Musculoskeletal misdiagnoses in pediatric patients with spinal tumors.

OBJECTIVE: Childhood spinal tumors often present with musculoskeletal symptoms, potentially causing a misdiagnosis and delays in diagnosis and treatment. This study aims to identify, characterize, and compare children with spinal tumors who had prior musculoskeletal misdiagnoses to those without, analyzing clinical presentation, diagnostic interval, and outcome. STUDY DESIGN: This retrospective cohort study evaluated all children aged 0-14 years diagnosed with a spinal tumor in Denmark from 1996 to 2018. The cohort was identified through the Danish Childhood Cancer Registry, and the registry data were supplemented with data from medical records. The survival was compared using the Kaplan-Meier method. RESULTS: Among 58 patients, 57% (33/58) received musculoskeletal misdiagnoses before the spinal tumor diagnosis. Misdiagnoses were mostly nonspecific (64%, 21/33), involving pain and accidental lesions, while 36% (12/33) were rheumatologic diagnoses. The patients with prior misdiagnosis had less aggressive tumors, fewer neurological/general symptoms, and 5.5 months median diagnostic interval versus 3 months for those without a misdiagnosis. Those with prior misdiagnoses tended to have a higher 5-year survival of 83% (95% confidence interval [CI]: 63%-92%) compared to 66% (95% CI: 44%-82%) for those without (p = .15). CONCLUSION: Less aggressive spinal tumors may manifest as gradual skeletal abnormalities and musculoskeletal symptoms without neurological/general symptoms, leading to misdiagnoses and delays.

Thirty-day surgical morbidity and risk factors in pediatric brain tumor surgery: a 10-year nationwide retrospective study.

OBJECTIVE: Pediatric neuro-oncological surgery is often associated with significant risk; however, comprehensive data on surgical morbidity remain limited. The purpose of this study was therefore to provide national population-based data on both the incidence and characteristics of poor postoperative outcomes following pediatric intracranial neuro-oncological surgery. Additionally, the authors aimed to evaluate key risk factors for poor postoperative outcomes including overall morbidity, significant morbidity, and the most frequent types of morbidity. METHODS: The authors conducted a registry-based, nationwide, retrospective study including all children receiving surgical treatment for a CNS tumor over a 10-year period. Patients were identified using the Danish Childhood Cancer Registry, and 30-day morbidity was assessed through manual review of electronic health records. Significant morbidity was defined as complications in need of treatment under general anesthesia, ICU admission, or persistent neurological deficits at 30 days following surgery or death. Risk factors including sex, age, tumor location, tumor malignancy grade, and preoperative hydrocephalus were investigated using multivariate logistic regression analysis. RESULTS: A total of 349 children undergoing 473 tumor procedures were included, with an overall morbidity rate of 66.0% and a significant morbidity rate of 34.2%. The most frequent complications included neurological deficits (41.4%) and CSF-related morbidity consisting of CSF leaks, pseudomeningoceles, and postoperative hydrocephalus. Highly significant associations between infratentorial tumor location and both significant morbidity (OR 1.26, 95% CI 1.11-1.43; p < 0.001) and neurological deficits (OR 1.38, 95% CI 1.21-1.57; p < 0.001) were identified. In addition, younger age was revealed as a major risk factor of both postoperative CSF leakage and CSF-related morbidity in general. CONCLUSIONS: In this large, population-based cohort, the authors show that postoperative morbidity is frequent, occurring in about two-thirds of all patients, largely driven by neurological deficits and CSF-related complications. In addition, infratentorial tumor location and younger age emerged as key risk factors for poor postoperative outcomes.

A novel serum calprotectin (MRP8/14) particle-enhanced immuno-turbidimetric assay (sCAL turbo) helps to differentiate systemic juvenile idiopathic arthritis from other diseases in routine clinical laboratory settings.

