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In addition to surgical management, corticosteroids have proven to be beneficial in the management of acute symptoms related to CNS tumors, and have been widely used for many decades, with dexamethasone (DM) representing the most commonly used agent. However, lately published in vitro data possibly indicates a DM-induced suppression of oncogene-induced senescence (OIS) in a preclinical pediatric low-grade glioma (pLGG) model, which, alongside data associating perioperative DM treatment with reduced event-free survival in adult glioma, raises questions concerning the safety of DM treatment in pLGG. A total of 172 patients with pLGG were retrospectively analyzed concerning the impact of perioperative DM application on postoperative short- and long-term tumor growth velocity and progression-free survival (PFS). Three-dimensional volumetric analyses of sequential MRI follow-up examinations were used for assessment of tumor growth behavior. Mean follow-up period accounted for 60.1 months. Sixty-five patients (45%) were perioperatively treated with DM in commonly used doses. Five-year PFS accounted for 93% following gross-total resection (GTR) and 57% post incomplete resection (IR). Comparison of short- and long-term postoperative tumor growth rates in patients with vs without perioperative DM application showed no significant difference (short-term: 0.022 vs 0.023 cm

Purpose Despite excellent long-term overall survival rates, pediatric low-grade gliomas (pLGG) show high variety of clinical behavior regarding progress or senescence post incomplete resection (IR). This study retrospectively analyzes tumor growth velocity (TGV) of pLGG before surgery and after IR to investigate the impact of surgical extent, tumor location and molecular BRAF status on postoperative residual tumor growth behavior. Methods Of a total of 172 patients with pLGG receiving surgical treatment, 107 underwent IR (66%). Fifty-three vs 94 patients could be included in the pre- and post-operative cohort, respectively, and were observed over a mean follow-up time of 40.2 vs 60.1 months. Sequential three-dimensional MRI-based tumor volumetry of a total of 407 MRI scans was performed to calculate pre- and postoperative TGV. Results Mean preoperative TGV of 0.264 cm3/month showed significant deceleration of tumor growth to 0.085 cm3/month, 0.024 cm3/month and −0.016 cm3/month after 1st, 2nd, and 3rd IR, respectively (p 2.03 cm3 associated with a higher risk of progress post IR (sensitivity 78,6%, specificity 76.3%, AUC 0.88). Postoperative TGV of BRAF V600E-mutant LGG was significantly higher than of BRAF wild-type LGG (0.123 cm3/month vs. 0.016 cm3/month, p = 0.047). Conclusion This data suggests that extensive surgical resection may impact pediatric LGG growth kinetics post incomplete resection by inducing a significant deceleration of tumor growth. BRAF-V600E mutation may be a risk factor for higher postoperative TGV.

Most individuals with rare diseases initially consult their primary care physician. For a subset of rare diseases, efficient diagnostic pathways are available. However, ultra-rare diseases often require both expert clinical knowledge and comprehensive genetic diagnostics, which poses structural challenges for public healthcare systems. To address these challenges within Germany, a novel structured diagnostic concept, based on multidisciplinary expertise at established university hospital centers for rare diseases (CRDs), was evaluated in the three year prospective study TRANSLATE NAMSE. A key goal of TRANSLATE NAMSE was to assess the clinical value of exome sequencing (ES) in the ultra-rare disease population. The aims of the present study were to perform a systematic investigation of the phenotypic and molecular genetic data of TRANSLATE NAMSE patients who had undergone ES in order to determine the yield of both ultra-rare diagnoses and novel gene-disease associations; and determine whether the complementary use of machine learning and artificial intelligence (AI) tools improved diagnostic effectiveness and efficiency.ES was performed for 1,577 patients (268 adult and 1,309 pediatric). Molecular genetic diagnoses were established in 499 patients (74 adult and 425 pediatric). A total of 370 distinct molecular genetic causes were established. The majority of these concerned known disorders, most of which were ultra-rare. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were delineated, mainly in individuals with neurodevelopmental disorders.To determine the likelihood that ES will lead to a molecular diagnosis in a given patient, based on the respective clinical features only, we developed a statistical framework called YieldPred. The genetic data of a subcohort of 224 individuals that also gave consent to the computer-assisted analysis of their facial images were processed with the AI tool Prioritization of Exome Data by Image Analysis (PEDIA) and showed superior performance in variant prioritization.The present analyses demonstrated that the novel structured diagnostic concept facilitated the identification of ultra-rare genetic disorders and novel gene-disease associations on a national level and that the machine learning and AI tools improved diagnostic effectiveness and efficiency for ultra-rare genetic disorders.

