A Girl with Limp and Rash on the Palms and Soles.

Abstract

A previously healthy 5-year-old white girl presents to her pediatrician’s office with a 2-day history of limp. She has no preceding trauma, fever, viral, or constitutional symptoms. At the primary care office, she walks with an antalgic gait, appearing to favor her left leg but has no localizable source of pain, visible swelling, or joint limitation. Radiographs of the pelvis and lower extremities are obtained and demonstrate a lucency of the left proximal tibial metaphysis. Magnetic resonance imaging (MRI) with intravenous contrast reveals hyperintense metaphyseal lesions of the bilateral proximal tibiae and right distal tibia concerning for infection (Fig 1).She is admitted to the hospital for additional evaluation. During the initial evaluation and treatment, she develops a nonpainful, nonpruritic rash on her palms and soles. Physical examination reveals erythematous plaques of 3 to 5 cm in diameter with overlying scale and few central pustules (Fig 2).Complete blood cell count is normal with the exception of a mildly elevated platelet count of 456 × 103/mcL. Erythrocyte sedimentation rate is 44 mm/h, C-reactive protein less than 0.5 mg/dL. Bone biopsies from the tibial lesions reveal focal marrow fibrosis and no evidence of malignancy or inflammation. Aerobic, anaerobic, and fungal cultures sent from bone biopsy are negative. Echocardiogram shows no vegetations. Additional infectious studies, including testing for Blastomyces, tuberculosis, and Bartonella, are negative. Whole-body MRI strongly supports the presumed diagnosis. The patient’s limp improves after starting scheduled naproxen.The care team’s initial differential included infectious osteomyelitis, malignancy, Langerhans cell histiocytosis, and chronic recurrent multifocal osteomyelitis (CRMO). Based on the symmetrical metaphyseal lesions, biopsy findings, and characteristic rash, CRMO with palmarplantar pustulosis was suspected. Whole-body MRI confirmed the presence of additional, asymptomatic lesions of the pubic ramus, bilateral distal tibial metaphyses, talus and calcaneus in addition to the known tibial lesions.CRMO is an autoinflammatory disease characterized by sterile bone inflammation. The term “autoinflammatory” is used to describe conditions mediated by dysregulated innate immunity. (1) Autoinflammatory diseases including CRMO produce intense systemic or localized inflammation in the absence of infection but lack autoantibodies that are seen in classic autoimmune disease. Because clinical variability is seen in CRMO, including cases that are neither recurrent nor multifocal, chronic nonbacterial osteomyelitis is sometimes used as an alternative term for this disease. (2) The peak age of onset in children is 7 to 12 years of age, and CRMO is more common in girls. (2)(3)(4)(5) The incidence and prevalence of this rare condition are not well-established.Patients with CRMO present with indolent or acute bone pain, sometimes with associated fever, arthralgia, or inflammatory arthritis. Although CRMO can affect any bone, classic locations include the clavicle, mandible, vertebral bodies, and metaphyses of the long bones, which are often symmetrical. (5)(6) Localized warmth, swelling, or tenderness can be present, although some patients have no focal findings on physical examination.Diagnosis of CRMO hinges on identification of characteristic bone lesions on imaging and exclusion of mimics. As laboratory and imaging findings are nonspecific, CRMO remains a diagnosis of exclusion. In early disease, radiographs can be normal or demonstrate lytic lesions; later, cortical thickening or sclerosis predominate. (7) MRI is useful in assessing disease activity evidenced by bone marrow edema, can detect early lesions, and can demonstrate inflammation of surrounding soft tissues including synovitis of adjacent joints. (7) Whole-body MRI with short tau inversion recovery images can be used to identify additional, asymptomatic lesions. (6)(7)(8) This strategy can establish additional support for a suspected diagnosis of CRMO by confirming multifocal involvement, particularly if a classic distribution of lesions is seen. Identification of asymptomatic lesions in critical locations, such as the spine, may also prompt more aggressive treatment to avoid complications including vertebral collapse. Although bone scan has previously been used for a similar purpose, the symmetric metaphyseal lesions often seen in CRMO can be misinterpreted as normal on bone scan in a growing child. (7) Whole-body MRI is significantly more sensitive than bone scan for detecting CRMO