Prevalence and implications of microplastic contaminants in general human seminal fluid: A Raman spectroscopic study.

Microplastics are ubiquitous environmental contaminants that have been detected in human semen from polluted areas, yet their prevalence and effects in the general population remain largely unexplored. To examine microplastic presence, abundance, polymer types, and associations with semen quality parameters in individuals without occupational exposures, this study was conducted by collecting semen samples from 40 participants undergoing premarital health assessments in Jinan, China. Raman microspectroscopy was employed to identify, quantify, and categorize microplastic polymers, sperm motility was assessed via computer-assisted analysis, and morphology was evaluated through Diff-Quik staining. Correlations between demographics, semen parameters, and microplastic content were examined by statistical analysis. We found that microplastics were detected in all semen samples, with 2 particles per sample (ranging from 0.72 to 7.02 µm). Eight distinct polymers were identified, with polystyrene (31 %) being most prevalent. Semen exposed to polystyrene demonstrated higher sperm progressive motility as compared to polyvinyl chloride exposure group (43.52 ± 14.21 % vs 19.04 ± 13.46 %). Sperm morphological abnormalities were observed but not significantly associated with specific plastic types. In conclusion, this study reveals microplastic contamination in semen from individuals without occupational exposure, with PS, PE, and PVC being the most prevalent and exhibiting differential correlations with sperm progressive motility, and highlight the need for further research into the potential reproductive impacts of microplastic exposure.

Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing.

BACKGROUND: Trio-based whole-exome sequencing (trio-WES) enables identification of pathogenic variants, including copy-number variants (CNVs), in children with unexplained neurodevelopmental delay (NDD) and neurodevelopmental comorbidities (NDCs), including autism spectrum disorder (ASD), epilepsy, and attention deficit hyperactivity disorder. Further phenotypic and genetic analysis on trio-WES-tested NDD-NDCs cases may help to identify key phenotypic factors related to higher diagnostic yield of using trio-WES and novel risk genes associated with NDCs in clinical settings. METHODS: In this study, we retrospectively performed phenotypic analysis on 163 trio-WES-tested NDD-NDCs children to determine the phenotypic differences between genetically diagnosed and non-genetically diagnosed groups. Additionally, we conducted genetic analysis of ASD genes with the help of Simons Foundation for Autism Research Institute (SFARI) Gene database to identify novel possible ASD-risk genes underlying genetic NDD conditions. RESULTS: Among these 163 patients, pathogenic variants were identified in 82 cases (82/163, 50.3%), including 20 cases with CNVs. By comparing phenotypic variables between genetically diagnosed group (82 cases) and non-genetically diagnosed group (81 cases) with multivariate binary logistic regression analysis, we revealed that NDD-NDCs cases presenting with severe-profound NDD [53/82 vs 17/81, adjusted-OR (95%CI): 4.865 (2.213 - 10.694), adjusted-P < 0.001] or having multiple NDCs [26/82 vs 8/81, adjusted-OR (95%CI): 3.731 (1.399 - 9.950), adjusted-P = 0.009] or accompanying ASD [64/82 vs 35/81, adjusted-OR (95%CI): 3.256 (1.479 - 7.168), adjusted-P = 0.003] and head circumference abnormality [33/82 vs 11/81, adjusted-OR (95%CI): 2.788 (1.148 - 6.774), adjusted-P = 0.024] were more likely to have a genetic diagnosis using trio-WES. Moreover, 37 genes with monogenetic variants were identified in 48 patients genetically diagnosed with NDD-ASD, and 15 dosage-sensitive genes were identified in 16 individuals with NDD-ASD carrying CNVs. Most of those genes had been proven to be ASD-related genes. However, some of them (9 genes) were not proven sufficiently to correlate with ASD. By literature review and constructing protein-protein interaction networks among these 9 candidate ASD-risk genes and 102 established ASD genes obtained from the SFARI Gene database, we identified CUL4B, KCNH1, and PLA2G6 as novel possible ASD-risk genes underlying genetic NDD conditions. CONCLUSIONS: Trio-WES testing is recommended for patients with unexplained NDD-NDCs that have severe-profound NDD or multiple NDCs, particularly those with accompanying ASD and head circumference abnormality, as these independent factors may increase the likelihood of genetic diagnosis using trio-WES. Moreover, NDD patients with pathogenic variants in CUL4B, KCNH1 and PLA2G6 should be aware of potential risks of developing ASD during their disease courses.

