Intussusception reduction methods in daily practice-a survey by the European Society of Paediatric Radiology Abdominal Imaging Taskforce.

BACKGROUND: Image-guided intussusception reduction has been practised internationally for many decades. The use of different modalities, delayed repeat attempts, and sedation/anaesthesia are unknown. OBJECTIVE: To survey the practice of image-guided intussusception reduction. MATERIALS AND METHODS: A 20-point questionnaire created by the European Society of Paediatric Radiology (ESPR) Abdominal Imaging Taskforce was distributed via the ESPR members' mailing list and shared on social media between 28 March and 1 May 2023. RESULTS: There were 69 responses from 65 worldwide institutions, with a mean of 18 intussusception reductions performed per year: 55/69 (80%) from 52 European institutions and 14/69 (20%) from 13 institutions outside of Europe. European centres reported using 19/52 (37%) fluoroscopy, 18/52 (35%) ultrasound, and 15/52 (28%) a mixture of both, with 30/52 (58%) offering a delayed repeat at 15 min to 24 h. Non-European centres reported using 5/13 (39%) fluoroscopy, 6/13 ultrasound (46%), and 2/13 (15%) a mixture of both, with 9/13 (69%) offering a delayed repeat attempt. Sedation or analgesia was used in 35/52 (67%) of European and 2/13 (15%) non-European institutions. CONCLUSION: There is wide variation in how image-guided intussusception reduction is performed, and in the use of sedation/anaesthesia.

Recommendations for neuroradiological examinations in children living with achondroplasia: a European Society of Pediatric Radiology and European Society of Neuroradiology opinion paper.

Children living with achondroplasia are at an increased risk of developing neurological complications, which may be associated with acute and life-altering events. To remediate this risk, the timely acquisition of effective neuroimaging that can help to guide clinical management is essential. We propose imaging protocols and follow-up strategies for evaluating the neuroanatomy of these children and to effectively identify potential neurological complications, including compression at the cervicomedullary junction secondary to foramen magnum stenosis, spinal deformity and spinal canal stenosis. When compiling these recommendations, emphasis has been placed on reducing scan times and avoiding unnecessary radiation exposure. Standardized imaging protocols are important to ensure that clinically useful neuroimaging is performed in children living with achondroplasia and to ensure reproducibility in future clinical trials. The members of the European Society of Pediatric Radiology (ESPR) Neuroradiology Taskforce and European Society of Neuroradiology pediatric subcommittee, together with clinicians and surgeons with specific expertise in achondroplasia, wrote this opinion paper. The research committee of the ESPR also endorsed the final draft. The rationale for these recommendations is based on currently available literature, supplemented by best practice opinion from radiologists and clinicians with subject-specific expertise.

Lung infections in immunocompromised children.

Pulmonary infection is the leading cause of infectious morbidity and mortality in children with immune defects. We provide a comprehensive review of lung infections in immunocompromised children, with a focus on imaging findings and imaging-based management. We include an overview of the immune defences of the respiratory tract, the aetiologies of immune defects in children, the features of specific infections and important differential diagnoses and describe diagnostic strategies using imaging and non-imaging-based techniques.

Use of genome sequencing to hunt for cryptic second-hit variants: analysis of 31 cases recruited to the 100 000 Genomes Project.

BACKGROUND: Current 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. METHODS: To 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. RESULTS: Using 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 CFTR and 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 ENPP1 variant structure was resolved using optical genome mapping and RNA analysis. CONCLUSION: Systematic 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.

Nosology of genetic skeletal disorders: 2023 revision.

The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine.

Impact of Tracheal Arborization and Lung Hypoplasia in Repair of Pulmonary Artery Sling in Combination With Long-Segment Tracheal Stenosis.

Background: Reimplantation of the left pulmonary artery (LPA) and slide tracheoplasty has been our standard approach of care for patients with pulmonary artery sling (PAS) and tracheal stenosis. We present our experience, with emphasis on tracheal arborization and hypoplastic lungs; and their impact on long-term outcome of children with PAS and tracheal stenosis. Methods: It is a retrospective comparative study. Data were classified and analyzed based on the type of tracheobronchial arborization and normal versus hypoplastic lungs. Results: Seventy-five children operated between January 1994 and December 2019 (67 with normal lungs and 8 with lung hypoplasia/agenesis) were included. Patients with hypoplastic lungs had higher rates of preoperative ventilation (87.5%), postoperative ventilation (10 vs 8 days, P = .621), and mortality (50% vs 9%, P = .009) compared with those with normal lungs. Nineteen patients had tracheal bronchus (TB) variety and 30 patients had congenital long-segment tracheal stenosis (CLSTS) variety of tracheobronchial arborization. Endoscopic intervention was needed in 47.4% of patients with TB type and 60% with CLSTS type. CLSTS patients had higher rates of preoperative ventilation (60% vs 47.4%, P = .386), longer periods of postoperative ventilation (13 vs 6.5 days, P = .006), and ICU stay (15 vs 11 days, P = .714) compared with TB type. Conclusion: Surgical repair of PAS with tracheal stenosis has good long-term outcomes. All variations of tracheal anatomy can be managed with slide tracheoplasty. Persistence of airway problems requires intervention during follow-up as tracheal stenosis continues to be the Achilles heel.

