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Osteogenesis imperfecta (OI) is a genetic disease with an estimated prevalence of 1 in 13,500 and 1 in 9700. The classification into subtypes of OI is important for prognosis and management. In this study, we established a clinical severity prediction model depending on multiple features of variants in COL1A1/2 genes.Ninety percent of OI cases are caused by pathogenic variants in the COL1A1/COL1A2 gene. The Sillence classification describes four OI types with variable clinical features ranging from mild symptoms to lethal and progressively deforming symptoms.We established a prediction model of the clinical severity of OI based on the random forest model with a training set obtained from the Human Gene Mutation Database, including 790 records of the COL1A1/COL1A2 genes. The features used in the prediction model were respectively based on variant-type features only, and the optimized features.With the training set, the prediction results showed that the area under the receiver operating characteristic curve (AUC) for predicting lethal to severe OI or mild/moderate OI was 0.767 and 0.902, respectively, when using variant-type features only and optimized features for COL1A1 defects, 0.545 and 0.731, respectively, for COL1A2 defects. For the 17 patients from our hospital, prediction accuracy for the patient with the COL1A1 and COL1A2 defects was 76.5% (95% CI: 50.1-93.2%) and 88.2% (95% CI: 63.6-98.5%), respectively.We established an OI severity prediction model depending on multiple features of the specific variants in COL1A1/2 genes, with a prediction accuracy of 76-88%. This prediction algorithm is a promising alternative that could prove to be valuable in clinical practice.

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.

Background The gold standard for the diagnosis of central precocious puberty (CPP) is gonadotropin-releasing hormone (GnRH) or GnRH analogs (GnRHa) stimulation test. But the stimulation test is time-consuming and costly. Our objective was to develop a risk score model readily adoptable by clinicians and patients. Methods A cross-sectional study based on the electronic medical record system was conducted in the Children’s Hospital, Fudan University, Shanghai, China from January 2010 to August 2016. Patients with precocious puberty were randomly split into the training (n = 314) and validation (n = 313) sample. In the training sample, variables associated with CPP (P Results CPP was diagnosed in 54.8% (172/314) and 55.0% (172/313) of patients in the training and validation sample, respectively. The CPP risk score model included age at the onset of puberty, basal luteinizing hormone (LH) concentration, largest ovarian volume, and uterine volume. The C-index was 0.85 (95% CI: 0.81–0.89) and 0.86 (95% CI: 0.82–0.90) in the training and the validation sample, respectively. Two cut-off points were selected to delimitate a low- ( Conclusions A risk score model for the risk of CPP had a moderate predictive performance, which offers the advantage of helping evaluate the requirement for further diagnostic tests (GnRH or GnRHa stimulation test).

Objective To evaluate the safety and efficacy of weekly PEGylated-recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS) in China. Design and methods This was a multicenter, phase II study in which all subjects were randomized 1:1:1 to weekly s.c. injections of PEG-rhGH 0.1 (low-dose (LD) group) or 0.2 mg/kg/week (high-dose (HD) group) or control for 52 weeks. The primary end point was change (Δ) in height s.d. score (HT-SDS) from baseline to week 52. Secondary end points were height velocity (HV), bone maturity, insulin-like growth factor-1 (IGF-1) SDS, and IGF-1/insulin-like growth factor-binding protein-3 (IGFBP-3) molar ratio. Results A total of 360 children with ISS were recruited in the study (n = 120 in each group). At week 52, ΔHT-SDS was 0.56 ± 0.26, 0.98 ± 0.35, and 0.20 ± 0.26 in the LD, HD, and control groups, respectively (within-group P < 0.0001; intergroup P < 0.0001). Statistically significant values of ΔHV, IGF-1, IGF-1/IGFBP-3 ratio, and IGF-1 SDS at week 52 from baseline were observed in both treatment groups (P < 0.0001). There were clear dose-dependent responses for all auxological variables. PEG-rhGH was well tolerated throughout the treatment period with treatment-emergent adverse events (TEAEs) reported in 86.5%, 84.6%, and 91.3% of children in the HD, LD, and control groups, respectively. The incidence of TEAEs was similar in all treatment groups despite the difference in doses. A total of 27 (8.7%) children experienced drug-related TEAEs. Conclusion Fifty-two-week treatment with PEG-rhGH 0.1 or 0.2 mg/kg/week achieved significant improvement in HT-SDS and other growth-related variables, including HV, IGF-1 SDS, and IGF-1/IGFBP-3 ratio, in a dose-dependent manner. Both doses were well tolerated with similar safety profiles.

