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.

Childhood primary large vessel CNS vasculitis: single-centre experience and review of the literature.

Ischaemic brain injuries are rare conditions in the paediatric age group. Main causes include non-arteriosclerotic arteriopathies, which in childhood usually result from primary vasculitis of large or small vessels and lead to impaired perfusion and subsequent ischaemic brain lesions. In accordance with the nomenclature of systemic forms, CNS vasculitis is subdivided into groups, based on the size of affected vessels: angiography-positive primary angiitis of medium-sized and large vessels (pPACNS), and angiography-negative angiitis of small vessels (svPACNS). We report the clinical presentation, diagnostic approach, and therapy of four children with progressive pPACNS. Patients were treated with high-dose corticosteroids and anticoagulation with unfractionated heparin in the acute phase, followed by immune modulatory treatment with mycophenolate mofetil (MMF) and dual antiplatelet therapy with acetylsalicylic acid and clopidogrel. In this manuscript, we illustrate the experience gained in our hospital, resulting in significantly faster diagnosis and treatment initiation, and discuss the applied immune modulating treatment regimen in the context of the literature. Based on our observations, we conclude that immune modulating therapy with initial high-dose corticosteroids, followed by steroid-sparing maintenance treatment with MMF, may be safe and effective in childhood progressive pPACNS.

Novel Mutation in the DKC1 Gene: Neonatal Hoyeraal-Hreidarsson Syndrome As a Rare Differential Diagnosis in Pontocerebellar Hypoplasia, Primary Microcephaly, and Progressive Bone Marrow Failure.

Primary microcephaly and severe developmental delay are complex but unspecific signs pointing to various genetic or acquired diseases. A concomitant finding of hematological failure may lead to the differential diagnosis of rare genetic diseases such as chromosome breakage disorders or diseases associated with telomere dysfunction. X-linked Hoyeraal-Hreidarsson syndrome (HHS) is a rare heterogenic disorder characterized by severe neurological impairment and progressive bone marrow failure. The latter represents the main cause of mortality, usually in early childhood. We report on the clinical course of an infant with HHS due to a novel mutation in the DKC1 gene and the particular finding of pontocerebellar hypoplasia.

Safety of gadobutrol in more than 1,000 pediatric patients: subanalysis of the GARDIAN study, a global multicenter prospective non-interventional study.

BACKGROUND: Gadobutrol is a gadolinium-based contrast agent, uniquely formulated at 1.0 mmol/ml. Although there is extensive safety evidence on the use of gadobutrol in adults, few studies have addressed the safety and tolerability of gadobutrol in pediatric patients. OBJECTIVE: This subanalysis of data from the GARDIAN study evaluated the safety and use of gadobutrol in pediatric patients (age <18 years). MATERIALS AND METHODS: The GARDIAN study was a large phase IV non-interventional prospective multicenter post-authorization safety study performed in Europe, Asia, North America and Africa. A total of 23,708 patients were included who were scheduled to undergo cranial or spinal MRI, liver or kidney MRI, or MR angiography with gadobutrol enhancement. The primary study endpoint was the overall incidence of adverse drug reactions (ADRs) and serious adverse events (SAEs) following gadobutrol administration. RESULTS: The GARDIAN study included 1,142 children (age <18 years) who received gadobutrol at a mean dose of 0.13 (range 0.04-0.50) mmol/kg body weight. Gadobutrol was well tolerated in these children, with low rates of ADRs (0.5%) and no SAEs, consistent with results in adults enrolled in the GARDIAN study. Rates of adverse events and ADRs were unrelated to pediatric age or gadobutrol weight-adjusted dose. There were no symptoms suggestive of nephrogenic systemic fibrosis. Investigators rated the contrast quality of gadobutrol-enhanced images as good or excellent in 97.8% of pediatric patients, similar to the main study population. CONCLUSION: Gadobutrol is very well tolerated and provides excellent contrast quality at the recommended weight-adjusted dose in children (age <18 years), similar to the profile in adults.

A five year-old child with clear cell petro-clival meningioma: case report with clinical and histopathological long-term follow-up.

