Validity of parental recall of children's fracture: implications for investigation of childhood osteoporosis.

UNLABELLED: Fracture history is an important component of osteoporosis diagnosis in children. One in six parentally reported lifetime fractures in children were not confirmed on review of radiographs. Care should be taken to avoid unnecessary investigations for possible osteoporosis due to parental over-reporting of soft tissue injuries as fractures. INTRODUCTION: The diagnosis of osteoporosis in children requires either a vertebral compression fracture, or a significant fracture history (defined as ≥2 long bone fractures <10 years or ≥3 long bone fractures <19 years, excluding high impact fractures) and low bone mineral density. As children with frequent fractures might benefit from further evaluation, we determined whether parental reports of lifetime fracture were accurate compared to radiological reports and if they appropriately selected children for further consideration of osteoporosis. METHODS: Parents of children (<18 years) with a musculoskeletal injury completed a questionnaire on their child's fracture history, including age, site and mechanism of previous fracture(s). Radiological reports were reviewed to confirm the fracture. RESULTS: Six hundred sixty parents completed the questionnaire and reported 276 previous fractures in 207 children. An injury treated at our hospital was recorded in 214 of the 276 parentally reported fractures. Thirty-four of 214 (16 %) were not a confirmed fracture. An injury was recorded for all parentally reported fractures in 150 children, but for 21 % children, there were inaccurate details (no evidence of fracture, incorrect site or forgotten fractures) on parent report. Eighteen of 150 children had a significant fracture history on parental report alone, but following review of radiology reports, 2 of 18 (11 %) did not have clinically significant fracture histories. CONCLUSIONS: Approximately one in six fractures reported by parents to have occurred in their child's lifetime had not resulted in a fracture. One in nine children with a significant fracture history could have been investigated unnecessarily.

Vitamin D and skeletal health in infancy and childhood.

During growth, severe vitamin D deficiency in childhood can result in symptomatic hypocalcaemia and rickets. Despite the suggestion from some studies of a secular increase in the incidence of rickets, this observation may be driven more by changes in population demographics than a true alteration to age, sex and ethnicity-specific incidence rates; indeed, rickets remains uncommon overall and is rarely seen in fair-skinned children. Additionally, the impact of less severe vitamin D deficiency and insufficiency has received much interest in recent years, and in this review, we consider the evidence relating vitamin D status to fracture risk and bone mineral density (BMD) in childhood and adolescence. We conclude that there is insufficient evidence to support the suggestion that low serum 25-hydroxyvitamin D [25(OH)D] increases childhood fracture risk. Overall, the relationship between 25(OH)D and BMD is inconsistent across studies and across skeletal sites within the same study; however, there is evidence to suggest that vitamin D supplementation in children with the lowest levels of 25(OH)D might improve BMD. High-quality randomised trials are now required to confirm this benefit.

Differential relationships between parent-child DXA and pQCT bone measures: Results from the Southampton Women's Survey.

AIM: To investigate the associations between indices of bone health in childhood and corresponding parental measures. METHODS: The Southampton Women's Survey characterised 12,583 non-pregnant women aged 20-34 years; 3158 subsequently had singleton live births. In a subset, dual-energy X-ray absorptiometry (DXA) measurements of bone area (BA), bone mineral content (BMC) and areal bone mineral density (aBMD) lumbar spine and total hip were obtained in the parent/offspring (aged 8-9 years) trios. Another subset of children (aged 6-7 years), and their parents, had peripheral quantitative computed tomography (pQCT; 4% and 38% tibia) measures. Using multivariable linear regression we examined relationships between mother/father and offspring, adjusting for parental age, habitual walking speed and education; offspring age and sex; and the corresponding bone measure in the other parent (ß-coefficients (95%CI) unit/unit for each bone measure). RESULTS: Data were available for 260 trios with DXA and 99 with pQCT. There were positive associations for BA, BMC and aBMD between either parent and offspring. Mother-child associations were of greater magnitude than father-child; for example, mother-child aBMD (ß = 0.26 g·cm-2/g·cm-2 (0.21,0.32)) and father-child aBMD (ß = 0.16 g·cm-2/g·cm-2 (0.11,0.21)), P-difference in ß = 0.007. In the subset with pQCT there was a positive association for mother-offspring 4% tibial total area (ß = 0.33 mm2/mm2 (0.17,0.48)), but little evidence of a father-offspring association (ß = -0.06 mm2/mm2 (-0.17,0.06)). In contrast offspring 38% cortical density was more strongly associated with this measure in fathers (ß = 0.48 mg·cm-3/mg·cm-3 (0.15,0.82)) than mothers (ß = 0.27 mg·cm-3/mg·cm-3 (-0.03,0.56)). In general mother-father differences were attenuated by adjustment for height. CONCLUSIONS: Whilst offspring bone measures are independently associated with those of either parent, the magnitude of the association is often greater for maternal than paternal relationships. These findings are consistent with an in utero influence on offspring growth but might also reflect genetic and/or epigenetic parent of origin effects. SUMMARY: In an established parent-offspring cohort, associations between parent and offspring bone indices were generally greater in magnitude for mother-offspring than father-offspring relationships.

