Rabson-Mendenhall syndrome (RMS) is a rare autosomal recessive disorder caused by mutations in the insulin receptor gene (INSR), leading to severe insulin resistance. Clinical manifestations of RMS include hypertrichosis and acanthosis nigricans. A 3-yr-old male patient presented with darkened skin on the neck, without any apparent precipitating factors, and did not exhibit symptoms of polyuria or polydipsia. Both the patient and his older sister displayed signs of hypertrichosis and acanthosis nigricans. Laboratory investigations revealed significantly elevated levels of insulin and C-peptide. Genetic testing identified two mutations in the INSR gene: c.3614C>T in exon 20 and c.3670G>A in exon 21, with the latter being a novel mutation previously unreported in RMS. His sister also exhibited similar clinical features and harbored the same mutations. Consequently, both siblings were diagnosed with RMS. The novel mutation c.3670G>A in exon 21, inherited from the father, is likely to impair insulin receptor function by disrupting tyrosine kinase activity, thereby contributing to the pathogenesis of genealogical RMS.

原发性肾上腺皮质功能减退症(primary adrenal insufficiency,PAI)是指肾上腺皮质本身病变所导致的皮质激素合成减少.临床病因较多,主要包括遗传性因素,如先天性肾上腺皮质增生症(congenital adrenal hyperplasia,CAH)、先天性肾上腺发育不全等,及其他免疫、感染、代谢、肿瘤等导致的肾上腺皮质功能不全.

Objective: Mutations in the ACAN gene have been reported to cause short stature. However, the prevalence estimates of pathogenic ACAN variants in individuals with short stature vary, and the correlation between ACAN genotype and clinical phenotype remain to be evaluated. To determine the prevalence of ACAN variants among Chinese people with short stature and analyze the relationship between genotype and main clinical manifestations of short stature and advanced bone age among patients with ACAN variants.Methods: We performed next-generation sequencing-based genetic analyses on 442 individuals with short stature. ACAN variants were summarized, previously reported cases were retrospectively analyzed, and an association analysis between genotype and phenotype was conducted.Result: We identified 15 novel and two recurrent ACAN gene variants in 16 different pedigrees that included index patients with short stature. Among the patients with ACAN variants, 12 of 18 had advanced bone age and 7 of 18 received growth hormone therapy, 5 (71.4%) of whom exhibited variable levels of height standard deviation score improvement. Further analysis showed that patients with ACAN truncating variants had shorter height standard deviation scores (p = 0.0001) and larger bone age-chronological age values (p = 0.0464). Moreover, patients in this Asian population had a smaller mean bone age-chronological age value than those that have been determined in European and American populations (p = 0.0033).Conclusion: Our data suggest that ACAN mutation is a common cause of short stature in China, especially among patients with a family history of short stature but also among those who were born short for their gestational age without a family history. Patients with truncating variants were shorter in height and had more obvious advanced bone age, and the proportion of patients with advanced bone age was lower in this Asian population than in Europe and America.

ObjectiveDefects in the insulin receptor (INSR) gene cause various severe insulin resistance conditions, including Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS) and type A insulin resistance (type A-IR). This study aimed to investigate the clinical characterization and molecular defects in three Chinese children with INSR-related insulin resistance syndrome.MethodsWe reviewed the clinical data of three Chinese children with INSR-related insulin resistance syndrome from two unrelated kindreds. Genetic analysis was performed using whole-exome sequencing and the effects of the novel variants were further assessed by in vitro functional assays.ResultsThe proband with type A-IR presented with acanthosis nigricans, hypertrichosis, and euglycemia with mild insulin resistance in early childhood. His sister presented with features typical of type A-IR and was diagnosed with diabetes mellitus with severe insulin resistance at the age of 9.8 years. The proband with DS showed typical dysmorphic characteristics, severe intrauterine growth retardation, extreme insulin resistance, fasting hypoglycemia and postprandial hyperglycemia from birth. The heterozygote variants c.[3670G>A]; c.[3614C>T] were identified in both siblings with type A-IR; and c.[749_751del]; c.[3355C>T] in the patient with DS. In vitro studies showed that the novel variant c.749_751del [p.(Thr250del)] in the α-subunit, reduced expression of the mature INSR protein and severely impaired INSR function. In contrast, the novel variant c.3670G>A [p.(Val1224Met)] in the β-subunit had no effect on total protein expression and phosphorylation of INSR and Akt, suggesting that the variant p.Val1224Met appeared to be tolerated and was not responsible for the severe insulin resistance.ConclusionOur study detailed the clinical features of three patients with type A-IR and DS, and identified two novel variants in the INSR gene. Functional assays indicated the novel variant p.Thr250del was pathogenic. In contrast, the novel variant p.Val1224Met was suggested to be tolerated by our experimental data, even though bioinformatics analyses predicted the variant as deleterious.

