Important Tools for Use by Pediatric Endocrinologists in the Assessment of Short Stature

Assessment and management of children with growth failure has improved greatly over recent years. However, there remains a strong potential for further improvements by using novel digital techniques. A panel of experts discussed developments in digitalization of a number of important tools used by pediatric endocrinologists at the third 360° European Meeting on Growth and Endocrine Disorders, funded by Merck KGaA, Germany, and this review is based on those discussions. It was reported that electronic monitoring and new algorithms have been devised that are providing more sensitive referral for short stature. In addition, computer programs have improved ways in which diagnoses are coded for use by various groups including healthcare providers and government health systems. Innovative cranial imaging techniques have been devised that are considered safer than using gadolinium contrast agents and are also more sensitive and accurate. Deep-learning neural networks are changing the way that bone age and bone health are assessed, which are more objective than standard methodologies. Models for prediction of growth response to growth hormone (GH) treatment are being improved by applying novel artificial intelligence methods that can identify non-linear and linear factors that relate to response, providing more accurate predictions. Determination and interpretation of insulin-like growth factor-1 (IGF-1) levels are becoming more standardized and consistent, for evaluation across different patient groups, and computer-learning models indicate that baseline IGF-1 standard deviation score is among the most important indicators of GH therapy response. While physicians involved in child growth and treatment of disorders resulting in growth failure need to be aware of, and keep abreast of, these latest developments, treatment decisions and management should continue to be based on clinical decisions. New digital technologies and advancements in the field should be aimed at improving clinical decisions, making greater standardization of assessment and facilitating patient-centered approaches.     

Prospective Study of Short Stature and Newly Diagnosed Asthma in Women

The authors tested the hypothesis that short stature predicts adult-onset asthma independent of obesity among women in the Nurses' Health Study. Height, weight, and physician-diagnosed asthma were assessed with validated questionnaire items. Proportional hazard models adjusted separately for weight and body mass index. The rate of newly diagnosed asthma was 1.55 times greater in the shortest versus the tallest quintile after adjustment for weight (95% CI, 1.26–1.91). After adjustment for body mass index, the rate ratio was 1.16 (95% CI, 0.94–1.42). Short stature predicted adult-onset asthma in a large cohort of women, but this association was not independent of obesity.     

Controversies in the Definition and Treatment of Idiopathic Short Stature (ISS)

The term idiopathic short stature (ISS) refers to short children with no identifiable disorder of the growth hormone (GH)/insulin like growth factor (IGF) axis and no other endocrine, genetic or organ system disorder. This heterogeneous group of short children without GH deficiency (GHD) includes children with constitutional delay of growth and puberty, familial short stature, or both, as well as those with subtle cartilage and bone dysplasias. In rare cases, ISS is due to IGF molecular abnormalities. In this review we tackle the major challenges in the definition and treatment of ISS.     

Detection of SHOX Gene Variations in Patients with Skeletal Abnormalities with or without Short Stature

Objective:SHOX gene mutations constitute one of the genetic causes of short stature. The clinical phenotype includes variable degrees of growth impairment, such as Langer mesomelic dysplasia (LMD), Léri-Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS). The aim of this study was to describe the clinical features and molecular results of SHOX deficiency in a group of Turkish patients who had skeletal findings with and without short stature.Methods:Forty-six patients with ISS, disproportionate short stature or skeletal findings without short stature from 35 different families were included. SHOX gene analysis was performed using Sanger sequencing and multiplex ligation-dependent probe amplification analysis.Results:Three different point mutations (two nonsense, one frameshift) and one whole SHOX gene deletion were detected in 15 patients from four different families. While 4/15 patients had LMD, the remaining patients had clinical features compatible with LWD. Madelung’s deformity, cubitus valgus, muscular hypertrophy and short forearm were the most common phenotypic features, as well as short stature. Additionally, hearing loss was detected in two patients with LMD.Conclusion:This study has presented the clinical spectrum and molecular findings of 15 patients with SHOX gene mutations or deletions. SHOX deficiency should be especially considered in patients who have disproportionate short stature or forearm anomalies with or without short stature. Although most of the patients had partial or whole gene deletions, SHOX gene sequencing should be performed in suspected cases. Furthermore, conductive hearing loss may rarely accompany these clinical manifestations.     