Reduced cortical bone density with normal trabecular bone density in girls with Turner syndrome.

SUMMARY: This study of 22 girls with Turner syndrome (TS) demonstrates a reduction in bone mineral apparent density (BMAD) at the femoral neck along with a reduction in cortical bone density at the radius (with sparing of trabecular bone). These findings may account for the increased fracture risk noted in this population. INTRODUCTION: Increased fracture risk is a feature of TS; however, the reasons for this are unclear. Little is known regarding cortical and trabecular bone mineral density (BMD) in TS. We have addressed this by measurement of volumetric bone mineral density (vBMD) using peripheral quantitative computed tomography (pQCT). METHODS: We studied 22 females with TS and 21 females without TS; mean ages 12.7 and 12.9 years, respectively. Bone mass measurements were made by dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femur and pQCT of the radius. BMAD was calculated from DXA values. We utilized published reference data to generate Z-scores for both populations. RESULTS: The mean BMAD Z-score at the lumbar spine was not significantly different in individuals with TS compared to the controls. At the femoral neck, individuals with TS had a significantly lower BMAD Z-score compared to the controls (-1.32 vs. -0.14, p = 0.001). At the distal radius, total vBMD Z-score and trabecular vBMD Z-score were not significantly different between the TS group and controls. A significant reduction in cortical vBMD at the proximal radius was noted in the TS group however (-2.58 vs. -1.38, p = 0.02). There was also a trend towards reduced cortical thickness at this site in the TS group (Z-score -2.89 vs. -1.73, p = 0.08). DISCUSSION: TS is associated with reduced BMAD at the femoral neck; pQCT data suggests that cortical density is reduced with sparing of trabecular bone. This differential of cortical and trabecular BMD may predispose to fracture.

Methods for determining pubertal status in research studies: literature review and opinions of experts and adolescents.

In lifecourse studies that encompass the adolescent period, the assessment of pubertal status is important, but can be challenging. We aimed to identify current methods for pubertal assessment and assess their appropriateness for population-based research by combining a review of the literature with the views of experts in the field. We searched bibliographic databases, extracted data and assessed study quality to inform a workshop with 21 experts. Acceptability of different approaches was explored with a panel of ten adolescents. We screened 11,935 abstracts, assessed 157 articles and summarised results from 38 articles. Combining these with the opinions of experts, self-assessment was found to be a practical method for use in studies where agreement with the gold standard of clinical assessment by physical examination to within one Tanner stage was acceptable. Serial measures of height and foot size accurately indicated timing of the pubertal growth spurt and age at peak height velocity, and were seen as feasible within longitudinal studies. Hormonal and radiological methods did not offer a practical means of assessing pubertal status. Assessment of voice maturation was promising, but needed validation. Young people thought that self-assessment, foot size and voice assessments were acceptable, and preferred an assessor of the same sex for clinical assessment. This review thus informs researchers working in lifecourse and adolescent health, and identifies future directions in order to improve validity of the methods.

Elemental formula associated hypophosphataemic rickets.