BACKGROUND: Differential diagnosis in children with signs of unprovoked inflammation can be challenging. In particular, differentiating systemic juvenile idiopathic arthritis (SJIA) from other diagnoses is difficult. We have recently validated the complex of myeloid-related proteins 8/14 (MRP8/14, also known as S100A8/A9 complex or serum calprotectin) as a helpful biomarker supporting the diagnosis of SJIA. The results were subsequently confirmed with a commercial ELISA. However, further optimization of the analytical technology is important to ensure its feasibility for large-scale use in routine laboratory settings. METHODS: To evaluate the accuracy in identifying children with SJIA, the performance of a particle-enhanced immuno-turbidimetric assay for serum calprotectin (sCAL turbo) on an automated laboratory instrument was analyzed. Samples from 615 children were available with the diagnoses SJIA (n = 99), non-systemic JIA (n = 169), infections (n = 51), other inflammatory diseases (n = 126), and acute lymphoblastic leukemia (ALL, n = 147). In addition, samples from 23 healthy controls were included. RESULTS: The sCAL turbo assay correlated well with the MRP8/14 ELISA used in previous validation studies (r = 0.99, p < 0.001). It could reliably differentiate SJIA from all other diagnoses with significant accuracy (cutoff at 10,500 ng/ml, sensitivity 84%, specificity 94%, ROC area under curve 0.960, p < 0.001). CONCLUSIONS: Serum calprotectin analyses are a helpful tool supporting the diagnosis of SJIA in children with prolonged fever or inflammatory disease. Here, we show that an immuno-turbidimetric assay for detection of serum calprotectin on an automated laboratory instrument can be implemented in clinical laboratory settings to facilitate its use as a diagnostic routine test in clinical practice.

A 9-year-old boy with a nonmalignant forehead tumor - a rare case of pediatric Pott's puffy tumor.

BACKGROUND: Pott's puffy tumor (PPT) is a rare and potentially deadly complication of frontal sinusitis consisting of subperiosteal abscess and osteomyelitis of the frontal bone. CASE PRESENTATION: We report the case of a 9-year-old boy who presented with fever and soft tissue swelling of the forehead. Magnetic resonance imaging (MRI) depicted an abscess in the subcutaneous tissue frontally and an epidural empyema, while a cranial computed tomography (CT) scan revealed bone erosion as a sign of osteomyelitis. The patient was treated accordingly. CONCLUSIONS: This rare condition is essential to keep in mind as it needs a multidisciplinary approach and relevant imaging to start proper treatment and thus decrease the risk of intracranial complications.

Musculoskeletal misdiagnoses in children with brain tumors: A nationwide, multicenter case-control study.

OBJECTIVE: Childhood brain tumors belong to the cancer type with the longest diagnostic delay, the highest health care utilization prior to diagnosis, and the highest burden of long-term sequelae. We aimed to clarify whether prior musculoskeletal diagnoses in childhood brain cancer were misdiagnoses and whether it affected the diagnostic delay. STUDY DESIGN: In this retrospective, chart-reviewed case-control study we compared 28 children with brain tumors and a prior musculoskeletal diagnosis to a sex and age-matched control group of 56 children with brain tumors and no prior musculoskeletal diagnosis. Using the Danish registries, the cases were identified from consecutive cases of childhood brain cancers in Denmark over 23 years (1996-2018). RESULTS: Of 931 children with brain tumors, 3% (28/931) had a prior musculoskeletal diagnosis, of which 39% (11/28) were misdiagnoses. The misdiagnoses primarily included torticollis-related diagnoses which tended to a longer time interval from first hospital contact until a specialist was involved: 35 days (IQR 6-166 days) compared to 3 days (IQR 1-48 days), p = 0.07. When comparing the 28 children with a prior musculoskeletal diagnosis with a matched control group without a prior musculoskeletal diagnosis, we found no difference in the non-musculoskeletal clinical presentation, the diagnostic time interval, or survival. Infratentorial tumor location was associated with a seven-fold risk of musculoskeletal misdiagnosis compared to supratentorial tumor location. CONCLUSION: Musculoskeletal misdiagnoses were rare in children with brain tumors and had no significant association to the diagnostic time interval or survival. The misdiagnoses consisted primarily of torticollis- or otherwise neck-related diagnoses.

