Population pharmacokinetic/pharmacodynamic analysis of PEG-rhGH enhances confidence in exploring dosing schemes with longer intervals.

BACKGROUND AND OBJECTIVES: PEG-rhGH (Jintrolong®, 0.2 mg/kg/week) is approved in China for the treatment of growth hormone deficiency (GHD) in children. Although 0.2 mg/kg/2 weeks PEG-rhGH failed the non-inferiority threshold of 20% compared with 0.2 mg/kg/week PEG-rhGH, it notably increases serum IGF-1 levels and height velocity in a phase IV trial. In the absence of investigation on the relationship between pharmacokinetics and pharmacodynamics, this analysis aimed to build a population pharmacokinetic/pharmacodynamic (PopPK/PD) model to characterize the relationship between serum PEG-rhGH concentration and serum insulin-like growth factor-1 (IGF-1) levels after subcutaneously administration of PEG-rhGH and to explore the possibility of flexible dosing schemes and improve the clinical monitor practice of IGF-1 levels. METHODS: A total of 41 subjects were included for the PopPK analysis, consisting of 30 healthy adults (single dose of 0.1-0.4 mg/kg) and 11 GHD children (multiple doses of 0.2 mg/kg/2 weeks for 26 consecutive weeks). Only GHD children were included for the PopPK/PD analysis. The time courses of serum PEG-rhGH concentrations in healthy adults and GHD children and those of serum IGF-1 levels stimulated by serum PEG-rhGH were well developed with non-linear mixed-effects modeling. RESULTS: Serum PEG-rhGH pharmacokinetics after subcutaneous administration were adequately described by a one-compartment model with a zero-order input into the absorption compartment followed by first-order absorption dictating absorption into the central compartment, with a dual elimination process consisting of a capacity limited process and a non-capacity limited process. Body weight was a significant covariate. The drug effects on IGF-1 levels were adequately described by a turnover model with saturable effect relationship. IGF-1 responses at the various dosing scheme scenarios were simulated, and illustrated that dosing schemes with intervals longer than the approved one week could be promising, which may provide comparable peaks and average IGF-1 levels and IGF-1 SDS to dosing schemes that have been clinically proven to be tolerated and effective. An accurate prediction of the time course of the effect of various dosing schemes may assist the clinical monitoring practice. CONCLUSIONS: This pharmacokinetic/pharmacodynamic analysis suggested that longer intervals or higher dosing strengths (e.g., 0.3 mg/kg/10 days) in children with GHD are promising compared with the approved dosing scheme (0.2 mg/kg/week). Our simulation may assist the clinical monitoring of the PEG-rhGH therapy.

Functional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes.

Gut dysbiosis has been linked to type 1 diabetes (T1D); however, microbial capacity in T1D remains unclear. Here, we integratively profiled gut microbial functional and metabolic alterations in children with new-onset T1D in independent cohorts and investigated the underlying mechanisms. In T1D, the microbiota was characterized by decreased butyrate production and bile acid metabolism and increased lipopolysaccharide biosynthesis at the species, gene, and metabolite levels. The combination of 18 bacterial species and fecal metabolites provided excellently discriminatory power for T1D. Gut microbiota from children with T1D induced elevated fasting glucose levels and declined insulin sensitivity in antibiotic-treated mice. In streptozotocin-induced T1D mice, butyrate and lipopolysaccharide exerted protective and destructive effects on islet structure and function, respectively. Lipopolysaccharide aggravated the pancreatic inflammatory response, while butyrate activated Insulin1 and Insulin2 gene expression. Our study revealed perturbed microbial functional and metabolic traits in T1D, providing potential avenues for microbiome-based prevention and intervention for T1D.

Characterization of the oral microbiome of children with type 1 diabetes in the acute and chronic phases.

