguson’s clinic. We all learned a lot from this medical encounter and hope that our lessons will be helpful to others as well.
As was predicted by the natural history of CRMO, as our granddaughter approaches her 12th birthday, she is a symptom-free, very active, healthy, happy tween and her bout of non-infectious osteomyelitis is, thankfully, a very distant memory.
If you would like to read more about CRMO, here are some additional resources:
- Costa-Reis, P., Sullivan, KE. Chronic Recurrent Multifocal Osteomyelitis, J Clin Immun 2013 Aug;33(6):1043-56
- Falip, C., Alison M, Boutry, N., et al. Chronic recurrent multifocal osteomyelitis (CRMO): a longitudinal case series review. 2013 Mar;43(3):355-75. Epub 2012 Dec 22.
- Ferguson, P.J., Sandu, M. Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis, Curr Rheumatol Rep. 2012 Apr;14(2):130-41