Chronic pleural cerebrospinal fluid (CSF) effusion is a rare complication after ventriculoperitoneal (VP) shunt insertion and only 18 cases in children and adults have been described so far without catheter dislocation to the intrathoracic cavity. We report on a 4-year-old girl with a complex history of underlying neurogenetic disorder, a hypoxic ischemic encephalopathy after influenza A Infection with septic shock and severe acute respiratory distress syndrome, followed by meningitis at the age of 10 months. In consequence she developed a severe cerebral atrophy and postmeningitic hydrocephalus requiring placement of a VP shunt. At age 4 she was admitted with community acquired mycoplasma pneumonia and developed increasing pleural effusions leading to severe respiratory distress and requiring continuous chest tube drainage (up to 1000 -1400 ml/day), that could not be weaned. ß trace protein, in CSF present at concentrations > 6 mg/l, was found in the pleural fluid at low concentrations of 2.7 mg/l. An abdomino-thoracic CSF fistula was finally proven by single photon emission computerized tomography combined with low dose computer tomography. After shunt externalization, the pleural effusion stopped and the chest tube was removed. CSF production rate remain high above 500 ml/24h. An atrial CSF shunt could not be placed, since a hemodynamically relevant atrial septum defect with frail circulatory balance would not have tolerated the large CSF volumes. Therefore, she underwent a total bilateral endoscopic choroid plexus laser coagulation (CPC) within the lateral ventricles via bi-occipital burr holes. Postoperatively CSF production rate went close to 0 ml and after external ventricular drain removal no signs and symptoms of hydrocephalus developed during a follow-up of now 2.5 years. In summary, pleural effusions in patients with VP shunt can rarely be caused by an abdomino-thoracic fistula, with non-elevated ß trace protein in the pleural fluid. The majority of reported cases in literature were treated by ventriculo-atrial shunt. This is the 2nd reported case, which has been successfully treated by radical CPC alone including the temporal horn choroid plexus, making the child shunt independent.

ZusammenfassungSialorrhoe, ein unkontrollierter, übermäßiger Speichelfluss aus dem Mund und in den Schlund, tritt als Begleitsymptom bei verschiedenen, v. a. neurologischen Erkrankungen im Kindes- und Erwachsenenalter auf. Mit IncobotulinumtoxinA (Xeomin, IncoBoNT/A, Merz Pharmaceuticals GmbH) steht seit 2019 ein zugelassenes Medikament für die Behandlung der Sialorrhoe zur Verfügung. Indikationsstellung, mögliche Therapieziele, Praxis der Behandlung und Management in besonderen Behandlungssituationen bilden den Schwerpunkt dieser konsentierten Praxis-Empfehlungen, die in interdisziplinärer Zusammenarbeit erfahrener Anwender entwickelt wurden. Ziel ist, den Zugang zur Therapie zu erleichtern und einen Beitrag zu einer qualifizierten Botulinumtoxin-Therapie zu leisten.

BackgroundPatients carrying pathogenic variants inGNAO1often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype–phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations.MethodsTo improve understanding of the clinical course and pathophysiology of this ultra-rare disorder, we built up a registry forGNAO1patients in Germany. In this retrospective, multicentre cohort study, we collected detailed clinical data, treatment effects and genetic data for 25 affected patients.ResultsThe main clinical features were symptom onset within the first months of life, with central hypotonia or seizures. Within the first year of life, nearly all patients developed a movement disorder comprising dystonia (84%) and choreoathetosis (52%). Twelve (48%) patients suffered life-threatening hyperkinetic crises. Fifteen (60%) patients had epilepsy with poor treatment response. Two patients showed an atypical phenotype and seven novel pathogenic variants inGNAO1were identified. Nine (38%) patients were treated with bilateral deep brain stimulation of the globus pallidus internus. Deep brain stimulation reduced hyperkinetic symptoms and prevented further hyperkinetic crises. The in silico prediction programmes did not predict the phenotype by the genotype.ConclusionThe broad clinical spectrum and genetic findings expand the phenotypical spectrum ofGNAO1-associated disorder and therefore disprove the assumption that there are only two main phenotypes. No specific overall genotype–phenotype correlation was identified. We highlight deep brain stimulation as a useful treatment option in this disorder.

PURPOSE Missense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy (DEE) with early-onset seizures and severe intellectual disability. METHODS By international collaboration we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders (NDDs). By western blotting we investigated the consequences of missense variants in vitro. RESULTS In accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe DEE in 16 individuals. We now identified also de novo missense variants in the GTPase domain in six individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences.Furthermore, we observed bi-allelic splice-site and truncating variants in nine families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well. CONCLUSION By identifying phenotype-genotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying bi-allelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2 related disorders including both autosomal dominant and recessive NDDs.

