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Logo of archdischArchives of Disease in ChildhoodVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
Arch Dis Child. 2007 April; 92(Suppl1): A45–A47.
PMCID: PMC2066107


Radiology and bone

G/WEDS/RAB1 Genetic polymorphisms and fracture risk in children

Z. Blades, W. Carlino, N. Bishop. University of Sheffield, Sheffield, UK

IntroductionSingle nucleotide polymorphisms (SNPs) in genes important in bone metabolism have been extensively investigated in adult populations to determine whether specific SNPs increase the risk of fracture, or affect bone mass and density. There have been relatively few such studies in children and data are available only for the effects of some SNPs on bone mass. We hypothesised that SNPs identified in adult premenopausal white women as being associated with increased fracture risk would also be associated with increased fracture risk in children.

MethodsWe recruited 93 cases and 32 controls by approaching families attending our A&E department with a history of trauma and suspected bony injury. The children underwent bone densitometry of the hip, spine and total body by DXA (Lunar Prodigy). Buccal brushings were taken to acquire DNA for SNP analysis. We tested for allelic distribution differences between the groups assessing COL1A1 Sp1, COL1A2 PvuII, TGFβ1 c29C>T, OPG g163A>G and MTHFR c677C>T SNP in fracture and non‐fracture groups.

ResultsFor COL1A1, there was a non‐significant excess (11.7% v 7.1%) in children with fracture for the TT allele associated with increased fracture risk in adults. For COL1A2, there was a non‐significant excess (8.0% v 4.1%) in children with fracture for the CC allele associated with increased fracture risk in adults. For TGFβ1, there was a non‐significant excess (46% v 27.6%) in children with fracture for the TT allele associated with increased fracture risk in adults. For OPG there were no homozygous individuals for the GG allele associated with fracture risk in adults. For MTHFR there was no clear trend or difference between the groups. The COL1A1 TT allele was associated with lower bone mass in the lumbar spine (p = 0.043) after adjusting for body size. Homozygosity for the A allele in OPG was associated with lower spine bone area (p = 0.035) with a trend towards similar associations for other bone parameters.

ConclusionsWe have not as yet shown an increased risk of fracture in children for any of the polymorphisms studied here, but there are relations with bone mass and size that are indicative of the expected underlying changes that predispose to fracture. These data need consolidation through larger studies, currently underway.

G/WEDS/RAB2 Bone mass and architecture in children with and without fractures

W. Carlino, Z. Blades, N. Bishop. University of Sheffield, Sheffield, UK

IntroductionWe have shown previously that children who fracture have reduced bone area and mass for body size. Many fractures in children are at sites where the bone is changing shape (eg, distal radius) and we hypothesised that in addition to altered size and mass we would be able to demonstrate altered architecture in bone of children with a fracture compared to those without.

MethodsWe recruited 93 cases and 32 controls by approaching families attending our A&E department with a history of trauma and suspected bony injury. The children underwent bone densitometry of the hip, spine and total body and spiral CT of the tibias with an in‐line calibration phantom that enabled us to create complete 3‐D images of both tibias with associated volumetric densitometry of the different compartments of bone. The vQCT measures of cortical bone were performed in the mid shaft of the left tibia (50% tibia). Measures of trabecular bone were acquired from sites where the distance to the distal tibial inferior articular cartilage corresponded to 6% and 8% of the length of the left tibia. The inferior articular cartilage was selected as a reference point as it is consistent throughout all age groups. We obtained data from single tomographic slices of 2.5 mm transectional thickness at a voxel size of 0.5 mm. A threshold algorithm was used to separate cortical and trabecular bone.

ResultsAs previously, we found significant differences in the relationship between the bone parameters—bone mass, areal bone density and bone area—and body size for children who had had a fracture compared with non‐fracture subjects. However, we found no significant difference between the groups in cortical bone volumetric bone density or cross‐sectional area at the mid tibia either before or after adjustment for potential confounders. Neither was there any clear difference between the groups in metaphyseal cross‐sectional area or volumetric density at either the 6% or 8% site.