Background and Aim: The relationship between the oral microbiota and type 1 diabetes (T1D) remains unclear. We aimed to evaluate the variations in the oral microbiome in T1D and identify potentially associated bacterial factors. Methods: We performed high-throughput sequencing of the V3-V4 area of the 16S rRNA gene to profile the oral bacterial composition of 47 healthy children (CON group), 46 children with new-onset T1D in the acute phase (NT1D group), and 10 children with T1D in the chronic phase receiving insulin treatment (CT1D group). Multivariate statistical analysis of sequencing data was performed. Results: Compared to the CON group, the NT1D group was characterized by decreased diversity and increased abundance of genera harboring opportunistic pathogens, while this trend was partially reversed in the CT1D group. Differential genera between groups could distinguish the NT1D group from the CON group (AUC = 0.933) and CT1D group (AUC = 0.846), respectively. Moreover, T1D-enriched genera were closely correlated with HbA1c, FBG and WBCs levels. Conclusion: Our results showed that the acute phase of T1D was characterized by oral microbiota dysbiosis, which could be partially ameliorated via glycemic control. The possible role of oral microbiota dysbiosis on oral health and systemic metabolic status in T1D warrants further mechanistic investigation.

Novel NPR2 Gene Mutations Affect Chondrocytes Function via ER Stress in Short Stature.

Natriuretic peptide receptor 2 (NPR2) plays a key role in cartilage and bone morphogenesis. The NPR2 gene mutations result in acromesomelic dysplasia, Maroteaux type (AMDM), short stature with nonspecific skeletal abnormalities (SNSK), and epiphyseal chondrodysplasia, Miura type (ECDM). However, the pathogenic mechanism remains unclear. In our study, we identified one de novo (R557C) and six novel variants (G602W, V970F, R767*, R363*, F857S, and Y306S) in five independent Chinese families with familial short stature. Three patients with heterozygous mutations (G602W, V970F, and R767*) were diagnosed with SNSK (height SD score ranged from -2.25 to -5.60), while another two with compound heterozygous mutations (R363* and F857S, R557C and Y306S) were diagnosed with AMDM (height SD score ranged from -3.10 to -5.35). Among three patients with heterozygous status, two patients before puberty initiation with rhGH treatment significantly improved their growth (height velocity 7.2 cm/year, 6.0 cm/year), and one patient in puberty had a poor response to the rhGH treatment (height velocity 2.5 cm/year). Seven NPR2 gene variants were constructed and overexpressed in HEK293T and ATDC5 cells, and we found that ATDC5 cells with mutant NPR2 gene showed decreased differentiation, as evidenced by lower expression of ColII, ColX, and BMP4 and higher expression of Sox9. Moreover, the apoptosis rate was elevated in ATDC5 cells expressing the mutant NPR2 gene. N-glycosylation modification, plasma membrane localization, and ER stress resulted from the accumulation of mutant protein in ER, as shown by the higher expression of GRP78 and p-IRE1α. Overall, our results provide a novel insight into NPR2 loss of function, which could promote chondrocyte apoptosis and repress cell differentiation through ER stress and the unfolded protein response.

Corrigendum: Glycated Hemoglobin (HbA1c) Concentrations Among Children and Adolescents With Diabetes in Middle- and Low-Income Countries, 2010-2019: A Retrospective Chart Review and Systematic Review of Literature.

[This corrects the article DOI: 10.3389/fendo.2021.651589.].

Association of ß-cell function and insulin resistance with pediatric type 2 diabetes among Chinese children.