Inflammatory Biomarkers Can Differentiate Acute Lymphoblastic Leukemia with Arthropathy from Juvenile Idiopathic Arthritis Better Than Standard Blood Tests.

OBJECTIVE: To evaluate the predictive value of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of inflammatory cytokines in order to differentiate the child with acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA). STUDY DESIGN: In this cross-sectional study, we measured S100A9, S100A12, and 14 cytokines in serum from children with ALL (n = 150, including 27 with arthropathy) and JIA (n = 236). We constructed predictive models computing areas under the curve (AUC) as well as predicted probabilities in order to differentiate ALL from JIA. Logistic regression was used for predictions of ALL risk, considering the markers as the respective exposures. We performed internal validation using repeated 10-fold cross-validation and recalibration, adjusted for age. RESULTS: In ALL, the levels of S100A9, S100A12, interleukin (IL)-1 beta, IL-4, IL-13, IL-17, matrix metalloproteinase-3, and myeloperoxidase were low compared with JIA (P < .001). IL-13 had an AUC of 100% (95% CI 100%-100%) due to no overlap between the serum levels in the 2 groups. Further, IL-4 and S100A9 had high predictive performance with AUCs of 99% (95% CI 97%-100%) and 98% (95% CI 94%-99%), respectively, exceeding both hemoglobin, platelets, C-reactive protein, and erythrocyte sedimentation rate. CONCLUSIONS: The biomarkers S100A9, IL-4, and IL-13 might be valuable markers to differentiate ALL from JIA.

Phagocyte-related S100 proteins and cytokines in acute lymphoblastic leukemia and their prognostic value.

In this retrospective cohort study, we evaluated the level of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of cytokines in 128 children with pre-B ALL and 22 with T-ALL. The biomarkers were evaluated at diagnosis and during antileukemic therapy (day 29 and after six months) and we evaluated their correlation with basic laboratory values. Further, for the children with pre-B ALL, we evaluated whether the biomarkers could predict the outcome of ALL expressed as minimal residual disease (MRD), relapse, and death.The levels of S100A9, S100A12, IL-1beta, IL-12p70, IL-13, IL-17, IL-18, and MPO serum levels increased significantly as chemotherapy was initiated. The difference was most pronounced for S100A9 and S100A12, which had strong positive correlations with the neutrophil counts. In contrast, TNF-alpha, IL-6, IL-10, CCL-2, MMP-3, and CD25 serum levels decreased after chemotherapy. Although none of these biomarkers appear to be an independent predictor of outcomes, in predictive models with MRD as the outcome, AUC increased from 76% (95% CI 68-84%) when using initial risk group stratification alone to 83% (95% CI 73-91%) in a multivariate predictive model including initial risk group stratification and the biomarkers S100A12, TNF-alpha, and IL-10.

The chance of spontaneous patent ductus arteriosus closure in preterm infants born before 32 weeks of gestation is high and continues to increase until 5 years of follow-up.

AIM: The primary aim was to estimate premature infants' spontaneous patent ductus arteriosus closure rate. Secondly, to identify criteria associated with the chance of spontaneous closure. METHODS: We performed a retrospective cohort study of 167 infants born before 32 weeks of gestation and diagnosed with a patent ductus arteriosus between 1 January 2008 and 31 December 2017. The spontaneous patent ductus arteriosus closure event rate was evaluated using the Kaplan-Meier estimator. RESULTS: The spontaneous closure rate within the first year of life was 66% (95% CI 58%-73%), increasing to 80% (95% CI 72%-86%) five years after birth. When including both spontaneous closure and closure following treatment, 96% (95% CI 86%-100%) closed within 5 years after birth. The chance of spontaneous closure was reduced in the case of a large patent ductus arteriosus: OR 0.16 (95% CI 0.05-0.52), left atrial enlargement: OR 0.16 (95% CI 0.05-0.51), and pulmonary hypertension: OR 0.23 (95% CI 0.07-0.74). CONCLUSION: The chance of spontaneous closure in premature infants born between 23 and 32 weeks of gestation was high, and the incidence continued increasing until 5 years of follow-up.

