Ultrasound of palpable lesions: a pictorial review.

Ultrasound (US) is the imaging modality of choice for evaluation of superficial palpable lesions. A large proportion of these lesions have characteristic sonographic appearance and can be confidently diagnosed with US without the need for biopsy or other intervention. The Society of Radiologists in Ultrasound (SRU) recently published a Consensus Conference Statement on superficial soft tissue masses. The goal of this manuscript is (a) to serve as a sonographic pictorial review for palpable lesions based on the SRU statement, (b) present the typical sonographic features of palpable lesions that can be confidently diagnosed with US, and (c) provide an overview of other palpable lesions with a framework to interpret the US studies and advise on appropriate further management.

Diversity of current ultrasound practice within and outside radiology departments with a vision for 20 years into the future: a position paper of the ESR ultrasound subcommittee.

Ultrasound practice is a longstanding tradition for radiology departments, being part of the family of imaging techniques. Ultrasound is widely practiced by non-radiologists but becoming less popular within radiology. The position of ultrasound in radiology is reviewed, and a possible long-term solution to manage radiologist expectations is proposed. An international group of experts in the practice of ultrasound was invited to describe the current organisation of ultrasound within the radiology departments in their own countries and comment on the interaction with non-radiologists and training arrangements. Issues related to regulation, non-medical practitioners, and training principles are detailed. A consensus view was sought from the experts regarding the position of ultrasound within radiology, with the vision of the best scenario for the continuing dominance of radiologists practising ultrasound. Comments were collated from nine different countries. Variable levels of training, practice, and interaction with non-radiologist were reported, with some countries relying on non-physician input to manage the service. All experts recognised there was a diminished desire to practice ultrasound by radiologists. Models varied from practising solely ultrasound and no other imaging techniques to radiology departments being central to the practice of ultrasound by radiologists and non-radiologist, housed within radiology. The consensus view was that the model favoured in select hospitals in Germany would be the most likely setup for ultrasound radiologist to develop and maintain practice. The vision for 20 years hence is for a central ultrasound section within radiology, headed by a trained expert radiologist, with non-radiologist using the facilities.Critical relevance statement The future of ultrasound within the radiology department should encompass all ultrasound users, with radiologists expert in ultrasound, managing the ultrasound section within the radiology department. The current radiology trainees must learn of the importance of ultrasound as a component of the 'holistic' imaging of the patient.Key points: 1. Ultrasound imaging within radiology departments precedes the introduction of CT and MR imaging and was first used over 50 years ago.2. Non-radiology practitioners deploy ultrasound examinations to either 'problem solve' or perform a comprehensive ultrasound examination; radiologists provide comprehensive examinations or use ultrasound to direct interventional procedures.3. Radiology does not 'own' ultrasound, but radiologists are best placed to offer a comprehensive patient-focused imaging assessment.4. A vision of the future of ultrasound within the radiology department is encompassing all ultrasound users under radiologists who are experts in ultrasound, positioned within the radiology department.5. The current radiology trainee must be aware of the importance of ultrasound as a component of the 'holistic' imaging of the patient.

MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia.

BACKGROUND: Despite advances in next generation sequencing technologies, the identification of variants of uncertain significance (VUS) can often hinder definitive diagnosis in patients with complex neurodevelopmental disorders. OBJECTIVE: The objective of this study was to identify and characterize the underlying cause of disease in a family with two children with severe developmental delay associated with generalized dystonia and episodic status dystonicus, chorea, epilepsy, and cataracts. METHODS: Candidate genes identified by autozygosity mapping and whole-exome sequencing were characterized using cellular and vertebrate model systems. RESULTS: Homozygous variants were found in three candidate genes: MED27, SLC6A7, and MPPE1. Although the patients had features of MED27-related disorder, the SLC6A7 and MPPE1 variants were functionally investigated. SLC6A7 variant in vitro overexpression caused decreased proline transport as a result of reduced cell-surface expression, and zebrafish knockdown of slc6a7 exhibited developmental delay and fragile motor neuron morphology that could not be rescued by L-proline transporter-G396S RNA. Lastly, patient fibroblasts displayed reduced cell-surface expression of glycophosphatidylinositol-anchored proteins linked to MPPE1 dysfunction. CONCLUSIONS: We report a family harboring a homozygous MED27 variant with additional loss-of-function SLC6A7 and MPPE1 gene variants, which potentially contribute to a blended phenotype caused by multilocus pathogenic variants. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Mapping the Ultrasound Landscape to Define Point-of-Care Ultrasound and Diagnostic Ultrasound: A Proposal From the Society of Radiologists in Ultrasound and ACR Commission on Ultrasound.

