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Backgroud: Rett syndrome is a neurodevelopmental disorder that affects 1 in 10,000 females. Various treatments have been explored; however, no effective treatments have been reported to date, except for trofinetide, a synthetic analog of glycine-proline-glutamic acid, which was approved by the FDA in 2023. Serological biomarkers that correlate with the disease status of RTT are needed to promote early diagnosis and to develop novel agents. Methods: In this study, we performed a high-depth proteomic analysis of extracellular vesicles containing preparations extracted from patient plasma samples to identify novel biomarkers. Results: We identified 33 upregulated and 17 downregulated candidate proteins among a total of 4273 proteins in RTT compared to the healthy controls. Among these, UBE3B was predominantly increased in patients with Rett syndrome and exhibited a strong correlation with the clinical severity score, indicating the severity of the disease. Conclusions: We demonstrated that the proteomics of high-depth extracellular vesicles containing preparations in rare diseases could be valuable in identifying new disease biomarkers and understanding their pathophysiology. [ABSTRACT FROM AUTHOR]

Simple Summary: Down syndrome (DS) is a genetic disorder caused by an additional partial or full copy of chromosome 21. Analysis of the brain's surface can potentially assist in providing a better understanding of structural brain differences, and may help characterize DS-specific brain development. We performed a study of 73 magnetic resonance imaging (MRI) examinations of DS patients (aged 1 day to 22 years) and compared them to a large cohort of 993 brain MRI examinations of neurotypical participants, aged 1 day to 32 years. A variety of measurements that characterize the surface of the brain were extracted from each brain region in each examination. Results demonstrate broad reductions in surface area and abnormalities of surface curvature measurements across the brain in DS. Findings suggest the presence of developmental abnormalities of the brain's surface in DS that can be characterized from clinical MRI examinations. Down syndrome (DS) is a genetic disorder characterized by intellectual disability whose etiology includes an additional partial or full copy of chromosome 21. Brain surface morphometry analyses can potentially assist in providing a better understanding of structural brain differences, and may help characterize DS-specific neurodevelopment. We performed a retrospective surface morphometry study of 73 magnetic resonance imaging (MRI) examinations of DS patients (aged 1 day to 22 years) and compared them to a large cohort of 993 brain MRI examinations of neurotypical participants, aged 1 day to 32 years. Surface curvature measurements, absolute surface area measurements, and surface areas as a percentage of total brain surface area (%TBSA) were extracted from each brain region in each examination. Results demonstrate broad reductions in surface area and abnormalities of surface curvature measurements across the brain in DS. After adjusting our regional surface area measurements as %TBSA, abnormally increased presentation in DS relative to neurotypical controls was observed in the left precentral, bilateral entorhinal, left parahippocampal, and bilateral perirhinal cortices, as well as Brodmann's area 44 (left), and the right temporal pole. Findings suggest the presence of developmental abnormalities of regional %TBSA in DS that can be characterized from clinical MRI examinations. [ABSTRACT FROM AUTHOR]

The article focuses on the relationship between growth differentiation factor 15 (GDF15) levels and influenza encephalopathy. Topics include the pathophysiology of influenza encephalopathy, the potential role of GDF15 as a biomarker for acute encephalopathy, and a case where the GDF15 levels drastically dropped, correlating with a good outcome in a child.