M-ficolin: a valuable biomarker to identify leukaemia from juvenile idiopathic arthritis.

OBJECTIVE: Distinction on clinical grounds between acute lymphoblastic leukaemia presenting with arthropathy (ALLarthropathy) and juvenile idiopathic arthritis (JIA) is difficult, as the clinical and paraclinical signs of leukaemia may be vague. The primary aim was to examine the use of lectin complement pathway proteins as markers to differentiate ALLarthropathy from JIA. The secondary aims were to compare the protein levels at baseline and follow-up in a paired number of children with ALL and to examine the correlation with haematology counts, erythrocyte sedimentation reaction (ESR), C-reactive protein (CRP), blasts, relapse and death. STUDY DESIGN: In this observational study, we measured M-ficolin, CL-K1 and MASP-3 in serum from children with ALL (n=151) and JIA (n=238) by time-resolved immunofluorometric assays. Logistic regression was used for predictions of ALL risk, considering the markers as the respective exposures. We performed internal validation using repeated '10-fold cross-validation' with 100 repetitions computing the area under the curve (AUC) as well as positive and negative predictive values in order to evaluate the predictive performance. RESULTS: The level of M-ficolin was higher in JIA than ALLtotal and the ALLarthropathy subgroup. The M-ficolin level normalised after remission of ALL. M-ficolin could differentiate ALL from JIA with an AUC of 94% and positive predictive value (PPV) of 95%, exceeding CRP and haemoglobin. In a dichotomised predictive model with optimal cut-offs for M-ficolin, platelets and haemoglobin, AUC was 99% and PPV 98% in detecting ALL from JIA. CONCLUSION: M-ficolin is a valuable marker to differentiate the child with ALL from JIA.

Musculoskeletal Diagnoses before Cancer in Children: A Danish Registry-Based Cohort Study.

OBJECTIVE: To identify the prevalence of musculoskeletal diagnoses recorded 6 months before the diagnosis of cancer and to evaluate whether preceding musculoskeletal diagnoses affected survival. STUDY DESIGN: We performed a nationwide registry-based cohort study including all children under 15 years of age diagnosed with cancer in Denmark over a 23-year period (1996-2018). The Danish National Patient Registry was used to identify musculoskeletal diagnoses and associated dates recorded within 6 months preceding the diagnosis of cancer. We compared the characteristics of children with and without a prior musculoskeletal diagnoses using prevalence ratios and 95% CI and diagnostic interval as median with IQR. We compared survival using Kaplan-Meier and Cox proportional hazards regression analysis adjusting for age, sex, and presence of metastasis at diagnosis. RESULTS: Of 3895 children with all types of cancer, 264 (7%) had a total of 451 hospital visits with musculoskeletal diagnosis within 6 months preceding the diagnosis of cancer; however, survival was not affected. The overall median diagnostic interval from first musculoskeletal diagnosis (within 6 months before cancer diagnosis) to cancer diagnosis was 15 days (IQR, 7-47 days). A diagnosis of juvenile idiopathic arthritis, unspecified arthritis, and arthropathy each accounted for 5% of the contacts, primarily in children with acute lymphoblastic leukemia, bone sarcomas, or neuroblastomas. CONCLUSIONS: A preliminary musculoskeletal diagnosis occurred in 7% of children with cancer, but did not affect the overall survival.

