(DE-2 - DE-27) Instructions for use (EN-28 - EN-53) (FR-54 - FR-79) Istruzioni per l'uso (IT-80 - IT-105) A Bestimmungsgemäße Verwendung B Sicherheitshinweise Vielen Dank, dass Sie sich für das Handgelenk-Blutdruckmessgerät visomat® handy 1. Wichtige Patientenhinweise (nachfolgend auch als Gerät bezeichnet) entschieden haben.
Most often, when a man first has problems with lowered potency or with sexual dysfunction levitra australia shipping to pharmacies, paying purveyors, training personnel, or having a huge advertising budget.
Imagingonline.co.ukArch Dis Child 2007;92:251–256. doi: 10.1136/adc.2006.106120 bone exceeds the ability of the bone to box). It is easier to show ligamentous laxity in this absorb the force by deforming. Fractures in older group than in infants.
children are common—approximately one third ofchildren will have a fracture by 16 years of age, PATHOPHYSIOLOGY OF BONE DISEASES with more boys experiencing fracture than girls.1 PRESENTING WITH FRACTURES IN This differentiation in fracture risk is apparent from 2 years of age. Before the age of 2 years, Metabolic bone disease of prematurity fracture incidence is equal and occurs at a rate of Metabolic bone disease of prematurity (also approximately 80/10 000 person years. For the UK, known as osteopenia of prematurity and preterm therefore, approximately 4800 infants will have a rickets) is seen in the UK mainly in infants born at clinically evident fracture before their first birth- ,28 weeks of gestation.7 Fractures occur typically day each year.
at an age of at least 10 weeks and usually stop Some long-bone fractures may occur at birth2 in before the age of 6 months (uncorrected for association with events such as shoulder dystocia3; skull fractures may occur during forceps4 and Three reviews of fractures occurring during the ventouse delivery.5 Some may (uncommonly) first year of life in premature infants8 9 12 found occur as a result of clearly defined trauma such that rib fractures often remain undetected and are as road accidents.6 Most, however, fall into the only discovered on x rays taken for other reasons.
‘‘unexplained'' category. This article reviews our Hence, the true incidence of fractures in infants current approach to identifying bone disease in the born prematurely remains unknown.
infant presenting with more than one unexplained Koo et al9 reported a prospective study of 78 fractures, and discusses the recognised disease infants, weighing ,1500 g and 23–26 weeks of processes that result in increased bone fragility.
gestation at birth, carried out during the mid to late The history should include inquiry into specific 1980s in Cincinnati, Ohio, USA. Infants were areas as listed in the box. The two most frequently examined for clinical signs of rickets and had recognised underlying disease processes causing x rays of both wrists and forearms at 1, 3, 6, 9 and bone fragility in infancy are metabolic bone disease 12 months of age. There were also x rays taken for of prematurity7 and osteogenesis imperfecta, and clinically suspected fractures and for other clinical directed questioning is appropriate for these condi- reasons. Skeletal surveys were not undertaken. By tions. For premature infants, the features commonly day 88, fractures along with rickets were present in associated with fracture are delivery at ,28 weeks 12 of the 78 infants, and a further 7 infants had fractures without any signs of rickets on x ray; (.30 days) establishment of full enteral feeds, clinical suspicion of fracture was recorded in only 3 conjugated hyperbilirubinaemia, chronic lung dis- of the 19 infants. The smaller the infant at birth, the ease, and use of furosemide.8 9 For a proportion of higher the risk of radiological abnormality. Almost infants with osteogenesis imperfecta, there will be a 30% of all the fractures were rib fractures. Affected family history either of osteogenesis imperfecta itself infants took longer to establish full enteral feeds, or of features that suggest osteogenesis imperfecta.
required longer periods in oxygen and in hospital The other elements of the history relating to the overall, received longer periods of furosemide, and possibility of non-accidental injury should of course were also more likely to have had physiotherapy.
be applied in every case.
Amir et al8 reported 12 of 973 premature infants Clinical examination, in addition to document- surviving for .6 months in a Tel Aviv hospital from ing signs of concern with respect to non-accidental 1977 to 1984 with fractures during their time in the injury, should include assessment of the musculo- neonatal unit; in all but one, the birth weight was skeletal system, looking specifically for the fea- ,1500 g. The overall incidence in the ,1500 g group tures detailed in the box. Gross bowing of long was 2.1%. Three infants died subsequently. The See end of article for authors' affiliations bones is uncommon in type I osteogenesis imper- fractures occurred from ages 24 to 160 days. All the fecta. Blue sclerae are present in many healthy rib fractures occurred silently, and were diagnosed infants and children without any associated bone only on ‘‘routine'' x ray—that is, full skeletal surveys Correspondence to: disease. Deep blue sclerae persisting beyond Dr N Bishop, Academic Unit were not undertaken. The authors identified four of Child Health, University 6 months of age should be regarded as potentially risk factors associated with fracture development: of Sheffield, Sheffield significant; Bauze et al10 found that blue sclerae cholestatic jaundice, prolonged intravenous nutri- Children's Hospital, Sheffield S10 2TH, UK; n.j.