TRMT10A Mutation in a Child with Diabetes,Short Stature,Microcephaly and Hypoplastic Kidneys

A new syndrome of diabetes, short stature, microcephaly and intellectual disability has been described in association with mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene. We report a patient who presented with fasting hyperglycemia, a raised hemoglobin A1c and positive islet cell autoantibodies. Additional clinical features included intellectual disability, hypoplastic kidneys and short stature. In view of the syndromic features coexistant with diabetes, genetic evaluation was carried out, revealing a homozygous mutation in the TRMT10A gene (c.616G>A, p.G206R). The case highlights the importance of genetic evaluation of patients with diabetes with atypical features that can further progress our understanding of the pathophysiology of the rarer subtypes of diabetes.     

Short stature in Korean women: a contribution to the multifactorial predisposition to gestational diabetes mellitus

Summary We examined the associations between demographic characteristics including short stature and the prevalence of gestational diabetes mellitus (GDM) in Korean women. In this study, a total of 9005 pregnant women underwent universal screening for GDM. Oral glucose tolerance tests (100 g OGTT) were performed in positive screenees (1 h plasma glucose ≥ 7.2 mmol/l) and GDM was diagnosed using National Diabetes Data Group criteria. Women with GDM were older and heavier than those with a positive screen and normal OGTT, as well as those with a negative screen. However, height of women with GDM was significantly shorter than those with a positive screen and normal OGTT, and a negative screen. When the study subjects were stratified according to height quartiles, the plasma glucose at the screening test decreased as height increased. Furthermore, the prevalence of GDM was highest in the shortest quartile ( ≤ 157 cm) group; the odds ratio for GDM was two times greater compared with the highest quartile ( ≥ 163 cm) group, even after controlling for age and body mass index (BMI). In addition, multiple logistic regression analysis revealed that greater prepregnancy BMI, age, weight gain, a parental history of diabetes mellitus, and shorter maternal height were directly and independently associated with the prevalence of GDM. We have found that short stature is an independent risk factor for GDM in the racially homogenous population of Seoul, Korea. It is suggested that this propensity may be conveyed primarily by environmental influences. However, genetic factors may also modify the response to the environmental insult. Our findings also emphasize the heterogeneity of factors which predispose to GDM. [Diabetologia (1998) 41: 778–783] Received: 15 December 1997 and in revised form: 16 February 1998     

Short stature, obesity and arterial hypertension in a very low income population in North-eastern Brazil

BACKGROUND AND AIM: This cross-sectional study involved the adult population (age >18 and <60 years) of a 315-shack slum on the outskirts of the city of Maceió in North-eastern Brazil. The purpose was to investigate whether short stature in adults (an indicator of undernutrition in early life) is associated with arterial hypertension and obesity. METHODS AND RESULTS: We collected the subjects socio-economic data, and arterial hypertension (AH), weight, height, waist circumference and waist/hip (W/H) circumference ratio measurements. Hypertension was diagnosed as diastolic AH f 90 mmHg and/or systolic AH f 140 mmHg. The body mass index (BMI) was used to determine nutritional status, with overweight/obesity being defined on the basis of a cut-off point of 25 kg/m2. A W/H ratio of f 0.80 for women or f 0.95 for men was considered indicative of abdominal obesity. Short stature was defined as falling into the 1st quartile (Q) of height distribution. Hypertension was prevalent in 28.5% of the population (women=38.5%; men=18.4%). The systolic and diastolic AH readings were significantly higher in women in the 1st Q than in those in the 4th Q, and the same was true of W/H. The prevalence of hypertension was statistically significant for the first two Q's in comparison with the last two: 22.1% vs 14.6% (men), and 42.4% vs 34.6% (women). Hypertension was more prevalent in women who were obese and short (50%) than in those who were obese but not short (OR=1.98; CI=1.22-2.96). CONCLUSIONS: Living conditions were extremely precarious and the prevalence of hypertension was quite high. Stature negatively correlated with hypertension and overweight in women but not in men.     

