Benjamin Jacobs

Nonbacterial osteitis: a clinical, histopathological, and imaging study with a proposal for protocol-based management of patients with this diagnosis

BackgroundNonbacterial osteitis (NBO), a term referring to sterile bone lesions with nonspecific histopathological features of inflammation, may be either unifocal or multifocal, acute (≤6 months) or chronic, and recurrent. Only when the condition is chronic, recurrent, and multifocal is it appropriate to use the term chronic recurrent multifocal osteomyelitis (CRMO). We present our clinical experience as the largest reported series of children with NBO to date.MethodsWe report a retrospective clinical, histopathological, and radiological study of 41 children with nonbacterial osteitis.ResultsOf 41 children (2–16 years of age) diagnosed with NBO in our institution over the last 6 years, 21 (51%) had recurrent disease and 18 (44%) had multifocal disease. The most common bones affected were the clavicle, femur, and tibia (in order of decreasing prevalence) accounting for 44 (63%) of a total of 70 lesions. Only one individual had SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) and no other patients had evidence of bowel or skin disease. In the absence of evidence for an infective etiology, we recommend nonsteroidal anti-inflammatory agents as the firstline therapy and bisphosphonates only in cases of resistant disease.ConclusionsOn the basis of our findings, we propose using a patient questionnaire and protocol for investigating and managing patients who present with NBO to orthopedic surgeons. We predict that this will benefit patients with this disorder by improving our knowledge of the presenting signs and symptoms and related disorders, rationalizing the therapeutic approach, and allowing us to learn about the natural history of the disease.

An infant with pseudohyperkalemia, hemolysis, and seizures: cation-leaky GLUT1-deficiency syndrome due to a SLC2A1 mutation.

CONTEXT GLUT1 (glucose transporter 1) deficiency syndrome is a well-known presentation in pediatric practice. Very rare mutations not only disable carbohydrate transport but also cause the red cell membrane to be constitutively permeant to monovalent cations, namely sodium and potassium. OBJECTIVE The aim of this study was to describe the pediatric presentation of a patient with GLUT1 deficiency with such a cation-leaky state. SUBJECT AND METHODS The infant presented with erratic hyperkalemia, neonatal hyperbilirubinemia, anemia, hepatic dysfunction, and microcephaly. Later, seizures occurred and developmental milestones were delayed. Magnetic resonance imaging and computerized tomography scans of the brain showed multiple abnormalities including periventricular calcification. Visual impairment was present due to the presence of both cataracts and retinal dysfunction. RESULTS Measurements of red cell cation content showed extremely leaky red cells (causing the hemolysis) and temperature-dependent loss of potassium from red cells (explaining the hyperkalemia as pseudohyperkalemia). A trinucleotide deletion in SLC2A1, coding for the deletion of isoleucine 435 or 436 in GLUT1, was identified in the proband. CONCLUSION This is the fourth pedigree to be described with this most unusual syndrome. The multisystem pathology probably reflects a combination of glucose transport deficiency at the blood-brain barrier (as in typical GLUT1 deficiency) and the deleterious osmotic effects of a cation-leaky membrane protein in the cells where GLUT1 is expressed, notably the red cell. We hope that this detailed description will facilitate rapid diagnosis of this disease entity.

Early clinical observations on the use of imatinib mesylate in FOP: A report of seven cases

BACKGROUND Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification (HO) for which there is presently no definitive treatment. Research studies have identified multiple potential targets for therapy in FOP, and novel drug candidates are being developed for testing in clinical trials. A complementary approach seeks to identify approved drugs that could be re-purposed for off-label use against defined targets in FOP. One such drug is imatinib mesylate, a tyrosine kinase inhibitor originally developed for use in patients with chronic myeloid leukemia (CML). Imatinib has the desirable effect of attacking multiple targets involved in the early hypoxic and inflammatory stages of FOP flare-ups, including HIF1-α, PDGFRα, c-KIT, and multiple MAP kinases. RESULTS Based on compelling biologic rationale, strong preclinical data, and a favorable safety profile, imatinib has been prescribed on an off-label basis in a non-trial setting in seven children with continuous FOP flare-ups, predominantly in the axial regions, and which were not responsive to standard-of-care regimens. Anecdotal reports in these seven isolated cases document that the medication was well-tolerated with a ubiquitous reported decrease in the intensity of flare-ups in the six children who took the medication. CONCLUSIONS These early clinical observations support the implementation of clinical trials in children with uncontrolled FOP flare-ups to determine if imatinib may ameliorate symptoms or alter the natural history of this debilitating and life-threatening disease.

