Early psychomotor development and growth hormone therapy in children with Prader-Willi syndrome: a review.

Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of imprinted gene expression on the paternal chromosome 15q11-q13. PWS is characterized by varying degrees of early psychomotor developmental deficits, primarily in cognition, language, and motor development. This review summarizes the early mental cognitive development, language development, and motor development in patients with PWS, compares the correlation of genotype with phenotype, and provides an update regarding the effects and concerns related to potential main side effects of treatment with recombinant human growth hormone on early psycho-cognitive and motor function development along with the linear growth and body composition of children with PWS.Conclusion: Early psychomotor development is strongly correlated with the prognosis of patients with PWS; moreover, current studies support that the initiation of interventions at an early age can exert significant beneficial effects on enhancing the cognitive and linguistic development of patients with PWS and allow them to "catch up" with motor development.  What is Known: • Prader-Willi syndrome is a rare genetic disorder characterized by multisystem damage, and children with Prader-Willi syndrome are typically characterized by early developmental delays, specifically in the areas of cognitive and motor development. • Recombinant human growth hormone therapy is the only medical treatment approved for Prader-Willi syndrome. What is New: • Extensive presentation of psycho-cognitive and motor development features and genotype-phenotype correlation in children with Prader-Willi syndrome.  • The effects of growth hormone on early psychomotor development in children with Prader-Willi syndrome were thoroughly reviewed, including their short- and long-term outcomes and any associated adverse effects.

[Recent advances in the genetic etiology of central precocious puberty]. / é—ä¼ ç¼ºé™·è‡´ä¸­æž¢æ€§æ€§æ—©ç†Ÿç— å› å­¦çš„ç ”ç©¶æ–°è¿›å±•.

Central precocious puberty (CPP) is a developmental disorder caused by early activation of the hypothalamic-pituitary-gonadal axis. The incidence of CPP is rapidly increasing, but the underlying mechanisms are not fully understood. Previous studies have shown that gain-of-function mutations in the KISS1R and KISS1 genes and loss-of-function mutations in the MKRN3, LIN28, and DLK1 genes may lead to early initiation of pubertal development. Recent research has also revealed the significant role of epigenetic factors such as DNA methylation and microRNAs in the regulation of gonadotropin-releasing hormone neurons, as well as the modulating effect of gene networks involving multiple variant genes on pubertal initiation. This review summarizes the genetic etiology and pathogenic mechanisms underlying CPP.

New insights into 5α-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype-phenotype profiling of SRD5A2 in 190 Chinese patients.

BACKGROUND: The 5α-reductase type 2 (5α-RD2) deficiency caused by mutations in the steroid 5α-reductase 2 (SRD5A2) gene results in variable degrees of undervirilisation in patients with 46,XY disorders of sex development. This study aims to profile the regional distribution and phenotype-genotype characteristics of SRD5A2 in a large Chinese 5α-RD2 deficiency cohort through multi-centre analysis. METHODS: 190 subjects diagnosed with 5α-RD2 deficiency were consecutively enrolled from eight medical centres in China. Their clinical manifestations and genetic variants were analysed. RESULTS: Hypospadias (isolated or combined with microphallus and/or cryptorchidism) was fairly common in the enrolled subjects (66.32%). 42 variants, including 13 novel variants, were identified in SRD5A2. Homozygous and compound heterozygous mutations presented in 38.42% and 61.58% of subjects, respectively, and predominated in exons 1, 4 and 5. The most prevalent variant was c.680G > A (52.37%), followed by c.16C > T, (10.79%), c.607G > A, (9.21%) and c.737G > A, (8.95%). However, their distributions were different: c.680G > A was more common in South China than in North China (62.62% vs 39.16%, p < 0.001), whereas the regional prevalence of c.16C > T was reversed (6.07% vs 16.87%, p = 0.001). Furthermore, c.680G > A prevailed in cases with normal meatus (68.75%) or distal hypospadias (66.28%), compared with those with proximal hypospadias (35.54%, p < 0.001). However, cases with proximal hypospadias showed a higher frequency of c.16C > T (20.48%) than those with normal meatus (3.13%) or distal hypospadias (3.49%, p < 0.001). CONCLUSIONS: This study profiled variable phenotypic presentation and wide mutational spectrum of SRD5A2, revealing its distinctive regional distribution in Chinese patients and further shaping the founder effect and genotype-phenotype correlation of SRD5A2.