ConclusionsThis study confirms previous observations of lower bone mass for body size in children who fracture but has not as yet indicated that there are significant accompanying changes in bone microarchitecture in weight‐bearing bones.

G/WEDS/RAB3 How common are radiologically apparent rib fractures in extremely low birth weight preterm born infants?

D. Smurthwaite, Z. Mughal, N. Wright, S. Russell, A. Emmerson. University of Manchester, Manchester, UK

AimTo establish the incidence and site of radiologically apparent rib fractures in extremely low birth weight (ELBW) preterm infants (<1000 g birth weight) receiving contemporary neonatal intensive care at a tertiary neonatal intensive care unit (NICU). This knowledge might assist health professionals in establishing the causation of rib fractures found incidentally on a chest radiograph carried out for clinical reasons in this group of infants after discharge from the NICU.

MethodsRetrospective examination of radiographs of infants cared for on a tertiary NICU between January 1998 and December 2002 was undertaken. Inclusion criteria included infants with a complete set of radiographs and who were born at, or transferred in to the NICU within 2 weeks of life, discharged home from the NICU, or died on the NICU.

ResultsFive out of 72 infants (7%) had radiologically apparent rib fracture. All the fractures were of the lateral or anterior rib shafts; 2 infants had a single, and 3 infants had multiple rib fractures. There were no fractures found in the posterior third of the rib. The median peak serum alkaline phosphatase activity of infants with rib fractures (2499 IU/l) was not different (p = 0.1) compared with that of infants without fractures (1760 IU/l). Number of doses of frusemide received did reach statistical significance (p = 0.006). All the infants with rib fractures died of complications associated with prematurity on the NICU.

ConclusionsFrom these results we conclude that radiologically apparent rib fractures are rare in ELBW preterm infants discharged from NICU. When present, fractures are likely to occur along the lateral shaft of the rib. When a child is seen after discharge from NICU and is found to have rib fractures, especially if they are posterior in site, the possibility of non‐accidental injury needs to be seriously considered and investigated, irrespective of the neonatal history.

G/WEDS/RAB4 A randomised controlled trial of hyperalimentation to improve head growth in the extreme preterms: quantitative MRI findings at term

M. J. Tan1, L. Abernethy2, R. W. I. Cooke1. 1School of Reproductive and Developmental Medicine, University of Liverpool, Liverpool, UK; 2Department of Radiology, Royal Liverpool Children's Hospital, Liverpool, UK

AimExtremely preterm infants are at risk of postnatal growth restriction and poor head growth. We describe the effect of early nutrition and postnatal growth on cerebral development using quantitative MRI techniques in a group of preterm infants recruited to a randomised controlled trial of hyperalimentation.

MethodsThe study was conducted in a tertiary neonatal intensive care unit. 142 infants who were born before 29 weeks gestation were recruited from January 2004 to January 2006. Infants were randomly assigned to receive enhanced parenteral and enteral nutrition (Group A) or standard parenteral and enteral nutrition (Group B) from the first week of life to 34 weeks postmenstrual age (PMA). Actual daily intake was recorded for each infant. Energy and protein balances were estimated by subtracting actual cumulative intakes from recommended intakes (120 kcal/kg/day and 3 g/kg/day). Weekly occipito‐frontal circumferences (OFC) and other growth parameters were measured from birth until 36 weeks PMA. The infants underwent cranial MRI at term equivalent. Total brain volume (TBV) and cortical brain volume (CBV) were estimated using stereological techniques and T2 relaxation time (a surrogate marker for brain maturation) was performed.

Results114 infants survived to 40 weeks PMA. 65 infants underwent MRI scan. Survivors in Group A had lower gestation (19 v 15 below 26 weeks) and birth weight (median 900 g v 965 g) compared to those in Group B. TBV, CBV and T2 values did not differ significantly in both groups. However, energy balance at 28 days of age correlated significantly with TBV (r = 0.35, p = 0.024). The Z scores of OFC at 36 weeks PMA correlated with TBV (r = 0.6, p<0.001), CBV (r = 0.38, p = 0.008) and T2 values (r = −0.38, p = 0.002). Other growth parameters including weight, length and lower leg length at 36 weeks PMA also correlated significantly with TBV and CBV.