Sialorrhea, uncontrolled, excessive drooling, accompanies different, mostly neurological disorders from childhood to adulthood. With incobotulinumtoxinA (Xeomin, IncoBoNT/A, Merz Pharmaceuticals GmbH), an approved medication for the treatment of sialorrhea has been available since 2019. Patient selection, possible therapy goals, treatment and the management of specific treatment situations build the focus of this interdisciplinary expert consensus recommendations with the intent to facilitate access to treatment and to contribute to qualified botulinum toxin therapy.Sialorrhoe, ein unkontrollierter, übermäßiger Speichelfluss aus dem Mund und in den Schlund, tritt als Begleitsymptom bei verschiedenen, v. a. neurologischen Erkrankungen im Kindes- und Erwachsenenalter auf. Mit IncobotulinumtoxinA (Xeomin, IncoBoNT/A, Merz Pharmaceuticals GmbH) steht seit 2019 ein zugelassenes Medikament für die Behandlung der Sialorrhoe zur Verfügung. Indikationsstellung, mögliche Therapieziele, Praxis der Behandlung und Management in besonderen Behandlungssituationen bilden den Schwerpunkt dieser konsentierten Praxis-Empfehlungen, die in interdisziplinärer Zusammenarbeit erfahrener Anwender entwickelt wurden. Ziel ist, den Zugang zur Therapie zu erleichtern und einen Beitrag zu einer qualifizierten Botulinumtoxin-Therapie zu leisten.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder primarily affecting the white matter of the nervous system that results from a deficiency of the arylsulfatase A (ARSA). Mesenchymal stem cells (MSCs) are able to secrete ARSA and have shown beneficial effects in MLD patients. In this retrospective analysis, 10 pediatric MLD patients [mesenchymal stem cell group (MSCG)] underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received two applications of 2 × 10

In hydrocephalic children, regular investigations of the ventricles are important for initial diagnosis and after initial treatment. Our recent study showed that changes of the third ventricle diameter (TVD) reliably reflect changes of the entire ventricular system at diagnosis and following initial therapy. This study compares changes of TVD with changes of ventricle indices at acute shunt failure and after shunt revision in hydrocephalic children. A total of 117 children with hydrocephalus were included in this study. MRI/CT images of 30 children were evaluated at the time of acute shunt dysfunction and after subsequent shunt revision. Measurements included axial TVD and three standard measures of lateral ventricles (Evans index, frontal occipital horn ratio (FOHR), and cella media index (CMI)). In 97 children, correlation between axial and coronal/diagonal TVD was evaluated at the time of initial diagnosis of hydrocephalus. At acute shunt dysfunction, the best linear correlation was found between TVD and CMI (r = 0.702, p

Over a relatively short period of time, the clinical geneticist’s “toolbox” has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe), the gene which encodes the nuclear envelope protein LEM domain-containing protein 2 (LEMD2). Despite different ages and ethnic backgrounds, both individuals share a progeria-like facial phenotype and a distinct combination of physical and neurologic anomalies, such as growth retardation; hypoplastic jaws crowded with multiple supernumerary, yet unerupted, teeth; and cerebellar intention tremor. Immunofluorescence analyses of patient fibroblasts revealed mutation-induced disturbance of nuclear architecture, recapitulating previously published data in LEMD2-deficient cell lines, and additional experiments suggested mislocalization of mutant LEMD2 protein within the nuclear lamina. Computational analysis of facial features with two different deep neural networks showed phenotypic proximity to other nuclear envelopathies. One of the algorithms, when trained to recognize syndromic similarity (rather than specific syndromes) in an unsupervised approach, clustered both individuals closely together, providing hypothesis-free hints for a common genetic etiology. We show that a recurrent de novo mutation in LEMD2 causes a nuclear envelopathy whose prognosis in adolescence is relatively good in comparison to that of classical Hutchinson-Gilford progeria syndrome, and we suggest that the application of artificial intelligence to the analysis of patient images can facilitate the discovery of new genetic disorders.

Despite the favourable outcome and excellent long-term overall survival rates, pediatric LGG show vast variety of clinical behavior and limited predictability regarding progress or senescence. We comparatively analyzed the tumor growth velocity (TGV) of PLGG post subtotal resection (STR) to investigate the impact of surgery, histological subtype, tumor location and the most frequent BRAF aberrations (BRAF V600E mutation vs KIAA1549-BRAF fusion) on tumor growth rates, aiming to identify potential variables to prognosticate further progress or senescence. A total of 53 patients vs 94 patients in the pre- and postoperative cohort, respectively, could be observed over a mean follow-up time of 40.2 vs 60.1 months. Distribution of histopathological diagnosis and tumor sites showed similarity to previously published cohort studies. Comparative analysis of pre- and postoperative TGV showed a significant difference as mean preoperative TGV accounted for 0.264 cm³/mo, while postoperative TGV after 1st, 2nd and 3rd STR showed reduction to 0.085 cm³/mo, 0.024 cm³/mo and -0.016 cm³/mo, respectively (p < 0.001). Results remained significant after excluding patients who had obtained (neo)adjuvant treatment. Resection extent showed remarkable correlation with postoperative reduction of TGV (R = 0.97, P < 0.001). Comparison of postoperative TGV of BRAF V600E mutant LGG and BRAF wild-type LGG showed significant difference of means (0.123 cm³/mo and 0.016 cm³/mo, p = 0.47), consistent to previous analyses, suggesting BRAF V600E positive LGG as a high-risk subgroup. Histological type, tumor location and BRAF-KIAA1549 fusion showed no significant impact on postoperative TGV. The results suggest that surgery, beyond cytoreductive purpose, impacts PLGG kinetics post STR by inducing a significant deceleration of tumor growth. As postoperative growth velocity showed clear correlation to resection extent and residual tumor burden, surgery, as radical as possible while preserving neurological function, appears to remain the mainstay of therapy besides advancing therapeutic approaches.