Identification of a novel phenotype of external ear deformity related to Coffin-Siris syndrome-9 and literature review.

De novo germline variants of the SRY-related HMG-box 11 gene (SOX11) have been reported to cause Coffin-Siris syndrome-9 (CSS-9), a rare congenital disorder associated with multiple organ malformations, including ear anomalies. Previous clinical and animal studies have found that intragenic pathogenic variant or haploinsufficiency in the SOX11 gene could cause inner ear malformation, but no studies to date have documented the external ear malformation caused by SOX11 deficiency. Here, we reported a Chinese male with unilateral microtia and bilateral sensorineural deafness who showed CSS-like manifestations, including dysmorphic facial features, impaired neurodevelopment, and fingers/toes malformations. Using trio-based whole-exome sequencing, a de novo missense variant in SOX11 (NM_003108.4: c.347A>G, p.Y116C) was identified and classified as pathogenic variant as per American College of Medical Genetics guidelines. Moreover, a systematic search of the literature yielded 12 publications that provided data of 55 SOX11 intragenic variants affecting various protein-coding regions of SOX11 protein. By quantitatively analyzing phenotypic spectrum information related to these 56 SOX11 variants (including our case), we found variants affecting different regions of SOX11 protein (high-mobility group [HMG] domain and non-HMG regions) appear to influence the phenotypic spectrum of organ malformations in CSS-9; variants altering the HMG domain were more likely to cause the widest range of organ anomalies. In summary, this is the first report of CSS with external ear malformation caused by pathogenic variant in SOX11, indicating that the SOX11 gene may be not only essential for the development of the inner ear but also critical for the morphogenesis of the external ear. In addition, thorough clinical examination is recommended for patients who carry pathogenic SOX11 variants that affect the HMG domain, as these variants may cause the widest range of organ anomalies underlying this condition.

Silica-induced macrophage pyroptosis propels pulmonary fibrosis through coordinated activation of relaxin and osteoclast differentiation signaling to reprogram fibroblasts.

Silica nanoparticle (SiNP) exposure induces severe pulmonary inflammation and fibrosis, but the pathogenesis remains unclear, and effective therapies are currently lacking. To explore the mechanism underlying SiNPs-induced pulmonary fibrosis, we constructed in vivo silica exposure animal models and in vitro models of silica-induced macrophage pyroptosis and fibroblast transdifferentiation. We found that SiNP exposure elicits upregulation of pulmonary proteins associated with pyroptosis, including NLRP3, ASC, IL-1ß, and GSDMD, while the immunofluorescence staining co-localized NLRP3 and GSDMD with macrophage-specific biomarker F4/80 in silica-exposed lung tissues. However, the NLRP3 inhibitor MCC950 and classical anti-fibrosis drug pirfenidone (PFD) were found to be able to alleviate silica-induced collagen deposition in the lungs. In in vitro studies, we exposed the fibroblast to a conditioned medium from silica-induced pyroptotic macrophages and found enhanced expression of α-SMA, suggesting increased transdifferentiation of fibroblast to myofibroblast. In line with in vivo studies, the combined treatment of MCC950 and PFD was demonstrated to inhibit the expression of α-SMA and attenuate fibroblast transdifferentiation. Mechanistically, we adopted high throughput RNA sequencing on fibroblast with different treatments and found activated signaling of relaxin and osteoclast differentiation pathways, where the expression of the dysregulated genes in these two pathways was examined and found to be consistently altered both in vitro and in vivo. Collectively, our study demonstrates that SiNP exposure induces macrophage pyroptosis, which subsequently causes fibroblast transdifferentiation to myofibroblasts, in which the relaxin and osteoclast differentiation signaling pathways play crucial roles. These findings may provide valuable references for developing new therapies for pulmonary fibrosis.