Current descriptions of ultrasound evaluations, including use of the term "point-of-care ultrasound" (POCUS), are imprecise because they are predicated on distinctions based on the device used to obtain images, the location where the images were obtained, the provider who obtained the images, or the focus of the examination. This is confusing because it does not account for more meaningful distinctions based on the setting, comprehensiveness, and completeness of the evaluation. In this article, the Society of Radiologists in Ultrasound and the members of the American College of Radiology Ultrasound Commission articulate a map of the ultrasound landscape that divides sonographic evaluations into four distinct categories on the basis of setting, comprehensiveness, and completeness. Details of this classification scheme are elaborated, including important clarifications regarding what ensures comprehensiveness and completeness. Practical implications of this framework for future research and reimbursement paradigms are highlighted.

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Contrast-enhanced Ultrasound-State of the Art in North America: Society of Radiologists in Ultrasound White Paper.

On October 24, 2017, in Chicago, the Society of Radiologists in Ultrasound convened a panel of specialists in contrast-enhanced ultrasound (CEUS) to arrive at a white paper regarding the use of CEUS in noncardiac applications in North America. Recommendations are based on analysis of the current literature and common practice strategies. They represent a reasonable approach to introduce the advantages of this safe and noninvasive technique for the benefit of our patients. Characterization of liver nodules with CEUS, as the approval indication worldwide, is the major focus of this endeavor. In addition, many off label uses are reviewed and literature supporting these indications provided.Key Points(1) Contrast-enhanced ultrasound (CEUS) allows cross-sectional imaging of the liver, kidneys and multiple other solid and hollow viscera, providing excellent characterization of identified focal mass lesions.(2) Performed with the injection of a microbubble contrast agent, CEUS provides a safe and readily available imaging technique which requires no ionizing radiation, making it appropriate for use in all ages, in those with renal insufficiency and when a portable examination is needed.(3) The CEUS can be considered in abdominal imaging whenever blood flow information is of value to diagnosis.(4) Dynamic real-time acquisition and the use of a purely intravascular contrast agent are the 2 most essential technical aspects of CEUS imaging which distinguish it from both computed tomography and magnetic resonance scan.

Contrast -Enhanced Ultrasound: State of the Art in North America.

The Society of Radiologists in Ultrasound convened a panel of specialists in contrast-enhanced ultrasound (CEUS) to produce a white paper on noncardiac CEUS in North America. The panel met in Chicago, Illinois, on October 24 and 25, 2017. The recommendations are based on analysis of current literature and common practice strategies and are thought to represent a reasonable approach to introduce the advantages of this safe and noninvasive technique for the benefit of our patients. Characterization of liver nodules, and pediatric vascular and intravesicular applications comprise the approved indications for CEUS in the United States. They, along with the very successful off-label use of CEUS for the kidney, are included in this publication.Other off-label uses are presented with emphasis on their value and literature support in the online version.

Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort.

