Search

IMPORTANCE: Physical abuse is a common but preventable cause of long-term childhood morbidity and mortality. Despite the strong association between abuse in an index child and abuse in contact children, there is no guidance outlining how to screen the latter, significantly more vulnerable group, for abusive injuries. Consequently, the radiological assessment of contact children is often omitted, or variably performed, allowing occult injuries to go undetected and increasing the risk of further abuse. OBJECTIVE: To report an evidence-based and consensus-derived set of best practices for the radiological screening of contact children in the context of suspected child physical abuse. EVIDENCE REVIEW: This consensus statement is supported by a systematic review of the literature and the clinical opinion of an internationally recognized group of 26 experts. The modified Delphi consensus process comprised 3 meetings of the International Consensus Group on Contact Screening in Suspected Child Physical Abuse held between February and June 2021. FINDINGS: Contacts are defined as the asymptomatic siblings, cohabiting children, or children under the same care as an index child with suspected child physical abuse. All contact children should undergo a thorough physical examination and a history elicited prior to imaging. Contact children younger than 12 months should have neuroimaging, the preferred modality for which is magnetic resonance imaging, and skeletal survey. Contact children aged 12 to 24 months should undergo skeletal survey. No routine imaging is indicated in asymptomatic children older than 24 months. Follow-up skeletal survey with limited views should be performed if abnormal or equivocal at presentation. Contacts with positive findings should be investigated as an index child. CONCLUSIONS AND RELEVANCE: This Special Communication reports consensus recommendations for the radiological screening of contact children in the context of suspected child physical abuse, establishing a recognized baseline for the stringent evaluation of these at-risk children and providing clinicians with a more resilient platform from which to advocate for them.

Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number. Copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment. In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2/14.8 Mb unequivocally disrupted GLI3and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45 kb from HOXA13. In the third family, long suspected to have Marfan syndrome, a 2.0 Mb inversion disrupting FBN1was identified. These findings resolved lengthy diagnostic odysseys of 9–20 years and highlight the importance of direct interaction between clinicians and data-analysts. These exemplars of a rare mutational class inform future SV prioritisation strategies within the NHS Genomic Medicine Service and similar genome sequencing initiatives. In over 30 years since these two disease-gene associations were identified, large inversions have yet to be described and so our results extend the mutational spectra linked to these conditions.

BackgroundCurrent clinical testing methods used to uncover the genetic basis of rare disease have inherent limitations, which can lead to causative pathogenic variants being missed. Within the rare disease arm of the 100 000 Genomes Project (100kGP), families were recruited under the clinical indication ‘single autosomal recessive mutation in rare disease’. These participants presented with strong clinical suspicion for a specific autosomal recessive disorder, but only one suspected pathogenic variant had been identified through standard-of-care testing. Whole genome sequencing (WGS) aimed to identify cryptic ‘second-hit’ variants.MethodsTo investigate the 31 families with available data that remained unsolved following formal review within the 100kGP, SVRare was used to aggregate structural variants present in <1% of 100kGP participants. Small variants were assessed using population allele frequency data and SpliceAI. Literature searches and publicly available online tools were used for further annotation of pathogenicity.ResultsUsing these strategies, 8/31 cases were solved, increasing the overall diagnostic yield of this cohort from 10/41 (24.4%) to 18/41 (43.9%). Exemplar cases include a patient with cystic fibrosis harbouring a novel exonic LINE1 insertion in CFTRand a patient with generalised arterial calcification of infancy with complex interlinked duplications involving exons 2–6 of ENPP1. Although ambiguous by short-read WGS, the ENPP1variant structure was resolved using optical genome mapping and RNA analysis.ConclusionSystematic examination of cryptic variants across a multi-disease cohort successfully identifies additional pathogenic variants. WGS data analysis in autosomal recessive rare disease should consider complex structural and small intronic variants as potentially pathogenic second hits.

BackgroundC-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2,encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2(natriuretic peptide receptor 2) and NPPC(natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models.MethodsExome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants.ResultsTwo homozygous PRKG2variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1and upregulate COL2A1expression through SOX9.ConclusionIn conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).