[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.

[Recurrent anorexia and pigmentation of skin for more than two months in an infant].

A 2-month-old boy presented with adrenal insufficiency, impaired liver function, hypertriglyceridemia, significantly elevated creatine kinase and electrolyte disturbance. Microarray comparative genomic hybridization (aCGH) analysis test showed a pathogenic 8.7 Mb deletion in the short arm of chromosome X (Xp21.3 - p21.1) and confirmed the diagnosis of complex glycerol kinase deficiency (cGKD). He was treated with hydrocortisone, coenzyme Q10 and L-carnitine and was subsequently followed up for 4 years. His serum cortisol levels returned to normal one week later after treatment, but the serum creatine kinase, triglyceride and aminotransferase levels were progressively increased along with mental retardation and decreased muscular strength. cGKD is also named as Xp21 contiguous gene syndrome. The clinical manifestations of this disease include hypertriglyceridemia, congenital adrenal hypoplasia (AHC), Duchenne muscular dystrophy, and mental retardation. This case highlights the necessity to screen the serum triglyceride and creatine kinase levels in infants with suspected adrenal insufficiency.

Clinical and genetic features of Prader-Willi syndrome in China.

UNLABELLED: We set out to delineate the phenotypic and genotypic characteristics of Prader-Willi syndrome (PWS), a congenital neurodevelopmental disorder caused by the lack of expression of the paternally inherited imprinted genes on chromosome 15q11-13 in 31 Chinese patients. They were genotyped to identify deletions using methylation-specific polymerase chain reaction analysis and subsequent methylation-specific multiplex ligation-dependent probe amplification analysis. Microsatellite linkage analysis was performed to distinguish maternal uniparental disomy (UPD) from imprinting defect. Clinical manifestations were recorded and compared between patients with paternal 15q11-13 deletion and UPD. Deletions in the 15q11-13 region were present in 26 (83.9 %) patients, and UPD was observed in 5 (16.1 %) patients. The mean maternal age at the time of childbirth for mUPD children (32.8 ± 5.1 years) was significantly higher than that of children with paternal 15q11-13 deletion (27.1±3.2 years, P < 0.05). All patients had neonatal hypotonia, feeding difficulties in infancy, and decreased fetal activity, but only 12.9 % of the patients showed short stature, 54.8 % presented typical facial features, and 35.5 % showed skin picking lesions. CONCLUSION: Significant heterogeneity in clinical phenotypes and genotypes in PWS were observed between Chinese and Western populations in this study. This suggests that ethnic differences may be relevant to the diagnostic criteria for PWS.

Population-based prevalence of self-reported pediatric diabetes and screening for undiagnosed type 2 diabetes in Chinese children in years 2017-2019, a cross-sectional study.

Background: The worldwide geographical and temporal variation in the prevalence of diabetes represents a challenge, but also an opportunity for gaining etiological insights. Encompassing the bulk of East Asians, a large and distinct proportion of the world population, China can be a source of valuable epidemiological insights for diabetes, especially in early life, when pathophysiology begins. We carried out a nationwide, epidemiological survey of Prevalence and Risk of Obesity and Diabetes in Youth (PRODY) in China, from 2017 to 2019, to estimate the population-based prevalence of diagnosed pediatric diabetes and screen for undiagnosed pediatric type 2 diabetes (T2D). Methods: PRODY was a nation-wide, school population-based, cross-sectional, multicenter survey by questionnaire, fasting urine glucose test and simple oral glucose tolerance test (s-OGTT), among a total number of 193,801 general-population children and adolescents (covered a pediatric population of more than 96.8 million), aged 3-18, from twelve provinces across China. The prevalence of the self-reported pediatric diabetes, the proportion of subtypes, the crude prevalence of undiagnosed T2D and prediabetes in general juvenile population and the main risk factors of type 1 (T1D) and type 2 (T2D) diabetes had been analyzed in the study. Findings: The prevalence of all self-reported pediatric diabetes was estimated at 0.62/1000 (95% CI: 0.51-0.74), with T1D at 0.44/1000 (95% CI: 0.35-0.54) and T2D at 0.18/1000 (95% CI: 0.13-0.25). For undiagnosed T2D, the crude prevalence was almost ten-fold higher, at 1.59/1000, with an estimated extra 28.45/1000 of undiagnosed impaired glucose tolerance (IGT) and 53.74/1000 of undiagnosed impaired fasting glucose (IFG) by s-OGTT screening. Maternal diabetes history is the major risk factors for all subtypes of pediatric diabetes in China. Interpretation: The PRODY study provides the first population-based estimate of the prevalence of pediatric diabetes China and reveals a magnitude of the problem of undiagnosed pediatric T2D. We propose a practical screening strategy by s-OGTT to address this serious gap. Funding: The National Key Research and Development Programme of China, Key R&D Program of Zhejiang, the National Natural Science Foundation of China and the Zhejiang Provincial Key Disciplines of Medicine, Key R&D Program Projects in Zhejiang Province.