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.

ContextLong-acting recombinant human growth hormone (rhGH) has transformed growth hormone deficiency (GHD) treatment. However, the possibility and rationality for flexible time regimen are pending.ObjectiveWe studied the efficacy of biweekly versus weekly PEGylated rhGH (PEG-rhGH) therapy in GHD children.Design, Setting, and PatientsThis multicenter, phase IV trial with a non-inferiority threshold ≥20% enrolled 585 Tanner stage I GHD children.InterventionSubjects randomly received 0.20 mg/kg once-weekly or biweekly PEG-rhGH, or 0.25 mg/kg.w rhGH once daily for 26 weeks.Main Outcome MeasureThe primary outcome was height SD scores for chronological age (HtSDSCA) at week 26 and safety measurements including adverse events (AEs), IGF-2, and IGFBP-2 changes.ResultsAt week 26, the median HtSDSCA changed from −2.75, −2.82, and −2.78 to −2.31, −2.43, and −2.28 with weekly and biweekly PEG-rhGH, and daily rhGH, respectively. The difference in HtSDSCA was 0.17 ± 0.28 between weekly and biweekly PEG-rhGH, and 0.17 ± 0.27 between daily rhGH and biweekly PEG-rhGH, failing the non-inferiority threshold. Nevertheless, the height velocity of children receiving biweekly PEG-rhGH reached 76.42%–90.34% and 76.08%–90.60% that of children receiving weekly PEG-rhGH and daily rhGH, respectively. The rate of AEs was comparable among the groups. No statistical difference was observed in IGF-2 and IGFBP-2 levels among the groups. IGFBP-2 levels decreased over time in all groups, with no notable difference in IGF-2 and IGFBP-2 changes among the three treatment groups.ConclusionsAlthough notably promoted height velocity, biweekly PEG-rhGH failed the non-inferiority threshold as compared with either weekly PEG-rhGH or daily rhGH. Compared with short-term rhGH, long-acting PEG-rhGH did not significantly increase tumor-associated IGF-2 and IGFBP-2 expressions.Clinical Trial Registrationclinicaltrials.gov, identifier NCT02976675.

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.

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. 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. 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

The current study investigated the merger-in-progress between word-initial nasal and lateral consonants in Fuzhou Min, examining the linguistic and social factors that modulate the merger. First, the acoustic cues to the l-n distinction were examined in Fuzhou Min. Acoustic analyses suggested a collapse of phonemic contrast between prescriptive L and N (phonemes in the unmerged system), with none of the six acoustic cues showing any difference across L and N. Linear discriminant analysis did identify acoustically distinct [l] and [n] tokens, although the mapping onto the phonetic space of prescriptive L and N substantially overlapped. Speakers of all ages and both genders tended to produce [l], and low vowels correlated with more [n]-like classification. In perception, AX discrimination data showed Fuzhou Min listeners confused both prescriptive L and N and acoustic [l] and [n]. Greater sensitivity to the acoustic differences occurred in the context of low vowels and a nasal coda, supported by the acoustics of the stimuli, and younger listeners were more sensitive to the difference between [l] and [n] than older listeners. In two-alternative forced choice (2AFC) identification, Fuzhou Min listeners also identified the merged form as L more frequently than N, with more L responses elicited in the context of low vowels and in the absence of nasal codas. Overall, although Fuzhou Min speakers produced some acoustically distinct [l] and [n] tokens in the context of a sound merger, these productions did not map onto prescriptive L and N. In addition, younger listeners were more sensitive to the acoustic distinction than older listeners, suggesting an emerging acoustic contrast possibly arising due to contact with Mandarin.