Lissencephaly (LIS) is a rare neurodevelopmental disorder with severe symptoms caused by abnormal neuronal migration during cortical development. It is caused by both genetic and non-genetic factors. Despite frequent studies about the cortex, comprehensive elucidation of structural abnormalities and their effects on the white matter is limited. The main objective of this study is to analyze abnormal neuronal migration pathways and white matter fiber organization in LIS1-associated LIS using diffusion MRI (dMRI) tractography. For this purpose, slabs of brain specimens with LIS (n = 3) and age and sex-matched controls (n = 4) were scanned with 3T dMRI. Our high-resolution ex vivo dMRI successfully identified common abnormalities across the samples. The results revealed an abnormal increase in radially oriented subcortical fibers likely associated with radial migration pathways and u-fibers and a decrease in association fibers in all LIS specimens. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids (PUFAs) undergo lipid peroxidation and conversion into malondialdehyde (MDA). MDA reacts with acetaldehyde to form malondialdehyde-modified low-density lipoprotein (MDA-LDL). We studied unsettled issues in the association between MDA-LDL and the pathophysiology of ASD in 18 individuals with autism spectrum disorders (ASD) and eight age-matched controls. Social behaviors were assessed using the social responsiveness scale (SRS). To overcome the problem of using small samples, adaptive Lasso was used to enhance the interpretability accuracy, and a coefficient of variation was used for variable selections. Plasma levels of the MDA-LDL levels (91.00 ± 16.70 vs. 74.50 ± 18.88) and the DHA/arachidonic acid (ARA) ratio (0.57 ± 0.16 vs. 0.37 ± 0.07) were significantly higher and the superoxide dismutase levels were significantly lower in the ASD group than those in the control group. Total SRS scores in the ASD group were significantly higher than those in the control group. The unbeneficial DHA/ARA ratio induced ferroptosis via lipid peroxidation. Multiple linear regression analysis and adaptive Lasso revealed an association of the DHA/ARA ratio with total SRS scores and increased MDA-LDL levels in plasma, resulting in neuronal deficiencies. This unbeneficial DHA/ARA-ratio-induced ferroptosis contributes to autistic social behaviors and is available for therapy. [ABSTRACT FROM AUTHOR]

Regional anatomical structures of the brain are intimately connected to functions corresponding to specific regions and the temporospatial pattern of genetic expression and their functions from the fetal period to old age. Therefore, quantitative brain morphometry has often been employed in neuroscience investigations, while controlling for the scanner effect of the scanner is a critical issue for ensuring accuracy in brain morphometric studies of rare orphan diseases due to the lack of normal reference values available for multicenter studies. This study aimed to provide across-site normal reference values of global and regional brain volumes for each sex and age group in children and adolescents. We collected magnetic resonance imaging (MRI) examinations of 846 neurotypical participants aged 6.0–17.9 years (339 male and 507 female participants) from 5 institutions comprising healthy volunteers or neurotypical patients without neurological disorders, neuropsychological disorders, or epilepsy. Regional-based analysis using the CIVET 2.1.0. pipeline provided regional brain volumes, and the measurements were across-site combined using ComBat-GAM harmonization. The normal reference values of global and regional brain volumes and lateral indices in our study could be helpful for evaluating the characteristics of the brain morphology of each individual in a clinical setting and investigating the brain morphology of ultra-rare diseases. [ABSTRACT FROM AUTHOR]

Cardio‐facio‐cutaneous syndrome (CFC) (OMIM 115150) is a congenital disease caused by constitutive activation of the Raf/MEK/ERK signaling cascade. Unlike aspects of morphological anomalies, metabolic functions related to the disease have garnered little attention. We present severe neuroglycopenic symptoms due to nonketotic hypoglycemia in two children with CFC (Case 1, a 4‐year‐old male with c.389A > G heterozygous variant in MAP2K1; Case 2, a 3‐year‐old male with c.770A > G heterozygous variant in BRAF). Case 1 exhibited a nonketotic hypoglycemic coma and clustered left‐hemispheric convulsions despite receiving infusion therapy, leading to severe sequelae with choreoathetosis. Brain magnetic resonance imaging of Case 1 showed T2‐elongation with restricted diffusion on the bilateral basal ganglia and thalamus, with the dominance of the right putamen. Case 2 presented a prolonged generalized seizure as an initial clinical symptom but fully recovered. The presence of growth hormone and cortisol deficiency was ruled out in both cases. Blood spots acylcarnitine profiles excluded the co‐occurrence of mitochondrial HMG‐CoA synthase deficiency and HMG‐CoA lyase deficiency. These cases demonstrate the potential vulnerability to nonketotic hypoglycemia, especially during lipid shortages. As children with CFC frequently have difficulties feeding, we suggest great attention should be paid to the potential risk of severe nonketotic hypoglycemia. [ABSTRACT FROM AUTHOR]

