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

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

OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (rg = 0.87), as well as subgroups of autoantibody status (rg ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10−8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10−8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10−232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10−20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10−12), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85–0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 × 10−11) and lower fasting C-peptide levels (P = 7.19 × 10−3) in individuals newly diagnosed with T1D. CONCLUSIONS Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.

Objective . To describe the demographic features of children with short stature and poor growth in the south of China and provide better guidance on clinical strategy and decisions. Study Design . This retrospective, chart review study analyzed children with short stature and poor growth admitted to the Department of Endocrinology of Children’s Hospital of Nanjing Medical University from Jan 2007 to Dec 2015. Results . The chart review yielded 4142 patients, including 2546 boys and 1596 girls ( P < 0.001); the number of patients gradually increased per year from 2007 to 2015. There was an upward trend in the average levels of height standard deviations (SDs) during the study period ( P < 0.001), both in males ( P < 0.001) and females ( P < 0.001). Mean height SDs were smaller in females (-2.42±1.09) than males (-2.33±1.03; P = 0.01). The percentage of females admitted at normal height (33.83%) was lower than that of males (37.20%; P = 0.028). The peak age range of hospitalization in males was 10–12 years of age, while females were generally admitted earlier—8–10 years. Conclusions . There was an increasing tendency to focus on children’s height. Parents and pediatricians were recommended to pay more attention to the treatment needs of girls while avoiding excessive treatment of those who merely appear not to be tall enough without a clear medical issue related to growth, especially for boys.

目的 分析Turner综合征(TS)患儿身高标准差(SDS)落后情况及影响因素.方法 回顾性分析2009年2月至2014年8月因身材矮小或生长缓慢至南京医科大学附属儿童医院内分泌科就诊的34例TS患儿的临床资料.结果 34例TS患儿,1例身高在1.1 SDS,余33例身高均在-2 SDS以下.回归分析显示,身高SDS与年龄负相关(r=-0.452,P<0.05),与体重SDS正相关(r=0.078,P<0.05),与骨龄、体质量指数、生长激素峰值、胰岛素样生长因子-1、染色体核型、雌激素、黄体生成素、促卵泡刺激素无相关性(P>0.05);按染色体核型将患儿分为45,X和嵌合体组,身高SDS均值比较差异无统计学意义(P>0.05).结论 身材矮小是TS最常见的临床表现,身高落后与年龄和体质量有关,与染色体核型无关.

Clinical controlled study was used in order to explore the correlation between the hormone levels and body mass index in pubertal children with short stature.In this study,208 children with short stature were selected as sample,including 122 males (10～14 years) and 86 females (8～13 years).There were 104 cases in pubertal group (Tanner stage Ⅱ～Ⅳ),while there were 104 cases in prepubertal group (Tanner stage Ⅰ) with age and sex matched.All patients received the clinical evaluation of height,weight and pubertal stage by pediatric endocrinologists.All of those patients underwent GH stimulation testing after overnight fast,with a combination of arginine and clonidine.And blood biochemistry,thyroid function,insulin,C-peptide,insulin-like growth factor 1 (IGF1) and bone age were also measured.The results showed that insulin in adolescence,IGF1,blood glucose and C peptide concentrations of the patients were statistically significant,while the growth stimulating test,increased bone age and thyroid function was not statistically significant,indicating that adolescent GH-IGF1 axis reaction of pubertal children with short stature was damaged.Although there was an increase in height in the pubertal group than in the prepubertal group,it was still lower than the normal.It was found that the perfect physical examination and laboratory examination,especially on IGF1,insulin,C peptide and blood glucose were helpful for the early detection of patients with different causes of short stature,and could improve the level of diagnosis and treatment.

Two patients with neonatal diabetes tested as V59A and V59M mutations were chosen for the study. Clinical data were analyzed retrospectively. The results showed that the patient with V59A mutation was characteristic of spasm and hyperglycemia at the age of three month, and treated with insulin for a long time as unresponsive to the glibenclamide at the beginning. Myasthenia and delay of development were observed during the follow-up. At the age of two years, glibenclamide was tried for the second time with a high dose and fairly-controlled glucose level. The patient with V59M mutation was diagnosed with diarrhea, hyperglycemia, and ketosis at the age of two month, and was responsive to glibenclamide at a relatively low dose with well-controlled glucose level. These results suggest that KCNJ11 V59M mutation would show some milder clinical manifestations and better glibenclamide efficacy as compared with V59A mutation.

Sj(o)gren-Larsson综合征(SLS)是一种罕见的常染色体隐性遗传性神经皮肤综合征,临床表现主要包括先天性鱼鳞病、精神发育落后、双侧或四肢痉挛性瘫痪三联征.我国迄今报道10余例,其中相关基因报道较少,现对南京医科大学附属儿童医院康复科收治的1例SLS患儿家系进行ALDH3A2基因突变研究,探讨此病临床表现与基因的关系.