Identifying acute lymphoblastic leukemia mimicking juvenile idiopathic arthritis in children.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) may present with arthritis implying the risk of being misdiagnosed as juvenile idiopathic arthritis (JIA). The aim of this study was to identify predictors for ALL based on clinical and laboratory information. METHODS: This cross-sectional, retrospective study compared clinical presentation and laboratory results of 26 children with ALL and arthritis versus 485 children with JIA (433 non-systemic, 52 systemic JIA). Using a Bayesian score approach the findings were evaluated by calculating odds ratios (OR) and lnOR as a measure of diagnostic weight. RESULTS: Distinction on clinical grounds was difficult, as even a high number of joints involved did not exclude ALL. One or more hematologic cell counts were low (Hb <10 g/dL, platelet count <100 x 109/L, neutrophil count < 1.0 x 109/L) in 92% with ALL, 25% with systemic JIA and 10% with non-systemic JIA. Neutropenia and thrombocytopenia had the highest ORs of 128 (95% CI 43-387) and 129 (95% CI 26-638), each giving a diagnostic weight of 4. The estimated risks of ALL were 0.2% with normal cell counts and 9%, 67% and 100% when one, two or three cell lines were affected. CONCLUSION: A simple count of cell lines with low counts can serve as a basic diagnostic strategy. Children with tri- or bilinear involvement should be referred to a bone marrow, and those with unilinear involvement a thorough screen for further evidence of ALL (organomegaly, ESR, LDH, uric acid, and blood smear).

Mitochondrial Disease Caused by a Novel Homozygous Mutation (Gly106del) in the SCO1 Gene.

The cytochrome C oxidase assembly protein SCO1 gene encodes a mitochondrial protein essential for the mammalian energy metabolism. Only three pedigrees of SCO1mutations have thus far been reported. They all presented with lactate acidosis and encephalopathy. Two had hepatopathy and hypotonia, and the other presented with intrauterine growth retardation and hypertrophic cardiomyopathy leading to cardiac failure. Mitochondrial disease may manifest in neonates, but early diagnosis has so far been difficult. Here, we present a novel mutation in the SCO1 gene: in-frame deletion (Gly106del)with a different phenotype without encephalopathy, hepatopathy, hypotonia, or cardiac involvement. Within the first 2 h the girl developed hypoglycemia and severe chronic lactate acidosis. Because of the improved technique in whole exome sequencing, an early diagnosis was made when the girl was only 9 days old, which enabled the prediction of prognosis as well as level of treatment. She died at 1 month of age.

Characteristics of children with acute lymphoblastic leukemia presenting with arthropathy.

Acute lymphoblastic leukemia (ALL) is the most common childhood neoplasia and may present with arthralgia and arthritis, with the risk of misdiagnosis and diagnostic delay. We describe in detail arthropathy (arthritis/arthralgia) among children with leukemia as the children's laboratory results, misdiagnosis, and treatment before the diagnosis of ALL and the diagnostic delay. In this retrospective cohort study, we reviewed records of 286 children aged 1-15 years diagnosed with ALL from January 1992 to March 2013. We identified 26 children with arthralgia and 27 children with arthritis. The majority of the children had one or two joints involved (arthralgia 72%, arthritis 42%), and most often hips and knees. Morning stiffness was not reported. Imaging of affected joints was included in the initial workup of 77% of children with ALL and arthropathy, and 66% was abnormal. Misdiagnosis as JIA occurred in 26% and 71% of these children received treatment with intraarticular corticosteroids. The diagnostic delay was 3 weeks longer for the children with arthritis than those with arthralgia (median 54 vs 36 days), primarily as a consequence of a longer first doctor's delay. Compared to the children with arthralgia, the children with arthritis were more often misdiagnosed and treated with intraarticular steroid before the diagnosis of ALL. They also had longer diagnostic delay, primarily as a consequence of a longer first doctor's delay.