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With the changes in various factors such as genetics and the environment, the incidence of childhood precocious puberty has been gradually increasing. Improving height is one of the key issues in the clinical management of precocious puberty. Currently, gonadotropin-releasing hormone analogs (GnRHa) remain the preferred treatment for precocious puberty, but their effect on height improvement is influenced by multiple factors, which may result in lower-than-expected height benefits. Combining recombinant human growth hormone (rhGH) therapy with GnRHa treatment is an alternative strategy to enhance the efficacy of GnRHa, but there is still no clear recommendation regarding the timing of their combination. Considering the current status of precocious puberty treatment, it is crucial to reevaluate the effects of GnRHa monotherapy and combination therapy with rhGH on height improvement. This article discusses strategies such as combination therapy indications to guide clinical medication and help children with precocious puberty achieve optimal height benefits.

Efficacy and safety of leuprorelin 3-month depot (11.25 mg) for idiopathic central precocious puberty treatment of Chinese girls: a single-center retrospective study.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of 3-month leuprorelin acetate (3-month LA, 11.25 mg) for the treatment of idiopathic central precocious puberty (ICPP) in Chinese girls. METHODS: We conducted a single-center retrospective study in China on 28 girls with ICPP who received at least one year of 3-month LA treatment. Data from anthropometry, biochemistry, bone age (BA), and pelvic ultrasonography were assessed before and every 6 months during medication. RESULTS: At CPP diagnosis, the mean chronological age (CA) was 7.8±0.8 years, with bone age advancement (BA-CA) of 1.5±0.8 years. After treatment initiation, growth velocity decreased significantly from 8.5±1.6 cm/year to 5.8±1.1 cm/year at month 12 (p<0.001). GnRH-stimulated peak LH ≤3IU/L, the primary efficacy criterion, was observed in 27 out of 28 (96.4 %) children at month 3. Basal estradiol <20 pg/mL was achieved by all 28 girls (100 %) at month 6 and remained stable at month 12. Basal follicle-stimulating hormone (FSH) decreased from 4.1±3.5 to 1.7±0.9 (p<0.001), and basal LH was also significantly reduced from 3.3±6.5 to 0.7±0.8 (p=0.035) at month 12. The mean predicted adult height (PAH) at treatment initiation was 152.7±5.8 cm, it increased significantly to 157.5±5.5 cm (p=0.007) after one-year treatment. Pubertal development was slowed in most patients, and in some cases, it was even reversed. Only one patient (3.6 %) reported local intolerance. CONCLUSIONS: Three-month leuprorelin acetate is a safe and effective treatment for suppressing the pituitary-gonadal axis and restoring impaired adult height in Chinese girls.

ARID2, a rare cause of Coffin-Siris syndrome: A novel microdeletion at 12q12q13.11 causing severe short stature and literature review.

Coffin-Siris syndrome (CSS) 6 is caused by heterozygous pathogenic variants in the AT-rich interaction domain 2 (ARID2) gene on 12q12. Currently, only 26 cases with both detailed clinical and genetic information have been documented in the literature. Microdeletions of the entire ARID2 gene are rare. In this study, we report a 5-year-7-month-old Chinese female who underwent whole-exome sequencing to discover that she had a de novo 1.563 Mb heterozygous copy number loss at 12q12q13.11, involving an entire deletion of ARID2. The female had severe short stature with obvious dysmorphic facial features, global developmental delay and hypoplastic fingers and toes. Her growth hormone level was normal, with reduced IGF-1 and increased CA19-9 levels. After a review of the 27 patients with ARID2 deficiency, a significant positive correlation was observed between age and height standard deviation score (SDS) (r = 0.71, p = 0.0002), suggesting a possibility of growth catch-up. This study expands the genetic and phenotypic spectrum of CCS6 and provides a decision-making reference for growth hormone therapy.

