[Congenital brain malformations]. / Angeborene Hirnfehlbildungen.

CLINICAL ISSUE: Malformations of the central nervous system belong to the most common developmental disorders in humans. The clinical presentation of brain malformations is nonspecific including developmental delay, hypotonia, and/or epilepsy. The great heterogeneity concerning etiology, mechanisms of development and morphology is challenging for diagnosis and classification of brain malformations. Thereby recognizing specific malformations is essential for optimal patient management and prognostic evaluation. The aim of this article is to give an overview of several clinically relevant brain malformations occurring from different disrupted developmental processes in brain formation. STANDARD RADIOLOGICAL METHODS: Several brain malformations are already diagnosed during routine ultrasound in pregnancy. However pre- and postnatal magnetic resonance imaging remains the gold standard in detecting the partially subtle changes and to classify the malformations. METHODICAL INNOVATIONS: Advances in pre- and postnatal neuroimaging techniques and increasing investigation of genetic mechanisms underlying brain formation and its abnormalities have led to a better understanding of embryologic development and pathogeneses of brain malformations. CONCLUSION: Besides patient's history and clinical phenotype, neuroimaging plays a key role in diagnosis. Not always a specific diagnosis can be made, but neuroimaging patterns often enable a focused genetic testing and therefore are revolutionary for etiologic and prognostic assignment. Basic knowledge of brain development facilitates understanding and classifying of structural brain abnormalities.

Rapid and sustained response to JAK inhibition in a child with severe MDA5 + juvenile dermatomyositis.

BACKGROUND: Juvenile dermatomyositis (jDM) is the most common idiopathic inflammatory myopathy of childhood. Amyopathic or hypomyopathic courses have been described. CASE PRESENTATION: We present the case of a 4-year-old patient with MDA5 antibody positive jDM and interstitial lung disease. In our patient, typical symptoms of jDM with classical skin lesions, arthritis, proximal muscle weakness, and ulcerative calcifications were observed. Due to the severity of the disease and the pulmonary changes, therapy with the Janus kinase (JAK) inhibitor ruxolitinib was added to the therapy with corticosteroids, intravenous immunoglobulins (IVIG) and hydroxychloroquine leading to a fast and sustained remission. CONCLUSION: While there is growing evidence that JAK inhibition is a promising therapeutic option in jDM our case report shows that this approach may also be effective in MDA5-positive jDM with high risk features.

Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus (jSLE).

Systemic lupus erythematosus (SLE) is a rare autoimmune/inflammatory disease with significant morbidity and mortality. Approximately 15-20% of SLE patients develop the disease during childhood or adolescence (juvenile-onset SLE/jSLE). Patients with jSLE exhibit more variable and severe disease when compared to patients with disease-onset during adulthood. Neuropsychiatric (NP) involvement is a clinically heterogenous and potentially severe complication. Published reports on the incidence and prevalence of NP-jSLE are scarce, and the exact pathophysiology is poorly understood.This manuscript provides a review of the existing literature, suggesting NP involvement in 13.5-51% of jSLE patients. Among patients with NP-jSLE affecting the CNS, we propose two main subgroups: (i) a chronic progressive, predominantly type 1 interferon-driven form that poorly responds to currently used treatments, and (ii) an acutely aggressive form that usually presents early during the disease that may be primarily mediated by auto-reactive effector lymphocytes. While this hypothesis requires to be tested in large collaborative international cohort studies, it may offer future patient stratification and individualised care.

Null and missense mutations of ERI1 cause a recessive phenotypic dichotomy in humans.