External hydrocephalus (eHC) is commonly defined as a subtype of infant “hydrocephalus” consisting of macrocepahly associated with enlarged subarachnoid space and no or mild ventriculomegaly. This status is thought to be related to impaired CSF absorption because of arachnoid villi immaturity. However, other factors like the venous system might be involved in the development of the clinical picture. All patients diagnosed with eHC received prospectively contrast-enhanced 3D MR phlebography. Venous sis abnormalities were graded depending on the number of affected sinus segments and type. External CSF space volume was quantified planimetrically. Seventeen patients with the typical clinical feature of eHC were included. In 15, venous sinus abnormalities were found. There was a significant correlation between the volume of the widened cortical subarachnoid space (CSAS) and the number of venous sinus segments affected. Conversely, ventricular volume was not correlated. These results support the hypothesis that impaired venous outflow plays a major role in external hydrocephalus development. Raised venous pressure increases intracranial pressure accelerating head growth, resulting in an enlargement of the cortical subarachnoid space. Increased venous pressure increases the capillary bed pressure and brain turgor preventing ventricular space to enlarge forcing displacement of ventricular CSF to the subarachnoid space. As a result, ventriculomegaly is rarely found. The descriptive term “external hydrocephalus” implying a primary etiology within the CSF system is misleading and this work supports the notion that venous hypertension is the leading cause of the clinical picture.

Qualitative, noninvasive assessment of intracranial pressure is of eminent importance in pediatric patients in many clinical situations and can reliably be performed using transorbital ultrasonographic measurement of the optic nerve sheath diameter (ONSD). MRI-based determination of ONSD can serve as an alternative if ultrasound (US) is not possible or available for various reasons, for example, in small, incompliant children. This study investigates repeatability and observer reliability of US ONSD and correlation and bias of US- versus MRI-based ONSD assessment in pediatric patients.One hundred fifty children diagnosed with tumor (n = 40), hydrocephalus (n = 42), and other cranial pathologies (n = 68) were included. Bilateral ONSD was quantified by US using a 12-MHz linear array transducer. This was compared with ONSD measured in simultaneously acquired (≤24 h) T2-weighted MRI scans of the orbit.Repeatability of individual US values and intraobserver ONSD was outstanding (Cronbach's α = 0.984 and 0.996, respectively). Overall mean values for ONSD were 5.8 ± 0.88 mm and 5.7 ± 0.89 mm for US and MRI, respectively. Correlation between US and MRI-based ONSD was strong (r = 0.976, P 0.01). Bland and Altman analysis showed a mean bias of 0.078 mm. A repeated-measures correlation (rRepeatability and reliability of US ONSD determination is excellent. In case US ONSD assessment is not possible or available, MRI scans can serve as an excellent alternative. The difference of US and MRI ONSD is minimal and insignificant, and thus, both techniques can complement each other.

Paediatric ventriculomegaly without obvious signs or symptoms of raised intracranial pressure (ICP) is often interpreted as resulting from either relative brain atrophy, arrested “benign” hydrocephalus, or “successful” endoscopic third ventriculostomy (ETV). We hypothesise that the typical ICP “signature” found in symptomatic hydrocephalus can be present in asymptomatic or oligosymptomatic children, indicating pressure-compensated, but active hydrocephalus. A total of 37 children fulfilling the mentioned criteria underwent computerised ICP overnight monitoring (ONM). Fifteen children had previous hydrocephalus treatment. ICP was analysed for nocturnal dynamics of ICP, ICP amplitudes (AMP), magnitude of slow waves (SLOW), and ICP/AMP correlation index RAP. Depending on the ONM results, children were either treated or observed. The ventricular width was determined at the time of ONM and at 1-year follow-up. The recordings of 14 children (group A) were considered normal. In the 23 children with pathologic recordings (group B), all ICP values and dependent variables (AMP, SLOW) were significantly higher, except for RAP. In group B, 12 of 15 children had received a pre-treatment and 11 of 22 without previous treatment. All group B children received treatment for hydrocephalus and showed a significant reduction of frontal-occipital horn ratio at 1 year. During follow-up, a positive neurological development was seen in 74% of children of group A and 100% of group B. Ventriculomegaly in the absence of signs and symptoms of raised ICP was associated in 62% of cases to pathological ICP dynamics. In 80% of pre-treated cases, ETV or shunt failure was found. Treating children with abnormal ICP dynamics resulted in an outcome at least as favourable as in the group with normal ICP dynamics. Thus, asymptomatic ventriculomegaly in children deserves further investigation and, if associated with abnormal ICP dynamics, should be treated in order to provide a normalised intracranial physiology as basis for best possible long-term outcome.