Rate and severity of radiological features of physical abuse in children during the first UK-wide COVID-19 enforced national lockdown.ObjectiveTo assess the number, type and outcome of radiological investigations for children presenting to hospital with suspected physical abuse (SPA; including abusive head trauma) during the first national COVID-19 enforced lockdown compared with the prelockdown period.DesignMulticentre, retrospective, observational, interrupted time series analysis.SettingEight secondary/tertiary paediatric centres between January 2018 and July 2020 inclusive.Participants1587 hospital assessed children undergoing radiographic skeletal surveys (SkS) and head CT imaging performed for SPA/child protection concerns.Main outcome measuresIncidence and severity of fractures identified on SkS; head injury (composed of incidence rates and ratios of skull fracture, intracranial haemorrhage (ICH) and hypoxic ischaemic injury (HII)) on head CT imaging; and ratio of antemortem and postmortem SkS.Results1587 SkS were performed: 1282 (81%) antemortem, 762 (48%) male, and positive findings in 582 (37%). Median patient age was 6 months. There were 1.7 fractures/child prelockdown versus 1.1 fractures/child during lockdown. There was no difference between positive/negative SkS rates, the absolute ratio of antemortem/postmortem SkS or absolute numbers of head injury occurring between January 2018 and February 2020 and the lockdown period April–July 2020. Likewise, prelockdown incidence and rates of skull fracture 30/244 (12%), ICH 28/220 (13%) and HIE 10/205 (5%) were similar to lockdown, 142/1304 (11%), 171/1152 (15%) and 68/1089 (6%), respectively.ConclusionThe first UK COVID-19 lockdown did not lead to an increase in either the number of antemortem or postmortem radiological investigations performed for SPA, or the number or severity of fractures and intracranial injuries identified by these investigations.

BackgroundSecreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARCis located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape.MethodsWe describe a further two patients with previously unreported homozygous SPARCvariants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et aland Hayat et alwith clinical descriptions of patients with SPARCvariants.ResultsFrom the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARCvariants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup.ConclusionCommon phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of ‘myopathy’.

EDITOR--The case of a white female with sponastrime dysplasia is presented. Case report The patient is the first and only child of healthy, non-consanguineous parents. During routine ultrasound scanning, the [...]

Background: Several studies have revealed a substantial increase in the incidence of fractures in children in the past few decades.Aim: To assess the strength of the association between suggested risk factors and fracture prevalence in children.Method: A cross sectional observational study. Children aged 6–15 years and their guardians presenting to the Emergency Department of a single tertiary paediatric hospital were recruited. Self-reported data on vitamin D intake, calcium intake and physical activity were collected. All participants had a radiograph of their injured limb reported by a consultant radiologist, on the basis of which they were classified into fracture or no fracture groups. Statistical analysis included descriptive statistics and binary logistic regression.Results: Of the 130 patients recruited, 53 (41%) had sustained a fracture. The overwhelming majority of children (98%) did not consume the recommended daily dietary amount of vitamin D (400 IU/day). Low calcium intake and low levels of physical activity were also ascertained. However, there were no significant differences between fracture and no fracture groups for vitamin D intake, calcium intake or physical activity. Both site of injury (wrist) and sex (male) were associated with increased fracture risk (p= 0.001 and p= 0.05, respectively). Logistic regression showed a statistically significant relationship between calcium intake and fracture risk (every additional unit of calcium consumption (mg/day) decreased the likelihood of fracture by 0.002, 95% confidence interval, 0.001–0.003).Conclusions: Low dietary intake of calcium and vitamin D and low levels of physical activity were evident. Fracture risk was significantly associated with reduced calcium intake but showed no association with vitamin D intake or physical activity.

BackgroundElevated platelet counts are observed in cancer, autoimmunity and inflammation with concurrent illness. Proinflammatory cytokines are elevated in murine osteogenesis imperfecta (OI) models. We hypothesised that platelet counts might be elevated in children with moderate-severe OI.MethodsWe reviewed the hospital records of 71 children with moderate-severe OI, treated in the Sheffield Children’s Hospital’s Severe, Complex and Atypical Osteogenesis Imperfecta Highly Specialised Service. Data relating platelet count (below/above average, above upper limit) to prior and concurrent events were summarised as event proportions per child. Additionally, we created platelet SD scores to assess age and time-related trends, and relationship with OI type.Results1206 platelet counts were recorded. Platelet SD scores were right-shifted by 0.89 SD overall. 49 of 71 (69%) patients had at least one platelet count above the normal range and 246 (20.4%) of all counts were above the upper limit of normal. Of these, 101 (41%) were high despite no confounding factors being present. For the 47 children with data at age less than 2 years, 89 (30.0%) platelet counts were above the upper limit of normal and 39 (44%) had no associated confounding factor. Elevated platelet counts were recorded most often for children with new or existing vertebral fractures.ConclusionsRaised platelet counts were observed in association with new and healing vertebral fractures, but also (41%–44%) in the absence of identified proinflammatory factors or events. We speculate that these findings are evidence for a proinflammatory component to OI that could be a target for therapeutic intervention.