ERI1 is a 3'-to-5' exoribonuclease involved in RNA metabolic pathways including 5.8S rRNA processing and turnover of histone mRNAs. Its biological and medical significance remain unclear. Here, we uncover a phenotypic dichotomy associated with bi-allelic ERI1 variants by reporting eight affected individuals from seven unrelated families. A severe spondyloepimetaphyseal dysplasia (SEMD) was identified in five affected individuals with missense variants but not in those with bi-allelic null variants, who showed mild intellectual disability and digital anomalies. The ERI1 missense variants cause a loss of the exoribonuclease activity, leading to defective trimming of the 5.8S rRNA 3' end and a decreased degradation of replication-dependent histone mRNAs. Affected-individual-derived induced pluripotent stem cells (iPSCs) showed impaired in vitro chondrogenesis with downregulation of genes regulating skeletal patterning. Our study establishes an entity previously unreported in OMIM and provides a model showing a more severe effect of missense alleles than null alleles within recessive genotypes, suggesting a key role of ERI1-mediated RNA metabolism in human skeletal patterning and chondrogenesis.

Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision.

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.

Anthropometric Landmarking for Diagnosis of Cranial Deformities: Validation of an Automatic Approach and Comparison with Intra- and Interobserver Variability.

Shape analysis of infant's heads is crucial to diagnose cranial deformities and evaluate head growth. Currently available 3D imaging systems can be used to create 3D head models, promoting the clinical practice for head evaluation. However, manual analysis of 3D shapes is difficult and operator-dependent, causing inaccuracies in the analysis. This study aims to validate an automatic landmark detection method for head shape analysis. The detection results were compared with manual analysis in three levels: (1) distance error of landmarks; (2) accuracy of standard cranial measurements, namely cephalic ratio (CR), cranial vault asymmetry index (CVAI), and overall symmetry ratio (OSR); and (3) accuracy of the final diagnosis of cranial deformities. For each level, the intra- and interobserver variability was also studied by comparing manual landmark settings. High landmark detection accuracy was achieved by the method in 166 head models. A very strong agreement with manual analysis for the cranial measurements was also obtained, with intraclass correlation coefficients of 0.997, 0.961, and 0.771 for the CR, CVAI, and OSR. 91% agreement with manual analysis was achieved in the diagnosis of cranial deformities. Considering its high accuracy and reliability in different evaluation levels, the method showed to be feasible for use in clinical practice for head shape analysis.

Diagnosis and Treatment of Small Vessel Childhood Primary Angiitis of the Central Nervous System (sv-cPACNS): An International Survey.

Childhood primary angiitis of the Central Nervous System (cPACNS) is a rare autoimmune and inflammatory disease. It can result in significant neuronal damage, neurodevelopmental delay and potentially death. Childhood PACNS is divided into subcategories: angiography-positive p-cPACNS that affects medium and large vessels, and angiography-negative small vessel sv-cPACNS. Due to its rarity, variable clinical representation, and the lack of a diagnostic criteria and therapeutic plans, diagnosis and treatment of cPACNS is challenging and approaches vary. This survey collected information on diagnostic and therapeutic approaches to sv-PACNS. It was shared with international clinician networks, including the German Society for Paediatric Rheumatology, the Paediatric Rheumatology European Society, the "Network Paediatric Stroke," and members of the American College of Rheumatology/CARRA Paediatric Rheumatology list server. This project has shown consensus in numerous diagnostic and therapeutic treatment approaches, highlighting key areas which will be utilised to develop statements in the use of expert consensus meetings to standardise diagnostic and therapeutic approaches in this rare inflammatory disease.

Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents-Consensus-Based Practice Guidelines.

Disorders of the peripheral nerves can be caused by a broad spectrum of acquired or hereditary aetiologies. The objective of these practice guidelines is to provide the reader with information about the differential diagnostic workup for a target-oriented diagnosis. Following an initiative of the German-speaking Society of Neuropaediatrics, delegates from 10 German societies dedicated to neuroscience worked in close co-operation to write this guideline. Applying the Delphi methodology, the authors carried out a formal consensus process to develop practice recommendations. These covered the important diagnostic steps both for acquired neuropathies (traumatic, infectious, inflammatory) and the spectrum of hereditary Charcot-Marie-Tooth (CMT) diseases. Some of our most important recommendations are that: (i) The indication for further diagnostics must be based on the patient's history and clinical findings; (ii) Potential toxic neuropathy also has to be considered; (iii) For focal and regional neuropathies of unknown aetiology, nerve sonography and MRI should be performed; and (iv) For demyelinated hereditary neuropathy, genetic diagnostics should first address PMP22 gene deletion: once that has been excluded, massive parallel sequencing including an analysis of relevant CMT-genes should be performed. This article contains a short version of the guidelines. The full-length text (in German) can be found at the Website of the "Arbeitsgemeinschaft der Wissenschftlichen Medizinischen Fachgesellschaften e.V. (AWMF), Germany.