Additional file 2. Method: Risk score system.

Additional file 1: Additional Table 1. Association of clinical characteristics and pelvic sonographic variables with central precocious puberty in the training sample (n = 314). Additional Table 2. Selected prediction model for central precocious puberty in the training sample (n = 314). Additional Figure 1. Calibration plot for the selected logistic regression model and risk score model in the training and validation sample (A. Training sample B. Validation sample).

In speech perception, when a primary acoustic cue (e.g., VOT) is ambiguous, listeners may increase the weight of a secondary cue (e.g., F0). In experiment 1, we compared the cue-weighting adjustment strategies across younger and older normal-hearing adults with a distributional learning paradigm. Two groups of native English listeners were exposed to voicing contrasts that were ambiguous in either VOT or F0. Additionally, listeners may access lexical information to help resolve the ambiguity in the acoustic signal. Older listeners have been reported to use lexical information to a greater degree than younger listeners. In experiment 2, using a lexically guided learning paradigm, we tested if younger and older adults differ in their use of lexical information when learning to interpret ambiguous acoustic tokens. There were four types of exposure, in which stimuli differed in lexical status ( day-*tay; *doy-toy ) and the acoustic ambiguity involved either only VOT or both VOT and F0. Preliminary results from younger normal-hearing, listeners showed significant speech adaptation effects, with a significant change in cue weights in distributional learning and salient lexical bias in lexically guided learning. More data will be collected from older adults to assess the extent of perceptual learning relative to younger adults.

BackgroundIn 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.MethodsA 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.ResultsAmong 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.ConclusionsWe 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.

Background: Leuprorelin is an analog of gonadotropin-releasing hormone that is used for the therapy of central precocious puberty (CPP). The aims of this prospective, open label, multicenter clinical trial were to establish its efficacy and safety during long-term use. Methods: Patients, who were all children, were treated with 1.88 to 3.75 mg leuprorelin subcutaneously once every 4 weeks for a total of 96 weeks between 2015 and 2018. The primary endpoint was the rate of occurrence of adverse events (AEs) and the secondary endpoint was no progression in the Tanner stage or regression by week 96 compared to baseline. Results: A total of 307 CPP patients, 305 (99.3%) females and 2 males (0.7%), completed the 96-weeks of treatment. Due to limited data for male patients, they are not discussed in the efficacy results. Treatment-emergent AEs (TEAEs) were reported for 252 (82.1%) patients, mostly (79.5%) being mild or moderate and only 33 (10.7%) of patients experienced TEAEs related to leuprorelin therapy. The most frequent (>2%) drug-related TEAEs were injection site induration (4.6%, 14/307) and vaginal bleeding (2.3%, 7/305). After treatment, 83.5% of patients had regression or no progression in the Tanner stage (95% confidence interval: 78.68%, 87.62%) and the majority had decreased gonadotropin-releasing hormone-stimulated peak luteinizing hormone and follicle-stimulating hormone concentrations, as well as reduced sex hormone concentrations and a reduction in the bone age/chronological age ratio compared to baseline. Conclusions: The trial revealed that CPP was effectively treated in most patients who received leuprorelin for nearly 2 years. Any drug-related AEs were reported with low incidence (

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.