Imaging in osteopetrosis.

Imaging investigations are critical in the management of children with suspected and confirmed osteopetrosis. In severe cases, imaging can provide rapid confirmation of the diagnosis, whilst in milder cases, imaging findings may be the first or only indicators of the disease. Imaging can also identify major complications, including fractures and neurological compromise. We review the pathophysiological basis for the imaging findings in osteopetrosis, focusing on the impact of loss of various osteoclast functions leading to elevated bone density, hyperostosis, modelling abnormalities and bone fragility. We give an overview of the specific imaging findings, both skeletal and neuroradiological, in the spectrum of osteopetrotic disorders, including in the related entities of pyknodysostosis and dysosteosclerosis. We also explore potential radiological differential diagnoses.

Sedaghatian spondylometaphyseal dysplasia in two siblings.

Sedaghatian type spondylometaphyseal dysplasia (SSMD) is a rare skeletal dysplasia with only 24 reported cases to date. Despite the limited literature available, evidence suggests this is a multi-system disorder, with neurological and cardiovascular abnormalities reported in addition to the skeletal features. We report a new family with two affected siblings and detailed phenotypic description of the affected proband. Diagnosis in the neonatal period led to retrospective genetic diagnosis of a previous affected pregnancy that was terminated due to severe ventriculomegaly. We suggest that a diagnosis of SSMD should be considered when shortened long bones are found in combination with significant brain abnormalities.

Kosaki Overgrowth Syndrome: Report of a Family with a Novel PDGFRB Variant.

Heterozygous activating missense variants of PDGFRB are associated with the phenotype of Kosaki overgrowth syndrome (KOGS). Here, we present a family including a father and 2 siblings with a novel variant, c.2567A>T (p.Asn856Ile), localized in the cytoplasmic tyrosine kinase domain, exhibiting a KOGS phenotype. The coarsening of the facial features, enlargement of the hands/feet, and progressive scoliosis started to appear after an average age of 6. There were no signs of thin/fragile skin, premature aging appearance, myofibroma, white matter findings, and intellectual disability in any of them. Corneal pterygium and evidence of cerebral vasculopathy were only detected in the father. One sibling exhibited café-au-lait spots. Posterior fossa enlargement was revealed only in one sibling. KOGS is an extremely rare overgrowth syndrome. No familial cases of KOGS have been reported so far. Hereby, we demonstrated that the features of KOGS can show mild intrafamilial variability, and the risk of vascular complications may arise with age.

Orthopaedic Aspects of SAMS Syndrome.

The combination of short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS, OMIM: 602471) has been reported as an ultra-rare, autosomal-recessive developmental disorder with unique skeletal anomalies. To the present date, only four affected individuals have been reported. There are several striking orthopaedic diagnoses within the SAMS syndrome. In particular, the scapulohumoral synostosis and the bilateral congenital ventral dislocation of the hips. The purpose of this report is to underline the importance of recognizing pathognomic features of SAMS syndrome. Whenever a bilateral congenital ventral dislocation of the hips and/or a scapulohumoral synostosis is found or clinically suspected, SAMS syndrome should be considered as the primary diagnosis until proven otherwise.

Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.

Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (DVL1, DVL3, FZD2, NXN, ROR2, and WNT5A). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1, DVL2, and DVL3 variants, demonstrating no phenotypic distinction between the NXN-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A, FZD2, and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.

Abdominal US in Pediatric Inflammatory Multisystem Syndrome Associated with SARS-CoV-2 (PIMS-TS).