Chronic nonbacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO).

Chronic nonbacterial osteomyelitis (CNO) is an inflammatory bone disorder that most frequently affects children and adolescents. Chronic recurrent multifocal osteomyelitis (CRMO) is a severe form of CNO, usually characterized by symmetrical inflammatory bone lesions and its waxing and waning character. Sometimes severe and chronic pain can significantly affect the quality of life and psychosocial development of individuals affected. In the absence of prospectively tested and widely accepted diagnostic criteria or disease biomarkers, CNO remains a diagnosis of exclusion, and infections, malignancy and other differentials require consideration (1). The pathophysiology of CNO is not fully understood, but imbalanced cytokine expression and increased inflammasome activation in monocytes from CNO patients contribute to a pro-inflammatory phenotype that contributes to bone inflammation (2). Currently, no medications are licensed for the use in CNO. Most patients show at least some response to nonsteroidal anti-inflammatory drugs, others require more aggressive treatment that can include corticosteroids, cytokine-blocking agents and/or bisphosphonates (3). While under the care of an experienced team and sufficient treatment, the prognosis is good, but some patients will develop sequalae which can include vertebral compression fractures (1).

Diagnosis and Treatment of Angiography Positive Medium to Large Vessel Childhood Primary Angiitis of Central Nervous System (p-cPACNS): An International Survey.

Childhood Primary Angiitis of Central Nervous System (cPACNS) is rare, but can cause significant damage and result in disability or even death. Because of its rarity, the sometimes acute and variable presentation, limited awareness, and the absence of widely accepted diagnostic and therapeutic standards, cPACNS is a diagnostic and therapeutic challenge. Three subcategories of cPACNS exist, including angiography-positive non-progressive p-cPACNS, angiography-positive progressive p-cPACNS which both affects the medium to large vessels, and angiography-negative small vessel sv-cPACNS. Diagnosis and treatment of cPACNS relies on personal experience, expert opinion and case reports/case series. To collect information on diagnostic and therapeutic approaches to transient and progressive cPACNS, a survey was shared among international clinicians (German Society for Pediatric Rheumatology, the Pediatric Rheumatology European Society, the German speaking "Network Pediatric Stroke," and members of the American College of Rheumatology/CARRA Pediatric Rheumatology list server). Results from this survey will be used to define statements toward a consensus process allowing harmonization of diagnostic and therapeutic approaches and the generation of evidence in a rare condition.

Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis.

Human induced pluripotent stem cells (hiPSCs) hold great potential for modeling human diseases and the development of innovative therapeutic approaches. Here, we report on a novel, simplified differentiation method for forming functional osteoclasts from hiPSCs. The three-step protocol starts with embryoid body formation, followed by hematopoietic specification, and finally osteoclast differentiation. We observed continuous production of monocyte-like cells over a period of up to 9 weeks, generating sufficient material for several osteoclast differentiations. The analysis of stage-specific gene and surface marker expression proved mesodermal priming, the presence of monocyte-like cells, and of terminally differentiated multinucleated osteoclasts, able to form resorption pits and trenches on bone and dentine in vitro. In comparison to peripheral blood mononuclear cell (PBMC)-derived osteoclasts hiPSC-derived osteoclasts were larger and contained a higher number of nuclei. Detailed functional studies on the resorption behavior of hiPSC-osteoclasts indicated a trend towards forming more trenches than pits and an increase in pseudoresorption. We used hiPSCs from an autosomal recessive osteopetrosis (ARO) patient (BIHi002-A, ARO hiPSCs) with compound heterozygous missense mutations p.(G292E) and p.(R403Q) in CLCN7, coding for the Cl- /H+ -exchanger ClC-7, for functional investigations. The patient's leading clinical feature was a brain malformation due to defective neuronal migration. Mutant ClC-7 displayed residual expression and retained lysosomal co-localization with OSTM1, the gene coding for the osteopetrosis-associated transmembrane protein 1, but only ClC-7 harboring the mutation p.(R403Q) gave strongly reduced ion currents. An increased autophagic flux in spite of unchanged lysosomal pH was evident in undifferentiated ARO hiPSCs. ARO hiPSC-derived osteoclasts showed an increased size compared to hiPSCs of healthy donors. They were not able to resorb bone, underlining a loss-of-function effect of the mutations. In summary, we developed a highly reproducible, straightforward hiPSC-osteoclast differentiation protocol. We demonstrated that osteoclasts differentiated from ARO hiPSCs can be used as a disease model for ARO and potentially also other osteoclast-related diseases. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Clinical Perspective on Primary Angiitis of the Central Nervous System in Childhood (cPACNS).