OBJECTIVES: Hypophosphataemic rickets (HR) is usually secondary to renal phosphate wasting but may occur secondary to reduced intake or absorption of phosphate. We describe a series of cases of HR associated with the use of Neocate®, an amino-acid based formula (AAF). METHODS: A retrospective review of cases with HR associated with AAF use presenting to centres across the United Kingdom. RESULTS: 10 cases were identified, over a 9 month period, all associated with Neocate® use. The age at presentation was 5 months to 3 years. The majority (8/10) were born prematurely. Gastro oesophageal reflux disease (6/10) was the most frequent indication for AAF use. Radiologically apparent rickets was observed after a median of 8 months (range 3-15 months) of exclusive Neocate® feed. The majority (7/10) were diagnosed on the basis of incidental findings on radiographs: rickets (6/10) or fracture with osteopenia (5/10). All patients had typical biochemical features of HR with low serum phosphate, high alkaline phosphatase, normal serum calcium and 25 hydroxyvitamin D. However, in all cases the tubular reabsorption of phosphate (TRP) was ≥96%. Phosphate supplementation resulted in normalisation of serum phosphate within 1-16 weeks, and levels remained normal only after Neocate® cessation. In patients with sufficient follow up duration (4/10), normalisation of phosphate and radiological healing of rickets was noted after 6 months (range: 6-8 months) following discontinuation of Neocate®. CONCLUSION: The presence of a normal TRP and resolution of hypophosphataemia and rickets following discontinuation of Neocate® indicates this is a reversible cause likely mediated by poor phosphate absorption. Close biochemical surveillance is recommended for children on Neocate®, especially in those with gastrointestinal co-morbidities, with consideration of a change in feed or phosphate supplementation in affected children.

Precisely dating the Frasnian-Famennian boundary: implications for the cause of the Late Devonian mass extinction.

The Frasnian-Famennian boundary records one of the most catastrophic mass extinctions of the Phanerozoic Eon. Several possible causes for this extinction have been suggested, including extra-terrestrial impacts and large-scale volcanism. However, linking the extinction with these potential causes is hindered by the lack of precise dating of either the extinction or volcanic/impact events. In this study, a bentonite layer in uppermost-Frasnian sediments from Steinbruch Schmidt (Germany) is re-analysed using CA-ID-TIMS U-Pb zircon geochronology in order to constrain the date of the Frasnian-Famennian extinction. A new age of 372.36 ± 0.053 Ma is determined for this bentonite, confirming a date no older than 372.4 Ma for the Frasnian-Famennian boundary, which can be further constrained to 371.93-371.78 Ma using a pre-existing Late Devonian age model. This age is consistent with previous dates, but is significantly more precise. When compared with published ages of the Siljan impact crater and basalts produced by large-scale volcanism, there is no apparent correlation between the extinction and either phenomenon, not clearly supporting them as a direct cause for the Frasnian-Famennian event. This result highlights an urgent need for further Late Devonian geochronological and chemostratigraphic work to better understand the cause(s) of this extinction.

End-Triassic mass extinction started by intrusive CAMP activity.

The end-Triassic extinction is one of the Phanerozoic's largest mass extinctions. This extinction is typically attributed to climate change associated with degassing of basalt flows from the central Atlantic magmatic province (CAMP). However, recent work suggests that the earliest known CAMP basalts occur above the extinction horizon and that climatic and biotic changes began before the earliest known CAMP eruptions. Here we present new high-precision U-Pb ages from CAMP mafic intrusive units, showing that magmatic activity was occurring ∼100 Kyr ago before the earliest known eruptions. We correlate the early magmatic activity with the onset of changes to the climatic and biotic records. We also report ages from sills in an organic rich sedimentary basin in Brazil that intrude synchronously with the extinction suggesting that degassing of these organics contributed to the climate change which drove the extinction. Our results indicate that the intrusive record from large igneous provinces may be more important for linking to mass extinctions than the eruptive record.

Whole-mantle convection with tectonic plates preserves long-term global patterns of upper mantle geochemistry.