However, many children with a moderately severe form of osteogenesis imperfecta, type IV osteogenesis Abbreviations: DXA, dual energy x ray absorptiometry; Accepted 13 October 2006 imperfecta, have white sclerae.11 It is certainly worth FEVR, familial exudative vitreoretinopathy; IJO, idiopathic examining siblings and parents who may show juvenile osteoporosis Bishop, Sprigg, Dalton acquisition and hence compromise bone strength. However, Summary of bone fracture during infancy both Koo and Dabezies identified physiotherapy as beingassociated with fracture in their studies. Prolonged intravenous Features of bone disease in infancy—history nutrition and failure to establish full oral feeds quickly indicatea continuing poor supply of mineral substrates necessary for N Age at first fracture bone formation and mineralisation. Furosemide is a diuretic N Number of fractures, sites and timing that unfortunately promotes the loss of calcium in the urine, N Apparent causation: mechanism and force adding to the deficit and increasing the activity of homoeostatic mechanisms designed to keep the serum calcium concentration Associated features: swelling and pain in the normal range. These mechanisms result in increased N Infantile hernia bone turnover and release of calcium from the skeleton. The N Family history of recurrent fractures with minor trauma, increased bone turnover increases bone fragility because the dislocations, hernia, early-onset deafness, dentinogen- bone turnover sequence involves initial removal of bone esis imperfecta (discoloured, translucent teeth, cracking followed by its replacement.
or chipping of teeth), late walking in siblings, osteoporo- A case–control study of fracture frequency in children born sis in older family members (especially when apparent preterm up to age 5 years14 showed no increase in fracture risk before the age of 50 years), eye disease (retinopathy, for such children overall, but an increase in risk up to the age of 2 years. All children in the latter group were born at ,32 weeks N Pregnancy/delivery/neonatal course: prematurity, of gestation.
gestation, birth weight, necrotising enterocolitis, time to Metabolic bone disease in preterm infants is a self-limiting disease. Growth slows postnatally and the supply of mineral establish full enteral feeds, conjugated hyperbilirubinae- substrate improves, so that the needs of the skeleton for mia, use of furosemide, chronic lung disease and calcium and phosphate to mineralise newly formed bone are metabolic bone disease of prematurity more consistently met and the skeletal envelope is ‘‘filled in''.
Features of bone disease in infancy—examination (apply to Bone mass rises consistently until it is similar to that of infants the infant and any available family members) born at term by the age of 2 years15; this fits with theobservation that the increased fracture risk for children born prematurely seems most apparent in the first 2 years of life.
N Large anterior fontanelle/sutural diastasis without hydro- Severe rickets in term infants Rickets is increasingly reported in the developed world.16 Vitamin D deficiency is most common in infants wholly N Blue sclerae: scleral hue variable in infancy but blue breastfed and whose mothers are of non-white Caucasian sclerae persist in cases of mild osteogenesis imperfecta origin. Vitamin D deficiency in a term infant sufficient to result N Harrison's sulcus in bone weakening and fracture will be accompanied by N Translucent skin unequivocal radiological and biochemical evidence of deranged N Ligamentous laxity: use the Beighton scale for children skeletal structure and homoeostasis. Vitamin D deficiency is and adults. In infants, check whether the knees and extremely rare in formula-fed infants and should lead to elbows extend beyond 180 investigations for malabsorption.
˚ and whether the thumbs can be apposed to the forearm.
Osteogenesis imperfecta Type I collagen is the most abundant protein in bone, and is N Bowing deformity of limbs composed of a heterotrimer of two type I collagen a-1 protein N Easy bruising is reported in some cases of osteogenesis chains and one type I collagen a-2 protein chain. The three imperfecta, but is not a universal finding chains coil tightly around one another to form a molecule that N Dentinogenesis imperfecta (translucent teeth that chip or self-assembles into fibrils, creating the template on which crack easily, and may wear excessively, more so in mineral is deposited to make bone material. Osteogenesis primary dentition) may not be clinically apparent.47 imperfecta is caused in 90% of cases by mutations in the type Icollagen genes COL1A1 and COL1A2, which encode type Icollagen a-1 and a-2 protein chains, respectively.17 The (chronic lung disease), and prolonged diuretic treatment with spectrum of the disease is wide and now encompasses seven furosemide (.2 weeks). Only one of the 12 infants had none of distinct types; the more recently described types V,18 VI19and the above risk factors. However, the number of infants overall ‘‘rhizomelic''20 are not due to type I collagen mutations and are with these risk factors was not recorded.
associated with more severe forms of bone disease.