Long-term Pegylated GH for Children With GH Deficiency: A Large, Prospective, Real-world Study.

CONTEXT: The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited. OBJECTIVE: This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes. DESIGN: A prospective, observational, posttrial study (NCT03290235). SETTING, PARTICIPANTS AND INTERVENTION: Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to <0.2 mg/kg/wk (low-dose) PEG-rhGH for 30 months. MAIN OUTCOMES MEASURES: Height SD score (Ht SDS) at 12, 24, and 36 months. RESULTS: A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred. CONCLUSIONS: PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.

Description of the molecular and phenotypic spectrum in Chinese patients with aggrecan deficiency: Novel ACAN heterozygous variants in eight Chinese children and a review of the literature.

Objective: This study analyzed eight Chinese short stature children with aggrecan deficiency, and aimed to investigate potential genotype-phenotype correlations, differences in clinical characteristics between the Chinese and the Western populations, and effectiveness of recombinant human growth hormone therapy in patients with ACAN variants through a review of the literature. Methods: Pediatric short stature patients with ACAN heterozygous variants were identified using whole-exome sequencing. Subsequently, a literature review was carried out to summarize the clinical features, genetic findings, and efficacy of growth-promoting therapy in patients with ACAN variants. Results: We identified seven novel ACAN mutations and one recurrent variant. Patients in our center manifested with short stature (average height SDS: -3.30 ± 0.85) with slight dysmorphic characteristics. The prevalence of dysmorphic features in the Chinese populations is significantly lower than that in the Western populations. Meanwhile, only 24.24% of aggrecan-deficient Chinese children showed significantly advanced bone age (BA). Promising therapeutic benefits were seen in the patients who received growth-promoting treatment, with an increase in growth velocity from 4.52 ± 1.00 cm/year to 8.03 ± 1.16 cm/year. Conclusion: This study further expanded the variation spectrum of the ACAN gene and demonstrated that Chinese children with short stature who carried ACAN heterozygous variants exhibited early growth cessation, which may remain unnoticed by clinicians as most of these children had very mild dysmorphic characteristics and showed BA that was consistent with the chronological age. Genetic testing may help in the diagnosis.

Clinical application of artificial intelligence in longitudinal image analysis of bone age among GHD patients.

Objective: This study aims to explore the clinical value of artificial intelligence (AI)-assisted bone age assessment (BAA) among children with growth hormone deficiency (GHD). Methods: A total of 290 bone age (BA) radiographs were collected from 52 children who participated in the study at Sun Yat-sen Memorial Hospital between January 2016 and August 2017. Senior pediatric endocrinologists independently evaluated BA according to the China 05 (CH05) method, and their consistent results were regarded as the gold standard (GS). Meanwhile, two junior pediatric endocrinologists were asked to assessed BA both with and without assistance from the AI-based BA evaluation system. Six months later, around 20% of the images assessed by the junior pediatric endocrinologists were randomly selected to be re-evaluated with the same procedure half a year later. Root mean square error (RMSE), mean absolute error (MAE), accuracy, and Bland-Altman plots were used to compare differences in BA. The intra-class correlation coefficient (ICC) and one-way repeated ANOVA were used to assess inter- and intra-observer variabilities in BAA. A boxplot of BA evaluated by different raters during the course of treatment and a mixed linear model were used to illustrate inter-rater effect over time. Results: A total of 52 children with GHD were included, with mean chronological age and BA by GS of 6.64 ± 2.49 and 5.85 ± 2.30 years at baseline, respectively. After incorporating AI assistance, the performance of the junior pediatric endocrinologists improved (P < 0.001), with MAE and RMSE both decreased by more than 1.65 years (Rater 1: ΔMAE = 1.780, ΔRMSE = 1.655; Rater 2: ΔMAE = 1.794, ΔRMSE = 1.719), and accuracy increasing from approximately 10% to over 91%. The ICC also increased from 0.951 to 0.990. During GHD treatment (at baseline, 6-, 12-, 18-, and 24-months), the difference decreased sharply when AI was applied. Furthermore, a significant inter-rater effect (P = 0.002) also vanished upon AI involvement. Conclusion: AI-assisted interpretation of BA can improve accuracy and decrease variability in results among junior pediatric endocrinologists in longitudinal cohort studies, which shows potential for further clinical application.