The evolution of the planetary interior during plate tectonics is controlled by slow convection within the mantle. Global-scale geochemical differences across the upper mantle are known, but how they are preserved during convection has not been adequately explained. We demonstrate that the geographic patterns of chemical variations around the Earth's mantle endure as a direct result of whole-mantle convection within largely isolated cells defined by subducting plates. New 3D spherical numerical models embedded with the latest geological paleo-tectonic reconstructions and ground-truthed with new Hf-Nd isotope data, suggest that uppermost mantle at one location (e.g. under Indian Ocean) circulates down to the core-mantle boundary (CMB), but returns within ≥100 Myrs via large-scale convection to its approximate starting location. Modelled tracers pool at the CMB but do not disperse ubiquitously around it. Similarly, mantle beneath the Pacific does not spread to surrounding regions of the planet. The models fit global patterns of isotope data and may explain features such as the DUPAL anomaly and long-standing differences between Indian and Pacific Ocean crust. Indeed, the geochemical data suggests this mode of convection could have influenced the evolution of mantle composition since 550 Ma and potentially since the onset of plate tectonics.

Osteonecrosis following treatment for childhood acute lymphoblastic leukaemia: The Southampton Children's Hospital experience.

Purpose: To determine the prevalence of osteonecrosis (ON) in children following treatment of acute lymphoblastic leukaemia (ALL), characterise these cases and review treatment methods. Methods: All children diagnosed and treated for ALL between 01 January 2003 and 31 December 2013 at our centre were retrospectively reviewed. Logistic regression was used to investigate risk factors for ON occurrence. Results: Of 235 children treated for ALL, 48/235 (20.4%) children suffered musculoskeletal symptoms necessitating radiological investigation. A total of 13 (5.5%) had MRI-diagnosed ON, with a median diagnosis time of 12 months (interquartile range 10 to 14) following initiation of chemotherapy.ON affected 40 joints in 13 children. The most commonly involved joints were hips (14 joints in eight patients) and knees (12 joints in seven patients).Older age at ALL diagnosis was associated with significantly increased risk of development of ON per year (odds ratio 1.35, 95% confidence interval 1.17 to 1.57, p < 0.001).Eight children underwent at least one surgical intervention. Joint arthroplasty was undertaken in nine joints of four children at a mean age of 18.3 years. All patients who underwent hip arthroplasty had previously received core decompression, with a mean time of 27.8 months (18 to 33) between treatments. Conclusions: ON is a significant complication of ALL treatment. Our results suggest risk stratification for development of ON by age, and targeted monitoring of high-risk joints is possible. ON treatment is varied with little evidence base.

Subcutaneous leiomyosarcoma of the frenulum.

Leiomyosarcomas of the penis are rare, with only 29 reported cases to date. We record the case of a patient who presented with a 2-year history of a seemingly indolent penile skin lesion. On histopathology of the local resection, a diagnosis of subcutaneous leiomyosarcoma was made. Specifically, leiomyosarcoma of the penile frenulum has not been clearly reported previously. The patient underwent a further excision to ensure an adequate resection margin and has had no disease recurrence at subsequent follow-up. Our case was of a lesion that, although clinically benign, was malignant and this possibility should be borne in mind when assessing patients.

Effects of chemotherapeutic agents on the function of primary human osteoblast-like cells derived from children.

Studies in children treated with chemotherapy suggest that chemotherapeutic agents have deleterious effects on bone metabolism. We therefore evaluated the in vitro effects of clinically relevant concentrations of chemotherapeutic agents on the synthesis of type I collagen, alkaline phosphatase (AP) activity, and mineralization by primary human osteoblast-like (HOB) cells derived from children. Because serum 1,25-dihydroxyvitamin D(3) concentrations may be reduced during treatment with chemotherapy, the effect of chemotherapeutic agents on HOB cells cultured in the presence or absence of 1,25-dihydroxyvitamin D(3) was also evaluated. Type I collagen synthesis was reduced by all agents (P < 0.01) other than methotrexate, whereas the relative AP activity was increased (P < 0.01) by all agents. The relative number of cells staining intensely for AP after culture with agents increased (P < 0.05), and AP mRNA expression was increased (P < 0.01) with vincristine. 1,25-Dihydroxyvitamin D(3) ameliorated (P < 0.01) the depletion of HOB cell numbers by chemotherapeutic agents. Furthermore, vincristine and daunorubicin inhibited 1,25-dihydroxyvitamin D(3)-mediated AP activity (P < 0.01). We conclude that chemotherapeutic agents can adversely affect HOB cell function, and we speculate that this observation may account, in part, for the osteopenia observed during and after treatment of children with chemotherapy.

In vitro effects of combination chemotherapy on osteoblasts: implications for osteopenia in childhood malignancy.