目的 总结Prader-Willi综合征(PWS)患儿儿童期的临床特征,加强对PWS的认识,以便早期干预.方法 回顾性分析南京医科大学附属南京儿童医院2012年7月至2014年12月收治的10例PWS患儿的病例资料,采用甲基化特异性聚合酶链式反应(MS-PCR)方法进行基因分析.结果 10例患儿均有新生儿期肌张力低下,随后出现食欲亢进、摄食过度及体质量增长过快.4例男性患儿均有隐睾,1例女性患儿青春期发育延迟.1例为矮小症,且生长激素完全缺乏.2例出现胰岛素抵抗,1例患儿出现糖耐量异常.1例患儿为极度肥胖PWS,出现严重阻塞性睡眠呼吸暂停低通气综合征而最终死亡.MS-PCR均检出父源片段丢失,结合临床确诊为PWS患者.结论 PWS是一种累及多系统的遗传性疾病,表现不具特异性,易被漏诊、误诊.早期诊断和早期生活方式干预可减缓过度肥胖引起的并发症、提高生活质量、减少早期病死率.

目的:探讨促炎性细胞因子对胰岛β细胞miR-29家族及抗凋亡蛋白水平的影响.方法:将大鼠胰岛细胞系INS-1细胞在加或不加促炎性细胞因子混合物(IL-1β 10 ng/mL、TNF-α 50 ng/mL、IFN-γ 50 ng/mL)的培养液中培养24 h,设立对照组、促炎性细胞因子干预组.流式细胞仪测细胞凋亡,实时荧光定量PCR检测INS-1细胞miR-29a/b/c表达以及抗凋亡基因骨髓细胞白血病蛋白1 (myeloid cell leukemia 1,Mcl-1)mRNA、B细胞淋巴瘤蛋白2(B-cell lymphoma 2,Bcl-2)mRNA的表达水平,Western blot技术检测Mcl-1、Bcl-2蛋白的表达情况.结果:①促炎性细胞因子干预的INS-1细胞miR-29a/b表达水平较正常对照组增加,差异有统计学意义(P＜0.05),miR-29c表达水平较正常对照组有上升趋势,但无统计学差异(P＞0.05);②促炎性细胞因子干预组INS-1细胞Mcl-1 mRNA、Bcl-2 mRNA表达水平较对照组减少,但差异无统计学意义(P＞0.05);③促炎性细胞因子干预组INS-1细胞抗凋亡蛋白Mcl-1、Bcl-2表达水平较正常对照组明显下降,差异有统计学意义(P＜0.01);④促炎性细胞因子干预组细胞凋亡率增高,与正常对照组相比差异有统计学意义(P＜0.05).结论:促炎性细胞因子刺激处理的INS-1细胞miR-29a/b表达均上调,抗凋亡蛋白Mcl-1、Bcl-2下调,凋亡率上升,推测促炎性细胞因子可能通过调节miR-29家族及抗凋亡蛋白的表达水平诱导胰岛β细胞凋亡,从而促进1型糖尿病的发生.

ObjectiveThe aim of this study is to analyze the etiology and status of bone age of children with short stat-ure.MethodsAnthropological and physical examination data were retrospectively collected and studied in 2132 children with short stature in the department of endocrinology between 2009 and 2014. Growth hormone (GH) levels were determined by ar-ginine-clonidine test. Bone age was determined by CHN scoring.ResultsAmong the 2132 patients, 1333 were males and 799 were females. Mean age is 9.03 ± 3.04 years old, mean bone age is 6.81 ± 3.05 years. Of them, 324 cases (15.2%) were diagnosed complete GH deifciency, 780 cases (36.59%) were partial GH deifciency, 27cases (1.27%) were multiple pituitary hormone de-ifciency, 13 cases (1.64%) were hypothyroidism, 893 cases (41.89%) were idiopathic short stature, 19 cases (0.89%) were small for gestational age (SGA), 40 cases (1.88%) were chromosomal disorders, etc. Signiifcant difference in age and bone age was found using t test (P<0.05). Signiifcant differences in Δage were found between etiological categories using ANOVA (P=0.000). Δage was signiifcantly and negatively associated with peak GH using Pearson's correlation.ConclusionsGH deifciency is the most common cause of short stature. Bone age of children with short stature is commonly delayed. Δage was signiifcantly and negatively associated with peak GH. Multiple pituitary hormone deifciency has a signiifcant effect on bone age. The etiology of patients with short stature cannot be determined just by bone age.

Combined with the literature, recognize the clinical features and molecular genetic mechanism of the disease. 17a-hydroxylase/17,20-lyase deficiency, a rare form of congenital adrenal hyperplasia, is caused by mutations in the cytochrome P450c17 gene (CYP17A1), and characterized by hypertension, hypokalemia, female sexual infantilism or male pseudohermaphroditism. We presented the clinical and biochemical characterization in two patients (a 13 year-old girl (46, XX) with hypokalemia and lack of pubertal development, a 11 year-old girl (46, XY) with female external genitalia and severe hypertension). CYP17A1 mutations were detected by PCR and direct DNA sequencing in patients and their parents. A homozygous mutation c.985_987delTACinsAA (p.Y329KfsX418) in Exon 6 was found in patient 1, and a homozygous deletion mutation c.1459_1467delGACTCTTTC (p.Asp487_Phe489del) in exon 8 in patient 2. The patients manifested with hypertension, hypokalemia, sexual infantilism should be suspected of having 17a-hydroxylase/17,20-lyase deficiency. Definite diagnosis is depended on mutation analysis. Hydrocortisone treatment in time is crucial to prevent severe hypertension and hypokalemia.