ConclusionsQuantitative MRI is a useful adjunct in the assessment of head growth among extremely preterm infants. Brain volume at term may be improved by reducing energy deficit in the early postnatal period. Cortical and overall brain growth is positively associated with postnatal growth.

G/WEDS/RAB5 Regional changes in bone area and bone mineral content in boys with Duchenne muscular dystrophy receiving steroid therapy

N. Crabtree1, N. Shaw2, H. Roper3. 1Queen Elizabeth Hospital, Birmingham, UK; 2Birmingham Children's Hospital, Birmingham, UK; 3Heartlands Hospital, Birmingham, UK

IntroductionDuchenne muscular dystrophy (DMD) is a muscular disease causing loss of ambulation in early childhood. Steroids are currently used to improve muscle strength and prolong ambulation although the effect on bone health in this group of children is still unclear. The aim of this study was to report the bone densitometry results in patients prior to starting steroid therapy and evaluate bone changes after one year's treatment.

MethodsLumbar spine (LS) and subcranial (SC) DXA were performed on 25 boys (mean age 7.5 years) at baseline, and on 13 boys following 1 year of intermittent steroid treatment. Percentage fat for age, lean body mass (LBM) for height, LS and SC bone area for height, LS and SC bone mineral content (BMC) for bone area and LS and SC BMC for LBM were calculated using local reference data.

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Abstract G/WEDS/RAB5

ResultsBefore therapy, LS bone area was normal for height however, LS BMC was low for bone area but appropriate for reduced LBM. SC bone area for height and SC BMC for area and LBM were all reduced. After 1 year on steroids there were no significant changes in height but significant increases in weight and %fat. An increase in SC bone area for height was noted alongside a reduction of SC BMC for area while at the LS there was no change in bone area and a small increase in LS BMC both for bone area and LBM.

ConclusionsIn summary, baseline values demonstrated that reduced mechanical load on the skeleton from diminished muscle function results in light narrow bones more noticeably in the SC region than at the LS. Increases observed in bone area at 1 year suggest a gradual adaptation to increased gravitational load. Interestingly, the LS demonstrated no apparent detrimental effects after 1 year on intermittent steroid therapy.

G/WEDS/RAB6 The effect of chemotherapeutic agents on osteoclastogenesis and mature osteoclasts

R. Cox1, J. Gregory1, M. Jenney2, J. Davies3, B. Evans1. 1Department of Child Health, Cardiff University, Southampton, UK; 2Department of Paediatric Oncology, University Hospital of Wales, Cardiff, UK; 3Department of Child Health, Southampton University Hospitals NHS Trust, Southampton, UK

IntroductionChemotherapeutic agents used in the treatment of childhood malignancy are known to have a deleterious effect on osteoblast activity leading to osteopenia associated with their use. Little is known about the effects of these treatments on osteoclast activity.

AimTo study the effect of chemotherapeutic agents on human osteoclasts.

MethodWhole blood from adult volunteers was used to generate osteoclasts using an established technique to differentiate osteoclasts from mononuclear cells using M‐CSF and RANKL. Cultures were undertaken with varying concentrations of chemotherapeutic agents, with differing modes of cytotoxicity. These were added at day 0 to determine the effects on osteoclastogenesis and day 14 to determine effects on mature osteoclasts.

ResultsOsteoclastogenesis was reduced by all agents although there was a varied response between agents at equi‐molar concentrations. L‐asparaginase caused complete inhibition at all concentrations tested, whereas the lowest concentration affecting cell numbers for the other agents tested was doxorubicin 10−7M (p = 0.004), vincristine 10−8M (p = 0.002) and methotrexate 10−5M (p = 0.0002). Dexamethasone (Dex) suppressed osteoclastogenesis at all concentrations tested (10−5M–10−10M). Methotrexate 10−7M led to complete inhibition of resorption when added for 21 days; however resorption occurred when added to mature osteoclasts at day 14. Vincristine inhibited resorption at concentrations as low as 10−11M when added for 21 days however when added to mature osteoclasts resorption occurred. When Dex was added to maturing osteoclasts at day 14 it reduced numbers, leading to an absence of resorption at 10−7M but not at 10−9M.