A third retrospective study by Dabezies et al12 identified Of the traditional four types of osteogenesis imperfecta, type fractures in 26 (10.5%) of 247 infants over a 42-month period in II (lethal) and type III (severe, progressively deforming) are the early 1990s, with the same risk factors and similar timing readily diagnosed on clinical and radiological grounds.11 Infants for fracture as in the other two studies.
with type I (mild) and type IV (moderate to severe) osteogen- None of these studies undertook skeletal surveys; the esis imperfecta may be difficult to differentiate from normal preponderance of rib fractures probably reflects the frequency infants. Type I infants typically have mutations in the COL1A1 of chest x rays as opposed to other radiographs. Longer periods or COL1A2 genes that result in reduced type I collagen a-1 and in oxygen might simply be a proxy for inactivity. In addition to a-2 chains, respectively.21 This means that although most of the the plethora of literature on the effect of different calcium and type I collagen protein produced is normal, the total amount of phosphate supplementation regimens on bone mass accretion protein is reduced. The effect is to reduce the overall bone mass during the first 3–6 months of life, a clear effect of physical within the skeletal envelope. In addition, bone biopsies in older exercise and stress on bone mass accretion is evident.13 Lack of children with type I disease indicate that the cortex is thinner physical activity, a more common problem in the smallest, and more porous, and the trabecular bone, a honeycomb-like sickest infants, will probably contribute to reduced bone mass structure that provides internal bracing at the ends of long Unexplained fractures in infancy bones, is reduced in amount and is less well interconnected syndrome, with ,50 cases reported worldwide.30 This disorder than in healthy bone.22 Overall, tubular bones in children with is characterised by a progressively deforming bone disease with osteogenesis imperfecta are narrower, adding to their propen- multiple fractures, low bone mass and reduced stature, similar sity to fracture. Those with type IV osteogenesis imperfecta have more pronounced changes of a similar nature. Some cases Additionally, patients having eye disease (pseudoglioma) of type IV are also due to null alleles, presumably with brought about by failure of vascularisation of the peripheral additional influences from other genes of importance to bone retina, with hyperplasia of the vitreous, corneal opacity and health modifying the phenotype to increase the severity.21 secondary glaucoma are also described. The wnt-signalling Others have mutations in the COL1A1 gene leading to the pathway through LRP5 also has the function of patterning the production of an abnormal protein, which then interferes with peripheral retinal vasculature during embryogenesis.31 the three-dimensional arrangement of the collagen molecules.
Apart from being associated with vertebral crush fractures How common is osteogenesis imperfecta in cases of and metaphyseal fractures in children with the clinical unexplained fracture in infancy? A study by Marlowe et al23 diagnosis of IJO, heterozygotic defects in LRP5 are associated showed that of 262 infants and children up to the age of 3 years with familial exudative vitreoretinopathy (FEVR). Two children with unexplained fractures referred for genetic testing for in the series reported by Toomes had fractures starting in osteogenesis imperfecta to the major US centre in Seattle, 11 infancy.31 LRP5 heterozygosity produces an eye disease that is definitely had mutations in the type I collagen genes, and similar in some respects to retinopathy of prematurity, and that mutations could not be excluded in a further 11. Of the 11 who is associated with hyperpermeable blood vessels, neovascular- were definitely affected, 6 were identified as likely to have isation, retinal folds and exudates in some individuals. Both the osteogenesis imperfecta on clinical grounds, 3 were thought not eye and bone features are variable in LRP5 heterozygotes; some to have osteogenesis imperfecta, and inadequate information family members may have reduced bone mass and no eye signs, was given in the remaining two cases. Of the 11 in whom whereas some have eye signs and no fractures.
osteogenesis imperfecta could not be excluded in the labora- It is unclear whether LRP5 heterozygosity is associated with tory, none was thought to have osteogenesis imperfecta. Of the metaphyseal fractures and retinal haemorrhages occurring remaining 240 cases not found to have genetic changes together in infancy; to suggest that it is would be purely indicating osteogenesis imperfecta, four were thought to have speculative. The appearance of the peripheral retina and pattern osteogenesis imperfecta on the basis of a blue scleral hue. This of haemorrhages is likely to be important in distinguishing study was clearly biased in terms of the selection of candidates between FEVR and retinal haemorrhage due to non-accidental for testing, but nevertheless suggests that a proportion of cases of unexplained fracture is due to type I collagen mutations.
No information is available at present regarding the Failure to continue to fracture after removal from a potentially frequency with which LRP5 mutations occur. Clinically abusive environment should not be taken as unequivocal apparent IJO is much less common than osteogenesis imper- evidence of the lack of an underlying bone disease. The natural fecta; the estimate of IJO incidence is approximately 1 in history of fractures in mild cases of osteogenesis imperfecta is 100 000, with osteogenesis imperfecta being 1 in 10–15 000.
often episodic in nature, with long periods where no fracture may FEVR is similarly very rare.31 There have been no reports as yet occur. By contrast, if a child continues to experience fracture in of LRP5 mutations in infants with unexplained fractures, with care, this suggests either a more severe form of underlying bone or without retinal haemorrhage. This is clearly a matter of great fragility or abuse on the part of the new carers.
interest but also of great uncertainty at the present time.