Primary erythromelalgia mainly manifested by hypertensive crisis: A case report and literature review.

Background: Primary erythrocytic (PEM) is a rare autosomal dominant single gene disease. Most of the changes of gene loci can be found by whole exon gene sequencing, and the clinical symptoms and patient survival can be improved by specific site-to-site drug treatment. The other manifestations of this patient population are not remarkable. After the application of common drugs, the toxicity and side effects can be limiting. In addition to other common clinical manifestations, we found that the only unique manifestation of this patient was hypertensive crisis. Following multidisciplinary diagnosis and treatment (MDT), we decided to first control hypertension to alleviate the acute and critical patients. However, after controlling the hypertensive crisis, we unexpectedly found that the clinical symptoms of the patients had been significantly improved. Therefore, we concluded that the use of antihypertensive drugs can treat erythematous limb pain with the clinical manifestation of hypertensive crisis. Here, we describe a typical PEM disease, primary clinical features, diagnosis and treatment. Methods: Medical records of an 8-year-old boy with PEM were analyzed retrospectively, which included clinical characteristics, follow-up information, and SCN9A (Sodium Voltage-Gated Channel Alpha Subunit 9) gene analysis. Results: The 8-year-old boy had complained of abnormal paresthesia in his feet and ankles with burning sensation and pain for 2 years. The skin of both lower legs was red and underwent ichthyosis and lichenification. Genetic analysis confirmed the existence of a SCN9A gene mutation. The symptoms were gradually improved by treating with intravenous drip and oral administration of nitroglycerin to slow his heart rhythm. Conclusion: Primary erythrocytic is characterized by skin ulceration, redness, elevated temperature, and severe burning pain primarily in both lower extremities. PEM can be diagnosed by genetic analysis. As this case demonstrates, treating with nitroglycerin as the drug of choice to control the hypertensive crisis significantly improved the symptoms of PEM and hypertension in this patient.

Polyethylene glycol recombinant human growth hormone in Chinese prepubertal slow-growing short children: doses reported in a multicenter real-world study.

BACKGROUND: To evaluate the effectiveness of individualized-dose polyethylene glycol recombinant human growth hormone (PEG-rhGH) for short stature. METHODS: This real-world study enrolled children with short stature in 19 hospitals throughout China. They were treated with PEG-rhGH for 6 months. The starting dosage ranged from 0.10 to 0.20 mg/kg/week. The primary outcome was the change in height standard deviation score (ΔHt SDS). RESULTS: Five hundred and ten patients were included and grouped based on dosage as A (0.10-0.14 mg/kg/week), B (0.15-0.16 mg/kg/week), C (0.17-0.19 mg/kg/week), and D (0.20 mg/kg/week). The mean 6-month ΔHt SDS for the total cohort was 0.49 ± 0.27, and the means differed among the four dose groups (P = 0.002). The ΔHt SDS was lower in group A than in groups B (LSM difference [95%CI], -0.09 [-0.17, -0.01]), C (LSM difference [95%CI], -0.10 [-0.18, -0.02]), and D (LSM difference [95%CI], -0.13 [-0.21, -0.05]) after adjusting baseline covariates. There were no significant differences among groups B, C, and D. When the baseline IGF-1 was < -2 SDS or > 0 SDS, the △Ht SDS was not different among the four groups (P = 0.931 and P = 0.400). In children with baseline IGF-1 SDS of -2 ~ 0 SDS, a higher dosage was associated with a better treatment effect (P = 0.003), and the △Ht SDS was lower in older children than in younger ones (P < 0.001). CONCLUSIONS: PEG-rhGH could effectively increase height in prepubertal short children. When the baseline IGF-1 was < -2 SDS, 0.10 mg/kg/week could be a starting dose. In other IGF-1 statuses, 0.15-0.20 mg/kg/week might be preferred. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03249480 , retrospectively registered.