ConclusionWe conclude that clinically relevant concentrations of chemotherapeutic agents reduced osteoclast numbers and activity, with varying sensitivity. Contrary to published data with human mononuclear cells, we have shown that Dex inhibits osteoclastogenesis in vitro.

G/WEDS/RAB7 Are antenatal scans sufficient to rule out renal tract abnormalities in selected conditions?

N. K. Athiraman1, R. Arya2, A. Jones2, S. Taylor2. 1Royal Shrewsbury Hospital, Shrewsbury, Shropshire, UK; 2Great Western Hospital, Swindon. Wiltshire, UK

AimTo assess the presence of renal abnormality in the children with the selected conditions such as pre‐auricular skin tag, single umbilical artery, hypospadias and family history of renal problems and correlate with their antenatal scan findings.

MethodsThis is a retrospective audit of renal tract ultrasounds performed on children of less than one year of age and reviewed together with their antenatal scan findings. This was done over a period of 27 months between January 2003–March 2005.

ResultsOf the 149 infants scanned during the 27‐month study period, 49 (33%) were screened for conditions mentioned in the table below. Off the 49 infants, 25% were for pre‐auricular skin tags, 22% each for single umbilical artery and hypospadias and 31% for family history of renal problems. Here one had unilateral mild pelvic dilatation antenatally, and another had antenatal oligohydramnios, but all infants had normal postnatal scans.

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Abstract G/WEDS/RAB7

ConclusionIn our study, we did not detect any renal pathology in postnatal scans when antenatal scans were normal. However this is a small study. We would like to recommend that if an antenatal scan is of sufficient quality and is normal, then there is no need for a routine postnatal scan in babies with above mentioned conditions. This policy would decrease the number of scans in our hospital by one third. This is cost effective. This would also decrease parents' time, effort and anxiety.

G/WEDS/RAB8 In juvenile dermatomyositis, do MRI T2 relaxation times affect treatment decisions?

P. J. C. Davis1, A. Tabor1, J. E. McDonagh2, C. A. J. Ryder1, T. R. Southwood2, K. Johnson1. 1Birmingham Children's Hospital NHS Trust, Birmingham, UK; 2University of Birmingham, Birmingham, UK

AimTo determine whether use of T2 relaxation times (T2RTs) alters clinical treatment decisions in juvenile dermatomyositis (JDMS), and to assess their correlation with childhood myositis assessment score (CMAS), muscle enzymes and acute phase reactants.

MethodEvery patient with confirmed JDMS since the implementation of T2RTs in the trust underwent CMAS score, laboratory assessment (muscle enzymes and acute phase reactants) and MRI scan for T2RTs and disease distribution. The number of scans with associated assessments per patient ranged from 1–10. The MRI results were not available to the clinician until after the patients' clinical assessment.

ResultsData were obtained for 19 patients who underwent a total of 71 scans. 63% were female. Mean age at diagnosis was 87 months (range 22–168) and mean age at most recent scan was 128 months (range 58–203). In 65% of patient episodes, T2RTs confirmed clinical assessment and hence there was no alteration in treatment. In 4% of patient episodes, T2RTs were higher than was expected by clinical assessment and hence there was a step‐up in treatment. In 31% of patient episodes the clinician deferred making a treatment decision until T2RTs were available.

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Abstract G/WEDS/RAB8

ConclusionDisease activity and severity in JDMS is known to be difficult to assess clinically. CMAS score and laboratory parameters may reflect muscle atrophy rather than disease activity. T2RTs have previously been shown to provide a valid, objective and quantitative assessment of disease activity. These results show that T2RTs do not correlate with clinical or laboratory assessment of disease activity; however, our data also show that CMAS score does not correlate with laboratory assessment (data not shown). The high percentage of deferred treatment decisions reflects a change in practice whereby clinicians use MRI data regarding disease distribution and activity to guide management.