Infants with this disorder have ocular proptosis, usually present There are several rare bone diseases that can cause fractures in from birth, and develop hydrocephalus and fractures during the infancy. These include panostotic fibrous dysplasia/McCune– first 12 months of life.24 On plain x ray, the bones appear Albright syndrome, osteopetrosis, infantile severe hypophos- osteopenic. The genetic origin of this syndrome is unknown, phatasia, congenital insensitivity to pain with anhidrosis, and the number of reported cases is very small. Another congenital rickets, and congenital cytomegalovirus infection.
syndrome of microcephaly, cataracts and fractures in infancy All these disorders have radiologically apparent bone disease was reported in 1978,25 but no further cases have emerged.
and should not present diagnostic difficulty. Infants withcongenital disorders affecting nerve and muscle function may also have slim bones that are mechanically inadequate. The Infants with this disorder are born with joint contractures and accompanying clinical features in such cases should alert the bone fragility. There are two distinct forms. In one, the genetic clinician. Having a bone disease or fragile bones does not defect has been identified in the PLOD2 gene,26 resulting in a preclude the possibility of non-accidental injury, however. In failure of hydroxylation of lysine residues in collagen 1 disorders in which bone strength is diminished, the pattern of telopeptides. The second locus is 17p12, but the gene is as yet fractures is typically of a series of individual fractures over time.
It is unusual to see multiple rib fractures of the same age in achild with mild osteogenesis imperfecta or bone disease of Familial osteoporosis prematurity without a clear explanation.
Osteoporosis may run in families. Recently, a group in Torontoidentified 3 of 20 children with idiopathic juvenile osteoporosis (IJO) as having heterozygotic defects in the gene LRP5.27 LRP5 All fractures are painful, whether in children with normal has been the topic of much interest over recent years. It is a bones or in those with bone disorders. Fracture-related pain is receptor in the canonical wnt-signalling pathway.28 Activation likely to recur when the affected site is disturbed in any way, of the pathway increases bone formation by upregulating the and will probably be more intense and persist longer when the growth of preosteoblasts and the activity of differentiated affected area is not splinted by surrounding structures. Thus, osteoblasts. Activating mutations in LRP5 are associated with a rib fractures in particular may go unsuspected by both parents high bone mass phenotype, with no fractures reported in family and clinical staff, as previously indicated, but fractures of the mid-shaft of a long bone will be associated with protective function mutations result in the osteoporosis pseudoglioma Bishop, Sprigg, Dalton bone mass in both the lumbar spine and total body is often Plain film radiography within the normal range (own unpublished data); however, Plain film radiographs are required for assessing structural these mildly affected children will frequently have other changes in long bones, ribs, skull and spine. Radiography radiologically apparent features such as a change in bone provides data in both suspected non-accidental injury and shape, particularly in the vertebrae and femurs, which may be suspected bone dysplasia. In addition to imaging of a fractured difficult to discern in infancy.
limb at presentation, a full skeletal survey must be performed.
Dating fractures is the province of experienced paediatric This requires an agreed protocol with the radiology department radiologists. Patterns of fracture may suggest, in some and dedicated radiographers with a paediatric interest. The instances, inflicted injury. Fractures in infants born prema- survey should be performed to include all long bones, frontal and turely tend to be in the diaphyses of long bones and the ribs, as both oblique views of the chest, two views of the skull, the lateral indicated previously. Skull fractures are rarely reported, but whole spine and views of both hands and feet. The British Society have not been sought systematically. Fractures can be found in of Paediatric Radiology has established agreed standards for almost any site or combination of sites in osteogenesis imperfecta. However, metaphyseal fractures are rare in both (www.bspr.org.uk). As soon as a skeletal survey has been osteogenesis imperfecta and ex-premature infants, and multi- performed, an experienced radiologist interested in paediatric ple fractures in infants with osteogenesis imperfecta are usually imaging should review it. A report should be issued or accompanied by some degree of bony deformity.
arrangements made for a referral opinion. Acute rib fractures Plain film radiography is not the final arbiter of bone fragility may not be detectable on the initial chest film, and in suspected in infancy; as with the other forms of investigation discussed non-accidental injury, a single follow-up chest film is indicated here, it is a part of the overall approach to discriminating 2–3 weeks after original presentation to exclude rib fractures that between a diagnosis of bone fragility and one of non-accidental become evident as they heal. Each injury shown radiographically should be considered in its clinical context with the history ofmechanism of injury and any features that suggest an underlying Biochemical markers of bone disease bone disorder before confirming non-accidental injury.
Bone markers have been studied in infants and children with Skull x rays are suggested even if a computed tomography of osteogenesis imperfecta36 and with metabolic bone disease of the head has been performed, as it is accepted that computed prematurity.37 Where inadequate bone mineralisation due to tomography imaging may miss skull fractures that are rapid growth (rickets of prematurity) or vitamin D deficiency is detectable on plain radiographs. Skull x rays may also show suspected to contribute to the problem, the measurement of wormian bones. Cremin et al32 observed an excess of mosaic-like fasting serum 25-hydroxyvitamin D, parathyroid hormone, bones (.10, measuring at least 466 mm) within the sutures in alkaline phosphatase, calcium and phosphate should be 81 cases with osteogenesis imperfecta and not in 500 ‘‘normal'' undertaken. It is not clear whether reduced serum levels of individuals, of whom 39 were children. The relationship 25-hydroxyvitamin D and increased parathyroid hormone are between their occurrence and osteogenesis imperfecta type associated with an increased fracture risk in the absence of was not specified. The lack of skull vault ossification in severe cases may mean they are initially invisible; delayed films reduced and alkaline phosphatase activity increased in cases (6 months) may show them. Such mosaic bones are not of active rickets; such changes may also be seen in bone disease uncommon in normal infants, but are then usually restricted to of prematurity.