Microduplication of 16p11.2 locus Potentiates Hypertrophic Obesity in Association with Imbalanced Triglyceride Metabolism in White Adipose Tissue.

SCOPE: Copy number variation (CNV) of 16p11.2 is a common genetic factor contributing to the etiology of abnormal weight status, while the underlying mechanism is not fully elucidated yet. METHODS AND RESULTS: The 16p11.2 CNV mouse model with microduplication of the 7Slx1b-Sept1 region (dp/+) is evaluated under normal chow conditions. Compared to the wild type littermates (WT), the dp/+ mice exhibit obvious obese phenotype characterized by significant increase in body mass index, fat pad mass, and fat ratio, with visceral-dominant fat deposits at 12-week age. White adipose tissue (WAT), liver tissue, and plasma are sampled to assess the comorbid metabolic syndrome. In dp/+ mice, histopathologic analyses reveal hypertrophic adipocytes and hepatic steatosis; serological examinations show hyperlipemia and hyperinsulinemia. Further, by comparing lipidomic and transcriptomic profiling of epididymal WAT between dp/+ and WT mice, the study finds the triglyceride (TG) accumulation in dp/+ mice in association with the dysfunction of lipid droplets. Validation of TG-metabolism-associated genes in WAT and in primary cultured adipocytes show enhanced TG synthesis and declined TG hydrolysis in the dp/+ model. CONCLUSION: This study elucidates that the imbalanced TG synthesis/hydrolysis in adipocytic lipid droplets may contribute to the hypertrophic obesity and metabolic disorders in mice with 16p11.2 microduplication.

Indicators of glucose dysregulation and the relationship with iron overload in Chinese children with beta thalassemia major.

INTRODUCTION: Patients with beta thalassemia major (TM) have a higher risk of diabetes and an abnormal oral glucose tolerance test (OGTT), but there is no single agree monitoring parameter that reflects glycemic status. The possible mechanisms include iron overload and blood transfusion, but they require further investigation. PURPOSE: This study explored the role of glycated hemoglobin A1c (HbA1c), fructosamine, and glycated albumin (GA) in evaluating the glucose dysregulation and to determine the potential relationship between iron deposition and glucose metabolism disorder in beta TM. METHODS: A cross-sectional study was performed on 118 patients with beta TM and the control group consisted of 33 healthy children with no statistical differences in age, sex, and body mass index (BMI). Fast plasma glucose (FPG), fast insulin (FINS), insulin resistance index (HOMA-IRI), and insulin sensitivity index (HOMA-ISI) were compared between the patient and control groups. HbA1c, GA, fructosamine, and serum ferritin (SF) were measured in the patient group. OGTT, as well as heart and liver magnetic resonance imaging (MRI) T2*, was performed. For all statistical analyses, SPSS 21.0 was used and p < 0.05 was accepted as statistically significant. RESULTS: FPG, FINS, and HOMA-IRI were significantly increased while HOMA-ISI decreased in the beta TM patients when compared with those in the control group. In patients with beta TM, 17 (14.41%) of patients had been diagnosed with diabetes, while 48 (40.68%) had both impaired fasting glucose and impaired glucose tolerance. HbA1c, GA, and fructosamine were increased according to the degree of abnormal glucose metabolism. Statistically significant differences were found in age, SF, and cardiac T2* between the abnormal and normal OGTT groups. CONCLUSION: HbA1c may be used as a significant measure for monitoring glycemic levels in patients with beta TM. Furthermore, GA and fructosamine were alternative indicators of glucose status. Patients with heart iron deposition or an SF > 4000 µg/L were prone to abnormal glucose metabolism, so chelation therapy should be reinforced.