Clinical studies suggest that combination chemotherapy adversely affects bone metabolism and in vitro studies have demonstrated that a reduction in osteoblast numbers results in diminished bone formation. The aim of this study was to investigate the in vitro effects of combinations of chemotherapeutic agents on primary human osteoblast-like (hOB) cell numbers and apoptosis, and to assess the ability of hOBs and osteoprogenitor (HCC1) cells to recover from prior treatment with chemotherapy. As glucocorticoids are frequently administered during treatment with cytotoxic agents, we evaluated whether glucocorticoids influence the chemosensitivity of hOB and human osteosarcoma (MG63) cells. Culture with clinically relevant concentrations of the individual chemotherapeutic agents reduced hOB cell numbers compared with control (p < 0.01) and also increased the numbers of apoptotic cells (p < 0.05). Potentiation of cytotoxicity was observed when agents were given in combination, thus further reducing cell numbers, and this effect was greatest when vincristine was given in combination with asparaginase. Following culture with a chemotherapeutic agent, there was greater recovery of hOB compared with HCC1 cell numbers (p < 0.01). Pretreatment with glucocorticoids ameliorated the adverse effects of chemotherapeutic agents on hOB and MG63 cell numbers and apoptosis (p < 0.05). We conclude that the use of combination chemotherapy contributes to osteopenia in childhood malignancy by a reduction in osteoblast numbers. However, this effect may be attenuated by the concomitant use of glucocorticoids.

Signet-ring cell lymphoma of bone marrow.

A case of signet-ring cell lymphoma affecting bone marrow is reported. The tumour presented as multiple lytic lesions in the lumbosacral spine. A bone biopsy specimen showed the typical appearances of signet-ring cell lymphoma, and the cells stained positively with antiserum to CD20, though neither immunoglobulin light or heavy chains could be shown within the vacuoles. The patient subsequently responded to chemotherapy.

Chlorambucil and acute intermittent porphyria.

A 54-year-old women with quiescent acute intermittent porphyria (AIP) developed low-grade non-Hodgkin's lymphoma. She was successfully treated with chlorambucil without any significant rise in urinary proto-porphyrins. The case is described and a review of chemotherapy use in AIP is presented.

Identifying targets to reduce the incidence of diabetic ketoacidosis at diagnosis of type 1 diabetes in the UK.

BACKGROUND: Diabetic ketoacidosis (DKA) is the leading cause of mortality in childhood diabetes, and at diagnosis might represent delayed presentation. The extent and reasons for delays are unclear, but identifying and targeting factors associated with DKA could reduce this incidence. OBJECTIVE: To compare the patient pathway before diagnosis of type 1 diabetes mellitus (T1DM) in children presenting with DKA and non-acidotic hyperglycaemia. DESIGN, SETTING AND PATIENTS: Over a 3-month period, children newly diagnosed with T1DM were identified on admission to UK hospitals. Parents and medical teams completed a questionnaire about events before diagnosis. RESULTS: Data were available for 261 children (54% male), median age 10.3y (range 0.8-16.6 y). 25% presented with DKA, but more commonly in children <2y (80% vs 23%, p<0.001). Fewer children with DKA reported polyuria (76% vs 86%) or polydipsia (86% vs 94%) (both p<0.05), but more reported fatigue (74% vs 52%) and weight loss (75% vs 54%) (both p<0.01). 24% of children had multiple healthcare professional (HCP) contacts, and these children had lower pH on admission. 46% of children with a delayed presentation to secondary care had non-urgent investigations. 64% of parents had considered a diagnosis of diabetes, and these children were less likely to present with DKA (13% vs 47%, p<0.001). CONCLUSIONS: Multiple HCP contacts increased risk of presentation in DKA, whereas, parental awareness of diabetes was protective. Improved public and health professional education targeting non-classical symptoms, awareness of diabetes in under 2 y, and point-of-care testing could reduce DKA at diagnosis of diabetes.

Children with nephrotic syndrome have greater bone area but similar volumetric bone mineral density to healthy controls.