BACKGROUND: In addition to insulin resistance, impaired insulin secretion has recently been identified as a crucial factor in the pathogenesis of type 2 diabetes mellitus (T2DM). Scarce clinical data exist for pediatric T2DM. AIM: To investigate the association of ß-cell function and insulin resistance with pediatric T2DM in the first Chinese multicenter study. METHODS: This multicenter cross-sectional study included 161 newly diagnosed T2DM children and adolescents between January 2017 and October 2019. Children with normal glycemic levels (n = 1935) were included as healthy control subjects. The homeostasis models (HOMAs) were used to assess the ß-cell function (HOMA2-%B) and insulin resistance (HOMA2-IR) levels. The HOMA index was standardized by sex and age. We performed logistic regression analysis to obtain odds ratios (ORs) for T2DM risk using the standardized HOMA index, adjusted for confounding factors including sex, Tanner stage, T2DM family history, body mass index z-score, and lipid profile. RESULTS: The male-female ratio of newly diagnosed T2DM patients was 1.37:1 (OR = 2.20, P = 0.011), and the mean ages of onset for boys and girls were 12.5 ± 1.9 years and 12.3 ± 1.7 years, respectively. The prevalence of related comorbidities including obesity, elevated blood pressure, and dyslipidemia was 58.2%, 53.2%, and 80.0%, respectively. The T2DM group had lower HOMA2-%B levels (P < 0.001) and higher HOMA2-IR levels (P < 0.001) than the control group. Both the decrease in HOMA2-%B z-score (OR = 8.40, 95%CI: 6.40-11.02, P < 0.001) and the increase in HOMA2-IR z-score (OR = 1.79, 95%CI: 1.60-2.02, P < 0.001) were associated with a higher risk of T2DM, and the decrease in HOMA2-%B z-score always had higher ORs than the increase in HOMA2-IR z-score after adjusting for confounding factors. CONCLUSION: Besides insulin resistance, ß-cell function impairment is also strongly associated with Chinese pediatric T2DM. Gender difference in susceptibility and high comorbidities warrant specific T2DM screening and prevention strategies in Chinese children.

The efficacy of ultrasonic emulsification with IOL implantation in patients with primary angle-closure glaucoma combined with cataract.

PURPOSE: This study aimed to investigate the clinical efficacy of ultrasonic emulsification plus IOL implantation in patients with primary angle-closure glaucoma and cataract. METHODS: The clinical data of 81 patients (91 eyes) with primary angle-closure glaucoma comorbid with cataract in our hospital were retrospectively analyzed and divided into two groups based on surgical modality. Group A (n=40, 45 eyes) underwent trabeculectomy and group B (n=41, 46 eyes) underwent ultrasonic emulsification and IOL implantation. The success rate, best corrected visual acuity, intraocular pressure, anterior chamber depth, anterior chamber angle, visual field, cornea's endothelial cell count, complications, and patient satisfaction were compared between the two groups. RESULTS: The surgical success rate in group B was 97.83%, significantly higher than 86.67% in group A (P < 0.05); Compared with group A, group B had higher best-corrected visual acuity and lower intraocular pressure (P < 0.05) as well as higher central and peripheral anterior chamber depths at 3 months postoperatively (P < 0.05); After surgery, group A had significantly lower postoperative cornea's endothelial cell count (P < 0.05). Compared with group A, MS was higher and MD was lower in group B at 3 months postoperatively (P < 0.05); the complication rate in group B was 8.70%, lower than 28.89% in group A (P < 0.05). CONCLUSION: The clinical efficacy of ultrasonic emulsification combined with IOL implantation is remarkable in patients with primary angle-closure glaucoma and cataract, which is conducive to improving postoperative visual acuity, lowering intraocular pressure, increasing the atrial angle, and improving visual field defects. It is also with high safety, but has little effect on cornea's endothelial cell count.

Mutations in GH1 gene and isolated growth hormone deficiency (IGHD): A familial case of IGHD type I and systematic review.

BACKGROUND: Isolated growth hormone deficiency (IGHD) due to mutations in GH1 gene is a rare disease caused by deficient production of endogenous growth hormone (GH). METHODS: We reported the clinical manifestation and genetic diagnosis (whole exome sequencing [WES], nested PCR Sanger sequencing, and rtPCR) of a family with two children with IGHD type I. We conducted a systematic review of cases with IGHD and compared height, and treatment outcomes in subtypes of IGHD. RESULTS: The patients were siblings born of nonconsanguineous parents from the Chinese Han population. The siblings both presented significantly short stature without other apparent abnormalities. The patients carry compound heterozygous mutations in GH1: a deletion and c.456 + 1G > A mutation that led to abnormal splicing. The systematic review identified 365 IGHD cases with GH1 mutations. Among these patients, their body height was most severely impaired in patients with IGHD type Ia, and the height standard deviation score decreased with the age of diagnosis in IGHD type Ia. Patients with IGHD type II had the longest duration of rhGH treatment, while patients with IGHD type Ib had the highest relative height improvement. CONCLUSION: We identified two patients with IGHD type I caused by compound heterozygotic GH1 deletion and splicing mutation. The analysis of previously published IGHD patients suggests differences in linear growth among subtypes of IGHD.