Proper brain development requires the precise coordination and orchestration of various molecular and cellular processes and dysregulation of these processes can lead to neurological diseases. In the past decades, post-transcriptional regulation of gene expression has been shown to contribute to various aspects of brain development and function in the central nervous system. MicroRNAs (miRNAs), short non-coding RNAs, are emerging as crucial players in post-transcriptional gene regulation in a variety of tissues, such as the nervous system. In recent years, miRNAs have been implicated in multiple aspects of brain development, including neurogenesis, migration, axon and dendrite formation, and synaptogenesis. Moreover, altered expression and dysregulation of miRNAs have been linked to neurodevelopmental and psychiatric disorders. Magnetic resonance imaging (MRI) is a powerful imaging technology to obtain high-quality, detailed structural and functional information from the brains of human and animal models in a non-invasive manner. Because the spatial expression patterns of miRNAs in the brain, unlike those of DNA and RNA, remain largely unknown, a whole-brain imaging approach using MRI may be useful in revealing biological and pathological information about the brain affected by miRNAs. In this review, we highlight recent advancements in the research of miRNA-mediated modulation of neuronal processes that are important for brain development and their involvement in disease pathogenesis. Also, we overview each MRI technique, and its technological considerations, and discuss the applications of MRI techniques in miRNA research. This review aims to link miRNA biological study with MRI analytical technology and deepen our understanding of how miRNAs impact brain development and pathology of neurological diseases. [ABSTRACT FROM AUTHOR]

Background and Purpose: Alexander disease (AxD) is a neurodegenerative disorder caused by heterozygous Glial Fibrillary Acidic Protein mutation. The characteristic structural findings of AxD, such as leukodystrophic features, are well known, while association fibers of AxD remain uninvestigated. The aim of this study was to explore global and subcortical fibers in four brains with AxD using ex vivo diffusion tractography METHODS: High-angular-resolution diffusion magnetic resonance imaging (HARDI) tractography and diffusion-tensor imaging (DTI) tractography were used to evaluate long and short association fibers and compared to histological findings in brain specimens obtained from four donors with AxD and two donors without neurological disorders RESULTS: AxD brains showed impairment of long association fibers, except for the arcuate fasciculus and cingulum bundle, and abnormal trajectories of the inferior longitudinal and fronto-occipital fasciculi on HARDI tractography and loss of multidirectionality in subcortical fibers on DTI tractography. In histological studies, AxD brains showed diffuse low density on Klüver-Barrera and neurofilament staining and sporadic Rosenthal fibers on hematoxylin and eosin staining CONCLUSIONS: This study describes the spatial distribution of degenerations of short and long association fibers in AxD brains using combined tractography and pathological findings. [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT) is a severe progressive neurodevelopmental disorder characterized by various neurological symptoms. Almost all RTT cases are caused by mutations in the X-linked methyl-CpG-binding protein 2 (MeCP2) gene, and several mouse models have been established to understand the disease. However, the neuroanatomical abnormalities in each brain region of RTT mouse models have not been fully understood. Here, we investigated the global and local neuroanatomy of the Mecp2 gene-deleted RTT model (Mecp2 -KO) mouse brain using T2-weighted 3D magnetic resonance imaging with different morphometry to clarify the brain structural abnormalities that are involved in the pathophysiology of RTT. We found a significant reduction in global and almost all local volumes in the brain of Mecp2 -KO mice. In addition, a detailed comparative analysis identified specific volume reductions in several brain regions in the Mecp2 -deficient brain. Our analysis also revealed that the Mecp2 -deficient brain shows changes in hemispheric asymmetry in several brain regions. These findings suggest that MeCP2 affects not only the whole-brain volume but also the region-specific brain structure. Our study provides a framework for neuroanatomical studies of a mouse model of RTT. [ABSTRACT FROM AUTHOR]

Congenital genetic disorders often present with neurological manifestations such as neurodevelopmental disorders, motor developmental retardation, epilepsy, and involuntary movement. Through qualitative morphometric evaluation of neuroimaging studies, remarkable structural abnormalities, such as lissencephaly, polymicrogyria, white matter lesions, and cortical tubers, have been identified in these disorders, while no structural abnormalities were identified in clinical settings in a large population. Recent advances in data analysis programs have led to significant progress in the quantitative analysis of anatomical structural magnetic resonance imaging (MRI) and diffusion-weighted MRI tractography, and these approaches have been used to investigate psychological and congenital genetic disorders. Evaluation of morphometric brain characteristics may contribute to the identification of neuroimaging biomarkers for early diagnosis and response evaluation in patients with congenital genetic diseases. This mini-review focuses on the methodologies and attempts employed to study Rett syndrome using quantitative structural brain MRI analyses, including voxel- and surface-based morphometry and diffusion-weighted MRI tractography. The mini-review aims to deepen our understanding of how neuroimaging studies are used to examine congenital genetic disorders. [ABSTRACT FROM AUTHOR]