OBJECTIVE: To compare the performance of the 2017 McDonald criteria with that of the 2010 criteria for the diagnosis of multiple sclerosis (MS) in children in the clinical setting. METHODS: In this retrospective, multi-centre study, we identified children who presented with symptoms suggestive of a clinically isolated syndrome (CIS) and were followed up for at least 2 years or until their second attack. RESULTS: Of 156 children with CIS followed up for a median of 4.17 years, 94 (60.3%) were diagnosed with MS. In all, 83 (88.3%) of these fulfilled the 2010 dissemination in space (DIS) criteria at onset. Three additional children fulfilled the 2017 DIS criteria because of the inclusion of symptomatic lesions. Of the 59 children with MS who underwent post-gadolinium magnetic resonance imaging (MRI), 44 (74.6%) fulfilled the 2010 dissemination in time (DIT) criteria at baseline. When the presence of oligoclonal bands (OCBs) was used to substitute DIT, an additional 35 children (79/94, 84.0%) were diagnosed with MS according to the 2017 criteria. The 2017 criteria had higher accuracy (87.2% vs 66.7%), higher sensitivity (84.0% vs 46.8%), but reduced specificity (91.9% vs 96.8%) when compared to the 2010 criteria. CONCLUSION: The improved performance of the 2017 criteria when compared to the 2010 criteria was predominantly due to the inclusion of intrathecal OCBs.

Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development.

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell-cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

Esophageal pneumatosis: Case report and review of literature.

Pneumatosis of the gastrointestinal tract is defined as presence of air in the wall of the gastrointestinal tract and can occur in any part of the gastrointestinal tract. It is most commonly seen in the intestine and very rarely in the esophagus. The exact pathogenesis is still unknown. It is managed primarily by conservative and non-surgical therapy, unless there are findings to suggest an acute abdomen or other co-morbidities. On review of literature, very few case reports of esophageal pneumatosis have been published. We present a rare case of pneumatosis of the esophagus with cytomegalovirus (CMV) infection.

The neuroimaging mimics of abusive head trauma.

Abusive head trauma (AHT) is a significant cause of morbidity and mortality in the paediatric population, typically in children under the age of two years. Neuroimaging plays a key role in the diagnostic work up of these patients as information regarding the mechanism of injury is often lacking and the findings on examination can be nonspecific. A number of conditions, both traumatic and atraumatic can mimic AHT based on neuroimaging features alone. The repercussions associated with a diagnosis or misdiagnosis of AHT can be severe and radiologists therefore need to be aware of and familiar with the imaging differentials of AHT. In this paper we review the imaging findings of the radiological mimics of AHT and focus on features that can help differentiate these entities from AHT.

Correction: The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations.

Since the online publication of the article, the authors have noted errors with Table 2; this has now been corrected in both the HTML and the PDF.

Comprehensive genotype-phenotype correlation in lissencephaly.

Malformations of cortical development (MCD) are a heterogenous group of disorders with diverse genotypic and phenotypic variations. Lissencephaly is a subtype of MCD caused by defect in neuronal migration, which occurs between 12 and 24 weeks of gestation. The continuous advancement in the field of molecular genetics in the last decade has led to identification of at least 19 lissencephaly-related genes, most of which are related to microtubule structural proteins (tubulin) or microtubule-associated proteins (MAPs). The aim of this review article is to bring together current knowledge of gene mutations associated with lissencephaly and to provide a comprehensive genotype-phenotype correlation. Illustrative cases will be presented to facilitate the understanding of the described genotype-phenotype correlation.

Evaluating Renal Transplant Status Using Viscoelastic Response (VisR) Ultrasound.

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p <0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics.

Intracranial hemorrhage in neonates: A review of etiologies, patterns and predicted clinical outcomes.

Intracranial hemorrhage (ICH) in neonates often results in devastating neurodevelopmental outcomes as the neonatal period is a critical window for brain development. The neurodevelopmental outcomes in neonates with ICH are determined by the maturity of the brain, the location and extent of the hemorrhage, the specific underlying etiology and the presence of other concomitant disorders. Neonatal ICH may result from various inherited and acquired disorders. We classify the etiologies of neonatal ICH into eight main categories: (1) Hemorrhagic stroke including large focal hematoma, (2) Prematurity-related hemorrhage, (3) Bleeding diathesis, (4) Genetic causes, (5) Infection, (6) Trauma-related hemorrhage, (7) Tumor-related hemorrhage and (8) Vascular malformations. Illustrative cases showing various imaging patterns that can be helpful to predict clinical outcomes will be highlighted. Potential mimics of ICH in the neonatal period are also reviewed.