G357 Chronic recurrent multifocal osteomyelitis (crmo): the value of whole body mri demonstrated by a series of 13 adult and 34 paediatric patients

Aim To assess the role of whole-body MRI (WB MRI) in the diagnosis and management of patients with Chronic Recurrent Multifocal Osteomyelitis (CRMO). CRMO is a benign and non-infective autoinflammatory bone disorder characterised by multiple and recurrent inflammatory bone lesions. No universal diagnostic criteria exist. Methods Retrospective review of CRMO cases diagnosed at this hospital between 2008 to 2014. Cases were identified from patient records, and clinical information was collated from radiology and histopathology records and individual case notes. Results Forty seven CRMO patients were identified who had had WB MRI, of these 34 were paediatric patients up to the age of 18 years. The number of WB MRI scans per case ranged from 1 to 5 [mean 1.5]. WB MRI identified multifocal lesions in 30 patients. The clavicle, tibia and femur were most frequently involved. All cases were managed with non-steroidal anti-inflammatory medication or bisphosphonates. No children required steroid or anti-TNF treatment or surgical resection. Conclusions In the absence of specific diagnostic criteria, WB MRI in combination with clinical assessment can aid in the diagnosis of CRMO. WB MRI has almost entirely replaced bone biopsy in the diagnosis of CRMO at our institution.

G591(P) The Treatment of Camurati-Englemann Disease with Losartan

Objective Camurati-Engelmann disease (CED) is a rare, autosomal dominant bone dysplasia characterised by hyperostosis and sclerosis of the diaphyses of the long bones and skull. It typically presents in childhood with bone pain, myopathy and progressive immobility. It is caused by a number of mutations that increase activity of transforming growth factor β1 (TGF-β1). Evidence for treatment is based on a number of case reports, most of which describe the response to glucocorticoids. Losartan is known to reduce expression of TGF-β1 and there are reports of two children with CED who showed significant improvement in pain and mobility in response to this treatment. Here we report a child with CED treated with losartan. Methods A 10 year old child with a clinical and radiological diagnosis of CED (Figures 1 and 2) was commenced on losartan at a dose of 0.6 mg/kg daily. We assessed the response to treatment using the 6 min walk test, Functional Mobility Scale, Child Health Assessment Questionnaire (CHAQ), formal assessment of gait, biochemical markers of inflammation and bone turnover and radiological appearance including radiographs and densitometry. We observed for side effects, including specific monitoring for hypotension and electrolyte abnormalities.Abstract G591(P) Figure 1Abstract G591(P) Figure 2 Results Four weeks into treatment we observed improvement in his 6 min walking test from 357m to 366 m, and in the global evaluation portion of his CHAQ score from 1.5 to 0.9 on a scale of 0–3. Conclusions The early response to treatment with losartan in our patient has led to modest improvement in pain and mobility; further outcomes will be evaluated in due course.

Bone health and SATB2-associated syndrome

SATB2‐associated syndrome (SAS) is a rare disorder caused by alterations in the special AT‐rich sequence‐binding protein 2 (SATB2). Skeletal abnormalities such as tibial bowing, osteomalacia, osteopenia or osteoporosis have been reported suggesting a higher frequency of skeletal complications in SAS. The optimal timing, necessity, and methodology for routine assessment of bone health in individuals with SAS, however, remain unclear. We report molecular and phenotypic features of 7 individuals with SAS documented to have low bone mineral density (BMD) ascertained by dual‐energy X‐ray absorptiometry (DXA), often preceded by tibial bowing. The lowest BMD Z‐scores ranged −2.3 to −5.6. In 4 individuals, total alkaline phosphatase levels were elevated (2 with elevated bone fraction) around the time of low BMD documentation. A clinically significant fracture history and a diagnosis of pediatric osteoporosis were present in 4 individuals. Pamidronate treatment in 2 children improved BMD. In conclusion, low BMD, fractures, and tibial bowing are relatively common skeletal complications in individuals with SAS. DXA is a useful tool when evaluating a child with SAS suspected to have low BMD and the results might alter clinical management.

