chronic recurrent multifocal osteomyelitis ( crmo ) , a disorder that primarily affects children and adolescents , is characterized by episodic osseous pain over several years .
crmo is an idiopathic , aseptic , auto - inflammatory disease with no uniformly effective treatment .
the long bones of the lower extremities are frequently affected , and skull involvement is rare .
although in the majority of patients with crmo , symptoms resolve post - puberty , the bone pain that accompanies the active disease is severe .
the critical factors leading to its diagnosis are patient demographics , clinical course , and lesion localization .
at the time of symptom onset , an 11-year - old boy initially reported right coxalgia at rest , without edema or fever .
a review of the patient s family history showed that his father had idiopathic bilateral femur head necrosis .
the patient could not run and had stopped exercising , but his pain did not improve .
one month later , he visited an orthopedic surgeon , where a radiograph of the pelvis showed sclerosis of the right side of the sacrum and decreased bone mineral density in the right femur .
an outpatient examination was performed to determine his height ( 142 cm [ 0.1 sd ] ) , body weight ( 36 kg [ 0.2 sd ] ) , current heart rate ( 85 beats / min , with a regular rhythm ) , blood pressure ( 124/73 mmhg ) , respiratory rate ( 15 breaths / min ) , oxygen saturation ( 99% , ambient air ) , and body temperature ( 36.3 ) .
the patient did not present any remarkable chest or abdominal findings , or other abnormalities such as a rash .
the patient s hematological workup revealed a slight elevation of inflammatory markers , but the complete blood count , liver enzyme levels , renal function , and coagulation were normal ( table ) .
the patient had a slightly elevated c - reactive protein ( crp ) level and an erythrocyte sedimentation rate ( esr ) of 41 mm / h .
urinalysis revealed extreme elevation of type i collagen cross - linked n - telopeptide ( ntx ) , with an ntx / creatinine ratio of 429.1 nmol bone collagen equivalent ( bce)/mmol creatinine ( cre ) ( normal range 1366 ) , suggestive of bone resorption .
the patient s urine 2 microglobulin ( mg ) level was normal ( 111 g / l ) , with slight elevation of serum complement levels . his interleukin ( il)-6 level was 9.6 pg / ml ( normal < 9.5 ) , and il-10 level was 3.1 pg / ml ( normal < 6.8 ) . magnetic resonance imaging ( mri ) using fat - suppressed t2-weighted images ( wi ) showed a heterogeneous , high - intensity area on the right side of the sacrum ( fig .
1 ) . a coronal view showed a low - intensity area within the same lesion using t1wi ; there were no abscess formations . computed tomography ( ct ) of the pelvis showed a high - density area in the same lesion , suggesting sclerosis , chronic osteomyelitis , or osteosarcoma .
low attenuation imaging of the area anterior to the sacrum showed soft tissue edema . at this point ,
fat suppressed t2-weighted magnetic resonance images show a heterogeneous high intensity area on the right side of the sacrum ( white arrow ) .
a course of antibiotics was administered for 14 days but did not alter the disease course .
the non - steroidal anti - inflammatory drug ( nsaid ) ibuprofen was started at 200 mg / day and the symptoms improved , but complete relief was not attained .
three months later , a bone biopsy was performed to rule out the possibility of malignant bone tumors , such as an osteosarcoma . upon pathologic examination ,
mild , mainly lymphocytic , inflammatory cell infiltration indicated chronic osteomyelitis , without suppurative infection ( fig .
one year later , the patient developed occipital headaches , accompanied by a decrease in pelvic pain .
there was palpable edema in the occipital lesion , and the size of the swelling was 3 cm .
axial and sagittal fat - suppressed t2wi demonstrated a focus of increased signal intensity in the occipital bone , with the area of increased intensity extending into the epidural space and scalp ( fig .