Maternal tobacco smoke exposure during pregnancy impairs fetal body size, including head circumference (HC) at birth; however, the mechanism still remains unclear. This analysis using a large prospective cohort study evaluated the impact of maternal tobacco exposure on their offspring's HC and the relationship with placental weight ratio (PWR) and placental abnormalities. Parents-children pairs (n = 84,856) were included from the 104,065 records of the Japan Environmental and Children's Study. Maternal perinatal clinical and social information by self-administered questionnaires, offspring's body size, and placental information were collected. Data were analyzed with binominal logistic regression analysis and path analysis. Logistic regression showed significantly elevated adjusted odds ratio (aOR) (1.653, 95% CI 1.387–1.969) for the impact of maternal smoking during pregnancy on their offspring's smaller HC at birth. Maternal exposure to environmental tobacco smoke in the non-smoking group did not increase aOR for the smaller HC. Path analysis showed that maternal smoking during pregnancy decreased the offspring's HC directly, but not indirectly via PWR or placental abnormalities. The quitting smoking during pregnancy group did not increase aOR for the smaller HC than the non-smoking group, suggesting that quitting smoking may reduce their offspring's neurological impairment even after pregnancy. [ABSTRACT FROM AUTHOR]

Background: Nevoid basal cell carcinoma syndrome (NBCCS) is a neurocutaneous disease, characterized by tumorigenesis and developmental anomalies due to aberrant sonic hedgehog (Shh) signaling. Patients with NBCCS typically appear calm and carefree, suggesting that a specific personality in these patients may be associated with an enhanced hedgehog pathway. Our study aimed to determine the personality type in these patients. Methods: We enrolled 14 mentally normal patients with genetically confirmed NBCCS (seven males and seven females; mean age = 25.2 years) and 20 controls (10 males and 10 females; mean age = 27.9 years). The patients were assessed with the Japanese version of the Temperament and Character Inventory, based on the seven‐dimensional model of temperament and character, and their clinical symptoms were evaluated. The amygdala volumes of six patients with NBCCS were measured using magnetic resonance imaging with image‐processing software. Results: Patients with NBCCS scored significantly lower on harm avoidance (0.89) than controls (1.00; P = 0.0084). Moreover, patients with NBCCS and developmental malformations such as rib anomalies, who may have experienced Shh signaling enhancement from the prenatal period, scored significantly lower on harm avoidance (0.80 [P = 0.0031]). The left amygdala volume was also significantly reduced in patients with NBCCS (P = 0.0426). Conclusions: Patients with NBCCS who experienced increased Shh signaling from the prenatal period showed significantly lower harm avoidance related to serotonin. The left amygdala volume was significantly reduced in these patients. Our results indicate that Shh signaling may influence the human personality. [ABSTRACT FROM AUTHOR]

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12‐year‐old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1‐related disorders has not been reported so far. [ABSTRACT FROM AUTHOR]

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1‐weighted and 9 diffusion‐weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high‐angular resolution diffusion MRI (HARDI) tractography analyses. Mega‐corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto‐occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS. [ABSTRACT FROM AUTHOR]

Low-prevalence mosaicism of chromosome 18q distal deletion identified by exome-based copy number profiling in a child with cerebral hypomyelination Partial deletions of chromosome 18q distal lead to diverse congenital dysmorphic features such as hypomyelination short stature cleft lip and palate foot deformity and aural atresia.[1] In contrast mosaicism of 18q distal deletion is a rarer situation with a highly variable phenotype,[2] leading to clinical diagnostic challenges A Japanese female was born at term with no asphyxia. However, in the deletion interval, BAF showed four lines, suggesting that two types of heterozygous alleles (mosaic A or B allele deletion in the A/B heterozygous allele) were present in this region (Figure D). [Extracted from the article]

