Profile close up preteen girl 1500 x 1000 px

CRMO lytic lesions in tibiaWhen 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.

 

Granddaughter’s story

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.

Polly Ferguson MD, Pediatric Rheumatologist at University of Iowa
Polly Ferguson MD, Pediatric Rheumatologist at University of Iowa

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?

Here is a bit about the condition (thanks to conversations with Dr. Ferguson, a perusal of Wikipedia, and a brief literature review courtesy of Pub Med):

Bone biopsies in early (top) & late states of CRMO
Bone biopsies in early (top) & late states of CRMO

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.

Arrow points to CRMO lesion in left clavicle
Arrow points to CRMO lesion in left clavicle

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

Palmar pustulosis in SAPHO syndrome
Palmar pustulosis in SAPHO syndrome

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.

 

Granddaughter’s homecoming

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.

 

Post script

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.

 

3 years post CRMO with no symptoms
3 years after her bout of CRMO, our granddaughter is symptom-free and quite a runner

 

If you would like to read more about CRMO, here are some additional resources:

28 COMMENTS

  1. Those impacted by CRMO have now found a home on my prayer list. May each of you experience complete resolution of symptoms and have CRMO self-limit with an excellent prognosis for a long symptom free life with no recurrence. Garrett began his remicaid infusion yesterday with neither signs of rejection nor allergic reaction detected.

  2. Hi,my daughter Maggie is 13 and was diagnosed with CRMO four years ago.She injects herself with Enbrel twice a week,takes a methotrexate tablet once a week and is on a pamidronate infusion for three days every three months.She plays a lot of sports at a high level but she does go through the pain barrier to do it.We are in Ireland so she’s looked after in Crumlin Children’s Hospital.

  3. Thanks for sharing this. My 11 year old son is scheduled for a biopsy after his first bought, with what is suspected to be CRMO. Over thepastweek ge has had 2 MRIS. Both have revealed lesions accompanied by sterile labs. I have psoriasis and just learned approximately 2 weeks ago that my older brother was recently diagnosed with CROHN’S.

    All three conditions appear to have a genetic link. He will receive treatment at CHOP in Philadelphia if the dx is comfirmef. I’ll look to initiate a consult with the clinician referenced in the article if this is what we’ll be managing.

  4. My daughter is 10 years old and she is diagnosed with CRMO recently. Her case is simmiler to your granddaughter, she gets very high fever at night. She’s got better after treated with Naproxen for a month, but just a few days ago she started having a pain on her hipbone, and fever at night.
    Did your granddaughter get a steroid treatment at some point? My daughter still take Naproxen but I’m wondering if she needs a steroid instead. I hope my daughter can overcome this disease like your granddaughter. Thanks.

    • Hi Yoshiko, I’m sorry that you and your daughter are going through this. My daughter was taking Naproxen and it was effective, but caused stomach ulcers. The next step was to begin off-label use of Enbrel which is effective in CRMO as well as RA. Dr. Ferguson wrote a letter to our insurance company and it was approved for coverage, but before our daughter started the Enbrel, the inflammation sites began to diminish on their own. She was never treated with a steroid. I would encourage you to explore the possibility of Enbrel with your daughter’s doctor. From the Mayo site: “Enbrel is not a steroidal anti-inflammatory medication like prednisone and such. Enbrel is a TNF-inhibitor (TNF = tumor necrosis factor, a soluble inflammatory cytokine) and works by suppressing TNF-alpha which triggers an inflammatory response in many auto-immune diseases, including RA.”

      • Thank you so much for the reply. My daughter ended up getting steroid for 5 days. After that, she’s got better, no fever and no pain. She was just taking Naproxen again, but her fever and pain is back now. I will ask her doctor about Enbrel… I’m just hoping this will go away on it’s own like your daughter. How long did it take to go away for your daughter’s case? It’s been almost 5 months for my daughter now. We live in Ann Arbor, good thing is we are very close to the Children’s hospital.

  5. My daughter had osteomyelitis when she was nine in 2002 she had a pain in her left leg. confirmed by an MRI scan she was treated with antibiotics, she is now 22. She was diagnosed with fibromyalgia and ME when she was 18 and has just got worse and worse. She also has pain everywhere at sometime or another but particularly on her left shoulder above her clavicle. Do you think her symptoms could be caused by chronic recurrent multifascial osteomyelitis. She has various blood tests done including for rheumatism and arthritis all have shown nothing. She gets pains in her coxyx and chest pains caused by Costochondtitis . I also remember having leg pains which were so bad I could just not run when I was about 13 but they put them down as growing pains. Thank you for sharing your story about your granddaughter and really pleased she is better now. Regards Pam Spychalski