the lambdoid sutures. The cortical thickness of long bones can Bone turnover markers are increased in children with be estimated from plain radiographs. Overtubulation may be osteogenesis imperfecta36 and are also increased after fracture.
seen in osteogenesis imperfecta. It results in bones that have a It is unclear exactly how long the serum alkaline phosphatase smaller transverse diameter than is appropriate for their length.
level remains raised, but activity should reflect both new bone Cortical thickening and bone deformity may be the result of formation at the fracture site and remodelling of callus. Once previous fracture.
that is complete, serum alkaline phosphatase should return to a Radiologically apparent osteopenia (sometimes reported by value within the normal range. The ranges for bone formation radiologists) implies that there is less attenuation of the x ray and resorption markers in healthy infants are wide.38 In a study beam, due to a reduction in the total amount of calcium in bone of bone markers in older children, markers reflecting the tissue. The older radiology literature33 34 describes studies production of type I collagen were reduced in more than half indicating that a 20–40% loss of mineralised bone mass is the children with osteogenesis imperfecta who were tested,39 needed before osteopenia is radiologically detectable, and that but there is no evidence that the tests would be discriminatory this value changes according to the site assessed. The converse in individual cases or in infants. However, persistently raised is clearly that it is difficult to detect losses of up to 20% of values of formation and resorption markers should alert the mineralised bone tissue, and the percentage loss of tissue that clinician to the possibility of underlying bone disease with occurs before becoming radiologically evident may be higher at increased bone turnover.
some sites in the skeleton.
Osteopenia can result from demineralisation (as in rickets) or Postmortem testing loss of bone material (as in osteogenesis imperfecta). Although This can be undertaken at the radiological, tissue and molecular necessarily less precise than dual-energy x ray absorptiometry levels. DNA and skin samples can be taken after death and (DXA) in quantifying bone mineral density, it does provide the treated as indicated below. Investigation at tissue level for radiologist with an initial indication of the likelihood of an osteogenesis imperfecta is possible in terms of looking directly underlying bone disorder. However, quantitation of bone mass at bone. Bone biopsy has been used as a research tool by DXA has not been shown to be helpful in infancy in principally in Montreal,40 41 and to assess bone architecture discriminating those with bone disease from normal infants.35 before starting bisphosphonate treatment. As stated above, Normative data are lacking for infants ,2 years of age; the data there are clear architectural differences in the bones of children available from manufacturers relate to the older pencil beam who are normal and in those with type I osteogenesis DXA instruments and not to the current generation of fan beam imperfecta, but it is not clear when these first emerge. It is devices. In older children with mild osteogenesis imperfecta, technically difficult to take biopsies of sufficient quality before Unexplained fractures in infancy the age of 1 year in living children, and hence applicability in initially may go on to develop vertebral crush fractures and this setting is likely to be limited to postmortem examination.
need medical intervention. Where a clinician suspects thatosteogenesis imperfecta is present, on the basis of the clinical Molecular diagnosis of bone disease and/or family history and examination or imaging findings There are three routes to laboratory diagnosis: biochemical described in this paper, genetic testing may assist in reaching a analysis of collagen species, mutation analysis of RNA and diagnosis, but the cost is substantial (see Appendix) and needs mutation analysis of DNA. The first two require skin fibroblasts to be justified by a considerable effect on clinical management.
and hence a skin biopsy, which is often thought to be Where the only indication is unexplained or inadequately unacceptable, particularly in infants in whom no surgical explained fractures in the absence of the clinical features of procedure is required for treatment, and when there is an osteogenesis imperfecta, the situation is more complex, and alternative testing strategy available.
there are currently no clear guidelines regarding suspected non- Where fibroblasts are available, biochemical analysis involves accidental injury. Consideration must be given to any possible isotopic labelling of protein in the skin fibroblasts, isolation of explanation offered, the level of proof required (eg, family or protein including collagen species, and gel electrophoresis criminal court) and the effect any result will have.
(sodium dodecyl sulphate–polyacrylamide gel electrophoresis).