Genetic aetiology of primary adrenal insufficiency in Chinese children.

BACKGROUND: Primary adrenal insufficiency (PAI) is life-threatening, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features. METHODS: Seventy children were enrolled in this cross-sectional study. Clinical information was collected, and combined genetic tests were performed according to the children's manifestations. Statistical analysis was performed among the different groups. In silico or in vitro experiments were applied to determine the pathogenicity of novel variants. RESULTS: Among the 70 children, 84.3% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and 21-hydroxylase deficiency (21-OHD) was genetically confirmed in 91.5% of these cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.1% (39/59), 30.5% (18/59), and 3.4% (2/59) of the cases, respectively. The 17-hydroxyprogesterone (17-OHP) and testosterone (TES) levels were significantly higher in children with SW than with SV. The 17-OHP and cortisol levels in female SW patients were significantly higher than those in males. The 17-OHP, cortisol, dehydroepiandrosterone (DHEAS) and TES levels in female SW patients were significantly higher than those in female SV patients. Additionally, 72.7% (8/11) of uncharacterized PAI patients had positive genetic findings. Among all the patients, two novel variants in the CYP21A2 gene (c.833dupT and c.651 + 2T > G) were found. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (c.323-324CG > GA and c.1231_1234delCTCA), 2 in the AAAS gene (c.399 + 1G > A and c.250delT) and 1 in the NNT gene (c.2274delT), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 skipping during mRNA transcription and produce a truncated ALADIN protein. CONCLUSIONS: We found ethnicity-based differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and TES levels, which warrants caution in relation to the effects of virilization. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of PAI, however, further improvement of genetic testing tools beyond our protocol are still needed to uncover the complete aetiology of PAI in children.

E3 ligase MKRN3 is a tumor suppressor regulating PABPC1 ubiquitination in non-small cell lung cancer.

Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non-small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor growth and proliferation. MKRN3 knockout mice are susceptible to urethane-induced lung cancer, and lung cell-specific knockout of endogenous MKRN3 accelerates NSCLC tumorigenesis in vivo. A mass spectrometry-based proteomics screen identified PABPC1 as a major substrate for MKRN3. The tumor suppressor function of MKRN3 is dependent on its E3 ligase activity, and MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Furthermore, MKRN3 modulates cell proliferation through PABPC1 nonproteolytic ubiquitination and subsequently, PABPC1-mediated global protein synthesis. Our integrated approaches demonstrate that the CPP-associated gene MKRN3 is a tumor suppressor.

Glycated Hemoglobin (HbA1c) Concentrations Among Children and Adolescents With Diabetes in Middle- and Low-Income Countries, 2010-2019: A Retrospective Chart Review and Systematic Review of Literature.

Objectives: To explore the glycemic control [represented by glycated hemoglobin (HbA1c) concentrations] in children with diabetes mellitus (DM) in east China and middle- and low-income countries, from 2010 to 2019. Methods: Retrospective data of children with DM from two hospital-based health records were reviewed. Data on HbA1c concentrations, hospitalization due to diabetic ketoacidosis, and patient demographics were collected and analyzed. A systematic review was subsequently performed to analyze publications that report HbA1c concentrations in patients aged <18 years. Patients' characteristics extracted from each publication were used to generate simulated individual data for pooled analysis. HbA1c estimates were derived from steady-state iterations. Results: Data of 843 diabetic children (aged 11.2 ± 3.9 years) with 2,658 HbA1c measures were retrieved from the two hospitals during the period 2010-2020. The duration of diabetes in the patients was 4.4 ± 2.8 years, and their HbA1c was 8.1 ± 2.2%. Patients who were internal migrants had significantly higher HbA1c concentration than resident patients (8.4 vs. 7.9%). The literature review yielded 1,164 publications, and the majority (74.1%) of patient data were published in high-income countries. The patient data extracted from these publications generated 486,416 HbA1c concentration estimates between 2005 and 2019. The average HbA1c concentration during the 15 years was 9.07 ± 2.15%. The mean HbA1c concentrations among children were 8.23, 8.73, 9.20, and 10.11% in high-income country (HIC), upper-middle income country (UMIC), lower-middle income country (LMIC), and low-income country (LIC) respectively. The mean rate of optimized glycemic control (HbA1c <7.5%) among children was 32.4, 27.5, 21.7, and 12.7% in HIC, UMIC, LMIC, and LIC, respectively. Conclusions: The current study indicated that there is substantial room for improvement in glycemic control in children with DM worldwide, especially in middle- and low-income countries.