Dandy-Walker malformation (DWM) is a posterior fossa anomaly characterized by hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. The cyst of DWM rarely extends posteriorly to almost completely fill the entire posterior fossa, which mimics primary cerebellar agenesis, a cerebellar porencephalic cyst, and an arachnoid cyst due to the lack of clarity of the thin cystic wall. A 10-month-old female born at 23 weeks’ gestation with cerebellar hemorrhage in the neonatal period was admitted to our hospital with dysphagia and side-to-side head bobbing. The detection of hemosiderin deposits enveloping the cyst wall by T2 star-weighted angiography (SWAN) was useful for the differential diagnosis of an acquired form of DWM from primary cerebellar agenesis. Cyst fenestration successfully improved dysphagia and head bobbing. A pathological specimen of the perforated cyst consisted of collagen fibers with hemosiderin deposits but lacked congenital cyst components. In infants with posterior fossa cysts, SWAN will be useful for a differential diagnosis between DWM and primary cerebellar agenesis. [ABSTRACT FROM AUTHOR]

Brain morphology is tightly regulated by diverse signaling pathways. Hedgehog signaling is a candidate pathway considered responsible for regulating brain morphology. Nevoid basal cell carcinoma syndrome (NBCCS), caused by a PTCH1 mutation in the hedgehog signaling pathway, occasionally exhibits macrocephaly and medulloblastoma. Although cerebellar enlargement occurs in ptch1 heterozygous-deficient mice, its impact on human brain development remains unknown. We investigated the brain morphological characteristics of children with NBCCS. We evaluated brain T1-weighted images from nine children with NBCCS and 15 age-matched normal control (NC) children (mean [standard deviation], 12.2 [2.8] vs. 11.6 [2.3] years old). The diameters of the cerebrum, corpus callosum, and brain stem and the cerebellar volume were compared using two-tailed t-tests with Welch's correction. The transverse diameters (150.4 [9.9] vs. 136.0 [5.5] mm, P = 0.002) and longitudinal diameters (165.4 [8.0] vs. 151.3 [8.7] mm, P = 0.0007) of the cerebrum, cross-sectional area of the cerebellar vermis (18.7 [2.6] vs. 11.8 [1.7] cm2, P = 0.0001), and total volume of the cerebellar hemispheres (185.1 [13.0] vs. 131.9 [10.4] cm3, P = 0.0001) were significantly larger in the children with NBCCS than in NC children. Thinning of the corpus callosum and ventricular enlargement were also confirmed in children with NBCCS. We demonstrate that, on examination of the brain morphology, an increase in the size of the cerebrum, cerebellum, and cerebral ventricles is revealed in children with NBCCS compared to NC children. This suggests that constitutively active hedgehog signaling affects human brain morphology and the PI3K/AKT and RAS/MAPK pathways. [ABSTRACT FROM AUTHOR]

Williams syndrome is a contiguous gene deletion syndrome resulting from a heterozygous deletion on chromosome 7q11.23, and is characterized by distinctive facial features and supravalvular aortic stenosis (SVAS). This syndrome rarely presents unpredictable cardiac death, and yet, as illustrated in the present case, it is still not possible to predict it, even on close monitoring. We herein describe the case of a 6-year-old Japanese girl with Williams syndrome, who had sudden cardiac collapse due to cardiac infarction after pharyngitis. Cardiac failure followed a critical course that did not respond to catecholamine support or heart rest with extracardiac mechanical support. Although marked coronary stenosis was not present, the left coronary cusp abnormally adhered to the aortic wall, which may synergistically cause coronary ostium occlusion with SVAS. Altered hemodynamic state, even that caused by the common cold, may lead to critical myocardial events in Williams syndrome with SVAS. [ABSTRACT FROM AUTHOR]