In such situations, a positive test result provides evidence of Abnormalities can be either quantitative or qualitative.
underlying bone fragility, but determining the degree of force Specificity is high, but up to 20% of abnormalities may be likely to give rise to fractures when such fragility exists is missed.42 43 Mutation analysis of COL1A1 and COL1A2 from essentially impossible. When there are only one or two fibroblast RNA can then be carried out. Using message-based fractures, occurring together or at different times, it is easier techniques, about 15% of samples from individuals with to believe that the fractures could have occurred with normal clinically apparent osteogenesis imperfecta will be recorded as handling and without the parents being immediately aware of negative; as many as half of the remainder can be detected as the problem. Where there are many fractures, without having mutations by direct sequencing.42 accompanying bony deformity, or with additional extraskeletal Mutation analysis of DNA for COL1A1 and COL1A2 can be injury, it is more difficult to believe that the injuries have conducted by scanning methodologies such as conformation- occurred accidentally, even allowing for the underlying bone sensitive capillary electrophoresis, or by direct sequencing.
fragility. These are judgements that are rightly the province of However, neither will detect other mutational mechanisms the courts, but consideration should be given in each case to the such as large deletions/duplications of DNA, although these are appropriateness of testing.
likely to be rare (,3%) and if the mutation has occurred in If skin biopsy samples are available through clinical inter- another gene regulating bone formation, it will be missed.
ventions for treatment such as surgery or through postmortem However, large deletions/duplications can be detected by RNA examination, biochemical and molecular testing is as complete analysis from a skin biopsy.
a test as possible. Taking a skin biopsy simply for diagnostic No comprehensive large study has been published comparing purposes is more problematic; clinicians have refused to take a the positive predictive value of biochemical versus molecular blood sample for diagnostic purposes in the belief that this analysis. It is likely that the two methods complement each constitutes further abuse to an already abused child. A negative other,44 with molecular analysis showing a high positive result, which will never be completely definitive, must be predictive value for mutations in COL1A1 or COL1A2, whereas considered in the context of the full clinical and social history.
biochemical analysis may show abnormalities in collagen Properly conducted prospective studies are needed to clarify potentially arising from mutations in other genes in the bone the exact place of genetic testing in these circumstances.
formation pathway, as well as large deletions/duplications inCOL1A1 or COL1A2. Other genes are likely to be involved in ,10%of all cases. The sensitivity of mutation scanning methodologies versus direct sequencing is variable, although extensive experi- Clinical history and examination supplemented by radiology ence in other disorders indicates that recent scanning methodol- are currently the mainstays of detection of bone disease in ogies such as conformation-sensitive capillary electrophoresis are infants presenting with one or more unexplained fractures.
very sensitive. However, the final arbiter of the presence of a Osteogenesis imperfecta and prematurity are the commonest mutation is direct sequencing, and the advantage of only established causes of bone fragility leading to fracture in requiring a blood sample for analysis is important.
infancy, but these are infrequent compared with non-accidental Molecular diagnostic testing for LRP5 mutations currently injury. Mutations in LRP5 are associated with both eye disease remains a research tool.
and fractures, but the extent to which such mutationscontribute to unexplained fractures in infancy is entirely When should genetic testing be requested? unclear. The role of genetic testing in discriminating bone The incidence of osteogenesis imperfecta in the general disease from non-accidental injury in infants with unexplained population is 1 in 10–20 000.45 46 NHS funding for molecular fractures still needs to be properly evaluated in an appropriate testing has been recommended by the UK Genetics Testing Network (UKGTN) for cases where there is a clinical diagnosisof types II and IV, with further clarification of referral pathways currently being sought for types I and III. If a diagnosis of We thank Tim David, Christine Hall, Roger Harris and Philip Holland osteogenesis imperfecta of any type is made, referral to the local for their very helpful comments and advice with the preparation of this clinical genetics service is appropriate. Diagnostic, predictive and prenatal testing in the family will then be considered in the light of the clinical need and the circumstances of the family.
Authors' affiliations In addition, in unequivocal cases of osteogenesis imperfecta, Nick Bishop, Academic Unit of Child Health, University of Sheffield, referral to a specialist centre that has experience in the long- Sheffield Children's Hospital, Sheffield, UK term management of the condition should be made (see Alan Sprigg, Sheffield Children's NHS Foundation Trust, Sheffield Appendix) so that optimum management can be put in place.
Children's Hospital, Sheffield, UK Severely affected infants need input from a specialist multi- Ann Dalton, Sheffield Molecular Genetics Service, Sheffield Children's disciplinary team, but even those apparently mildly affected NHS Foundation Trust, Sheffield Children's Hospital, Sheffield, UK Bishop, Sprigg, Dalton Competing interests: NB receives grant support from the Arthritis Research 32 Cremin B, Goodman H, Spranger J, et al. Wormian bones in osteogenesis Campaign and the Wellcome Trust to study bone disease in children and imperfecta and other disorders. Skeletal Radiol 1982;8:35–8.
infants, and from Procter and Gamble, Sanofi-Aventis and Novartis 33 Lachman E, Whelan M. The roentgen diagnosis of osteoporosis and its limitations. Radiology 1936;26:165–77.
pharmaceuticals to undertake studies of bisphosphonates in children with 34 Lachman E. Osteoporosis: the potentialities and limitations of its roentgenologic osteogenesis imperfecta. NB and AS undertake medical work remunerated diagnosis. Am J Roentgenol 1955;74:712–15.
through the Legal Aid Fund in the field of unexplained fractures in infancy.