[The establishment of "two-step sequential filtration method" on the yield rate of purified islets in rats].

OBJECTIVE: To develop a simple, rapid and reliable method of purifying Sprague-Dawley (SD) rat islets by sequential filtration through two cell strainers of different sizes and to evaluate the efficacy of the method. METHODS: Islets were isolated from 8 to 12-week-old clean grade Sprague-Dawley rat pancreases using the standard collagenase digestion procedure and purified with either the generally used Ficoll density gradient method or the innovative two-step sequential filtration method. The purity and vitality of the isolated islets were visualized and assessed with DTZ and AO/PI staining. Glucose stimulating tests were performed to assay cell activity, and immunohistochemical staining was used to evaluate the synthesis function of islet cells. RESULTS: The yield of islets in the two-step filtration method group was 782±115 IEQ per rat, which was significantly higher than in the conventional Ficoll density gradient method group (598 ± 135 IEQ per rat, P < 0.01). Purity of the isolated islets in the two-step filtration method group was 90%-100% and vitality was over 95%. In the conventional Ficoll density gradient method group, islet purity was 65%-85% and vitality was 85%-95%. With regard to the high-sugar stimulation test in the two-step filtration method group, insulin concentrations in islets cultured for 24 hours were significantly higher than in those that were freshly purified (76.9 ± 6.1 µg/L vs 49.4 ± 3.9 µg/L; P < 0.01). CONCLUSIONS: A two-step sequential filtration method for rat islet purification was developed and the method was simple and reliable, with high islet vitality, purity and yield.

Early recombinant human growth hormone treatment improves mental development and alleviates deterioration of motor function in infants and young children with Prader-Willi syndrome.

BACKGROUND: Recombinant human growth hormone (rhGH) therapy has shown to improve height and body composition in children with Prader-Willi syndrome (PWS), the evidence of early rhGH treatment on motor and mental development is still accumulating. This study explored the time effect on psychomotor development, anthropometric indexes, and safety for infants and young children with PWS. METHODS: A phase 3, single-arm, multicenter, self-controlled study was conducted in six sites. Patients received rhGH at 0.5 mg/m2/day for first four weeks, and 1 mg/m2/day thereafter for up to 52 weeks. Motor development was measured using Peabody Developmental Motor Scales-second edition, mental development using Griffiths Development Scales-Chinese (GDS-C). Height standard deviation score (SDS), body weight SDS, and body mass index (BMI) SDS were also assessed. RESULTS: Thirty-five patients were enrolled totally. Significant improvements were observed in height, body weight, and BMI SDS at week 52; GDS-C score showed significant improvement in general quotient (GQ) and sub-quotients. In a linear regression analysis, total motor quotient (TMQ), gross motor quotient (GMQ), and fine motor quotient were negatively correlated with age; however, treatment may attenuate deterioration of TMQ and GMQ. Changes in GQ and locomotor sub-quotient in < 9-month group were significantly higher than ≥ 9-month group. Mild to moderate severity adverse drug reactions were reported in six patients. CONCLUSION: Fifty-two-week treatment with rhGH improved growth, BMI, mental development, and lessened the deterioration of motor function in infants and young children with PWS. Improved mental development was more pronounced when instituted in patients < 9 months old.