Based on the concept of system thinking and system design, a systematically mechanistic network of glucose conversion toward fructose, 5-hydroxymethyl furfural, 1,6-anhydroglucose, 1,2,4-Benzenetriol, levulinic acid, furfural, erythrose, glyceraldehyde, dihydroxyacetone, pyruvaldehyde, lactic acid, glycolaldehyde in subcritical water were performed by employing dispersion-corrected density functional theory. Fukui functions results predict the most highest reactivity of O(5) of glucose to suffer protonation in subcritical water, which may readily lead to the formation of 1,6-anhydroglucose or fructose with the comparable apparent activation energies (29.441 vs 29.305 kcal/mol). Further dehydration of monosaccharide to 5-HMF is more favorable via cyclic pathway for fructose in comparison to the acyclic pathway for glucose. The formation of levulinic acid has an apparent activation energy of 33.321 kcal/mol but the rate is limited by the numerous steps. The consumption of 5-HMF to 1,2,4-Benzenetriol exhibits a high activation energy of 76.682 kcal/mol. Retro-aldol condensation of C4 compounds prefer to give C2 rather than C3 compounds. The thermodynamic results involving the generation of C2, C3 and C4 compounds by retro-aldol condensation of open-chain C6 intermediates agree with the experimental product distribution and reactivity over temperature at the initial stage of glucose or fructose subcritical hydrolysis. Furthermore, the assistance of H+ may be responsible for the isomerization and retro-aldol condensation in glucose conversion. This comprehensive reaction network provides a fundamental understanding and deeper insight into glucose conversion, which reasonably explains experimental activity and selectivity reported for glucose and fructose conversion in subcritical water.

Type 1 diabetes (T1D) is an autoimmune disease that has strong contribution of genetic factors to its etiology. We aimed to assess the genetic association between non-HLA genes and T1D in a Chinese case-control cohort recruited from multiple centers consisting of 364 patients with T1D and 719 unrelated healthy children. We genotyped 55 single nucleotide polymorphisms (SNP) markers located in 16 non-HLA genes (VTCN1, PTPN22, CTLA4, SUMO4, CD274, IL2RA, INS, DHCR7, ERBB3, VDR, CYP27B1, CD69, CD276, PTPN2, UBASH3A, and IL2RB) using SNaPshot multiple single-base extension methods. After multivariate analysis and correction for multiple comparisons, we identified the SNP rs2292239 in ERBB3 gene were significantly associated with T1D. The frequency of the major G allele was significantly decreased in patients with T1D (68.8% in T1D vs 77.3% in controls, OR 0.65, 95% CI 0.53–0.79, P = 0.02), and the minor allele T was associated with an increased risk of T1D (OR 1.55, 95% CI 1.26–1.90, P = 0.02). Our haplotype analysis confirmed that rs2292239 was the primary T1D association locus in our current investigation. These results indicated that the ERBB3-rs2292239 was the primary T1D association locus among the investigated 55 SNPs in 16 non-HLA genes in Chinese Han population., Highlights • A large scale case-control genetic association study on type 1 diabetes in Chinese investigating on-HLA genes. • rs2292239 in the ERBB3 gene conferred the primary non-HLA association in Chinese type 1 diabetes. • Markers in the common candidate genes, such as PTPN22, CTLA4, IL2RA, and INS, were not significantly associated with T1D in our Chinese cohort.

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. Electronic supplementary material The online version of this article (10.1186/s12881-018-0591-z) contains supplementary material, which is available to authorized users.

Figure S2. Black arrow: Cervical-vertebral cleft in the spine. White arrows: Apophyses in the upper and lower thoracic vertebrae. (PDF 2309Â kb)

Figure S1. The amino acid "Q" in red represents the conservative property in position "p. Gln2364Pro" among differet species. (PDF 416Â kb)

Background Exogenous androgen supplement is an optional treatment for micropenis; however, its use in childhood is controversial due to potential side effects. Methods Twenty-three children (mean age: 4.07±3.4 years) with micropenis of unknown causes harboring the 46,XY karyotype were recruited in an open prospective study. Androgen receptor (AR), steroid 5α-reductase-2 (SRD5A2), and SRY genes were sequenced; 2.5% dihydrotestosterone (DHT) transdermal gel (0.1-0.3 mg/kg/day) was applied and titrated within the normal DHT serum reference ranges. Stretched penile length (SPL) was measured before therapy, and after 1, 3 and 6 months of DHT gel treatment, respectively. Results Two patients were found with AR gene mutations and five patients with SRD5A2 gene mutations. Average stretched penile lengths (SPLs) were 1.68±0.6 cm at baseline and 2.2±0.66 cm, 2.6±0.59 cm and 2.9±0.55 cm (mean ± 1 SD) after 1, 3 and 6 months of treatment, respectively. Fourteen cases (61%) reached standard penile length ranges (>-2.5 SD) and medication was discontinued; six cases (26%) were satisfied with the improved penile lengths despite failing to reach the aged matched standards. Three infants (13%) discontinued the medication after 3 months due to anxiety about the potential side effects. No significant side effects were found except the elevated DHT serum levels after therapy. Conclusions Short term and local application of DHT at low doses in patients with micropenis could accelerate penile growth effectively without evident side effects; however, precautions still need be taken due to the paucity of long term study and the lack of ideal DHT dosage.