Whole-exome sequencing identifies the first French MODY 6 family with a new mutation in the NEUROD1 gene

AimThe aim of the present study was to identify the affected gene in a French family with maturity-onset diabetes of the young (MODY) using whole-exome sequencing (WES).MethodsWES was performed in one patient with MODY, and candidate variants were confirmed in members of the immediate family by Sanger sequencing.ResultsIn the proband, a new heterozygous missense mutation (c.340A>C) was identified in the NEUROD1 gene by WES analysis and confirmed by Sanger sequencing. Additional Sanger sequencing of the proband's sister and mother revealed the same heterozygous mutation. The proband and his sister displayed typical clinical characteristics of MODY, while their mother had the same typical MODY features except for later onset. When clinical and biological profiles were established for all three patients, the severity of diabetes-related complications varied substantially from one family member to another.ConclusionA novel missense mutation found in NEUROD1 was associated with MODY 6 features in a single French family.     

The Effect of Recombinant Growth Hormone Treatment in Children with Idiopathic Short Stature and Low Insulin-Like Growth Factor-1 Levels

Objective:

Idiopathic short stature (ISS) constitutes a heterogeneous group of short stature which is not associated with an endocrine or other identifiable cause. Some ISS patients may have varying degrees of insulin-like growth factor-1 (IGF-1) deficiency. Recombinant growth hormone (rGH) treatment has been used by some authors with variable results. Reports on long-term rGH treatment are limited.

Methods:

In this study, 21 slowly growing, non-GH-deficient ISS children who received rGH treatment for 3.62±0.92 years were evaluated at the end of a 5.42±1.67-year follow-up period. The study group included patients with low IGF-1 levels who also responded well to an IGF generation test. The patients were divided into two groups as good responders [height increment >1 standard deviation (SD)] and poor responders (height increment <1 SD) at the end of the follow-up period.

Results:

The height of the patients improved from -3.16±0.46 SD score (SDS) to -1.9±0.66 SDS. At the end of the follow-up period, mean height SDS was -1.72. Eleven of the patients showed a good response to treatment. Clinical parameters were essentially similar in the good responders and the poor responders groups. A female preponderance was noted in the good responders group.

Conclusion:

rGH treatment can safely be used in ISS children. Long-term GH treatment will ameliorate the height deficit and almost 40% of patients may reach their target height.     

Evaluation of the application value of the whole genome sequence analysis tools,TB Profiler v2.8.0, Mykrobe v0.7.0 and PhyResSE v1.0, in testing drug-resistant tuberculosis

目的 评估3种针对结核分枝杆菌开发的全基因组数据分析工具,即TB Profiler v2.8.0、Mykrobe v0.7.0和PhyResSE v1.0(简称“TB Profiler、Mykrobe和PhyResSE”)在耐药结核病诊断中的性能。方法 从美国国立生物技术信息中心核酸数据库(National Center for Biotechnology Information Sequence Read Archive, NCBI SRA)收集了先前2项研究所上传的534株中国结核分枝杆菌临床分离株的全基因组测序数据和表型药物敏感性试验(drug susceptibility testing, DST)结果,其中包括457株耐多药菌株和77株敏感菌株。使用TB Profiler、Mykrobe和PhyResSE对全基因组数据进行分析,检测一线和二线抗结核药品的耐药性,并将其与DST结果进行比较,评价这3种工具的检测效能。结果 以DST结果为参照标准,TB Profiler、Mykrobe和PhyResSE检测利福平耐药的敏感度相近,分别为90.81%(415/457)、87.75%(401/457)和90.81%(415/457)。Mykrobe和PhyResSE检测异烟肼耐药的敏感度分别为76.42%(350/458)和76.20%(349/458),略高于TB Profiler(69.43%,318/458)。3种工具检测乙胺丁醇和链霉素耐药的敏感度相近,范围从76.00%到81.61%不等。对于吡嗪酰胺,TB Profiler的敏感度(72.82%,150/206)高于Mykrobe(61.65%,127/206)和PhyResSE(50.97%,105/206)。PhyResSE检测氟喹诺酮类和阿米卡星耐药的敏感度分别为88.27%(143/162)和60.00%(27/45),高于TB Profiler的81.48%(132/162)和48.89%(22/45)和Mykrobe的82.10%(133/162)和55.56%(25/45)。3种工具检测抗结核药品耐药的特异度相近并且均较高,除乙胺丁醇为82.42%~83.88%外,对其余药品的特异度均高于90%。结论 3种工具检测效能良好,可以快速检测抗结核药品耐药性,有良好的发展前景,但是目前对吡嗪酰胺和一些二线抗结核药品耐药检测的敏感度较低,需要加强耐药机制研究。     