OBJECTIVE:To explore the genetic basis for a sib pair featuring 17beta-hydroxysteroid dehydrogenase type 3 deficiency.METHODS:Genomic DNA was extracted from the proband, her sister, and their parents, and was subjected to sequencing analysis with a gene panel for sexual development. Suspected variant was verified by Sanger sequencing and bioinformatic analysis.RESULTS:Both the proband and her sister were found to harbor novel compound heterozygous missense variants of the HSD17B3 gene, namely c.839T>C (p.Leu280Pro) and c.239G>T (p.Arg80Leu), which were derived respectively from their mother and father. The variants were unreported previously and predicted to be deleterious by PolyPhen2, MutationTaster and other online software. Based on the American College of Medical Genetics and Genomics standards and guidelines, both c.839T>C(p.Leu280Pro) and c.239G>T (p.Arg80Leu) were predicted to be likely pathogenic (PM2+PP1+PP2+PP3+PP4, PM2+PM5+PP1+PP2+PP3+PP4).CONCLUSION:The compound heterogeneous variants of the HSD17B3 gene probably underlay the disease in this sib pair. 17beta-hydroxysteroid dehydrogenase type 3 deficiency may lack specific clinical features and laboratory index, genetic testing can facilitate a definitive diagnosis.

目的 分析非自身免疫性甲状腺功能亢进症的临床及遗传学特征.方法 回顾分析1例非自身免疫性甲状腺功能亢进症患儿的临床资料和基因检测结果.结果 患儿,男,9月龄,以心率增快为主要表现,合并全面性发育迟缓、先天性心脏病等.实验室检测提示促甲状腺激素降低,游离三碘甲状腺原氨酸及游离甲状腺素均升高,相关抗体检查全部阴性.基因检测发现TSHR基因第10外显子c.1894 A>G(p.T 632 A)的错义变异,为新发变异,尚未见报道,经软件预测为致病性变异.予患儿甲巯咪唑口服治疗,甲状腺功能明显好转,发育落后改善.结论 基因检测有利于非自身免疫性甲状腺功能亢进症的诊断.

Background To date, the gonadotropin-releasing hormone (GnRH) stimulation test is still the gold standard for precocious puberty (PP) diagnosis. However, it has many disadvantages, including low sensitivity, high cost, and invasive operation. This study aims to evaluate whether magnetic resonance imaging (MRI)-derived variables, including pituitary volume (PV), could be used as diagnostic factors for PP in girls, providing a non-invasive diagnostic approach for PP. Methods A total of 288 young female patients who presented to the Clinic of Pediatric Endocrinology for evaluation of PP from January 2015 to December 2017 were enrolled. The sample included 90 girls diagnosed with premature thelarche (PT), 133 girls determined as idiopathic central precocious puberty (ICPP), 35 early pubertal girls, and 30 normal girls. All patients received pituitary MRI examinations. Results The largest PV and pituitary height were shown in the ICPP and pubertal groups, followed by the PT group. The receiver operating characteristic (ROC) curve analysis showed that PV is a predictive marker for ICPP, with a sensitivity of 54.10% and a specificity of 72.20% at the cutoff value of 196.01 mm(3). By univariate analysis, PV was positively associated with peak luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH), age, bone age, and body mass index (BMI) (allP < 0.05). However, bone age and peak LH were the only significant predictors of PV as demonstrated by the stepwise multivariate regression analysis (Model: PV = 9.431 * bone age + 1.230 * peak LH + 92.625 [P = 0.000, R-2 = 0.159]). Conclusions The PV in the ICPP group was significantly higher than in PT and control groups, but there was no reliable cutoff value to distinguish ICPP from PT. Pituitary MRI should be combined with clinical and laboratory tests to improve the diagnostic value of PV for PP.