The aim of this study was to investigate incidence trend of childhood type 1 diabetes in Shanghai, a megalopolis in east China. We established a population-based retrospective registry for the disease in the city's registered population during 1997-2011 and collected 622 incident type 1 diabetes in children aged 0-14 years. Standardized incidence rates and 95 % CI were estimated by applying the capture-recapture method and assuming Poisson distribution. Incidence trend was analyzed using the Poisson regression model. The mean annual incidence of childhood type 1 diabetes was 3.1 per 100,000 person-years. We did not observe significant difference in incidence between boys and girls. The incidence is unstable and had a mean annual increase 14.2 % per year during the studied period. A faster annual increase was observed in boys, warmer seasons, and in the outer regions of the city. If present trends continue, the number of new type 1 diabetes cases will double from 2016 to 2020, and prevalent cases will sextuple by 2025. Our results showed the incidence of childhood type 1 diabetes was rising rapidly in Shanghai. More studies are needed to analyze incidence changes in other regions of China for appropriate allocation of healthcare resources.

The contrast between word-initial [n] and [l] is disappearing in many Chinese languages, including Eastern Min. Before investigating the status of the merger, we need to identify the acoustic cues that distinguish [n] from [l]. In English and Mandarin, languages with the [n] and [l] contrast, we examined: (1) Duration: consonant duration and consonant-vowel transition duration; (2) Formant frequencies: F1, F2 and F3 at the midpoint of the consonant; (3) Formant intensities: I1, I2, and I3 at the midpoint of the consonant; and (4) Relative amplitude (the amplitude difference between the consonant and the following vowel). Preliminary results show that [n] is significantly longer than [l] in Mandarin and English but not in Eastern Min. F2 of [n] is higher than F2 of [l] in English and Mandarin, whereas the direction is reversed in Eastern Min. Finally, the difference in relative amplitude between [n] and [l] is greater in English and Mandarin than in Eastern Min. Together, these results suggest a merger in progress in Eastern Min . Moreover, older Eastern Min speakers showed the merger to a greater degree than younger speakers, presumably because the older speakers use Mandarin less frequently.

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.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.The patient with PNDM had c.848GA (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.A novel SLC19A2 mutation (c.848GA; 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.

Objective The pathogenic base of neonatal diabetes mellitus (NDM) is highly heterogeneous. Sulfonylurea (SU) has been successfully applied in majority of NDM patients with KATP channel mutations; however, its rationality and effectiveness among patients with NDM stemmed from other genetic mutations have not been established. The objective of the present study was to investigate the effectiveness of SU therapy in NDM patients with heterogeneous genetic backgrounds. Methods We identified 16 patients with NDM. These patients underwent SU titration and were followed after successful SU monotherapy. All patients were sequenced for all exons and adjacent intron-exon junctions of ABCC8, KCNJ11, and INS, and analyzed for 6q24 methylation defects. SU regimens were applied and glycemic status was evaluated in each patient. Results Of the 16 patients, 15 (94%) reached glycemic goal (7-10 mmol/L) after SU monotherapy except one patient with the INS mutation. No significant side effects or organ damage were found in any of the 16 patients. Among these patients, five were found to harbor ABCC8 mutations, another five had mutations in KCNJ11, two had INS gene mutations, one with 6q24 hypomethylation, and three were absent for defects in genes tested. Conclusion Our study showed that SU monotherapy resulted in satisfactory glycemic control in most of the patients with NDM whose genetic defects are heterogeneous. The usage of SU may be considered as first-line therapy for patients with NDM in developing countries where effective genetic screening is not established.