Eosinophil alveolitis in two patients with idiopathic pulmonary fibrosis.

Bronchoalveolar lavage fluid (BALF) in patients with idiopathic pulmonary fibrosis (IPF) is typically characterized by a neutrophil inflammatory pattern and to a lesser extent (<25%) a mild eosinophil alveolitis. We here present two patients with a definite usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography of the thorax (HRCT) which demonstrated unusually high eosinophil counts in the BALF (40% and 51%). Based on HRCT, lack of response to steroids and the disease course they were both diagnosed as IPF after a multidisciplinary team discussion. This report discusses the diagnostic and etiological considerations of a coexisting UIP pattern and an eosinophil alveolitis. We conclude that these cases illustrate that high level BALF eosinophilia (40-50%) may occur among patients with IPF.

Arthritis as presenting manifestation of acute lymphoblastic leukaemia in children.

BACKGROUND: At disease onset, children with acute lymphoblastic leukaemia (ALL) may present with arthralgia or even signs of arthritis. This might cause misdiagnosis and thereby lead to prolonged diagnostic delay. The present study aimed to identify children with ALL with joint involvement and to compare their characteristics and outcome with children with ALL without joint involvement. METHODS: Case records of 286 children diagnosed with ALL between 1992 and 2013 were reviewed and analysed in this retrospective, descriptive study. RESULTS: Fifty-three (18.5%) children with ALL presented with localised joint pain, and half of them had objective signs of arthritis. The mean number of joints involved was 2.5, most frequently presenting as asymmetric oligoarthritis. The suspected misdiagnosis were reactive arthritis (19/53), osteomyelitis (9/53) and juvenile idiopathic arthritis (8/53). Children with joint involvement had less objective signs of haematological disease. Cytopenia was absent in 24% in children with joint involvement (vs 8% without, p=0.001), 50% had only one cell line affected (vs 21%, p=0.0005) and 44% had no organomegaly (vs 29%, p=0.05). Median diagnostic delay was 4 vs 2 weeks. The 5-year event-free and overall survival was superior for children with joint involvement: 94% vs 87% (p=0.049), and 96% vs 83% (p=0.044). CONCLUSIONS: ALL with joint involvement is a frequent finding (18.5%). The clinical signs of leukaemia are less prominent, but non-articular pain should alert the clinician of a possible diagnosis of leukaemia. The overall and event-free survivals were superior compared with the children without joint involvement.

Bone marrow involvement is not manifest in the early stages of childhood acute lymphoblastic leukaemia.

INTRODUCTION: Acute lymphoblastic leukaemia (ALL) in children may have atypical presentations causing diagnostic delay. Guidelines for prompt referral have been published. The utility of the specified criteria is unknown. MATERIAL AND METHODS: Symptoms, signs and laboratory findings at the time of diagnosis were reviewed in a consecutive series of 100 children with ALL in order to determine the frequency of atypical features and to evaluate the Danish referral guideline. RESULTS: Only 36% had involvement of all three haematopoietic cell lines, and 23% presented with the classic clinical triad of pallor, fever and purpura. Symptoms of bone marrow insufficiency had been present in 77% for an average of two weeks as a late occurrence following musculoskeletal pains (in 49%, duration eight weeks) and constitutional symptoms (in 82%, duration four weeks). Organ infiltration was manifest in 71%. In 22%, only one or no cell count was abnormal; in this group, musculoskeletal symptoms were more frequent and symptom duration longer (two months versus one month). In 15%, lymphoblasts could not be detected in the blood. At the time of diagnosis, the Danish criteria for accelerated investigation were fulfilled in 98% of cases. CONCLUSION: The clinical presentation of ALL is variable, and full-blown bone marrow insufficiency is a late occurrence as the disease progresses. Reduction of the diagnostic interval requires meticulous examination for organomegaly and attention to subtle haematologic changes. FUNDING: Not relevant. TRIAL REGISTRATION: Not relevant.