    • Hi Pamela, I am sorry your daughter has had so much pain. We do not give medical advice on this site beyond encouraging you to talk this over with your daughter’s physician or to seek care from someone expert in rheumatology. I hope this helps. We are delighted that you have found TDWI helpful. Pat

  6. I was diagnosed with SAPHO/CRMO by the Mayo Clinic in 2012 after battling severe back/chest/rib pain and several scans over the course of 2.5 yrs depicting bone growth/possible infection but no one – cardio thoracic surgeon, infectious disease, neuro spine surgeon, rheumatologist, oncologist, pain management could diagnose. The radiologist at Mayo assisted the oncologist with diagnosis. Was told to follow up with rheumatologist but my frustration lies with no one really knowing about this illness and how to treat. Chronic pain combined with every doc I have seen admitting they know nothing about CRMO. Can you recommend any ways to f/u or get seen by doctors who specialize in this condition? The Mayo clinic didn’t want to see me back bc at the time I was doing alright with pain scale.

  7. My son also has #CRMO . He Is still effected by it at 12 yrs old. He is active and still playing football, but he relies on daily NSAIDS to get through it. He is taking 2 different immunosuppressents, but they haven’t seemed to help yet. We are hoping they are working internally, even if his pain is still there. Thanks for bringing light to this very rare disease.

    • Hi Jennifer, I am glad you found it helpful. It is always so scary when our children (and grandchildren) get sick. I thought it would be helpful to share what I learned. I hope your son continues to improve.

  8. Patricia,
    Good to hear your granddaughter is doing well. How long before she got well and was back to normal activities?
    Kind Regards,
    Ilona

  9. A related condition is psoriasis. I believe there is a hereditary relationship? Given that, is CRMO necessarily a diagnosis of exclusion?

    • A very informative article about your grand daughter. My daughter is also suspected for CRMO. Briefly it went like this-
      I am writing from India. My daughter has turned seven in November 2015. Since 3rd October 2015, she is limping and complaining of pain in her right leg. Initially the pediatric referred us to an Orthopedic, who suspected Transient Synuvitis. A week of rest and Ibugesic (TDS) was given. When we went to him again on 10th October for review, the orthopedic checked her joints, made her to sit on haunches and cross legged, and since she was able to do these, pronounced her fit.

      However, she continued to limp and complain about intermittent pain, with varying intensity (sometimes high, other times low) and at different places i.e., the Rt hip, the Rt thigh, Rt knee and Rt shin and Rt ankle. She also complained of pain around ribs but that was rare. So we went back to the Orthopedic on 12th October. He recommended an MRI of Rt pelvis and a CBC. We got both done. On checking the MRI, the doctor suggested iv antibiotic treatment as he suspected infective osteomyelitis.

      To take a second opinion, we went to a Pediatric Rheumatologist. On the basis of MRI report, the doctor suggested few tests and recommended antibiotic course. My daughter was admitted on 16 Oct and IV antibiotic was started. Two antibiotics were given Clyndamycin and monocef. On 18th Oct CBC, ASO, USG test were done. The antibiotics started on 16 Oct 15 at 11pm were given till the morning of 20th Oct 15 after which the doctors, on checking the reports of the various tests concluded that the case may not be of infective osteomyelitis. Only Combiflam (TDS) and temp charting was suggested. On 23rd Oct 15, Procalcitonin, quantiferon TB Gold, LDH, CBC, ESR (which was 60 ) and triple phase bone scan were done. Bone scan showed uptake at all the places where she was complaining of pain plus rib area at two places.

      My daughter is still limping and complains about intermittent pain, with varying intensity at same places as earlier. CT guided biopsy was inconclusive and therefore Open Biopsy was carried out on 04 Nov 15. The doctors said that the frozen tissue sample suggested LCH. However, CD1a, CD68, s100 and CD 99 markers are negative. After the review of biopsy blocks it was diagnosed as inflammatory pathology.

      Overall health is fine. No visible swelling in any area and no rashes as of now. Her appetite, stool, urine are normal. Temperature throughout this period range from 97F to 98.8F. She usually sweats near neck and forehead area while sleeping in the night. Could it be symptoms of TB?
      No definite diagnosis till date. The blood report show Plt-450, Hb 11.1, ESR 29, CRP- negative.
      The doc started med naproxen since 19 nov 15. A little improvement in limp is observed. Azithromycin syrup is also suggested.
      Patricia whats your view….

      • Did your pediatric rheumatologist definitively say it was CRMO? And, BTW, did they culture the bone biopsy? If so, what did it show?

        It may be worth checking in with someone knowledgeable about CRMO if it hasn’t been ruled out. I mention the name of the pediatric rheumatologist from Univ. of Iowa who took care of our granddaughter. Perhaps she could do a SKYPE consult or at least recommend someone knowledgeable about CRMO closer to where you live.

        I hope your daughter has an uneventful recovery in any event.

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