糖尿病遗传学研究进展——2010年美国糖尿病协会年会侧记

在2010年美国糖尿病协会(ADA)年会中,糖尿病遗传学的相关报道引人瞩目,由于全基因组关联技术的广泛开展,人们得以开展多中心、大样本、反复验证的基因与糖尿病的关联研究,全面揭示与糖尿病发生、发展及治疗相关的遗传基因.这次大会中报道了许多新的1型及2型糖尿病发病相关基因位点,并发现一些基因多态性可影响糖尿病患者的空腹血糖及胰岛素敏感性.另外,有关磺脲类、噻唑烷二酮类、二甲双胍药物的疗效及安全性的遗传学研究也收获颇丰,从而为利用基因检测技术指导个体化治疗带来了希望.此外,人们发现基于多个高风险基因的遗传风险评分可提高对2型精尿病患者冠心病发病的预测能力.     

长QT综合征一家系的遗传学定位研究

目的 寻找中国人长QT综合征(LQTS)的遗传易感位点，选择并确立LQTS患者症状前诊断的短串联重复序列(short tandem repeats,STR)和单核苷酸多态性(single nucleotide polymorphism,SNP)，初步建立LQTS遗传学诊断方法。方法 采集一个LQTS家系四代共37个成员，用聚合酶链反应(PCR)方法扩增位于KCNQl、HERG基因内的SNP(K546、K367、H489、和H564)和位于KCNQl、NERG、和SCN5A基因邻近的SIR(DllSl323、DllS2362、DllSl318、D7S636、D7S246l、D7S1824、D3S1298、D3S1767、D3Sll00、D4S1564)，所得产物经6％一10％变性聚丙烯酰胺凝胶电泳后进行等位基因片段长度多态性分析或直接测序。结果 通过单倍体分析排除LQTl、LQT3、和LQT4位点，初步确定该LQTS家系的致病基因位于LQT2位点。NERG基因全部外显于的直接测序结果表明7名患者均出现相同的HERG基因单碱基转换(CGA2587TGA)，与之相对应的编码氨基酸由精氨酸(Arg)突变为终止密码于TGA,即R863X。结论 STR和SNP单倍体分析方法可以有效地区分正常及患病个体，确定LQTS致病基因的位点，可用于LQTS患者的症状前诊断。     

Short stature and ischemic stroke in nonvalvular atrial fibrillation: New insight into the old observation

Background

For decades, repeated epidemiologic observations have been made regarding the inverse relationship between stature and cardiovascular disease, including stroke. However, the concept has not been fully evaluated in patients with atrial fibrillation (AF). We investigated whether patient’s height is associated with ischemic stroke in patients with nonvalvular AF and attempted to ascertain a potential mechanism.

Methods

All 558 AF patients were enrolled: 211 patients with ischemic stroke (144 men, 68 ± 10 years) and 347 no-stroke patients (275 men, 56 ± 11 years) as a control group. Clinical characteristics and echocardiographic parameters were compared between the two groups.

Results

(1) Stroke patients were shorter than those in the control group (164 ± 8, vs. 169 ± 8 cm, p < 0.001). However, body mass index failed to predict ischemic stroke; (2) Short stature (OR 0.93, 95% CI 0.91– 0.95, p < 0.001) along with left atrial (LA) anterior-posterior diameter and diastolic mitral inflow velocity (E) to diastolic mitral annuls velocity (E’) (E/E’) were independent predictor of stroke; (3) Height showed inverse correlation with E/E’ independently, even after adjusting for other variables, including age, sex, and body weight, and comorbidities β − 0.20, p = 0.003); (4) LA size showed no correlation with stature (R = − 0.06, p = 0.18), whereas left ventricular size increases according to height of patients.

Conclusions

Short stature is associated with occurrence of ischemic stroke and diastolic dysfunction in patients with AF and preserved systolic function. Height is a non-modifiable risk factor of stroke and might be more important than obesity in Asian AF patients, who are relatively thinner than western populations.     