Objective: 11β-hydroxylase deficiency (11βOHD) is a rare autosomal recessive disorder caused by mutations in the CYP11B1 gene. It is characterized by virilization, hypertension, and significant final height impairment. In this study, we aim to investigate the clinical and molecular characteristics of four unrelated Chinese patients with 11βOHD disorder. Methods: The clinical information of four 11βOHD patients were carefully reviewed. Genetic analysis was performed using next-generation sequencing (NGS) based panel analysis. NGS coverage depth was analyzed to detect exonic copy-number variants (CNVs) on patient 1. Quantitative PCR (qPCR) was subsequently performed to confirm the CNVs detected from the NGS coverage depth analysis. Results: The mean age of the patients at diagnosis was 4.7 years (range, 2.0-9.3 years). Two genetically female patients (patients 1 and 2) with 11βOHD presented severe virilization of external genitalia and were raised as males. Two genetically male patients (patients 3 and 4) presented precocious puberty. Additionally, patients 1, 3, and 4 presented with hypertension. In patient 4, unilateral adrenal mass was detected and removed at the age of 9 years. Interestingly, the height of patient 4 (174.4 cm, +6.7 SD) wasn't impaired and reached his mid-parental height (173 cm). Three novel variants in the CYP11B1 gene (c.1150_1153del, c.217C>T, and c.400G>C) were identified by NGS. Various bioinformatics tools revealed potential pathogenic effects for the novel variants, and evolutionary-conservation revealed that the novel missense variant affected an amino acid that is highly conserved among species. Furthermore, NGS coverage depth analysis and qPCR identified a novel heterozygous deletion of exons 1-6 in patient 1. Conclusion: Our study expands the spectrum of mutations of the CYP11B1 gene in Chinese population. In addition, We reported the first case of a patient with classical 11βOHD disorder, whose final height wasn't compromised.

This report describes a clinically rare and atypical case of 46,X,idic(X)(q21.32)/45,X-type Turner syndrome with rapidly progressive puberty development. After 11 months of treatment with recombinant human growth hormone (rhGH), the child's height increased. After 18 months of treatment with rhGH, the child showed secondary sex characteristics. The child was followed up for 1 year after the appearance of the secondary sex characteristics, and regular menses were still present. This case indicates that modern molecular biology techniques should be used rationally to further investigate the existence of X-chromosome translocations and occult chimeras to prevent misdiagnosis.

Artemisinin (ART) and dihydroartemisinin (DHA) are first-line antimalarial drugs and have been reported to have anti-obesity effects. Hyperlipidemia is associated with β-cell damage in obese subjects, which could contribute to the pathogenesis of type 2 diabetes. In addition to their anti-obesity effects, ART and DHA also have protective roles in some diseases. Thus, we investigated the effects of ART and DHA in palmitate-induced β-cell apoptosis and the underlying mechanism. In this study, the rat pancreatic β-cell line INS-1 and mouse pancreatic β-cell line MIN6 were cultured with palmitate (PA) (0.1 mM) to induce cell apoptosis in the presence or absence of ART or DHA. Cell apoptosis was investigated by using flow cytometry, and the expression of ER stress markers, including CHOP, GRP78 and PDI, was detected by Western blotting and/or qRT-PCR. The results showed that ART and DHA significantly increased the apoptosis of β-cells induced by PA and exacerbated the ER stress caused by PA. An inhibitor of ER stress, 4-phenylbutyric acid (4-PBA), significantly ameliorated cell apoptosis caused by ART and DHA in PA-treated β-cells, consistent with the inhibition of ER stress. Together, the findings from the current study suggested that ART and DHA may promote lipid disorder-associated β-cell injury via enhancing ER stress when they were used to treat obesity.