PURPOSE: This study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. METHODS: We compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts. RESULTS: In 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient-derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. CONCLUSION: Taken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.

ObjectiveTo compare disease progression between different onset forms of metachromatic leukodystrophy (MLD) and to investigate the influence of the type of first symptoms on the natural course and dynamic of disease progression.MethodsClinical, genetic, and biochemical parameters were analyzed within a nationwide study of patients with late-infantile (LI; onset age ≤2.5 years), early-juvenile (EJ; onset age 2.6 to ResultsNinety-seven patients with MLD were enrolled. Patients with LI (n = 35) and EJ (n = 18) MLD exhibited similarly rapid disease progression, all starting with motor symptoms (with or without additional cognitive symptoms). In LJ (n = 38) and adult-onset (n = 6) patients, the course of the disease was as rapid as in the early-onset forms, when motor symptoms were present at disease onset, while patients with only cognitive symptoms at disease onset exhibited significantly milder disease progression, independently of their age at onset. A certain genotype-phenotype correlation was observed.ConclusionsIn addition to age at onset, the type of first symptoms predicts the rate of disease progression in MLD. These findings are important for counseling and therapy.Classification of EvidenceThis study provides Class II evidence that in patients with MLD, age at onset and the type of first symptoms predict the rate of disease progression.

International audience; We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.

Introduction In a retrospective magnetic resonance imaging (MRI)-based study, we showed that changes of the third ventricle diameter (TVD) are a reliable mirror of changes of the entire ventricular system. The third ventricle is easily accessible in more than 90% of children and adults using ultrasound (US) via the transtemporal bone-window; thus it can be assessed quickly and free of radiation. In order to use transtemporal US determination of TVD instead of MRI/CT in clinical practice, it is important to know if there is a correlation and bias between both methods, which is addressed in this study. Materials and Method This prospective study investigates 122 children (newborn–18 years). Diagnoses encompassed hydrocephalus (50%), tumors (14.8%), and other intracranial pathologies (35.2%). US-based TVD was measured via the transtemporal bone-window using a phased array 1 to 4MHz transducer. Results were compared with TVD measured on simultaneously acquired axial T1-weighted axial MRI or computed tomography (CT) scans. Results Overall mean values for TVD were 6.56 ± 5.84 and 6.47 ± 5.64 mm for US and MRI, respectively. There was an outstanding correlation between TVD measured by MRI and US (r = 0.991, p Conclusion US- and MRI-based TVD measurements correlate excellently and measure almost identical TVD values. US-based TVD is in mean ∼0.096 mm larger than MRI-based TVD due to a more angulated measurement plane. US is equal to the gold-standard MRI, a fact, opening new avenues for US-based TVD as a first-line assessment tool of ventricular width.

A fibrolipomatous hamartoma (FLH) is a rare lesion leading to an enlargement of the affected nerve and commonly manifests at the median nerve. Symptomatic patients are mostly adolescents or adults. In children below 10 years, this entity is rather unknown and likely to be misdiagnosed. We report three children with FLH, two severely and one mildly symptomatic, all below 4 years of age at the time of first presentation. Two of three children were initially misdiagnosed. We provide a review of the pertinent clinical and radiological findings of the entity. Two patients had a characteristic macrodactyly. The two symptomatic children underwent surgical carpal tunnel decompression. The intervention relived their symptoms with a long-lasting effect. Surgical reduction of the hamartoma mass is not indicated and medical treatment non-existent.A symptomatic FLH of the median nerve is rare in children below the age of 5 years but has to be kept in mind as differential diagnosis in case of wrist and/or palm swelling, macrodactyly, and pain in hand or forearm. MRI is diagnostic, with very characteristic features, which can also be identified in high-resolution nerve ultrasound. This article aims to increase the knowledge about the entity including the diagnostic features and the management options. What is Known: • Fibrolipomatous hamartomas (FLHs) of the median nerve are rare, possibly associated with macrodactyly and tissue growth at the wrist and thenar side of the palm. • An associated carpal tunnel syndrome typically occurs, if at all, in adulthood. What is New: • We describe two children below 4 years with symptomatic carpal tunnel syndrome, experiencing a long-lasting favorable outcome after carpal tunnel decompression. In this age group, only one other child undergoing surgery has been published so far. • MRI and high-resolution ultrasound demonstrate the characteristic features of FLHs and are the diagnostic modalities of choice. Biopsy is not recommended.