Developmental conduction aphasia after neonatal stroke.

OBJECTIVE: Impairment of speech repetition following injury to the dorsal language stream is a feature of conduction aphasia, a well-described "disconnection syndrome" in adults. The impact of similar lesions sustained in infancy has not been established. METHODS: We compared language outcomes in term-born individuals with confirmed neonatal stroke (n = 30, age = 7-18 years, left-sided lesions in 21 cases) to matched controls (n = 40). Injury to the dorsal and/or ventral language streams was assessed using T1 - and T2 -weighted magnetic resonance imaging (MRI) and diffusion tractography. Language lateralization was determined using functional MRI. RESULTS: At the group level, left dorsal language stream injury was associated with selective speech repetition impairment for nonwords (p = 0.021) and sentences (p < 0.0001). The majority of children with significant repetition impairment had retained left hemisphere language representation, but right hemisphere dominance was correlated with minimal or absent repetition deficits. Post hoc analysis of the repetition-impaired group revealed additional language-associated deficits, but these were more subtle and variable. INTERPRETATION: We conclude that (1) despite the considerable plasticity of the infant brain, early dorsal language stream injury can result in specific and long-lasting problems with speech repetition that are similar to the syndrome of conduction aphasia seen in adults; and (2) language reorganization to the contralateral hemisphere has a protective effect. Ann Neurol 2018;83:664-675 Ann Neurol 2018;83:664-675.

Imaging with ultrasound contrast agents: current status and future.

Microbubble ultrasound contrast agents (UCAs) were recently approved by the Food and Drug administration for non-cardiac imaging. The physical principles of UCAs, methods of administration, dosage, adverse effects, and imaging techniques both current and future are described. UCAs consist of microbubbles in suspension which strongly interact with the ultrasound beam and are readily detectable by ultrasound imaging systems. They are confined to the blood pool when administered intravenously, unlike iodinated and gadolinium contrast agents. UCAs have a proven safety record based on over two decades of use, during which they have been used in echocardiography in the U.S. and for non-cardiac imaging in the rest of the world. Adverse effects are less common with UCAs than CT/MR contrast agents. Compared to CT and MR, contrast-enhanced ultrasound has the advantages of real-time imaging, portability, and reduced susceptibility to metal and motion artifact. UCAs are not nephrotoxic and can be used in renal failure. High acoustic amplitudes can cause microbubbles to fragment in a manner that can result in short-term increases in capillary permeability or capillary rupture. These bioeffects can be beneficial and have been used to enhance drug delivery under appropriate conditions. Imaging with a mechanical index of < 0.4 preserves the microbubbles and is not typically associated with substantial bioeffects. Molecularly targeted ultrasound contrast agents are created by conjugating the microbubble shell with a peptide, antibody, or other ligand designed to target an endothelial biomarker associated with tumor angiogenesis or inflammation. These microbubbles then accumulate in the microvasculature at target sites where they can be imaged. Ultrasound contrast agents are a valuable addition to the diagnostic imaging toolkit. They will facilitate cross-sectional abdominal imaging in situations where contrast-enhanced CT and MR are contraindicated or impractical.

A child with Apert syndrome and Sturge-Weber syndrome: could fibronectin or the RAS/MAPK signaling pathway be the connection?