Clinical Incidence and Characteristics of Newly Diagnosed Type 1 Diabetes in Chinese Children and Adolescents: A Nationwide Registry Study of 34 Medical Centers.

Objective: To investigate the clinical incidence and characteristics of type 1 diabetes mellitus (T1DM) of children and adolescents at the time of initial diagnosis in China. Methods: Data on all pediatric patients with newly diagnosed T1DM were retrospectively collected from 34 medical centers in 25 major cities in China from January 2015 to January 2020. Patients were classified into three age groups: <5 years, 5 to <10 years, and ≥10 years of age. The same patient population was also categorized into diabetic ketoacidosis (DKA) and non-DKA groups based on clinical criteria. Results: The mean annual clinical incidence of T1DM was 3.16/100,000 from the years 2015 to 2019. A total of 6,544 patients with newly diagnosed T1DM aged 0-16 years (median 7.84 ± 3.8) were studied [ages <5 years (29.3%), 5 to <10 years (38.7%), and ≥10 years (32%)], 52.4% of them were women. In total, 90.5% of the cases were occurred in individuals without a family history. Patients had lower C-peptide (CP) and body mass index (BMI) z scores when compared with healthy children, 41.8% of them had measurable T1DM-related antibodies and 52.7% had DKA. Among all three age groups, the <5 years group had the lowest BMI z score, CP, and glycated hemoglobin (HbA1c) on average, while it had the highest incidence rate of DKA (56.9%). Compared to the non-DKA group, the DKA group was significantly younger, with a lower BMI z score and CP, higher antibody positive rate, HbA1c, and the rate of insulin pump therapy. Conclusion: The clinical incidence of T1DM in children and adolescents in China was 3.16/100,000. Patients with DKA at the first diagnosis of T1DM have a worse ß-cell function. Public health measures for the prevention and treatment of T1DM should focus on preschoolers (aged <5 years) in particular, considering the severity and the highest frequency of DKA in this age group. More efforts should be dedicated to early screening and diagnosis of the T1DM.

Association between new onset type 1 diabetes and real-world antibiotics and neonicotinoids' exposure-related gut microbiota perturbation.

BACKGROUND: The real-world exposure levels of non-therapeutic antibiotics and neonicotinoids in type 1 diabetes (T1D) children and their associations as environmental triggers through gut microbiota shifts remained unknown. We thus investigated the antibiotics and neonicotinoids' exposure levels and their associations with gut microbiota in pediatric T1D. METHODS: Fifty-one newly onset T1D children along with 67 age-matched healthy controls were recruited. Urine concentrations of 28 antibiotics and 12 neonicotinoids were measured by mass spectrometry. Children were grouped according to the kinds of antibiotics' and neonicotinoids' exposures, respectively. The 16S rRNA of fecal gut microbiota was sequenced, and the correlation with urine antibiotics and neonicotinoids' concentrations was analyzed. RESULTS: The overall detection rates of antibiotics were 72.5% and 61.2% among T1D and healthy children, whereas the neonicotinoids detection rates were 70.6% and 52.2% (P = 0.044). Children exposed to one kind of antibiotic or two or more kinds of neonicotinoids had higher risk of T1D, with the odd ratios of 2.579 and 3.911. Furthermore, co-exposure to antibiotics and neonicotinoids was associated with T1D, with the odd ratio of 4.924. Antibiotics or neonicotinoids exposure did not affect overall richness and diversity of gut microbiota. However, children who were exposed to neither antibiotics nor neonicotinoids had higher abundance of Lachnospiraceae than children who were exposed to antibiotics and neonicotinoids alone or together. CONCLUSION: High antibiotics and neonicotinoids exposures were found in T1D children, and they were associated with changes in gut microbiota featured with lower abundance of butyrate-producing genera, which might increase the risk of T1D.

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.

[Lipoprotein lipase gene mutations and the risk of cardiovascular diseases in children with obesity].