BackgroundCole-Carpenter syndrome (CCS) is commonly classified as a rare Osteogenesis Imperfecta (OI) disorder. This was following the description of two unrelated patients with very similar phenotypes who were subsequently shown to have a heterozygous missense mutation in P4HB.ObjectivesHere, we report a 3-year old female patient with severe OI who on exome sequencing was found to carry the same missense mutation in P4HBas reported in the original cohort. We discuss the genetic heterogeneity of CCS and underlying mechanism of P4HB in collagen production.MethodsWe undertook detailed clinical, radiological and molecular phenotyping in addition, to analysis of collagen in cultured fibroblasts and electron microscopic examination in the patient reported here.ResultsThe clinical phenotype appears consistent in patients reported so far but interestingly, there also appears to be a definitive phenotypic clue (crumpling metadiaphyseal fractures of the long tubular bones with metaphyseal sclerosis which are findings that are uncommon in OI) to the underlying genotype (P4HBvariant).DiscussionP4HB(Prolyl 4-hydroxylase, betasubunit) encodes for PDI (Protein Disulfide isomerase) and in cells, in its tetrameric form, catalyses formation of 4-hydroxyproline in collagen. The recurrent variant in P4HB, c.1178A>G, p.Tyr393Cys, sits in the C-terminal reactive centre and is said to interfere with disulphide isomerase function of the C-terminal reactive centre. P4HB catalyses the hydroxylation of proline residues within the X-Pro-Gly repeats in the procollagen helical domain. Given the inter-dependence of extracellular matrix (ECM) components in assembly of a functional matrix, our data suggest that it is the organisation and assembly of the functional ECM that is perturbed rather than the secretion of collagen type I per se.ConclusionsWe provide additional evidence of P4HBas a cause of a specific form of OI-CCS and expand on response to treatment with bisphosphonates in this rare disorder.

Our goal was to set up a clinical service for minimally invasive postmortem examination for the fetal and neonatal age group. The minimally invasive service consisted of imaging, external review, placental examination, and ancillary tests that form part of the formal autopsy process. Eleven patients had imaging and relevant conditions at death successfully determined with the minimally invasive service. We conclude that a minimally invasive autopsy service for fetal and neonatal cases is possible and acceptable to patients and professionals.

The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRAthat affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2.

Post-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children.

Conventional whole-body MRI at 1·5 T does not provide adequate image quality of small fetuses, thus reducing its potential for use as an alternative to invasive autopsy. High-field whole-body MRI at 9·4 T provides good images of small animals. We therefore compared the diagnostic usefulness of high-field MRI with conventional MRI for post-mortem examination of human fetuses.

Background: Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement and functional distress. Objective: To provide an overview of the current understanding of vertebral malformations, at both the clinical level and the molecular level, and factors that contribute to their occurrence. Methods: The literature related to the following was reviewed: recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformations; and complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and non-syndromic congenital vertebral malformations. Results/conclusion: Expert opinions extend to discussion of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families.

Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality.Trial registrations:ClinicalTrials.gov, NCT04554940; EudraCT number, 2020-001055-40

More than 10 years ago, conventional whole-body MRI at 1.5 Tesla (T) was proposed as a more rapid, less invasive alternative to conventional invasive perinatal autopsy. However, there is poor agreement between the perinatal autopsy findings and the postmortem MRI at 1.5 T. Studies in small animals have shown that good images of anatomy can be obtained using high-field MRI at 9.4 T and have led to the present investigation. This prospective blinded study compared the diagnostic accuracy of high-field MRI at 9.4 T and conventional MRI for postmortem examination of small human fetuses. A total of 18 fetuses of less than 22 weeks’ gestation were examined using 3-dimensional T2-weighted fast-spin echo sequences for whole-body MRI with 1.5 T and 9.4 T scanners before invasive autopsy. The MRI images for each system were compared to the invasive autopsy findings by investigators who were blinded to the MRI settings. Tissue contrast in 14 different regions for MRI images at 1.5 T and 9.4 T was compared separately and in a random order. The quality of the MRI images was rated on a 4-point scale.