35 Bishop NJ, Plotkin H. When is a fracture child abuse? Bone 1998;23:S458.
NB has a particular interest in the genetic causes of bone fragility in infancy 36 Rauch F, Travers R, Plotkin H, et al. The effects of intravenous pamidronate on the and childhood. AD is director of the Sheffield Molecular Diagnostic Service, bone tissue of children and adolescents with osteogenesis imperfecta. J Clin Invest which provides testing of COL1A1 and COL1A2.
37 Crofton PM, Shrivastava A, Wade JC, et al. Bone and collagen markers in preterm infants: relationship with growth and bone mineral content over the first10 weeks of life. Pediatr Res 1999;46:581–7.
38 de Ridder CM, Delemarre-van de Waal HA. Clinical utility of markers of bone turnover in children and adolescents. Curr Opin Pediatr 1998;10:441–8.
1 Cooper C, Dennison EM, Leufkens HG, et al. Epidemiology of childhood fractures 39 Brenner RE, Schiller B, Vetter U, et al. Serum concentrations of procollagen I C- in Britain: a study using the general practice research database. J Bone Miner Res terminal propeptide, osteocalcin and insulin-like growth factor-I in patients with non-lethal osteogenesis imperfecta. Acta Paediatr 1993;82:764–7.
2 Kleinman PK. Differential diagnosis III: accidental and obstetric trauma. In: 40 Rauch F, Plotkin H, Travers R, et al. Osteogenesis imperfecta types I, III, and IV: Kleinman PK, eds. Diagnostic imaging of child abuse, 2nd edn. St Louis: Mosby, effect of pamidronate therapy on bone and mineral metabolism. J Clin Endocrinol Metab 2003;88:986–92.
3 Habek D. Fetal shoulder dystocia. Acta Med Croatica 2002;56:57–63.
41 Rauch F, Travers R, Norman ME, et al. Deficient bone formation in idiopathic 4 Kleinman PK. Head trauma. In: Kleinman PK, eds. Diagnostic imaging of child juvenile osteoporosis: a histomorphometric study of cancellous iliac bone. J Bone abuse, 2nd edn. St Louis: Mosby, 1998:285–342.
Miner Res 2000;15:957–63.
5 Choy CM, Tam WH, Ng PC. Skull fracture and contralateral cerebral infarction 42 Korkko J, Ala-Kokko L, De Paepe A, et al. Analysis of the COL1A1 and COL1A2 after ventouse extraction. BJOG 2001;108:1298–9.
genes by PCR amplification and scanning by conformation-sensitive gel 6 Johnstone AJ, Zuberi SH, Scobie WG. Skull fractures in children: a population electrophoresis identifies only COL1A1 mutations in 15 patients with study. J Accid Emerg Med 1996;13:386–9.
osteogenesis imperfecta type I: identification of common sequences of null-allele 7 Bishop N. Metabolic bone disease. In: Rennie JM, eds. Roberton's textbook of mutations. Am J Hum Genet 1998;62:98–110.
neonatology, 4th edn. Philadelphia: Elsevier Churchill Livingstone, 2005:922–8.
43 Lund AM. Biochemical and molecular genetic studies of osteogenesis imperfecta.
8 Amir J, Katz K, Grunebaum M, et al. Fractures in premature infants. J Pediatr Copenhagen: Copenhagen, 2002.
44 RiesLevavi L, Ish-Shalom T, Frydman M, et al. Genetic and biochemical analyses 9 Koo WW, Sherman R, Succop P, et al. Fractures and rickets in very low birth of Israeli osteogenesis imperfecta patients. Hum Mutat 2004;23:399–400.
weight infants: conservative management and outcome. J Pediatr Orthop 45 Andersen PE Jr, Hauge M. Osteogenesis imperfecta: a genetic, radiological, and epidemiological study. Clin Genet 1989;36:250–5.
10 Bauze RJ, Smith R, Francis MJ. A new look at osteogenesis imperfecta. A clinical, 46 Kuurila K, Grenman R, Johansson R, et al. Hearing loss in children with radiological and biochemical study of forty-two patients. J Bone Joint Surg Br osteogenesis imperfecta. Eur J Pediatr 2000;159:515–19.
47 Waltimo J, Ojanotko-Harri A, Lukinmaa PL. Mild forms of dentinogenesis 11 Sillence DO, Rimoin DL, Danks DM. Clinical variability in osteogenesis imperfecta in association with osteogenesis imperfecta as characterized by light imperfecta-variable expressivity or genetic heterogeneity. Birth Defects Orig Artic and transmission electron microscopy. J Oral Pathol Med 1996;25:256–64.
12 Dabezies EJ, Warren PD. Fractures in very low birth weight infants with rickets.
Clin Orthop 1997;335:233–9.
13 Moyer-Mileur LJ, Brunstetter V, McNaught TP, et al. Daily physical activity program increases bone mineralization and growth in preterm very low birth WHERE GENETIC TESTING IS PERFORMED IN THE UK weight infants. Pediatrics 2000;106:1088–92.