Background Children with pediatric inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children, present with abdominal pain among other nonspecific symptoms. Although initial imaging features of PIMS-TS have been reported, the duration of sonographic features remains unknown. Purpose To describe the abdominal US features of PIMS-TS at initial presentation and follow-up. Materials and Methods A retrospective review of children and young adults presenting with clinical features suspicious for PIMS-TS between April 2020 and June 2021 was carried out. US features were documented and reviewed at initial presentation and follow-up. Descriptive statistics were used and interobserver variability was calculated. Results Of 140 children and young adults presenting with suspected PIMS-TS, 120 had confirmed PIMS-TS (median age, 9 years; interquartile range, 7-12 years; 65 male patients) and 102 underwent abdominal US at presentation. PIMS-TS was present as a single abnormality in 109 of the 120 patients (91%) and abdominal symptoms were present in 104 of the 109 (95%). US examinations were abnormal in 86 of 102 patients (84%), with ascites being the most common abnormality in 65 (64%; 95% CI: 54, 73). Bowel wall thickening was present at US in 14 of the 102 patients (14%; 95% CI: 7, 20) and mesenteric inflammation was present in 16 (16%; 95% CI: 9, 23); all of these patients presented with abdominal symptoms. Among the patients with bowel wall thickening, the distal and terminal ileum were most involved (eight of 14 patients, 57%). Abdominal symptoms decreased to seven of 56 patients (13%) in those followed up at 6 months. Thirty-eight patients underwent follow-up US, and the presence of bowel inflammation had decreased to three of 27 patients (11%; 95% CI: -1, 23) in those followed up for less than 2 months and 0 of 17 (0%) in those followed up for more than 2 months. Conclusion Of 102 patients with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 who underwent US at presentation, 14 (14%) had abdominal US findings of bowel inflammation and 16 (16%) had mesenteric edema. All US abnormalities resolved after 2 months. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by van Rijn and Pajkrt in this issue.

Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review.

BACKGROUND: Secreted 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. SPARC is 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. METHODS: We describe a further two patients with previously unreported homozygous SPARC variants 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 al and Hayat et al with clinical descriptions of patients with SPARC variants. RESULTS: From the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants 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. CONCLUSION: Common 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'.

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.

Diagnostic yield of rare skeletal dysplasia conditions in the radiogenomics era.

BACKGROUND: Skeletal dysplasia (SD) conditions are rare genetic diseases of the skeleton, encompassing a heterogeneous group of over 400 disorders, and represent approximately 5% of all congenital anomalies. Developments in genetic and treatment technologies are leading to unparalleled therapeutic advances; thus, it is more important than ever to molecularly confirm SD conditions. Data on 'rates-of-molecular yields' in SD conditions, through exome sequencing approaches, is limited. Figures of 39% and 52.5% have been reported in the USA (n = 54) and South Korea (n = 185) respectively. METHODS: We discuss a single-centre (in the UK) experience of whole-exome sequencing (WES) in a cohort of 15 paediatric patients (aged 5 months to 12 years) with SD disorders previously molecularly unconfirmed. Our cohort included patients with known clinical diagnoses and undiagnosed skeletal syndromes. Extensive phenotyping and expert radiological review by a panel of international SD radiology experts, coupled with a complex bioinformatics pipeline, allowed for both gene-targeted and gene-agnostic approaches. RESULTS: Significant variants leading to a likely or confirmed diagnosis were identified in 53.3% (n = 8/15) of patients; 46.7% (n = 7/15) having a definite molecular diagnosis and 6.7% (n = 1/15) having a likely molecular diagnosis. We discuss this in the context of a rare disease in general and specifically SD presentations. Of patients with known diagnoses pre-WES (n = 10), molecular confirmation occurred in 7/10 cases, as opposed to 1/5 where a diagnosis was unknown pre-test. Thus, diagnostic return is greatest where the diagnosis is known pre-test. For WGS (whole genome sequencing, the next iteration of WES), careful case selection (ideally of known diagnoses pre-test) will yield highest returns. CONCLUSIONS: Our results highlight the cost-effective use of WES-targeted bioinformatic analysis as a diagnostic tool for SD, particularly patients with presumed SD, where detailed phenotyping is essential. Thorough co-ordinated clinical evaluation between clinical, radiological, and molecular teams is essential for improved yield and clinical care. WES (and WGS) yields will increase with time, allowing faster diagnoses, avoiding needless investigations, ensuring individualised patient care and patient reassurance. Further diagnoses will lead to increased information on natural history/mechanistic details, and likely increased therapies and clinical trials.

Sibling screening in suspected abusive head trauma: a proposed guideline.

Abusive head trauma (AHT) is the leading cause of death from child abuse in children younger than 5 years. It is well documented that the infant contacts of children presenting with suspected AHT are at an increased risk of abuse when compared to the general infant population. Despite this association, a paucity of literature stratifies this risk and translates it to the clinic such that this high-risk group is stringently screened for abusive injuries. In this light, the authors propose a standardised screening method for all contact children of the index case and call for further consensus on the subject.

AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination.

Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy. Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination. Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1. We describe their clinical course and radiological and genetic findings, providing further insight into the natural history of this condition.

Pediatric radiology in the diagnosis and management of skeletal dysplasias - welcome to the era of genomic medicine and modern drug pipelines.

Radiologists have long played a key role in the diagnosis and management of children with suspected skeletal dysplasia. Advancing molecular sciences, including the emergence of next generation sequencing and the development of modern rapid drug pipelines have the potential to transform this role.