Non-arteriosclerotic arteriopathies have emerged as important underlying pathomechanism in pediatric arterial ischemic stroke (AIS). The pathogenesis and classification of cerebral arteriopathies in childhood are heterogeneous. Different classifications base on (i) the anatomic site; (ii) the distribution and size of the affected vessel; (iii) the time course, for example, transient vs. progressive, monophasic vs. recurrent; (iv) the putative pathogenesis; (v) the magnetic resonance imaging morphology of the vasculopathies. Inflammation affecting the cerebral vessels is increasingly recognized as common cause of pediatric AIS. Primary cerebral vasculitis or primary angiitis of the central nervous system (CNS) in childhood (cPACNS) is an important differential diagnosis in pediatric AIS. Primary angiitis of the CNS is a rare disorder, and the pathogenesis is poorly understood so far. The current classification of cPACNS is based on the affected cerebral vessel size, the disease course, and angiographic pattern. Two large subtypes are currently recognized comprising large- and medium-sized vessel CNS vasculitis referred to as angiography-positive cPACNS and angiography-negative small vessel cPACNS. As the clinical manifestations of cPACNS are rather diverse, precise diagnosis can be challenging for the treating pediatrician because of the lack of vital laboratory tests or imaging features. Initial misdiagnosis is common because of overlapping phenotypes and pediatric AIS mimics. As untreated cPACNS is associated with a high morbidity and mortality, timely diagnosis, and induction of immunomodulatory and symptomatic therapy are essential. Survival and neurological outcome depend on early diagnosis and prompt therapy. Primary angiitis of the central nervous system in childhood differs in several aspects from primary cerebral angiitis in adults. The aim of this article is to give a brief comprehensive summary on pediatric primary cerebral vasculitis focusing on the clinical perspective regarding the classification, the putative pathogenesis, the disease course, the diagnostic tools, and emerging treatment options. A modified terminology for clinical practice is discussed.

Orbital inflammation and colitis in pediatric IgG4-related disease: A case report and review of the literature.

IgG4-related disease (IgG4-RD) is an inflammatory disorder characterized by tumor-like swelling in one or more organs, elevated serum IgG4 levels, and histological alterations with infiltration of IgG4-positive plasma cells. IgG4-RD is rare and likely underdiagnosed in children. We report a case of a 16-year-old girl with IgG4-positive colitis that developed weeks after IgG4-related ophthalmic disease and discuss diagnosis and treatment in the context of the literature available. Since the pathophysiology of IgG4-RD is unknown, treatment options are empiric and, for the most part, untargeted. Systemic corticosteroid treatment is the basis of anti-inflammatory treatment in IgG4-RD and induced early remission in our patient. During corticosteroid taper, the patient developed weight loss and intestinal inflammation. Histopathological assessment of the intestinal walls confirmed IgG4-positive colitis. Immune-modulating treatment with non-biologic (e.g., methotrexate (MTX) and mycophenolate mofetil) or biologic (rituximab) disease-modifying antirheumatic drugs has been reported in treatment refractory or corticosteroid-dependent patients. The patient responded to treatment with anti-inflammatory therapy with food rich in TGF-ß2 (modulen) and MTX. This is one of the first pediatric patients reported with IgG4-related colitis extending the phenotype of pediatric IgG4-RD. International collaboration to prospectively document clinical presentation and treatment responses may help to further establish the phenotype and treatment options and to raise awareness for IgG4-RD.