The aim of this study is to investigate the frequency distribution of exon 3 deleted (d3-GHR) genetic polymorphism of growth hormone receptor (GHR) in growth hormone deficient (GHD) Chinese children and to explore the correlation between the growth promoting effects of recombinant human growth hormone (rhGH) and exon 3 genetic polymorphism of GHR in GHD children. In this study, 111 GHD (excluded small for gestational age) children were treated with rhGH (0.20 mg/kg/week) for six months. The body height (Ht), body weight, bone age (BA) and growth velocity (GV) were measured before and after six months of treatment. The d3-GHR and full length GHR (fl-GHR) were analyzed to detect the frequency distribution of two isoforms and their influence on growth promoting effect of rhGH. The results indicated that the frequencies of fl/fl, fl/d3 and d3/d3 GHR genotypes were 67.6%, 18.9% and 13.5%. After six months of GH therapy, there were significant differences of ΔGV (ΔGV: 10.77±3.40 cm/year vs 12.18±3.08 cm/year) (P

Aims To examine single nucleotide polymorphisms in the protein tyrosine phosphatase N22 gene (PTPN22) and to study their association with Type 1 diabetes in a Chinese cohort. Methods Three hundred and sixty-four young patients with Type 1 diabetes and 719 healthy children were included in this case-controlled study. The genotypes of rs1217385, rs2488457 (–1123C>G), rs1217414, rs1217419, rs3765598 and rs2476601 (1858C>T) in the PTPN22 gene were determined using the SNaPshot method. Alleles, genotypes and haplotype frequencies were compared between patients with Type 1 diabetes and healthy control subjects. The association between single nucleotide polymorphisms and clinical traits/autoantibody status was also analysed. Results The single nucleotide polymorphism, rs1217419, located in the second intron of the PTPN22 gene was associated with Type 1 diabetes (odds ratio 1.5, 95% CI 1.14–1.97, P = 0.003). An additional single nucleotide polymorphism, rs1217385, was also associated with Type 1 diabetes; however, the association was secondary to that of rs1217419. The previously reported single nucleotide polymorphism that is associated with Type 1 diabetes (–1123G>C) had only marginal association with Type 1 diabetes in our study. A marginal association was also identified between –1123G>C and glutamic acid decarboxylase autoantibody positivity in patients with Type 1 diabetes. There was no association between the single nucleotide polymorphism 1858C>T and Type 1 diabetes in our studied cohort. Conclusions Our study confirmed that PTPN22 is a gene that contributes to Type 1 diabetes susceptibility. The primary association occurs with single nucleotide polymorphism rs1217419 and there is clear heterogeneity of the association between PTPTN22 polymorphisms and Type 1 diabetes in a Chinese population compared with other populations.

Gao L, Zheng Z, Cao L, Shen S, Yang Y, Zhao Z, Zhi D, Cheng R, Pei Z, Yongfu Y, Luo F. The growth hormone receptor (GHR) exon 3 polymorphism and its correlation with metabolic profiles in obese Chinese children. Objective: We investigated the correlation between the growth hormone receptor (GHR) exon 3 polymorphism and the metabolic profiles of Chinese children with obesity. Subjects and methods: A total of 409 obese/overweight children and 206 normal weight children were recruited. Anthropological and biochemical indexes including insulin and lipid profiles were measured. Genomic DNA was extracted from the peripheral blood leukocytes, and the GHR exon 3 polymorphism was genotyped by polymerase chain reaction. Homeostasis model of assessment for insulin resistance index (HOMA-IR) and insulin sensitivity index (ISI) were calculated using the homeostasis model. Results: The frequency of the exon 3-deleted GHR (d3-GHR) polymorphism within the obese group was significantly higher than that of the control group (p < 0.05). Body mass index (BMI), fasting insulin (FIns), HOMA-IR, total cholesterol, and triglycerides were significantly lower in the d3-GHR (d3/d3 and d3/fl) group than in the full-length GHR (fl/fl, fl-GHR) group (p < 0.05). After adjustment for BMI, cholesterol level was still significantly lower and HOMA-IR was marginally lower (p = 0.079) in the d3-GHR obese group. There was no statistically significant difference in BMI, FIns, HOMA-IR, ISI, total cholesterol, or triglyceride levels between the two genotypes in the control group. Conclusion: We report that the d3-GHR polymorphism has a significant effect on BMI and the metabolic parameters of Chinese children with obesity. The d3 allele may have a protective effect on the development of metabolic syndrome by increasing insulin sensitivity.