Previous studies correlating ultrasound (US)-based optic nerve sheath diameter (ONSD) and intracranial pressure (ICP) in children were performed under general anesthesia. To apply ONSD in daily clinical routine, it is necessary to investigate patients awake. It is furthermore essential for ICP-assessment with ONSD to know if ONSD-ICP correlation varies within individuals. In this study, we report on the influence of wakefulness, method of ICP measurement, intraindividual correlations, and dynamic changes of ONSD and ICP after ICP decreasing therapy. The overall study included 72 children with a median age of 5.2 years. US ONSD determination was performed immediately prior to invasive ICP measurement, and the mean binocular ONSD was compared to ICP. In 10 children, a minimum of 3 ONSD/ICP measurements were performed to investigate a correlation within subjects. In 30 children, measurements were performed before and after therapy. Twenty-eight children were investigated awake with an excellent correlation of ONSD and ICP (r = 0.802, p

Interstitial deletions encompassing chromosome bands 1p32.1p32.3 are rare. Only nine unrelated patients with partially overlapping 1p32.1p32.3 deletions of variable size and position have been reported to date. We report on a 17-month-old boy with choanal atresia, hearing loss, urogenital anomalies, and microcephaly in whom an interstitial de novo deletion of 6.4 Mb was detected in 1p32.1p32.3 (genomic position chr1:54,668,618-61,113,264 according to GRCh37/hg19). The deleted region harbors 31 RefSeq genes. Notable genes in the region are PCSK9, haploinsufficiency of which caused low LDL cholesterol plasma levels in the patient, and DAB1, which is a candidate gene for cognitive deficits, microcephaly, and cerebral abnormalities such as ventriculomegaly and agenesis of the corpus callosum. Choanal atresia, microcephaly, and severe hearing loss were previously not known to be associated with 1p32 deletions. Our reported patient thus broadens the spectrum of clinical findings in this chromosome region and further facilitates genotype-phenotype correlations. Additional patients with overlapping deletions and/or point mutations in genes of this region need to be identified to elucidate the role of individual genes for the complex clinical manifestations. © 2015 Wiley Periodicals, Inc.

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205∗) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).

Background : Krabbe disease (KD) is an inherited leukodystrophy due to a defect in the GALC gene which encodes the lysosomal galactosylceramide β-galactosidase (GALC). About two thirds of patients show the early onset form of KD dominated by cerebral demyelination leading to death in early infancy. Late onset forms include a spectrum of late infantile, juvenile and adult clinical courses. The deficiency of GALC leads to a galactosylceramide lipidosis in which lysosomal storage phenomena are seen almost only at the ultrastructural level. Results : In a 4-year-old boy, the clinical suspicion of KD was high according to neurologic and neuroimaging findings. However, laboratory results were inconclusive; white blood cell GALC activity being at 23 to 25% of the normal level, and GALC genotyping revealing the new homozygous p.Ala543Pro variant which, ex silico, was of unclear significance. Studying a skin biopsy, cultured fibroblasts showed the GALC activity at 21 to 30% of the normal level; ultrastructurally, clearly KD-specific inclusions were seen in the eccrine sweat gland cells, confirming a KD diagnosis. Conclusion : The high clinical suspicion combined with the morphologic evidence for KD predict that the p.Ala543Pro variant is pathogenic for (late onset) KD. A hypothesis linked to the proline in the mutant GALC may explain the in vitro effect with high residual GALC activity. This patient would not have been correctly diagnosed, despite the strong clinical criteria of KD, if the electron microscopic results had not been available. The detailed knowledge of neurologic and neuroimaging signs is important in diagnostically problematic KD patients in which also an electron microscopic approach can be crucial.