Non-invasive estimation of brain-volume in infants.

BACKGROUND: Neurological development is determined by brain growth. Methods to measure total brain volume (TBV) in clinical settings are limited. MR-imaging represents the gold-standard. AIMS: The present study tests the hypotheses that in infants without any brain pathology, TBV - as determined by MRI - can be accurately estimated by cranial volume (CrV), measured by 3D-laser scanning. In case of good correlation of CrV with TBV it was further tested, whether CrV can be also estimated by (I) head circumference (HC) or (II) by other technology than laser scanning. STUDY DESIGN & SUBJECTS: To test the hypothesis, that TBV can be reliably estimated by CrV-measurement, data from routine MRI and 3D-laser-scanner measurements were analyzed in infants if no major structural brain anomaly was found in MR-imaging. To test whether CrV can be predicted by HC-measurements during infancy, data from routine follow-up visits were used from preterms born in a two year period. Preterms are invited for a routine follow-up visit (which includes laser scanning of the head) at an age of 3 months and, for further follow-ups at 6, 9 or 12 months. To compare accuracy of CrV measurement by other techniques, a puppet head was measured, using different 3D-measurement principles: (i) Structured light projection system, (ii) The non-invasive laser-shape-digitizer, and (iii) Structure-from-motion (SFM) technique. OUTCOME MEASURES: TBV was compared with CrV using a Passing-Bablok-Regression. To determine how well HC predicts CrV, the coefficient of determinant (R2) was calculated for each age group. RESULTS: CrV and TBV of 25 infants (median age 19 month, body weight of 11 kg) showed a median bias of -86.7 mm3 with a slightly smaller TBV (median of 1034.1 mm3, IQR 875.9 … 1179.8 mm3) than CrV (median 1092.2, IQR 950.5 … 1258.4 mm3). CrV was poorly estimated by HC, with R2 between 0.79 and 0.87 at 3 and 9 month of age respectively. For the non-invasive laser-shape-digitizer and the SFM-technique the accuracy was good (radial coordinate differences ±0.3 vs. ±0.5 mm). CONCLUSION: The present study provides convincing evidence that CrV can be used to estimate TBV in routine care, whereas HC is a poor predictor of individual CrV.

Whole-Body MRI in Children and Adolescents - S1 Guideline. / Ganzkörper-Magnetresonanztomografie im Kindes- und Jugendalter ­ S1-Leitlinie.

Whole-body MRI is an imaging method that uses advanced modern MRI equipment to provide high-resolution images of the entire body. The goal of these guidelines is to specify the indications for which whole-body MRI can be recommended in children and adolescents and to describe the necessary technical requirements. CITATION FORMAT: · Schaefer JF, Berthold LD, Hahn G et al. Whole-Body MRI in Children and Adolescents - S1 Guidelines. Fortschr Röntgenstr 2019; 191: 618 - 625.

Child Abuse or Bleeding Disorder-An Interdisciplinary Approach.

Children with an unexplained bleeding tendency are frequently referred to a haemostaseologist for further evaluation. Careful standardized history taking and clinical evaluation should allow for distinguishing bleeds after minor injury and trauma which are very common in all children. However, in two groups of children bleeding symptoms may be more significant than expected: those with an underlying coagulation disorder and those who have been subjected to physical child abuse. The coexistence of child abuse and a bleeding disorder must always be considered. An extended coagulation diagnostic is required if the morphology of bleedings is not clearly suspicious for child abuse and in the absence of typical concomitant injuries, e.g., bone fractures. An interdisciplinary approach involving a forensic pathologist and a paediatric haemostaseologist for assessment of bleeding symptoms, the explanation of the clinical findings, and the critical evaluation of laboratory results are essential in such cases. This review is focussed on symptoms in accidental and nonaccidental injuries in children assisting haemostaseologists in decision making in cases of child protection issues.