ContextCongenital generalized lipodystrophy (CGL) is a rare and heterogeneous disease of autosomal recessive inheritance. Until now, no genetic findings had been reported in Chinese patients with CGL.ObjectiveTo analyze Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) and 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) gene variation in a Chinese boy with CGL and his family.Design, setting, and participantsAll exons of BSCL2 and AGPAT2 with adjacent intron–exon junctions were analyzed using direct sequencing.Main outcome measuresSequences of each exon and nearby intron of the BSCL2 and AGPAT2 genes of the family members were compared with the gene bank genomic sequences.ResultsDNA sequence analysis of the entire coding regions and surrounding uncoding regions disclosed a novel homozygous G→T mutation at nucleotide 909 in exon 5 of the BSCL2 gene in the affected child. A heterozygous state of the G→T mutation of the BSCL2 gene was also found in other family members. This mutation predicts the substitution of glutamic acid at codon 189 by the stop codon (Glu189X or E189X). No variation was found in the AGPAT2 gene.ConclusionE189X is a novel BSCL2 gene mutation that contributes to CGL formation in a family of Chinese origin.

Subjects and methods We reviewed the records for all patients undergoing GHRT at our hospital over the study period. Patients were included if they had received CP resection, GHRT for at least 12 months, and records of serial magnetic resonance imaging data and data for treatment, pituitary hormone profiles and growth chart were available. GHnaive control patients were selected from our hospital database of patients carried out the same surgery. Patients were matched for date of surgery, age, site of primary diagnosis and sex.

Autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) in newly diagnosed and young adult type 1 diabetes mellitus (T1DM) was reported. We report our first year AHST experience in newly diagnosed childhood T1DM. 7 patients with T1DM (HbA1c 11.7%-14%, 4 with diabetic ketoacidosis, aged 5.0-13.7 years) diagnosed within the previous 3 months by clinical findings and hyperglycemia and confirmed with positive antibodies against GAD65, IA2, ICA or insulin. Hematopoietic stem cells were mobilized with cyclophosphamide and granulocyte colonystimulating factor and then collected from peripheral blood by leukapheresis and cryopreserved. The cells were injected intravenously after conditioning with cyclophosphamide and rabbit antithymocyte globulin. Major side effects, changes in exogenous insulin requirements, HbA1c, C-peptide levels are analyzed. During a 12- to 18-month follow-up, 6 (6/7, 85.7%) patients became insulin free 1-3 months after AHST, 1 patients failed (5 year old) to acquire insulin free, all the patients resumed normal school study. The preprandial, predormital blood glucose were ranged from 3.9-6.0 mmol/L with the HbA1c level between 4.6%-6.1% in insulin-independent patients. Vomiting, anorexia, short-term fever, hair loss occurred in all the patients during AHST, convulsion occurred in 1 patients due to severe sodium water retention, leukocytopenia was evident in the first 1-3 months after AHST, one patients suffered from acute bronchitis 2 months after AHST. No other systemic organ lesions were found in all the patients. High-dose immunosuppression and AHST were performed with acceptable toxicity in 7 patients with newly diagnosed childhood T1DM. With AHST, beta cell function was improved and induced insulin independence in the majority of the patients.