G/WEDS/RAB9 Bone status of adolescent girls in Pune, India compared with age‐matched South Asian and Caucasian UK Girls

A. Khadilkar1, N. Crabtree2, K. Ward3, V. Khadilkar1, N. Shaw4, Z. Mughal5. 1Hirabai Cowasji Jehangir Medical Research Institute, Pune, India; 2Queen Elizabeth Hospital, Birmingham, UK; 3The University of Manchester, Manchester, UK; 4Birmingham Children's Hospital, Birmingham, UK; 5St Mary's Hospital, Manchester, UK

MethodsThe GE Lunar Dual Energy X‐Ray Absorptiometry (DXA) was used to measure total body (TB) bone area (BA), bone mineral content (BMC) and lean body mass (LBM) in 50 postmenarcheal girls from a state run school, in Pune, India. Data for 34 South Asian and 82 white girls, age‐matched with Pune girls, were selected from the Lunar DXA database, comprising of 1508 healthy children from Birmingham, UK.

ResultsThe Pune girls were shorter, lighter and had less LBM for height, compared to their UK South Asian and white counterparts. TBBA for height SDS or size of bones adjusted for height, were similar in 3 groups.The TBBMC for TBBA SDS of Pune girls was lower than that of UK South Asian and white girls, indicating that their bones were under mineralised. The TBBMC for LBM SDS of Pune girls was not different from that of UK South Asian and white girls.

ConclusionsIn summary, Pune girls had undermineralised bones relative to UK South Asian and white girls, but they had appropriate amount of bone mineral content for their low lean body mass.

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Abstract G/WEDS/RAB9 Anthropometric and bone variables for the three groups presented as means (SD)

Coleet alArch Dis Child199573 pp 25-9 Crabtreeet alBone. 2005;36;S42

G/WEDS/RAB10 Abnormalities in the wnt‐signalling pathway through LRP5 found in children with recurrent fractures and low bone mass

A. Patel, N. Bishop. Sheffield University, Sheffield, UK

IntroductionFractures in children are common, affecting 40% of boys and 27% of girls by age 16 years. Recurrent fractures occur in 15% of cases. There is increasing interest in the wnt‐signalling through LRP5 pathway as a potential target for osteoporosis treatment in adults. Homozygous mutations in LRP5 are associated with severe bone and eye disease, and heterozygous mutations are reported as a cause of low bone mass and fractures in children with idiopathic juvenile osteoporosis (IJO). We hypothesised that UK children with recurrent fractures and low bone mass (RF), as well as those with classical IJO, might have heterozygous mutations in LRP5.

MethodsWe undertook full length sequencing of LRP5 in 21 children and young adults (IJO = 7, RF = 14; age range 4–21 years). Subjects were selected on the basis of three or more fractures together with low bone mass for age or body size, or because they had classic features of IJO; including low bone mass with vertebral and/or metaphyseal fractures.

ResultsThe study participants were found to have a statistically significant low bone mass compared with 50 controls measured on the same DXA instrument; polymorphisms or mutations were found in all. One previously reported mutation (R1036Q) was found in two patients. Four novel polymorphisms/mutations, one previously reported and 16 known (referenced in genetic databases) were also found. Three of the putative mutations were in the RF group. Two coded for non‐conservative amino acid changes—R221P and P1528L. P1528L is in a region of LRP5 that is highly conserved across species and across the homologous genes LRP6 and Arrow. This suggests that it may well be a mutation that would affect protein folding in a critical fashion. The other two changes coded for no amino acid change (F617F) and for a conservative change (D843N, found in an IJO subject).

ConclusionsThe finding of such mutations in a small number of children with recurrent fractures but without the classical features of IJO broadens the range of clinical manifestations attributable to wnt‐signalling defects in children. Understanding the downstream effects of such defects on bone architecture and function will give insight into possible interventions in children with low bone mass. The findings also raise issues around the diagnosis of bone fragility at all ages in the growing skeleton and suggest the need for larger prospective studies.

Articles from Archives of Disease in Childhood are provided here courtesy of BMJ Publishing Group