G592(P) An audit of the recognition of low serum alkaline phosphatase levels in children

Objective Low serum alkaline phosphatase (ALP) is the hallmark of hypophosphatasia and a sign of a number of other conditions, such as zinc deficiency. There is evidence that it is often unrecognised by clinicians leading to delay in diagnosis, inappropriate treatment and, in some cases, harm. We conducted an audit of our practice looking at the recognition of abnormally low serum ALP results by clinicians. We used the standard that the clinician should recognise the abnormal result and that a consideration of the potential cause and need for further investigation should be documented in the patient’s notes. Methods Using the age specific reference ranges produced by Pathology Harmony we searched the biochemistry database to find all patients aged under 18 years with an abnormally low serum ALP. We then reviewed the notes of these patients to identify if the abnormal result was recognised, the medical situation in which the ALP was measured and what further investigation was done. Results Searching 3,031 samples we identified 19 patients with an abnormally low serum ALP. We did not find documentation to show recognition of the abnormal result in any of the patients’ notes. We found no evidence that for any of the patients the potential cause of the abnormal result was considered. Conclusions To the best of our knowledge, this is the first audit of the recognition of abnormally low serum ALP levels in children. The results correspond to existing studies and show that clinicians may frequently miss abnormally low levels. This will lead to undiagnosed cases of hypophosphatasia. This is a crucial omission for the paediatric population as a specific treatment is licensed and available. We propose two necessary changes. Firstly, that the awareness of the potential significance of low ALP values is increased and secondly, it is of critical importance that ALP values are reported using an age adjusted lower limit of normal such as those produced by Pathology Harmony.

G205(P) Fibrodysplasia ossificans progressiva (fop) an unfamiliar disease that is now important to diagnose

Background FOP is a rare but disabling condition characterised by congenital malformation of the great toes and progressive heterotopic endochondral ossification (HEO). FOP is the most catastrophic disorder of HEO in humans. Flare-ups are episodic; immobility is cumulative. The discovery of the ACVR1 gene as the cause of FOP has allowed identification of possible therapeutic targets. Palovarotene, a retinoic acid receptor gamma agonist, is currently in Phase 2 clinical trials to reduce HEO during acute flares. Aim To describe the clinical presentation and current management of FOP. Methods A 7 year old boy with a history of hallux valgus, recurrent painful episodes of soft tissue swelling and new abnormal bone formation, was assessed clinically and radiologically. Results Review of the clinical history and radiographs taken in infancy revealed the diagnosis of FOP. This had not been previously recognised, although he had been seen in a specialist Hallux Valgus clinic as a baby. Conclusions As specific treatments are now becoming available for this life-limiting condition, it is essential that all neonatologists, paediatricians, paediatric oncologists and orthopaedic surgeons consider a diagnosis of FOP if a baby or child presents with bilateral hallux valgus and/or episodes of swelling with evidence of ossification. These children should now be referred to a paediatric metabolic bone clinic to consider genetic testing and for specialist management.

‘Ping-pong skull’ after a fall from bed

A 9-month-old boy of South Asian origin presented to the emergency department with a head injury after falling out of his parents’ bed onto a carpeted floor. On examination, he had a 2 cm×2 cm smooth concavity in the right parietal region. He was playful, with an otherwise normal examination. The skull bones did not appear soft or brittle when pressed. There was nothing in the presentation that warranted a safeguarding investigation. He had recently completed 12 weeks of treatment for presumed latent …