Altered Serum Amino Acid and Acylcarnitine Profiles in Hyperinsulinemic Hypoglycemia and Ketotic Hypoglycemia.

Background: In addition to inborn metabolic disorders, altered metabolic profiles were reported to be associated with the risk and prognosis of some non-metabolic diseases, while as a rare metabolic disease, the overall secondary metabolic spectrum in congenital hyperinsulinemic hypoglycemia (HH) is largely undetermined. Therefore, we investigated metabolic profiles in HH patients and used ketotic hypoglycemia (KH) patients as a control cohort to unveil their distinct metabolic features. Methods: A total of 97 hypoglycemia children, including 74 with hyperinsulinemic hypoglycemia and 23 with ketotic hypoglycemia, and 170 euglycemia control subjects were studied retrospectively. Clinical and biochemical data were collected. The normoglycemic spectra of amino acids and acylcarnitines were determined by liquid chromatography tandem mass spectrometry. The serum insulin and fatty acid concentrations during standardized fasting tests in hypoglycemia patients were also collected. Receiver operating characteristic curve analysis was performed to screen potential biomarkers. Results: Among the normoglycemic spectra of amino acids, blood valine (p < 0.001), arginine (p < 0.001), threonine (p = 0.001), glutamate (p = 0.002), methionine (p = 0.005), ornithine (p = 0.008), leucine (p = 0.014), alanine (p = 0.017), proline (p = 0.031), citrulline (p = 0.042), aspartate (p = 0.046), and glycine (p = 0.048) levels differed significantly among the three groups. Significantly decreased levels of long- (C14:1, p < 0.001; C18, p < 0.001), medium- (C8, p < 0.001; C10, p < 0.001; C10:1, p < 0.001), and short-chain (C4-OH, p < 0.001; C5OH, p < 0.001) acylcarnitines were found in the hyperinsulinemic hypoglycemia group. Hyperinsulinemic hypoglycemia children with focal lesions and diffuse lesions had similar amino acid and acylcarnitine spectra. C10:1 < 0.09 µmol/L, threonine > 35 µmol/L, and threonine/C10:1 > 440 showed sensitivities of 81.1, 66.2, and 81.1% and specificities of 72.7, 78.3, and 81.8%, respectively, in distinguishing HH from KH. Conclusions: We found significantly different altered serum amino acid and acylcarnitine profiles at normoglycemia, especially decreased C10:1 and increased threonine levels, between HH and KH children, which may reflect the insulin ketogenesis inhibition effect in HH patients; however, the detailed mechanisms and physiological roles remain to be studied in the future.

Phenotypes and epigenetic errors in patients with Beckwith-Wiedemann syndrome in China.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is primarily caused by epigenetic errors. This study aimed to analyze the relationship between the epigenetic errors and phenotypes of BWS and to evaluate the efficacy of diagnosing BWS using patients' clinical characteristics. METHODS: Patients clinically diagnosed with BWS were subjected to methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) for (epi)genotyping. The patients' clinical characteristics were analyzed and compared using regression models. The diagnostic efficacy of previous criteria and scoring systems was compared using area under the receiving operating curve (ROC). RESULTS: The most common clinical features observed in BWS patients were macroglossia (83.2%), abdominal wall defects (71.3%), and ear creases/pits (55.3%). Patients with the loss of methylation at imprinting control 2 (IC2-LOM) and gaining of methylation at imprinting control 1 (IC1-GOM) subtypes had significantly higher frequencies of ear creases/pits and facial nevus flammeus, and visceromegaly, respectively. Paternal uniparental isodisomy (pUPD) was characterized by significantly less macroglossia but more hemihypertrophy. The area under the curve (AUC) was comparably good in both recently developed scoring systems (0.87 for Ibrahim and 0.82 for Brioude.) and in the scoring system developed using the current cohort (0.88). CONCLUSIONS: This study, which is the largest cohort study of BWS cases in China published to date, confirmed the diagnostic efficacy of a recently developed symptom-based BWS scoring system in a Chinese population. Significant differences exist between the phenotypes of BWS epigenetic subtypes; however, the pattern is similar between Asian and European populations.