3b ) . the previous osteolytic lesion improved , but another lesion appeared as an osteolytic change in the occipital bone ( fig .
technetium-99m - hydroxymethylene diphosphonate ( tc - hmdp ) scintigraphy showed increased uptake in the occipital bone and the right side of the sacrum , leading to a diagnosis of crmo , which was controlled using ibuprofen ( 200 mg / day ) .
we ruled out langerhans cell histiocytosis ( lch ) after considering the sacral biopsy and radiological findings , and because the head lesion appeared recently .
the bone pain and swelling of the occipital lesion gradually improved with nsaid treatment over one year .
one year and 4 months later , diffusion - weighted mri imaging showed a new , asymptomatic region on the left ( opposite ) side of the sacrum .
the serum cytokine profiles at this time were almost normal ; the values are as follows ( normal values in parentheses ) : il-6 was <3 pg / ml , neopterin was 3.9
nmol / l ( < 5 ) , soluble tumor necrosis factor receptor ( stnf - r)1 was 940 pg / ml ( 4841,407 ) , stnf - r2 was 2,630 pg / ml ( 8292,262 ) , and il-18 was 300 pg / ml ( < 500 ) . over the following two years , there were no cutaneous findings .
photomicrograph of the sacral bone biopsy , demonstrating connective tissue with mild infiltration by mononuclear inflammatory cells .
axial ( left ) and sagittal ( right ) fat - suppressed t2-weighted images demonstrate a focus of increased signal intensity on the occipital bone .
head ct shows that the previous osteolytic lesion improved ( upper ) , but a new lesion appeared as an osteolytic change ( lower ) .
crmo is a skeletal auto - inflammatory disorder of unknown cause that primarily affects children and adolescents .
the disease is a rare , nonpyogenic bone inflammation that was first described by giedion et al . in 1972 as " an unusual form of multifocal bone lesions with subacute and chronic symmetrical osteomyelitis . "
the prevalence of crmo is estimated to be less than 1/1,000,000 . a 5-year follow - up
study revealed the mean age of onset to be 10 years ( range 414 years ) .
symptoms include pain , local swelling , and warmth in the absence or presence of fever .
crmo mainly affects the metaphyses of the long bones , the pelvis , shoulder girdle , and , less commonly , the spine and skull . skull involvement , as described in this report , is very rare .
therefore , it is important to explore the etiology of crmo and the reason for its primary localization to the metaphyses and epiphyses of the long bones , which are areas involved in bone growth in children and adolescents .
it is likely that osteoclast cells or cytokines at the lesion sites in crmo are associated with the etiology .
for this patient , we could not evaluate the state of disease using the serum inflammation data , including the cytokine profiles .
we speculated about the reason for the onset of this rare skull involvement in this patient .
our patient s father had idiopathic bilateral femur head necrosis , suggesting that an examination of the genetic mutations common to them may be worthwhile , although there are no data to support the concept that crmo is a monogenic disease .
our patient demonstrated bone pain and swelling on the back of the head in the absence of fever .
reports of crmo involving skull lesions are scarce , and the well - documented cases involve flat bones such as the ilium and mandible .
we believe that the skull lesions were caused by crmo , although we could not examine the histopathological findings via skull biopsy because the patient experienced remission and exacerbation of his skull lesions .
as one of the differential diagnoses , we had to consider lch because our case had skull lesions , although we excluded malignancy and infectious osteomyelitis .
we discovered a report of a child with a frontal and sphenoid bone lesion , which was the first case report of crmo involving the skull . to the best of our knowledge
, this report provides the second description of skull involvement in a pediatric crmo patient .
the aim of publishing this case report is to indicate that crmo should be considered when the skull is affected in pediatric osteomyelitis patients .
crmo is a self - limited disease , but sequelae of the disease occasionally occur .
the clinical course is unpredictable , with considerable variation in the severity and time course .
exacerbations and spontaneous remissions , as well as inflammatory conditions of the skin and gastrointestinal tract , have been reported .