Constitutional 11q interstitial deletion syndrome presents with congenital anomalies including microcephaly with craniostenosis, minor dysmorphic features, vitreoretinopathy, and renal anomalies. This syndrome is occasionally associated with neuroblastoma (NB) as a life-threatening complication, which is important for clinical care. Although the corresponding locus to NB has been predicted to exist in 11q22-23 by previous deletion studies related to NB, the causative haploinsufficient genes have not yet been identified. We herein reported for the first time the simultaneous coexistence of adrenal NB and abdominal prevertebral ganglioneuroma in a 6-year-old girl with a constitutional hemizygous 11q14.1-23.3 deletion. Of the 11 haploinsufficient genes predicted with an in silico database, we focused on NCAM1 and CADM1 as the genes accountable for NB and ganglioneuroma. The deletion range, especially the 11q22.3 involvement, needs to be determined in 11q deletion cases in order to predict susceptibility to peripheral nerve tumors involving NB and ganglioneuroma. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT: Pallister‐Killian syndrome (PKS) is rare genetic disorder caused by tetrasomy 12p mosaicism with supernumerary isochromosome 12p that manifests with intellectual disability, craniofacial dysmorphism, and epilepsy. Although PKS presents as a multisystem morphological defect, respiratory system involvement is rare, except for diaphragmatic hernia. We are the first to report a case of PKS with progressive subglottic stenosis. Subglottic stenosis is a potentially lethal condition due to severe respiratory obstruction and difficult intubation; therefore, further accumulation of cases is required to assess the causal link between PKS and subglottic stenosis. [ABSTRACT FROM AUTHOR]

Oxidative stress has been progressively recognised as a key player in the development of osteoporosis. Although oxidative stress induces osteoporosis partly through inhibition of hedgehog signalling, the details of the signal interaction remain unclear. To elucidate this mechanism, we investigated osteoblast differentiation in C3H10T1/2 cells, murine embryonic mesenchymal cells, with recombinant sonic hedgehog (shh) in the presence or absence of hydrogen peroxide, and examined Gli transcriptional activity, with a focus on the interaction with mitogen-activated protein kinases (MAPKs) as possible mediators. The transcription of Gli1, Ptch1b, Alp and Bsp was facilitated by shh and strongly inhibited by oxidative stress with the hydrogen peroxide treatment; however, the other Gli isoforms, Bmp2, Runx2 and Osx, were unaffected. Oxidative stress also facilitated the phosphorylation of JNK1 and p38. Anisomycin treatment as a JNK activator or transient overexpression of the constitutive JNK1 active form inhibited hedgehog activity. Interestingly, the inhibitory effect of hydrogen peroxide on hedgehog signalling was blocked by a JNK inhibitor, but not by a p38 inhibitor. Osteoblast differentiation determined by calcium staining was, in part, rescued from oxidative stress by the JNK inhibitor. These findings suggest that oxidative stress inhibits hedgehog signalling and subsequent osteoblast differentiation through an interaction between phospho-JNK1 and GLI1. [ABSTRACT FROM AUTHOR]

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1, encoding a receptor for the secreted protein, sonic hedgehog. Recently, a Chinese family with NBCCS carrying a missense mutation in PTCH2, a close homolog of PTCH1, was reported. However, the pathological significance of missense mutations should be discussed cautiously. Here, we report a 13-year-old girl diagnosed with NBCCS based on multiple keratocystic odontogenic tumors and rib anomalies carrying a frameshift mutation in the PTCH2 gene (c.1172_1173delCT). Considering the deleterious nature of the frameshift mutation, our study further confirmed a causative role for the PTCH2 mutation in NBCCS. The absence of typical phenotypes in this case such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism and coarse face, together with previously reported cases, suggested that individuals with NBCCS carrying a PTCH2 mutation may have a milder phenotype than those with a PTCH1 mutation. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to investigate the efficacy of i.v. immune globulin (IVIG) therapy combined with corticosteroids for additional treatment of acute Kawasaki disease (KD) unresponsive to initial IVIG treatment. Methods: In 50 prospective KD patients, six IVIG non-responders without clinical improvement within 24-48 h after completion of initial IVIG, received 2 g/kg IVIG concurrently with 2 mg/kg i.v. prednisolone sodium succinate (PSL) until normalization of C-reactive protein level. Treatment was then changed to oral PSL, which was tapered over time. Clinical and coronary artery lesion (CAL) outcomes were compared with those of 13 IVIG non-responders who received additional heterogeneous therapies in 125 retrospective KD patients. In addition, the scoring system of Kobayashi et al. for prediction of non-responsiveness to initial IVIG treatment was retrospectively verified in 175 KD subjects, consisting of 50 prospective and 125 retrospective patients in order to evaluate the efficacy of the re-treatment regimen. Results: Incidence of CAL in the study patients was lower than in the control patients, although differences were not significant both in the acute stage (within 1 month: 1/6, 16.7% vs 7/13, 53.8%; P= 0.177) and in the convalescent stage (after 1 month: 0/6, 0.0% vs 4/13, 30.8%; P= 0.255). According to the non-responder prediction system, the scores of six study and 13 control patients before initial IVIG treatment were similar (7.2 ± 1.9 vs 5.3 ± 3.1; P= 0.200). No serious adverse effects related to each treatment were noted in patients of either group. Conclusions: Additional IVIG combined with concurrent PSL appears to be safe and worth evaluation for the treatment of acute KD unresponsive to initial IVIG treatment. [ABSTRACT FROM AUTHOR]