[Association of body fat ratio with precocious puberty in girls].

OBJECTIVE: To study the association of body fat ratio with precocious puberty in girls. Previous studies have shown that body mass index (BMI) is associated with the girls' age of puberty but have not revealed the association of body fat ratio with age of puberty. METHODS: Based on the consensus on the diagnosis and treatment of central precocious puberty (CPP), 128 children with precocious puberty who were admitted to the hospital from July to August, 2017, were divided into a CPP group with 87 children and a peripheral precocious puberty (PPP) group with 41 children. A total of 51 girls without any puberty development signs were enrolled as the control group. Dual-energy X-ray absorptiometry was used to measure the body fat ratios of upper limbs, legs, trunk, android area, gynoid area, and the whole body. The association between body fat ratios and precocious puberty was analyzed with reference to age, BMI, BMI-Z score, bone age, ovarian volume, and hormone levels. RESULTS: Compared with the control group, the CPP and PPP groups had significantly higher body fat ratios of upper limbs, legs, trunk, android area, gynoid area, and the whole body, legs/whole body fat ratio, and (upper limbs+legs)/trunk fat ratio (P<0.05), while there were no significant differences in the above body fat ratios and fat distribution indicators between the CPP and PPP groups (P>0.05). For the girls with precocious puberty, the high body fat ratio group had significantly higher luteinizing hormone (LH) base value, luteinizing hormone releasing hormone (LHRH)-stimulated LH peak value, and LH/follicle-stimulating hormone peak value than the low body fat ratio group (P<0.05). Compared with the control group, both the high body fat ratio and low body fat ratio groups had a significantly higher LH base value (P<0.05). CONCLUSIONS: The increase in body fat may be a factor inducing precocious puberty in girls, but further studies are needed to determine the mechanism.

Genotype and phenotype analysis of a cohort of patients with congenital hyperinsulinism based on DOPA-PET CT scanning.

Congenital hyperinsulinism (CHI) is a clinically, genetically, and morphologically heterogeneous disorder. 18F DOPA-PET CT scanning greatly improves its clinical outcome. Here, we presented the first Chinese 18F DOPA-PET CT scanning-based CHI cohort highlighting the variable ethic clinical phenotypes and genotypes. Fifty CHI patients were recruited. Median age at presentation was 2 days. Median fasting time was 2 h. Mean insulin level was 25.6 µIU/ml. Fifty-two percent of patients were diazoxide-unresponsive with significantly shorter fasting tolerance time and higher serum insulin level compared with the responsive patients. Seventy-four percent of patients experienced at least one adverse drug reaction. Tremendously increased focal lesions (32%) were detected and 75% of them were cured through surgery. Thirty-one nucleotide sequence changes were identified in 48% patients. Four novel variants (Q608X, Q1347X, Q289X, F1489S) in ABCC8 gene and 2 novel variants (G132A, V138E) in KCNJ11 gene were detected. Of the variants, 87.1% harbored in ABCC and KCNJ11 genes. T1042Qfs*75 in ABCC8 gene was the most common mutation.Conclusion: Highly increased portion of focal lesion was presented in Chinese CHI patients compared with that of the previous reports. Intolerance to diazoxide was much more evident in Chinese or East Asian than other populations. Certain hotspot mutations harbored in Chinese CHI patients. What is Known: • 18F DOPA-PET CT scanning can provide informative guidance for surgical procedure when medical therapy is not well responded in CHI patients. What is New: • Intolerance to diazoxide is much more evident in Chinese and East Asian CHI patients compared with the other ethnic populations. • Novel mutations were detected in ABCC8 and KCNJ11 gene. Hotspot mutations such as T1042Qfs*75, I1511K, E501K, G111R in ABCC8 gene, and R34H in KCNJ11 gene are predominantly responsible for Chinese CHI patients.