OBJECTIVE: To inquire into the relationship between lipoprotein lipase (LPL) gene D9N, N291S and S447X polymorphisms and the development of cardiovascular diseases in children with obesity. METHODS: The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RLFP) techniques were used to detect three common mutations of LPL gene exon D9N, N291S and S447X in 157 obese children and 175 normal controls. Plasma lipid and lipoprotein levels between children with different genotypes were compared. RESULTS: The D9N and N291S gene mutations were not detected in either the obese or the control groups. There were no significant differences in the frequency of S447X gene mutation between the two groups. There were no significant differences in the levels of plasma lipid and lipoprotein between children with S447 and X447 genotypes. CONCLUSIONS: D9N and N291S gene mutations may not be risk factors associated with cardiovascular diseases in children with obesity. S447X gene mutation might not play an important role in the development of cardiovascular diseases in childhood.

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.

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.

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.

Possible role of birth weight on general and central obesity in Chinese children and adolescents: a cross-sectional study.

PURPOSE: According to the developmental origins of health and disease theory, fetal nutrition is associated with obesity and chronic diseases in children and adults. However, previous findings regarding the association between birth weight and childhood obesity have been inconsistent. The aim of the present study was to investigate the relationship between birth weight and childhood obesity in China. METHODS: The 16,580 subjects (8477 boys and 8103 girls) aged 7-17 years, who participated in this study were recruited from a cross-sectional study in six cities in China. Epidemiological data, including birth information, were collected through face-to-face interviews, and anthropometric indices were measured by trained physicians. Overweight and obese cases were defined using sex-specific and age-specific 85th and 95th percentile body mass index (BMI) cutoffs for Han children and adolescents. Central obesity was defined using sex-specific waist-to-height ratio (WHtR) cutoffs (WHtR ≥0.48 in boys and WHtR ≥0.46 for girls). RESULTS: The overall rate of overweight status and obesity was 20.3% in the Chinese children and adolescents and that of central obesity was 18.9%. Subjects were stratified into eight groups according to weight at birth. J-shaped relationships were observed between birth weight and BMI for age Z-score and WHtR. After adjusting for confounders such as gender, gestational age, parental factors, and dietary factors, the risk of overweight and obese status was still higher in the children with higher birth weights than in children with birth weights of 3000-3499 g (3500-3999 g: odds ratio [OR] = 1.14, 95% confidence interval [CI] = 1.02-1.28; 4000-4499 g: OR = 1.39, 95% CI = 1.19-1.63; and 4500-4999 g: OR = 1.36, 95% CI = 1.06-1.76). Moderately high birth weight also increased the risk of central obesity. Relative to the children with normal birth weights (3000-3499 g), the adjusted OR and 95% CI were 1.33 (1.13-1.56) in children with birth weights of 4000-4499 g. Children with very low birth weight (lower than 1500 g) had the highest risk of central obesity. The adjusted OR was 2.30 (95% CI: 1.03-5.14) relative to children with birth weights of 3000-3499 g. CONCLUSIONS: Birth weight was associated with obesity in Chinese children and adolescents. J-shaped relationships were observed between birth weight and BMI and WHtR in childhood, and very low birth weight was associated with a mild increase in the risk of central obesity in Chinese children and adolescents.

Genetic variations in SEC16B, MC4R, MAP2K5 and KCTD15 were associated with childhood obesity and interacted with dietary behaviors in Chinese school-age population.

Both genetic predisposition and lifestyle factors are associated with the risk for obesity. Multiple obesity loci have been identified using genome-wide association studies mainly in European populations. The aims of this study were to examine the associations of these loci with obesity and gene×dietary behavior interactions among Chinese children and adolescents. Nineteen candidate SNPs were genotyped using Sequenom technology in the Chinese children (N=2977, 853 obese and 2124 controls, aged 7-17). Dietary behaviors were assessed using self-administered questionnaires. After adjusting for age, sex and multiple testing, MC4R rs17782313, SEC16B rs543874, MAP2K5 rs2241423 and KCTD15 rs11084753 were associated with obesity and obesity-related traits (all P<0.005), with odd ratios ranging from 1.22 to 2.15. Dose-response association was significant between genetic risk score, which was calculated by summing the risk alleles, and the risk of obesity (P<0.001). Multiplicative interaction was found between rs543874 and salt preference on obesity with an OR of 4.40 (95% CI, 1.12-17.30). Additive interactions with salt preference were found in rs17782313 and rs11084753. Our findings indicated that rs17782313, rs543874, rs2241423 and rs11084753 were associated with the risk for children obesity in China, and interaction of genetic variants with diet behaviors on obesity.