14 Dahlenburg SL, Bishop NJ, Lucas A. Are preterm infants at risk for subsequent Testing for osteogenesis imperfecta is available from Sheffield fractures? Arch Dis Child 1989;64:1384–5.
Molecular Genetics Service. For diagnostic testing the cost is 15 Rubinacci A, Sirtori P, Moro G, et al. Is there an impact of birth weight and early approximately £1560 for both the type I collagen genes and life nutrition on bone mineral content in preterm born infants and children? Acta includes sequencing of both genes and a clinical report. The 16 Robinson PD, Hogler W, Craig ME, et al. The re-emerging burden of rickets: a turnaround time is generally 8 weeks. For medico-legal cases decade of experience from Sydney. Arch Dis Child 2006;91:549–50.
the cost depends on what is required, particularly turnaround 17 Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004;363:1377–85.
time, reporting requirements and legal processes such as 18 Glorieux FH, Rauch F, Plotkin H, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000;15:1650–8.
attendance at court. For details contact Ann Dalton, Sheffield 19 Glorieux FH, Ward LM, Rauch F, et al. Osteogenesis imperfecta type VI: a form Molecular Genetic Service: Ann.firstname.lastname@example.org. Further of brittle bone disease with a mineralization defect. J Bone Miner Res development of the service is ongoing including dosage analysis for COL1A1 and COL1A2, analysis of other genes and biochem- 20 Ward LM, Rauch F, Travers R, et al. Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 2002;31:12–18.
ical analysis of collagen species.
21 Willing MC, Pruchno CJ, Byers PH. Molecular heterogeneity in osteogenesis imperfecta type I. Am J Med Genet 1993;45:223–7.
Centres providing multidisciplinary services for children 22 Rauch F, Travers R, Parfitt AM, et al. Static and dynamic bone histomorphometry with metabolic bone disease (Clinical leads) in children with osteogenesis imperfecta. Bone 2000;26:581–9.
Belfast, Musgrove Park—Catherine Duffy 23 Marlowe A, Pepin MG, Byers PH. Testing for osteogenesis imperfecta in cases of suspected non-accidental injury. J Med Genet 2002;39:382–6.
Birmingham Children's Hospital—Nick Shaw 24 Cole DE, Carpenter TO. Bone fragility, craniosynostosis, ocular proptosis, Bristol Children's Hospital—Christine Burren hydrocephalus, and distinctive facial features: a newly recognized type of Cardiff, University Hospital—John Gregory osteogenesis imperfecta. J Pediatr 1987;110:76–80.
Glasgow Yorkhill—Faisal Ahmed 25 Buyse M, Bull MJ. A syndrome of osteogenesis imperfecta, microcephaly, and cataracts. Birth Defects Orig Artic Ser 1978;14:95–8.
Great Ormond Street Hospital—Catherine De Vile (0I only), 26 Ha-Vinh R, Alanay Y, Bank RA, et al. Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) Manchester, St Mary's Hospital—Zulf Mughal caused by a recessive mutation in PLOD2. Am J Med Genet A2004;131A:115–20.
Royal London Hospital—Jeremy Allgrove 27 Hartikka H, Makitie O, Mannikko M, et al. Heterozygous mutations in the LDL Sheffield Children's Hospital—Nick Bishop receptor-related protein 5 (LRP5) gene are associated with primary osteoporosisin children. J Bone Miner Res 2005;20:783–9.
Other useful resources 28 Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in osteoblasts and bone UK Brittle Bone Society: www.brittlebone.org diseases. Gene 2004;341:19–39.
US Osteogenesis Imperfecta Foundation: www.oif.org Johnson ML. The high bone mass family—the role of Wnt/Lrp5 signaling in theregulation of bone mass. J Musculoskelet Neuronal Interact 2004;4:135–8.
Testing of collagen protein in the US and some additional 30 Ai M, Heeger S, Bartels CF, et al. Clinical and molecular findings in osteoporosis- information around their approaches to deciding if testing is pseudoglioma syndrome. Am J Hum Genet 2005;77:741–53.
31 Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q.
Am J Hum Genet 2004;74:721–30.
Unexplained fractures in infancy: looking for
Nick Bishop, Alan Sprigg and Ann Dalton 2007 92: 251-256 Arch Dis Childdoi: 10.1136/adc.2006.106120 Updated information and services can be found at: These include: This article cites 43 articles, 7 of which can be accessed free at: Article cited in: Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
To request permissions go to: To order reprints go to: To subscribe to BMJ go to:
ACTA DE LA SESIÓN EXTRAORDINARIA CELEBRADA POR EL AYUNTAMIENTO PLENO EL DIA 6 DE JULIO DE 2015 NÚM. 08/2015 Por el grupo municipal Partido Popular: D. FRANCISCO M. IZQUIERDO MORENO D. Juan Luis Barelles Adsuara, Dir. Dª. Mª ISABEL MIQUEL MARTICORENA D. FRANCISCO E. GIMENO MIÑANAD. JOSÉ BUSTAMANTE LUNADª. NOEMÍ MARTÍNEZ RAMOSD. ALFREDO SOLER GUNA