Clinical characteristics and beta-cell function of Chinese children and adolescents with type 2 diabetes from 2009 to 2018.

BACKGROUND: The limited available studies have unveiled different natural histories and prognosis associated with pediatric type 2 diabetes (T2D) and adult T2D. To date, data on the clinical features, metabolic profiles and beta-cell function characteristics are still limited in the Chinese pediatric T2D population. METHODS: A total of 56 children with T2D, 31 with prediabetes and 159 with obesity were recruited. Clinical characteristics, metabolic profiles, beta-cell function and insulin resistance were analyzed. RESULTS: The mean onset age of T2D was 12.35 ± 1.99 (7.9-17.8) years, and 7% of children were younger than 10 years; 55% of them were male, 57% had a family history of diabetes and 64% had classic symptoms, and 25% had a low or high birth weight. 89% of T2D patients were obese or overweight. A total of 58% of the patients with prediabetes were male. The fast serum C-peptide level was highest in the obesity group (P < 0.001), and there was no significant difference between the T2D and prediabetes groups. The mean homeostatic model of assessment of beta-cell function was the highest in the obesity group and was lowest in the T2D group (P < 0.001). The T2D group had the most serious lipid metabolism disorder, with the highest levels of total triglycerides, total cholesterol, and low density lipoprotein and the lowest high density lipoprotein level among the three groups. CONCLUSIONS: A younger onset age and greater male susceptibility were found in Chinese pediatric T2D patients, and there was a stepwise deterioration trend in beta-cell function among patients with obesity, prediabetes and T2D. Based on our results, together with the SEARCH study results, an early screening and intervention program for T2D is recommended in high-risk or obese Chinese pediatric populations starting at 7 years.

A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis.

Acute pancreatitis (AP), a common abdominal inflammatory disorder, is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. Although the mechanism remains to be fully understood, inflammation is the main cause of pancreatic damage in AP. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from danshensu, exhibits anti-inflammatory and anti-apoptotic properties in vitro. However, its potential beneficial effect in AP has not been demonstrated. This study aimed to investigate the effects and underlying mechanisms of DSC in experimental AP in mice. We found that DSC suppressed inflammatory responses in AP by inhibiting the activation of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3) and nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome. Furthermore, treatment with DSC modulated the infiltration of neutrophils and the phenotypes of macrophages in mice induced with AP. Interestingly, we found that the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) and its regulated antioxidant enzyme heme oxygenase-1 (HO-1), which modulate inflammatory activities, was significantly increased in DSC-treated groups. Together, our findings demonstrate that DSC alleviates pancreatic inflammation and damage in AP by inhibiting the activation of NF-κB, STAT3, and NLRP3 inflammasome and modulating immune cell responses.

IGF1R Variants in Patients With Growth Impairment: Four Novel Variants and Genotype-Phenotype Correlations.

Objective: IGF1R gene mutations have been associated with varying degrees of intrauterine and postnatal growth retardation, as well as microcephaly. Both autosomal-dominant and autosomal-recessive inheritance patterns have been reported. This study aimed to analyze the IGF1R gene in children with growth impairment using whole-exome sequencing (WES) and assess the clinical features with the autosomal-dominant and autosomal-recessive models. Methods: We performed WES in 28 unrelated patients and found three children harboring IGF1R gene variants. We compared the clinical findings in our cases carrying IGF1R mutations to those in patients reported in the Human Gene Mutation Database (HGMD). Results: We identified four IGF1R gene variations by WES in three unrelated patients, including one missense variant [c.3740T>C (p.M1247T)] (patient 1) inherited from an affected mother, one missense variant [c.744T>G (p.C248W)] (patient 2) inherited from an affected father, and two compound heterozygous variations [c.2305G>C (p.E769Q) and c.2684G>A (p.R895Q)] (patient 3). To date, 22 patients have been described as harboring pathogenic variations in IGF1R in the HGMD. We found that patients with compound heterozygous or homozygous variations displayed more severe phenotypes that were mainly characterized by developmental and speech delays, as well as mental retardation. Conclusion: We identified four pathogenic variations in the IGF1R gene, which expanded the known mutation spectrum. Through a comparison among patients with reported IGF1R pathogenic variations, this study determined that an autosomal-recessive inheritance model of the IGF1R gene may result in a more severe phenotype with developmental and speech delays, as well as mental retardation.

Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children.

BACKGROUND: Mutations in the aggrecan (ACAN) gene can cause short stature (with heterogeneous clinical phenotypes), impaired bone maturation, and large variations in response to growth hormone (GH) treatment. For such cases, long-term longitudinal therapy data from China are still scarce. We report that a previously unknown ACAN gene variant reduces adult height and we analyze the GH response in children from an affected large Chinese family. METHODS: Two children initially diagnosed with idiopathic short stature (ISS) and a third mildly short child from a large Chinese family presented with poor GH response. Genetic etiology was identified by whole exome sequencing and confirmed via Sanger sequencing. Adult heights were analyzed, and the responses to GH treatment of the proband and two affected relatives are summarized and compared to other cases reported in the literature. RESULTS: A novel ACAN gene variant c.7465 T > C (p. Gln2364Pro), predicted to be disease causing, was discovered in the children, without evident syndromic short stature; mild bone abnormity was present in these children, including cervical-vertebral clefts and apophyses in the upper and lower thoracic vertebrae. Among the variant carriers, the average adult male and female heights were reduced by - 5.2 and - 3.9 standard deviation scores (SDS), respectively. After GH treatment of the three children, first-year heights increased from 0.23 to 0.33 SDS (cases in the literature: - 0.5 to 0.8 SDS), and the average yearly height improvement was 0.0 to 0.26 SDS (cases in the literature: - 0.5 to 0.9 SDS). CONCLUSIONS: We report a novel pathogenic ACAN variant in a large Chinese family which can cause severe adult nonsyndromic short stature without evident family history of bone disease. The evaluated cases and the reports from the literature reveal a general trend of gradually diminishing yearly height growth (measured in SDS) over the course of GH treatment in variant-carrying children, highlighting the need to develop novel management regimens.

Recovered insulin production after thiamine administration in permanent neonatal diabetes mellitus with a novel solute carrier family 19 member 2 (SLC19A2) mutation.

BACKGROUND: Solute carrier family 19 member 2 (SLC19A2) gene deficiency is one of the causes of permanent neonatal diabetes mellitus (PNDM) and can be effectively managed by thiamine supplementation. Herein we report on a male patient with a novel SLC19A2 mutation and summarize the clinical characteristics of patients with SLC19A2 deficiency. METHODS: The genetic diagnosis of the patient with PNDM was made by sequencing and quantitative polymerase chain reaction. The clinical characteristics of PNDM were summarized on the basis of a systematic review of the literature. RESULTS: The patient with PNDM had c.848G>A (p.W283X) homozygous mutation in SLC19A2. His father had a wild-type SLC19A2 (c.848G) and his mother was c.848G/A heterozygous. The patient and his father both had a diploid genotype (c.848A/A and c.848G/G). After oral thiamine administration, the patient's fasting C-peptide levels increased gradually, and there was a marked decrease in insulin requirements. A search of the literature revealed that thiamine treatment was effective and improved diabetes in 63% of patients with SLC19A2 deficiency. CONCLUSIONS: A novel SLC19A2 mutation (c.848G>A; p.W283X) was identified, which was most likely inherited as segmental uniparental isodisomy. Insulin insufficiency in PNDM caused by SLC19A2 deficiency can be corrected by thiamine supplementation. The differential diagnosis of SLC19A2 deficiency should be considered in children with PNDM accompanied by anemia or hearing defects to allow for early treatment.