malignancy , pyogenic infections , and atypical presentation of juvenile arthritis need to be ruled out by correlating the history , clinical findings , and biopsy results .
pathogens are generally not cultured from the blood , bone , or joints of crmo patients , but patients may report symptoms of psoriatic skin involvement , including palmoplantar pustulosis .
such patients are categorized as having synovitis , acne , pustulosis , hyperostosis , and osteitis ( sapho ) syndrome , which represents an inflammatory spectrum .
this syndrome may or may not be associated with dermatological manifestations . to date , our patient has not presented skin lesions , but he will be followed to determine whether skin lesions appear in the future .
treatment typically involves nsaids , corticosteroids , tumor necrosis factor ( tnf ) inhibitors , and bisphosphonates .  
mutations in lpin2 cause a syndromic form of crmo known as majeed syndrome , while mutations in pstpip2 cause a murine form of the disorder .
recent studies in murine chronic multifocal osteomyelitis , majeed syndrome , deficiency of the interleukin-1 receptor antagonist ( dira ) syndrome , and sapho syndrome reveal abnormalities in innate immune system function .
il-1 pathway dysregulation is present in several of these disorders , and blocking il-1 therapeutically controlled the disease in dira , majeed syndrome , and some cases of sapho and crmo .
laboratory findings are of little diagnostic value because they typically reveal nonspecific evidence of inflammation , such as altered esr and crp levels .
novel insights into the pathogenesis of crmo suggest a link to the failure to produce il-10 and the resulting imbalance of pro - inflammatory il-6 and tnf - alpha levels , in conjunction with disease expression .
a diagnosis is supported by the presence of osteolytic lesions , with surrounding sclerosis apparent on radiographs ; asymptomatic lesions frequently appear in nuclear scans . in our patient ,
mri and ct revealed the involvement of the surrounding soft tissue , specifically the anterior soft tissue of the sacrum , the overlying scalp , and the underlying epidural space and dura mater of the head . at the time of our initial observation ,
the patient s bone alterations were limited to the occipital bone , but follow - up head ct scans revealed a new lesion in a different area of the occipital bone . in our patient , the bone scan readily detected lesions throughout the body .
the demonstration of lesions at various typical sites is crucial for a correct diagnosis . in a report involving 14 pediatric crmo cases ,
the mean age of symptomatic onset was 9.6 years and the mean disease duration was 5.3 years .
however , in a study of 22 crmo children , seven patients developed noticeable deformities and five had leg - length discrepancies lasting 2.520 years .
the conclusion of the second study was that crmo is not a benign condition , and if it is not followed to maturity , it can have disabling sequelae that include physical and psychological complications .
this report describes the second case of skull involvement in pediatric crmo , which occurred in an 11-year - old boy .
we thank akihiro yachie , md , department of pediatrics , kanazawa university and shunji hasegawa , md , department of pediatrics , yamaguchi university , for measuring the serum cytokine levels .  
 abstractan 11-year - old boy was diagnosed with chronic recurrent multifocal osteomyelitis ( crmo ) and presented with right sacro - femoral and occipital lesions . 
 initially , a tumor was suspected . however , the bone biopsy showed osteomyelitis with a negative bacterial culture . 
 bone scintigraphy revealed inflammatory changes on multiple bone lesions . 
 the slight elevation in inflammatory markers such as c - reactive protein was of little clinical value . 
 he was diagnosed with crmo by sacral biopsy , and the clinical course progressed , with the presence of a new occipital lesion observed after the 1-year follow - up . 
 the administration of non - steroidal anti - inflammatory drugs successfully improved his clinical symptoms . 
 the presence of a skull lesion in the occipital bone of a pediatric patient with crmo has not been previously reported . 
INTRODUCTION
CASE PRESENTATION
DISCUSSION
CONCLUSIONS
ACKNOWLEDGMENTS
CONFLICT OF INTEREST