BACKGROUND: Apert syndrome is one of the most common craniosynostosis syndrome caused by mutation in genes encoding fibroblast growth factor receptor 2 (FGFR2). Craniosynostosis, midfacial hypoplasia, and syndactyly/symphalangism are features of this syndrome. Sturge-Weber syndrome (SWS) on the other hand is a congenital neurocutaneous disorder characterized by facial port-wine stains (PWSs) and leptomeningeal vascular capillary malformations. In 2013, the causative mutation underlying SWS (p.R183Q somatic activating mutation in the guanine nucleotide-binding protein alpha-q (GNAQ) gene) was identified. This mutation increases downstream signaling along the RAS/MAPK pathway, resulting in increased cell proliferation. The interaction between FGFR and the RAS/MAPK signaling pathway was proposed in recent years. Elevated synthesis of fibronectin in the calvaria of patients with Apert syndrome and increased fibronectin gene expression in port wine-derived fibroblasts of patients with Sturge-Weber disease have also been reported. CASE PRESENTATION: We report a unique case of Apert and Sturge-Weber syndromes occurring in the same patient. The child was noted to demonstrate features suggestive of Apert syndrome at birth, including brachycephaly, midface hypoplasia, and syndactyly. In addition, a left-sided facial port wine stain in the forehead was noted. Magnetic resonance imaging (MRI) of the brain was performed and confirmed the diagnosis of Sturge-Weber syndrome by demonstrating the presence of left sided leptomeningeal vascular capillary malformation and left-sided cerebral hemiatrophy. CONCLUSION: To the best of our knowledge, there has been no prior described case of Apert and Sturge-Weber syndromes occurring in the same patient. This case report identifies an area of potential research on fibronectin and derangement of the RAS/MAPK signaling pathway in relation to Apert syndrome and Sturge-Weber syndrome. In view of the rare concurrence of Apert and Sturge-Weber syndromes, the underlying pathogenesis is thought to be multifactorial, one of which may be related to either increased fibronectin gene expression or derangement of the RAS/MAPK signaling pathway.

Diagnostic accuracy of contrast-enhanced ultrasound for characterization of kidney lesions in patients with and without chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease are at increased risk of cystic kidney disease that requires imaging monitoring in many cases. However, these same patients often have contraindications to contrast-enhanced computed tomography and magnetic resonance imaging. This study evaluates the accuracy of contrast-enhanced ultrasound (CEUS), which is safe for patients with chronic kidney disease, for the characterization of kidney lesions in patients with and without chronic kidney disease. METHODS: We performed CEUS on 44 patients, both with and without chronic kidney disease, with indeterminate or suspicious kidney lesions (both cystic and solid). Two masked radiologists categorized lesions using CEUS images according to contrast-enhanced ultrasound adapted criteria. CEUS designation was compared to histology or follow-up imaging in cases without available tissue in all patients and the subset with chronic kidney disease to determine sensitivity, specificity and overall accuracy. RESULTS: Across all patients, CEUS had a sensitivity of 96% (95% CI: 84%, 99%) and specificity of 50% (95% CI: 32%, 68%) for detecting malignancy. Among patients with chronic kidney disease, CEUS sensitivity was 90% (95% CI: 56%, 98%), and specificity was 55% (95% CI: 36%, 73%). CONCLUSIONS: CEUS has high sensitivity for identifying malignancy of kidney lesions. However, because specificity is low, modifications to the classification scheme for contrast-enhanced ultrasound could be considered as a way to improve contrast-enhanced ultrasound specificity and thus overall performance. Due to its sensitivity, among patients with chronic kidney disease or other contrast contraindications, CEUS has potential as an imaging test to rule out malignancy. TRIAL REGISTRATION: This trial was registered in clinicaltrials.gov, NCT01751529 .

The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations.

PurposeMutations in POLG, the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes. We aimed to improve the clinical recognition of POLG-related disorders in the pediatric population.MethodsWe performed a multinational, phenotype: genotype study using patients from three centers, two Norwegian and one from the United Kingdom. Patients with age at onset <12 years and confirmed pathogenic biallelic POLG mutations were considered eligible.ResultsA total of 27 patients were identified with a median age at onset of 11 months (range 0.6-80.4). The majority presented with global developmental delay (n=24/24, 100%), hypotonia (n=22/23, 96%) and faltering growth (n=24/27, 89%). Epilepsy was common, but notably absent in patients with the myocerebrohepatopathy spectrum phenotype. We identified two novel POLG gene mutations.ConclusionOur data suggest that POLG-related disease should be suspected in any child presenting with diffuse neurological symptoms. Full POLG sequencing is recommended since targeted screening may miss mutations. Finally, we simplify the classification of POLG-related disease in children using epilepsy as the crucial defining element; we show that Alpers and myocerebrohepatopathy spectrum follow different outcomes and that they manifest different degrees of respiratory chain dysfunction.