BACKGROUND: Glucocorticoid use has been associated with an increased fracture risk and reduced bone mineral density (BMD), particularly in the trabecular compartment. However the contribution of the underlying inflammatory disease process to these outcomes is poorly understood. Childhood nephrotic syndrome (NS) typically follows a relapsing-remitting course often requiring recurrent courses of glucocorticoids, but with low systemic inflammation during remission. NS therefore represents a useful clinical model to investigate the effects of glucocorticoids on BMD and bone geometry in childhood. METHODS: Children with NS were compared to age and sex matched healthy controls. Body composition and areal BMD (whole body, lumbar spine and hip) were assessed by DXA. Peripheral quantitative computed tomography (pQCT) scans were obtained at metaphyseal (4%) and diaphyseal (66%) sites of the tibia to determine volumetric BMD and bone cross-sectional geometry. Lifetime cumulative glucocorticoid exposure was calculated from medical records. RESULTS: 29 children with NS (55% male, age 10.7±3.1years) were compared to 29 healthy controls (55% male, age 11.0±3.0years). The children with NS were of similar height SDS to controls (p=0.28), but were heavier (0.65±1.28SDS vs -0.04±0.89SDS, p=0.022) and had greater body fat percentage SDS (0.31±1.01 vs -0.52±1.10, p=0.008). Tibial trabecular and cortical vBMD were similar between the two groups but bone cross-sectional area (CSA) was significantly greater in children with NS at both the metaphysis (954±234mm(2) vs 817±197mm(2), p=0.002) and diaphysis (534.9±162.7mm(2) vs 463.2±155.5mm(2), p=0.014). Endosteal and periosteal circumferences were greater in children with NS than controls (both p<0.01), resulting in reduced cortical thickness (2.4±0.7mm vs 2.8±0.7mm, p=0.018), but similar cortical CSA (p=0.22). The differences in cortical geometry were not statistically significant when weight was included as a confounding factor. There were no associations between cumulative steroid exposure, duration of NS or number of relapses and any bone parameter. CONCLUSIONS: Tibial bone CSA is increased in children with NS. We speculate that this is a compensatory response to increased body weight. Defects in trabecular BMD were not identified in this cohort of children with NS.

Maternal plasma polyunsaturated fatty acid status in late pregnancy is associated with offspring body composition in childhood.

CONTEXT: Maternal diet during pregnancy has been linked to offspring adiposity, but it is unclear whether maternal polyunsaturated fatty acid (PUFA) status during pregnancy affects offspring body composition. OBJECTIVE: We investigated the associations between maternal plasma n-3 and n-6 PUFA status at 34 wk gestation and offspring body composition. DESIGN AND SETTING: A prospective United Kingdom population-based mother-offspring cohort, the Southampton Women's Survey (SWS), was studied. PARTICIPANTS: A total of 12,583 nonpregnant women were recruited into the SWS, among whom 1987 delivered a baby before December 31, 2003; 293 mother-child pairs had complete measurements of maternal plasma PUFA concentrations in late pregnancy and offspring body composition at both ages 4 and 6 yr. MAIN OUTCOMES MEASURED: We measured offspring body composition by dual-energy x-ray absorptiometry, yielding fat mass, lean mass, percentage fat mass, and percentage lean mass. Results are presented as ß-coefficients for standardized variables, therefore reflecting the sd change of the outcome for every 1 sd of the predictor. RESULTS: After adjustment for maternal factors and child factors including height and duration of breast-feeding, maternal plasma n-6 PUFA concentration positively predicted offspring fat mass at 4 yr (ß = 0.14 SD/SD; P = 0.01) and 6 yr (ß = 0.11 SD/SD; P = 0.04), but there was no association with offspring lean mass at either age (ß = 0.005 SD/SD, P = 0.89; and ß = 0.008 SD/SD, P = 0.81, respectively). Maternal plasma n-3 PUFA concentration was not associated with offspring fat mass at 4 yr (ß = 0.057 SD/SD; P = 0.34) or 6 yr (ß = 0.069 SD/SD; P = 0.21). Maternal plasma n-3 PUFA status was positively associated with offspring lean mass on univariate analysis (4 yr, ß = 0.11, P = 0.06; 6 yr, ß = 0.14; P = 0.02); however, this was confounded by a positive association with offspring height. CONCLUSIONS: This observational study suggests that maternal n-6 PUFA status during pregnancy might influence offspring adiposity in childhood.