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder.

Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.2±) mouse model of ASD. We found downregulated expression of multiple myelin genes and decreased myelin thickness in the striatum of 16p11.2± mice versus wild type controls. Moreover, given that myelin is the main reservoir of brain lipids and that increasing evidence has linked dysregulation of lipid metabolism to ASD, we performed lipidomic analysis and discovered decreased levels of certain species of sphingomyelin, hexosyl ceramide and their common precursor, ceramide, in 16p11.2± striatum, all of which are major myelin components. We further identified lack of ceramide synthase 2 as the possible reason behind the decrease in these lipid species. Taken together, our data suggest a role for myelin and myelin lipids in ASD development.

A Multicenter Survey of Type I Diabetes Mellitus in Chinese Children.

Purpose: To investigate the features and treatment status of children with type 1 diabetes mellitus (T1DM) in China. Methods: We recruited patients <14 years of age with T1DM from 33 medical centers in 25 major cities of China between January 2012 and March 2015. All patients completed a questionnaire that was conducted by their pediatric endocrinologists at all centers. Results: A total of 1,603 children (755 males and 848 females) with T1DM participated in this survey. Of these, 834 (52.03%) of the patients exhibited diabetic ketoacidosis (DKA) at onset, while 769 patients (47.97%) did not exhibit DKA (non-DKA) at onset. There was a higher proportion of females (55.71%) in the cohort of patients exhibiting DKA at onset than in the non-DKA cohort (49.33%). The mean age of patients exhibiting DKA at presentation was 7.12 ± 0.14 years; this was significantly younger than that in non-DKA group (7.79 ± 0.15 years; P < 0.005). The frequency of DKA in 3 years old, 3-7 years old, and 7 years old or more was 77.21%, 26.17%, and 37.62%, respectively. Upon initial diagnosis, 29.4%, 15.2% and 11.8% of patients showed positivity for glutamic acid decarboxylase antibody (GADA), Insulin autoantibodies (IAA), or islet cell antibody (ICA), respectively. During six months follow-up, 244 patients (15.21%) reported receiving insulin pump therapy, and more than 60% of patients monitored their blood glucose levels less than 35 times per week. Although the majority of patients had no problems with obtaining insulin, 4.74% of the children surveyed were not able to receive insulin due to financial reasons, a shortage of insulin preparations, or the failure of the parents or guardians to acquire the appropriate medicine. Conclusion: DKA is more common in very young children. Treatment and follow-up of T1DM in China still face very serious challenges.

CNV profiles of Chinese pediatric patients with developmental disorders.

PURPOSE: To examine the overall genomic copy-number variant (CNV) landscape of Chinese pediatric patients with developmental disorders. METHODS: De-identified chromosomal microarray (CMA) data from 10,026 pediatric patients with developmental disorders were collected for re-evaluating the pathogenic CNV (pCNV) yields of different medical conditions and for comparing the frequency and phenotypic variability of genomic disorders between the Chinese and Western patient populations. RESULTS: The overall yield of pCNVs in the Chinese pediatric patient cohort was 21.37%, with variable yields for different disorders. Yields of pCNVs were positively associated with phenotypic complexity and intellectual disability/developmental delay (ID/DD) comorbidity for most disorders. The genomic burden and pCNV yield in neurodevelopmental disorders supported a female protective effect. However, the stratification analysis revealed that it was seen only in nonsyndromic ID/DD, not in nonsyndromic autism spectrum disorders or seizure. Furthermore, 15 known genomic disorders showed significantly different frequencies in Chinese and Western patient cohorts, and profiles of referred clinical features for 15 known genomic disorders were also significantly different in the two cohorts. CONCLUSION: We defined the pCNV yields and profiles of the Chinese pediatric patients with different medical conditions and uncovered differences in the frequency and phenotypic diversity of genomic disorders between Chinese and Western patients.