Enterovirus focal encephalitis is a rare clinical entity that is characterized by focal neurological signs including seizure, hemiparesis, hemichorea, and headache, which are mainly followed by rapid spontaneous improvement. We herein describe the case of a 9-month-old boy who developed Coxsackie virus B5 (CVB5) focal encephalitis with seizure clusters in the eruption stage of roseola infantum-like illness, which were followed by rapid improvement and benign outcome. Lumbar puncture indicated pleocytosis, and CVB5 infection in the cerebrospinal fluid was subsequently identified on genome sequencing and virus isolation. Magnetic resonance imaging and electroencephalography showed no abnormal findings at the acute stage or on 2 month follow up. Although the pathogenesis of enterovirus focal encephalitis currently remains unclear, the pure synchronism of seizure cluster and eruption in this case suggests the involvement of local vascular impairment as the underlying pathogenesis. [ABSTRACT FROM AUTHOR]

Langerhans cell histiocytosis ( LCH) is a rare proliferative disease accompanied by the accumulation of pathological Langerhans cells, which often spreads into multi-site and multi-organ systems. We here describe a girl with a history of Kawasaki disease and cervical lymphadenopathy who presented with occipital LCH. Adrenal tumor was detected on staging evaluation of LCH and was diagnosed as neuroblastoma on resection using laparoscopic surgery. Neither tumor relapsed following chemotherapy for LCH and resection of neuroblastoma. Although LCH often spreads into multi-organ lesions, invasive biopsy may be needed for tumors with atypical localization for LCH in consideration of the synchronous occurrence of malignancies. [ABSTRACT FROM AUTHOR]

The article presents case study of a 3-year-old girl who was diagnosed with acute myelitis associated with human herpesvirus 7 infection (HHV-7). Topics discussed include identification of HHV-7 upon use of polymerase chain reaction (PCR); use of intravenous (i.v.) immunoglobulin and methylprednisolone for treatment of the patient; and observation of HHV-7 related neurological disorders in patients with compromised immune systems.

The article focuses on intussusception and spontaneous ileal perforation in Henoch-Schönlein purpura (HSP) in children. The authors presented a case report describing a child with HSP who needed repeated emergency laprotomy for interssusception that occurred during the course of corticosteroid therapy. HSP is characterized by IgA-dominant deposition of immune complexes in the walls of small vessels and is also the common cause of non-thrombocytopenic purpura particularly in children.

Whole-exome sequencing (WES) is a useful method to identify disease-causing mutations, however, often no candidate mutations are identified using commonly available targeted probe sets. In a recent analysis, we also could not find candidate mutations for 20.9% (9/43) of our pedigrees with congenital neurological disorder using pre-designed capture probes (SureSelect V4 or V5). One possible cause for this lack of candidates is that standard WES cannot sequence all protein-coding sequences (CDS) due to capture probe design and regions of low coverage, which account for approximately 10% of all CDS regions. In this study, we combined a selective circularization-based target enrichment method (HaloPlex) with a hybrid capture method (SureSelect V5; WES), and achieved a more complete coverage of CDS regions (~97% of all CDS). We applied this approach to 7 (SureSelect V5) out of 9 pedigrees with no candidates through standard WES analysis and identified novel pathogenic mutations in one pedigree. The application of this effective combination of targeted enrichment methodologies can be expected to aid in the identification of novel pathogenic mutations previously missed by standard WES analysis. [ABSTRACT FROM AUTHOR]