目的:研究1型糖尿病(type 1 diabetes,T1D)患者甲状腺自身免疫抗体与胰岛自身抗体及甲状腺功能的关系、成人与儿童患者甲状腺自身免疫性的差异.方法:对491例T1D患者进行临床资料的收集及甲状腺功能、甲状腺及胰岛自身抗体的检测.结果:22.0％的T1D患者合并甲状腺自身抗体(T-Ab)阳性(女性占62％);T-Ab阳性患者其胰岛自身抗体阳性率均较T-Ab阴性者高(P均＜ 0.05);甲状腺过氧化物酶抗体(TPOAb)阳性率与5种胰岛自身抗体阳性率均成正相关(P＜0.05),而甲状腺球蛋白抗体(TGAb)仅与谷氨酸脱羧酶抗体(GADA)相关(P=0.005);多胰岛自身抗体阳性患者T-Ab阳性率显著高于单个胰岛自身抗体阳性及T-Ab阴性者(30.2％,P=0.000);成人T1D患者22.6％出现T-Ab,其中TGAb及TPOAb均阳性的患者较儿童多(双甲状腺抗体阳性:57.8％ vs 36.4％,P=0.028);TPOAb与TGAb均阳性的患者血清促甲状腺素(TSH)水平较高(P=0.008),其发生甲状腺功能异常风险高(甲状腺功能异常:64.2％ vs 30.9％,P=0.002).结论:成人及儿童T1D均易合并出现甲状腺抗体阳性,其中女性、GADA阳性、多胰岛自身抗体阳性者自身免疫性甲状腺疾病(AITD)发病风险更高;成人患者AITD发病风险与儿童无明显差异,但甲状腺自身免疫程度更剧烈;合并多甲状腺自身抗体阳性的患者更易出现甲状腺功能异常,需密切跟踪随访.

目的:比较1型糖尿病(type 1 diasetes,T1D)胰岛自身抗体阳性率与年龄和病程之间的关系.方法:对537例T1D患者检测其胰岛自身抗体,并收集一般信息和实验室检查结果,再将患者按年龄和病程进行分组,比较不同年龄和病程组患者胰岛自身抗体阳性率的差异.结果:537例患者平均年龄为(32.84±17.98)岁,平均病程为4.31年.谷氨酸脱羧酶抗体(GADA)、蛋白酪氨酸磷酸酶抗体(IA-2A)、锌转运体8自身抗体(ZnT8A)和胰岛细胞抗体(ICA)的阳性率分别为54.4％、30.8％、28.2％和23.5％,至少1个抗体阳性率为75.4％.青春期前后的患者抗体阳性率分别为GADA 76.9％vs 57.4％(P=0.039),IA-2A 65.4％ vs31.7％(P=0.001),ZnT8A 38.5％ vs 24.1％(P=0.108),至少1个抗体阳性83.3％vs 75.7％(P=0.014).病程5年以内至少1个抗体阳性率为55.7％,而5年以上的阳性率为44.1％(P=0.032).结论:随着T1D患者病程延长,抗体阳性率逐渐降低;患者年龄越小,抗体阳性率越高.因此对于成人T1D的诊断要应该更仔细,避免漏诊.

BACKGROUND:The hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by GATA3 gene mutation. We report here a case that both of a Chinese boy and his father had HDR syndrome which caused by a novel mutation of GATA3.METHODS:Polymerase chain reaction and DNA sequencing was performed to detect the exons of the GATA3 gene for mutation analysis.RESULTS:Sequence analysis of GATA3 revealed a heterozygous nonsense mutation in this family: a mutation of GATA3 at exon 2 (c.515C >A) that resulted in a premature stop at codon 172 (p.S172X) with a loss of two zinc finger domains.CONCLUSION:We identified a novel nonsense mutation which will expand the spectrum of HDR-associated GATA3 mutations.

Objective To explore the regulating effect of expressions of melatonin(MT)and its receptors(MT1,MT2)on puberty development.Methods On the basis of developmental phrases,40 SD female rats were equally divided into four groups of A(juvenile),B(preadolescence),C(early adolescence)and D(maturity),which were executed on the 15th,25th,35th and 45th day after birth,respectively.Plasma levels of MT and luteotropic hormone(LH)were detected by ELISA,and gonadotrophin releasing hormone(GnRH)mRNA,MT1mRNA and MT2mRNA were detected by RT-PCR.Results Plasma level of MT decreased during puberty development(P<0.05).Plasma level LH was higher in group C than that in groups of A and B(P<0.05).Plasma level of GnRH mRNA was the highest in group C and the lowest in group A(P<0.05).Expression of MT1 mRNA was significantly higher in groups of A and B,which was reduced in groups of C and D(P<0.05).Conclusion Plasma MT and its receptors have inhibitory effect on puberty development,which are involved in the regulation of GnRH and related to evocation of puberty development.