Gender roles and behavioral problems in children with 21-hydroxylase deficiency in Southern China.

PURPOSE: To assess the gender roles and behavioral outcomes in children with 21-hydroxylase deficiency (21-OHD) in Southern China. METHODS: A total of 50 individuals with 21-OHD participated in our study, (30 boys and 20 girls), as well as another 19 age-matched non-affected relatives of patients (12 boys and 7 girls). Psychological adjustment was assessed with a preschool activity survey and a Conner parent symptom questionnaire was modified for retrospective reporting. RESULTS: The response rate of the questionnaire in the control group was only 36.5%. All the patients were diagnosed with salt-wasting of 21-OHD. Our study revealed that the masculine score was higher in male patients with 21-OHD than male controls and female patients. Compared with that in the female 21-OHD patient group, the masculine score in the female control group was lower, while comparative masculinization was found in the male controls. Regarding behavioral problems, there was a higher incidence of parent-reported problems among children with 21-OHD than controls, including conduct problems, impulsive hyperactivity, anxiety, and hyperactivity index. CONCLUSION: Parents of 21-OHD patients in Southern China were unwilling to disclose the condition of their children to the society. Masculinization and behavioral problems were prevalent among patients with 21-OHD, which highlighted the importance of psychological and social support for 21-OHD patients and their families.

[Identification of a novel de novo variant of CSNK2A1 gene in a boy with Okur-Chung neurodevelopmental syndrome].

OBJECTIVE: To analyze pathogenic variant of CSNK2A1 gene in a boy with Okur-Chung neurodevelopmental syndrome (OCNS). METHODS: The 8-year-old boy presented with growth retardation, intellectual disability and spells of breath holding. With genomic DNA extracted from peripheral blood samples of the patient and his parents, whole exome sequencing was carried out. Putative pathogenic variants were verified with Sanger sequencing. The nature and impact of detected variants were predicted through bioinformatic analysis. RESULTS: A novel de novo missense variant c.149A>G (p.Tyr50Cys) of the CSNK2A1 gene was identified, which was unreported previously. The variant was predicted to be pathogenic by PolyPhen-2, Mutation Taster and SIFT software. Based on a HomoloGene system, 50 loci within the CK2alpha protein are highly conserved. The change of amino acid (Cys) at position 50 has destroyed the ATP binding loop domain, causing serious damage to its function. As predicted by a Swiss PDB viewer, the variant can significantly alter the spatial structure of CK2alpha, resulting in loss of protein function. CONCLUSION: The patient's condition may be attributed to the novel de novo missense variant c.149A>G (p.Tyr50Cys) of the CSNK2A1 gene.

[Identification of a novel missense NIPBL variant in a juvenile with severe type of Cornelia de Lange syndrome].

OBJECTIVE: To detect pathogenic variant in a juvenile with severe type Cornelia de Lange syndrome (CdLS). METHODS: A 12-year-old female presented with comprehensive developmental retardation and deformity of lower limbs. Genomic DNA was extracted from peripheral blood sample of the patient. Whole exome sequencing was performed to identify pathogenic variants. Putative variant was verified by Sanger sequencing. The impact of variants was predicted and validated by bioinformatic analysis. RESULTS: A de novo missense variant, c.1507A>G (p. Lys503Glu), was found in the NIPBL gene of the proband. The variant was unreported previously and predicted to be pathogenic by PolyPhen-2, MutationTaster and SIFT. Using HomoloGene system, the 503 loci in the NIPBL protein are highly conserved. The change of amino acid (Glu), locating in 503 locus, was found to cause the Neuromodulin_N superfamily domain destroyed, resulting in severe damage to the function of NIPBL protein. CONCLUSION: The de novo missense variant c.1507A>G (p. Lys503Glu) of the NIPBL gene probably underlies the disease in this patient.