BACKGROUND: Only a few cases have been previously published about clear cell meningiomas in children, the majority of them in the location of the spine. We describe an unusual case of clear cell meningioma occurring at the petro-clival region in a 5-year-old child. We further seek to determine the impact of several growth factors as well as the AKT1 mutation on the tumor growth pattern. CASE PRESENTATION: A five-year-old girl was presented with a one-week history of cephalgia, ataxia, and left sided torticollis. Magnetic resonance imaging (MRI) revealed a dumbbell-shaped homogeneously petro-clival gadolinium-enhancing mass. A staged operative approach was chosen, and a complete removal of the tumor was achieved. Due to recurrent tumor progression, the child underwent several tumor surgeries and two cranial radiations. None of the treatments were able to stop tumor progression. Consequently, the child died at the age of 14 after further extensive intracranial and extracranial tumor progression. The initial histological examination revealed a clear cell meningioma WHO grade II with an MIB-1 labeling index of <1%, which gradually increased with every recurrence up to 10% by the last progression at the age of 13 years. Analogically, an increasing overexpression of epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor (PDGFR), and the vascular endothelial growth factor receptor (VEGFR) was observed with each recurrence. The AKT1 (E17K) mutation in the tumor was not detectable in all investigated specimens. CONCLUSION: Pediatric clear cell meningiomas WHO grade II are very rare. Our data demonstrate the progressive overexpression of EGF-, PDGF-, and VEGF-receptors in each recurrence, providing one of these receptors as targeted therapy in such cases. Further evaluation of these growth factors in clear cell meningioma is required to establish the optimal treatment of these aggressive tumors.

[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.

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.

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.

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.

Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA.

Replication of human cytomegalovirus (CMV) requires the expression of the viral mitochondria-localized inhibitor of apoptosis (vMIA). vMIA inhibits apoptosis by recruiting Bax to mitochondria, resulting in its neutralization. We show that vMIA decreases cell size, reduces actin polymerization, and induces cell rounding. As compared with vMIA-expressing CMV, vMIA-deficient CMV, which replicates in fibroblasts expressing the adenoviral apoptosis suppressor E1B19K, induces less cytopathic effects. These vMIA effects can be separated from its cell death-inhibitory function because vMIA modulates cellular morphology in Bax-deficient cells. Expression of vMIA coincided with a reduction in the cellular adenosine triphosphate (ATP) level. vMIA selectively inhibited one component of the ATP synthasome, namely, the mitochondrial phosphate carrier. Exposure of cells to inhibitors of oxidative phosphorylation produced similar effects, such as an ATP level reduced by 30%, smaller cell size, and deficient actin polymerization. Similarly, knockdown of the phosphate carrier reduced cell size. Our data suggest that the cytopathic effect of CMV can be explained by vMIA effects on mitochondrial bioenergetics.

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 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.

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.

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.

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).

Importance of covalent and noncovalent SUMO interactions with the major human cytomegalovirus transactivator IE2p86 for viral infection.

The major transactivator protein IE2p86 of human cytomegalovirus (HCMV) has previously been shown to undergo posttranslational modification by the covalent attachment of SUMO proteins, termed SUMOylation, which occurs at two lysine residues located at amino acid positions 175 and 180. Mutation of the acceptor lysines resulted in the abrogation of IE2p86 SUMOylation in mammalian cells and a strong reduction of IE2p86-mediated transactivation. In this paper, we identify an additional SUMO interaction motif (SIM) within IE2p86, which mediates noncovalent binding to SUMO, as shown by yeast two-hybrid analyses. Transient-expression experiments revealed that an IE2p86 SIM mutant exhibited significantly reduced SUMOylation, strongly suggesting that noncovalent SUMO interactions affect the efficacy of covalent SUMO coupling. In order to define the relevance of IE2p86 SUMO interactions for viral replication, recombinant viruses originating from two different HCMV strains (AD169 and VR1814) were generated. Analysis of viruses expressing SUMOylation-negative IE2p86 revealed strongly impaired replication due to reduced viral DNA and protein accumulation, as well as diminished initiation of immediate-early gene expression. The additional introduction of the SIM mutation into the viral genome did not further compromise viral replication but resulted in altered expression of viral proteins at late times postinfection. In summary, this paper clearly shows that IE2p86 SUMOylation is necessary for efficient replication of the HCMV laboratory strain AD169 and the clinical isolate VR1814 and thus for the in vivo function of this viral transcription factor.