[Protective effect of cotransfection of A20 and HO-1 gene against the apoptosis induced by TNF-α in rat islets in vitro].

OBJECTIVE: To establish the method for cotransferring human A20 gene and human heme oxygenase-1 (HO-1) gene into the isolated rat islets using lentiviral transfection system, and to study the protective effect of A20 and HO-1 protein against the apoptosis induced by cycloheximide (CHX) and TNF-α, and finally to explore the underlying mechanism. METHOD: The A20 gene and HO-1 gene were cloned and inserted into the lentiviral transfection system. The efficacy of gene transfer was measured by the intensity of the enhanced green fluorescent protein (EGFP) fluorescence-positive islets. Western blot was applied to verify the expression of the A20 and HO-1 genes. To induce apoptosis in vitro, the isolated islets were treated with CHX+TNF-α, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and the fluorescence-activated cell sorting (FACS) methods were used to evaluate the apoptosis of the islet cells and Western blot was used to detect caspase-3 activation. RESULT: (1) A20 and HO-1 genes were introduced into the isolated islets by lentiviral transfection, both of the genes were highly expressed in the islets after 96 hours culture detected by Western blot method. (2) The insulin levels in the cell culture medium from A20 and/or HO-1 transgenic islets were significantly higher than that in non-transgenic controls (P < 0.01). (3)After CHX + TNF-alpha treatment, the cell culture medium insulin concentration in the A20 gene transfected group [(93.58 ± 4.12)µg/ml], HO-1 gene transfected group [(88.98 ± 4.77) µg/ml ] and A20/HO-1 co-transfected group [(103.33 ± 3.16) µg/ml] were significantly higher than that in the EGFP group [(9.03 ± 0.65) µg/ml ] and the control group [(8.86 ± 0.38) µg/ml] (P < 0.001). Minimum expression level of the activated caspase-3 was found in the A20/HO-1 co-transfected group. CONCLUSION: The lentiviral gene transfer system was an efficient and stable gene transfer vector, the over-expressed A20 and HO-1 protein delivered via lentivirus could preserve rats' islets function and act against the apoptosis induced by CHX and TNF-α.

Status and trends of diabetes in Chinese children: analysis of data from 14 medical centers.

BACKGROUND: Childhood diabetes has become a growing concern. We conducted a study to evaluate the status and trend of diabetes from 14 medical centers in China. Pre-diabetic status among obese children was also noted. METHODS: Hospital medical records were reviewed, and data of diabetes were collected from 1995 through 2010. We took every five years as a calculation unit to analyze the trend of new-onset diabetes. Data on obesity were collected in the recent five years. RESULTS: A total of 4 337 836 patients aged 0-18 years were discharged from the 14 centers. The prevalence (per 100 000 persons) of new-onset type 1 diabetes, type 2 diabetes and other types of diabetes were 96.8, 8.0, and 3.3, respectively. The prevalence of type 1 diabetes increased from 90.9 to 92.9 and 101.4, while type 2 diabetes increased from 4.1 to 7.1 and 10.0 in every five years (P<0.0001). The increasing trend was significant from Southwest to East and North China (type 1 diabetes from 59.76 to 80.02 and 120.45, type 2 diabetes from 2.52 to 3.77 and 15.64 (per 100 000 persons) (all P<0.0001). Well developed areas in China had a higher prevalence compared to less developed areas [type 1 diabetes: 151.51 vs. 32.2 (per 100 000 persons); type 2 diabetes: 15.16 vs. 1.64 and others: 7.54 vs. 0.42 (per 100 000 persons)]. Of the 3153 obese children, 18.24% had impaired fasting glucose (IFG), 5.99% had impaired gulose tolerance (IGT), and 4% had combined IFG and IGT. CONCLUSIONS: The prevalence of childhood diabetes in China has increased dramatically, with type 2 diabetes exceeding type 1 diabetes. The incidence rate of abnormal glucose metabolism in obese children has reached 28.26%.