Early postnatal infection with human cytomegalovirus (hCMV) may contribute to an adverse cognitive outcome in early preterm‐born children (PT). We here set out to explore whether long‐term neurobiological consequences of such an infection are detectable using fMRI in children and adolescents who were born very preterm and who either did (PT(hCMV+)) or did not (PT(hCMV−)) suffer from an early postnatal hCMV‐infection, when compared with typically developing healthy control (HC) subjects. Overall, data from 71 children and adolescents could be included, 34 PT (of which 15 were PT (hCMV) (+) and 19 were PT (hCMV−)) and 37 HC. Using a recently established “dual use” fMRI task, we investigated language and visuospatial functions. There were significant activation differences in the left hippocampus (PT > HC and PT(hCMV+) > HC), and in the right anterior cingulate cortex (PT(hCMV−) > PT(hCMV+)) when performing the language task. Surprisingly, only a small region in the occipital cortex showed a significant activation difference (HC > PT (HCMV−)) when performing the visuospatial task. Targeted analyses revealed differences in gray matter volume, but not density, in several brain regions. Our results suggest that long‐term neurobiological consequences of an early postnatal hCMV infection are detectable even in older children and adolescents formerly born very preterm, compatible with a higher effort when performing a cognitive task. This suggests that measures to prevent such an infection are warranted. Furthermore, an interrelation of brain structure and function was detected that may constitute a severe confound when using fMRI to compare structurally differing groups. Hum Brain Mapp 35:2594–2606, 2014. © 2013 Wiley Periodicals, Inc.

Contains fulltext : 167862.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. METHODS: Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. RESULTS: We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in

Background The contribution of growth parameters to the cognitive outcome of very low birth weight (VLBW)/very preterm (VP) infants is difficult to disentangle from other preterm-birth related factors. Aims We hypothesized that long-term cognitive and motor outcome of VLBW/VP infants is most strongly associated with growth in head circumference after hospital discharge. Study design Single-centre prospective longitudinal study: anthropometric measures at different time points (birth, discharge, school-age). Subjects 136 VLBW/VP infants ( Outcome measures Cognitive and motor function (Kaufman Assessment Battery for Children; Movement Assessment Battery for Children) at school-age (6.7–10.0years, mean=8.2). Results In hierarchical multiple regression analyses, growth from birth to discharge significantly predicted cognitive outcome (weight: R 2 change =0.063, p =0.014; length: R 2 change =0.078, p =0.007; HC: R 2 change =0.050, p =0.030), as well as weight gain ( R 2 change =0.096, p =0.001) and head growth ( R 2 change =0.134, p R 2 =0.151 to 0.605, all p ≤0.001), head growth after discharge was not ( R 2 =0.029, p =0.461). Conclusions Amongst all anthropometric measures, head growth between discharge and school-age is the best independent predictor for cognitive outcome in VLBW/VP infants. Determinants of head growth after discharge need further studies to identify targets for intervention.

Children born small for gestational age (SGA) are at risk for the metabolic syndrome (MetS) as adults. We examined whether indicators of MetS could be identified in pre-pubertal children born very preterm.Parameters associated with MetS were studied in 141 pre-pubertal schoolchildren with either very low birth weight (VLBW) or GA At 8.3±0.8 years, 36 children (SGA: n=15) were classified short. There were no differences between the SGA and appropriate for age (AGA) groups; nor were dissimilarities observed between short children and those with normal height for parameters such as body mass index (BMI), serum levels of hormones, HDL cholesterol, triglycerides, glucose, insulin, HOMA-IR, body composition, resting energy expenditure, grip strength and jump force.Neither SGA at birth nor short stature at follow-up (irrespective of size at birth), could be associated with parameters that indicate an increased risk for the MetS during childhood.

Background: Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are major causes of morbidity in infants with extremely low birth weight (ELBW). Objective: To evaluate the surgical procedures applied, and the survival and long-term outcome of ELBW infants with NEC and FIP in a single-center study. Methods: Inborn and outborn ELBW infants (Results: Out of 280 ELBW infants, 28 underwent surgery, 19 because of FIP and 9 for NEC. Fourteen infants in the FIP group were treated with primary laparotomy and 5 with peritoneal drainage (PD). In the NEC group, only 1 infant was treated with PD. PD was used for unstable patients and was always followed by secondary laparotomy after stabilization. Five of 28 (18%) surgically treated ELBW infants and 4 (14%) matched controls died. The following complications occurred in the surgical group: complete (n = 1) or minor wound dehiscence (n = 4), stoma prolapse (n = 5), parastomal hernia (n = 2), stoma fistula (n = 1), and wound infection (n = 2). Dependency on parenteral nutrition was significantly shorter in infants with FIP, while there were no differences in time to stoma closure and length of hospital stay between those with FIP and those with NEC. Eleven of 23 (47.8%) surviving patients with FIP or NEC showed developmental delay, compared with 9 of 24 (37.5%) in the controls. Conclusions: The management of EBLW infants with NEC and FIP remains challenging. Our treatment approach was associated with low mortality. Developmental delay seems to be caused by extreme prematurity rather than NEC- or FIP-related bowel perforation.