Obesity and its related diseases, such as type 2 diabetes, hypertension and cardiovascular disease, are steadily increasing worldwide. Over the past few decades, numerous studies have focused on the differentiation and function of brown and beige fat, providing evidence for their therapeutic potential in treating obesity. However, no specific novel drug has been developed to treat obesity in this way. Peptides are a class of chemically active substances, which are linked together by amino acids using peptide bonds. They have specific physiological activities, including browning of white fat. As signal molecules regulated by the neuroendocrine system, the role of polypeptides, such as neuropeptide Y, brain-gut peptide and glucagon-like peptide in obesity and its related complications has been revealed. Notably, with the rapid development of peptidomics, peptide drugs have been widely used in the prevention and treatment of metabolic diseases, due to their short half-life, small apparent distribution volume, low toxicity and low side effects. The present review summarizes the progress and the new trend of peptide research, which may provide novel targets for the prevention and treatment of obesity.

目的:探讨重组人生长激素(rhGH)对特发性矮小(ISS)患儿的治疗效果,并建立rhGH治疗后生长速率(GV)的预测模型.方法:回顾性分析确诊为ISS并应用rhGH治疗1年的130例患儿的疗效,以治疗12个月后的GV为因变量,采用多元逐步回归方法建立ISS患儿疗效的预测模型.结果:rhGH治疗6个月、12个月的身高、身高标准差分值(HtSDS)均逐渐升高(P＜0.05),治疗12个月的身高增长(△Ht)、GV低于治疗6个月(P＜0.05).治疗6个月、治疗12个月的GV均与初始治疗时的生活年龄(CA)、骨龄(BA)、身高、体重及垂体高度呈负相关(P＜0.05).将治疗12个月GV作为因变量,治疗前初始身高(X1)、治疗6个月Gv(x2)被纳入方程建立预测模型:Y=7.631-0.035X1+0.567X2,R2=0.791,并通过内外部验证.结论:rhGH治疗对ISS患儿的身高增长具有良好效果,前6个月的效果更好.rhGH治疗后ISS患儿的GV与治疗前CA、BA、身高、体重及垂体高度呈负相关.治疗前的身高、治疗6个月的GV能够较好地预测治疗12个月的GV.

目的:探讨新诊断1型糖尿病(type 1 diabetes mellitus,T1DM)患儿维生素D缺乏情况及维生素D水平与胰岛功能的关系.方法:选取2015年1月-2016年12月南京医科大学附属儿童医院就诊首次诊断的T1DM患儿,分析健康体检患儿与新诊断T1DM儿童血清25-羟维生素D[25(OH)D]水平;根据25(OH)D水平,将T1DM患儿分为4组(严重缺乏组、缺乏组、不足组及充足组),比较其一般情况;探讨不同性别、年龄、有无合并糖尿病酮症酸中毒(diabetic ketoacidosis,DKA)、糖化血红蛋白(HbA1c)及空腹、餐后C肽与血清25(OH)D水平的关系.结果:T1DM患儿25(OH)D水平较健康对照组降低.T1DM患儿中25(OH)D严重缺乏组空腹C肽水平明显低于25(OH)D充足组;年龄≥6岁患儿25(OH)D水平较＜6岁降低;秋冬组25(OH)D水平低于春夏组;合并DKA组25(OH)D水平低于无DKA组;HbA1c≥14％组25(OH)D水平低于＜14％组;T1DM患儿血清25(OH)D与血清空腹C肽呈正相关.结论:T1DM患儿普遍存在25(OH)D缺乏,尤其是年龄≥6岁、合并DKA且血糖控制不佳者,更需加强秋冬季25(OH)D的补充.

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.

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.