lesions and is thus emerging as the preferred modality for whole-body imaging. (9)Laboratory studies often demonstrate elevated markers of inflammation, although profound systemic inflammation should prompt consideration of an alternative diagnosis or underlying inflammatory bowel disease. As the differential diagnosis includes infectious osteomyelitis, malignancy, and Langerhans cell histiocytosis, bone biopsy is usually needed before a diagnosis of CRMO can be made, especially in monophasic or unifocal cases. (8) Biopsy findings vary depending on the age of the lesion sampled. A neutrophilic infiltrate is characteristic of early lesions, whereas lymphocytes and occasional granulomas are seen in later lesions. (3) Nonspecific findings including fibrosis in the absence of active inflammation can also be seen.Associations between CRMO and several other conditions are well-recognized. Palmoplantar pustulosis was the first skin condition described in patients with CRMO and has been reported in up to 31% in some cohorts. (4)(10)(11) Generalized pustulosis, severe acne, pyoderma gangrenosum, and psoriasis vulgaris can also occur. CRMO is seen more frequently in people with inflammatory bowel disease, particularly Crohn disease. These associated conditions are also seen more frequently in family members of people with CRMO than in the general population. (12)Treatment of CRMO is aimed at controlling bone inflammation to reduce symptoms and prevent irreversible damage. Once infectious osteomyelitis has been adequately excluded, ongoing antibiotic therapy has no role in CRMO treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line therapy, with indomethacin and naproxen used most commonly. Medications used for NSAID failure or in patients with extensive disease or spinal lesions include corticosteroids, methotrexate, sulfasalazine, tumor necrosis factor α inhibitors, and bisphosphonates. The reported effectiveness of each of these agents varies widely among cohorts of patients with CRMO. (4)(6)(8)(13)(14)(15) The Childhood Arthritis and Rheumatology Research Alliance recently published consensus treatment plans for CRMO refractory to NSAIDs or with spinal involvement. (8) As the optimal treatment approach for patients with severe disease remains unclear, the consensus treatment plans will be used in future comparative effectiveness research to evaluate the relative efficacy of methotrexate, sulfasalazine, tumor necrosis factor inhibitors, and bisphosphonates.Assessing response to therapy can be difficult in patients with CRMO, as pain symptoms may persist after inflammation is controlled due to damage or comorbid chronic pain syndromes. Thorough musculoskeletal examination, laboratory studies to assess for systemic inflammation, and periodic imaging, ideally with whole-body MRI, are recommended to assess level of disease activity. (8)The prognosis and disease course for patients with CRMO is variable. Although many patients experience periods of remission, there are reports of persistent disease lasting up to 25 years in some cohorts. (5)(16) Complications of CRMO include bone deformity, leg-length discrepancy, pathological fracture, and vertebral collapse. Patients with CRMO are also at risk for developing associated autoimmune diseases, including arthritis, psoriasis, and inflammatory bowel disease, which complicate treatment and outcomes. Close monitoring and aggressive treatment are critical to minimize the chronic pain and disability that often characterize of the natural history of this disease. (8)(11)(12)(13)(14)(15)The patient’s palmoplantar pustulosis and limp improved on naproxen and methotrexate (Fig 3), although her inflammatory markers remained elevated and she had ongoing active lesions on MRI. Addition of etanercept initially produced a good response. She later experienced a flare characterized by limp, tarsal and ankle swelling, and increased inflammatory markers and was switched from etanercept to infliximab. Currently, 3 years after her initial presentation, she continues with regular follow-up in the pediatric rheumatology clinic and her disease is well controlled on infliximab and methotrexate. Her CRMO disease activity is routinely assessed with serial physical examination, inflammatory markers, and imaging.Although CRMO is a complex disease best managed by a rheumatologist, this patient’s good outcome despite extensive disease demonstrates the importance of CRMO awareness among pediatricians. The vigilance of her primary care provider and familiarity with CRMO by the inpatient general pediatrics team contributed to her rapid diagnosis and treatment.