Aim: To investigate neurodevelopmental outcome and hearing in preterm children with breast milk transmitted human cytomegalovirus (HCMV) infection. Methods: Forty-one preterm children (born before 32 weeks of gestation or birth weight Results: In both groups, irrespective of the presence or absence of a history of HCMV infection, performance in assessments of cognitive and motor function was within the normal range. However, significant differences between the HCMV-positive and the HCMV-negative group were found in both motor and cognitive function, with poorer performance in the HCMV-positive group. There were no significant differences in anthropometric parameters, and all 20 HCMV-positive children had normal hearing function. Conclusions: In this study, cognitive and motor function in preterm children with early postnatally acquired HCMV infection transmitted via breast milk was within the normal range. However, the findings suggest that their outcome is poorer than outcome in preterm children without HCMV infection. These findings need to be replicated in larger scale studies.

Long-term follow-up data on preterm infants with breast milk-acquired postnatal cytomegalovirus (CMV) infection are sparse.To systematically evaluate the long-term cognitive outcome and prevalence of cerebral palsy (CP) in patients after postnatal CMV infection.All surviving infants1500 g born in our centre between 1 June 1995 and 1 June 2000, and with postnatal CMV infection acquired at up to 3 months of corrected age, were eligible for our study; this included neurological and neurocognitive assessment, using the Kaufman Assessment Battery for Children (K-ABC) at the age of4 years. A blinded and controlled matched-pairs design was used with gestational age, gender and date of birth as matching criteria.Of 50 eligible children, 42 (84%) could be tested. There was no difference in the prevalence of cerebral palsy. Following CMV infection during their hospital stay, infants had significantly lower results in the simultaneous processing scale of the K-ABC (p=0.029) after correction for additional risk factors like socioeconomic status (SES). Results for the sequential and achievement scales were only slightly reduced (p0.05).It seems possible that breast milk-acquired CMV infection has a detrimental influence on cognitive development of preterm infants.

Surgery in patients with neuromuscular scoliosis is associated with a higher rate of complications. It is still controversially discussed whether the patients truly benefit from deformity correction. The purpose of this study is to investigate if the quality of life has been improved and if the patients and their caregivers are satisfied with the results of surgery. This is a retrospective clinical outcome study of 46 patients with neuromuscular scoliosis which were treated with primary stable posterior pedicle screw instrumentation and correction. To achieve fusion only autologous bone was used. Follow up was minimum 2 years and maximum 5 years with an average of 36 months. The patients and/or their caregivers received a questionnaire based on the PEDI (pediatric disability inventory) and the GMFS (gross motor function score). The patients (and their caregivers) were also asked if the quality of life has improved after surgery. Only 32 of 46 patients answered the questionnaire. The answers showed a high approval-rate regarding the patients satisfaction with the surgery and the improvement of quality of life. The questionnaire could be answered from 1 (I do not agree) to 4 (I completely agree). The average agreement to the following statements was: i) the quality of life has improved: 3.35; ii) I am satisfied with surgery: 3.95; iii) the operation has fulfilled my expectations: 3.76. The average age at surgery was 12.7 years. The mean pre-operative cobb-angle of the main curve was 83.1° with a correction post-operatively to a mean of 36.9° and 42.6° at final follow-up. That is an average correction of 56.9%. Although spinal fusion in neuromuscular scoliosis is associated with a higher rate of complications our results show that the patients and their caregivers are satisfied with the operation and the quality of life has improved after surgery.

Objectives: To determine the frequency of KCNQ2 mutations in patients with neonatal epileptic encephalopathy (NEE), and to expand the phenotypic spectrum of KCNQ2 epileptic encephalopathy. Methods: Eighty-four patients with unexplained NEE were screened for KCNQ2 mutations using classic Sanger sequencing. Clinical data of 6 additional patients with KCNQ2 mutations detected by gene panel were collected. Detailed phenotyping was performed with particular attention to seizure frequency, cognitive outcome, and video-EEG. Results: In the cohort, we identified 9 different heterozygous de novo KCNQ2 missense mutations in 11 of 84 patients (13%). Two of 6 missense mutations detected by gene panel were recurrent and present in patients of the cohort. Seizures at onset typically consisted of tonic posturing often associated with focal clonic jerking, and were accompanied by apnea with desaturation. One patient diagnosed by gene panel had seizure onset at the age of 5 months. Based on seizure frequency at onset and cognitive outcome, we delineated 3 clinical subgroups, expanding the spectrum of KCNQ2 encephalopathy to patients with moderate intellectual disability and/or infrequent seizures at onset. Recurrent mutations lead to relatively homogenous phenotypes. One patient responded favorably to retigabine; 5 patients had a good response to carbamazepine. In 6 patients, seizures with bradycardia were recorded. One patient died of probable sudden unexpected death in epilepsy. Conclusion: KCNQ2 mutations cause approximately 13% of unexplained NEE. Patients present with a wide spectrum of severity and, although rare, infantile epilepsy onset is possible.

The name of the author Christian Thiel was rendered wrongly in the original publication but has since been corrected.