Short stature and coronary heart disease: a 35-year follow-up of the Finnish cohorts of The Seven Countries Study

OBJECTIVES: To examine whether short stature is associated with an increased risk of coronary heart disease. DESIGN: Follow-up study. SETTING: Two geographically defined areas in eastern and western Finland. SUBJECTS: A total of 1441 men who were free of coronary heart disease at the start of the follow-up. MAIN OUTCOME MEASURES: Hazard ratios for fatal and non-fatal coronary heart disease RESULTS: Height was inversely related to fatal coronary heart disease and incident non-fatal coronary heart disease during the follow-up. These relationships persisted after adjusting for other major cardiovascular risk factors. Comparing the high-risk area in eastern Finland with the low-risk area in south-western Finland, no difference in fatal coronary heart disease and cumulative incidence of non-fatal coronary heart disease was seen in tall men. The increase in risk of coronary heart disease death was 19% for a 10 cm decrease in height (OR = 0.81, 95% CI = 0.68-0.95). CONCLUSIONS: Our results show that short stature is an independent risk factor for coronary heart disease. Differences in stature partly explain the Finnish east-west difference in the incidence of coronary heart disease.     

Short chain fatty acids are effective in short-term treatment of chronic radiation proctitis

PURPOSE: Short chain fatty acids are the main energy source of coloncytes and their use may be impaired in chronic radiation proctitis. The aim of the present study was to evaluate the therapeutic effect of short chain fatty acid enemas in patients with chronic radiation proctitis. METHODS: A prospective, randomized, double-blind trial comparing short chain fatty acid enemas with placebo was conducted in 19 patients with chronic radiation proctitis. Short chain fatty acid enemas contained 60 mM sodium acetate, 30 mM sodium propionate, and 40 mM sodium butyrate. The treatment period lasted five weeks and patients were followed up for six months. RESULTS: On admission, both groups were similar regarding all parameters evaluated. After five weeks short chain fatty acid-treated patients showed a significant decrease in the number of days with rectal bleeding from the previous week (4.4±1.8 to 1.4±2.2;P=0.001) and an improvement of endoscopic score (4.8±1.4 to 2.2±1.2;P=0.001). Hemoglobin values were also significantly higher in short chain fatty acid-treated patients (13.1±0.9 g/dlvs. 10.7±2.1 g/dl;P=0.02). Mucosal DNA and protein concentrations decreased in both groups but significantly so only in placebotreated patients (P=0.05). Changes in histologic parameters were not significant in either group. Although short chain fatty acid-treated patients did not get worse in the next six months, placebo-treated ones gradually improved, and at the end of six months, differences between the two groups were no longer observed. CONCLUSIONS: Short chain fatty acid enemas can accelerate the process of healing in chronic radiation proctitis, but treatment has to be continuous if a complete and sustained clinical, endoscopic, and histologic response is to be obtained.Presented in part at The Digestive Disease Week Scientific Sessions, New Orleans, Louisiana, May 15 to 18, 1994.     

The Genetic Characterization of a Novel Natural Recombinant Pseudorabies Virus in China

We sequenced the complete genome of the pseudorabies virus (PRV) FJ epidemic strain, and we studied the characteristics and the differences compared with the classical Chinese strain and that of other countries. Third-generation sequencing and second-generation sequencing technology were used to construct, sequence, and annotate an efficient, accurate PRV library. The complete FJ genome was 143,703 bp, the G+C content was 73.67%, and it encoded a total of 70 genes. The genetic evolution of the complete genome and some key gene sequences of the FJ strain and PRV reference strains were analyzed by the maximum likelihood (ML) method of MEGA 7.0 software. According to the ML tree based on the full-length genome sequences, PRV FJ strain was assigned to the branch of genotype II, and it showed a close evolutionary relationship with PRV epidemic variants isolated in China after 2011. The gB, gC, gD, gH, gL, gM, gN, TK, gI, and PK genes of the FJ strain were assigned to the same branch with other Chinese epidemic mutants; its gG gene was assigned to the same branch with the classic Chinese Fa and Ea strains; and its gE gene was assigned to a relatively independent branch. Potential recombination events were predicted by the RDP4 software, which showed that the predicted recombination sites were between 1694 and 1936 bp, 101,113 and 102,660 bp, and 107,964 and 111,481 bp in the non-coding region. This result broke the previously reported general rule that pseudorabies virus recombination events occur in the gene coding region. The major backbone strain of the recombination event was HLJ8 and the minor backbone strain was Ea. Our results allowed us to track and to grasp the recent molecular epidemiological changes of PRV. They also provide background materials for the development of new PRV vaccines, and they lay a foundation for further study of PRV.