Definitive diagnosis in children with congenital hypothyroidism

OBJECTIVES: To investigate the definitive diagnosis and underlying causes of congenital hypothyroidism (CH) in eligible children through the use of a standardized protocol. STUDY DESIGN: Children > or =3 years of age with CH without an identified permanent cause underwent a diagnostic algorithm. Eligible subjects had an anatomically normal thyroid or had not undergone imaging studies. After thyroxine was discontinued for 4 weeks, thyroid function tests and a thyroid ultrasound were obtained. An abnormal ultrasound was followed by a (99m)Tc thyroid scan. A perchlorate washout test was performed in subjects with a normal ultrasound but abnormal thyroid function tests. Children with normal results were followed for 1 year. RESULTS: Of 33 children, 17 were boys. Nine (27%) had an absent or ectopic thyroid, 12 (36%) had dyshormonogenesis, and 12 (36%) had transient CH. Average thyroxine dose before medication discontinuation was 2.9 +/- 0.83 microg/kg in permanent cases versus 2.0 +/- 0.53 microg/kg in transient (P <.002). No complications from discontinuation of thyroxine occurred. CONCLUSIONS: A significant percentage of children with CH have a transient requirement for thyroid hormone. A standardized protocol with thyroid ultrasonography is a safe and sensitive approach to a trial off of thyroxine in select patients.     

Screening for congenital hypothyroidism in Turkey

Abstract A pilot study was performed to determine the incidence of congenital hypothyroidism (CH) in Turkey and to build a model for nationwide screening. From December 1991 to December 1992, 30097 newborns were screened for CH using a primary measurement of thyroid stimulating hormone in capillary blood on days 3–5 of life. Samples were obtained in collaboration with the ongoing nationwide phenylketonuria screening programme. Eleven cases of primary CH were detected giving the incidence of 12736. Recall rate was 2.3%. Replacement therapy withl-thyroxine was started after the confirmation of diagnosis. The median age at the initiation of replacement therapy was 23 days (range 7–35 days).Conclusion The incidence of CH is notably higher in Turkey than reported in most other countries. Iodine deficiency and/or dyshormonogenesis might contribute to this high incidence. This result emphasizes the necessity of a nationwide screening programme.     

Permanent and transient congenital hypothyroidism in preterm infants

Aim: Transient fluctuations in thyroid function are well recognized in preterm infants. We wanted to assess TSH variation in babies with transient and permanent congenital hypothyroidism (CHT). Methods: Whole bloodspot TSH data in preterm infants (<35 weeks; 2005–2010) were assessed, and infants with bloodspot TSH values >6 mU/L identified. Permanent CHT was defined as a requirement for thyroxine beyond 3 years of age. Results: A first TSH sample was obtained from 5518 infants (median gestational age, 32 w; range, 22–35), with a second sample obtained from 5134 infants (median gestational age, 32 w; range, 22–35). Five infants had raised TSH concentrations on both occasions. Three of the five infants had a serum TSH >80 mU/L on second screen but two came off thyroxine beyond 3 years of age. All preterm babies with permanent or transient hypothyroidism were detected by the first TSH cut‐off of 6 mU/L. Only one infant with a birth weight <1500 g remains on thyroxine treatment beyond 2 years of age. Conclusions: The incidence of permanent CHT in preterm infants is similar to term infants. Profound abnormalities of thyroid function can occur in preterm babies with transient hypothyroidism but both categories of hypothyroidism can be detected by a ‘once‐only’ TSH screening strategy with a relatively low cut‐off.     

山东地区儿童先天性甲状腺功能减低症伴甲状腺发育不全TUBB1基因突变的研究

目的 探讨山东地区先天性甲状腺功能减低症（CH）伴甲状腺发育不全（TD）患儿TUBB1基因突变的类型和特点。方法 对山东地区289例确诊CH伴TD患儿进行TUBB1基因全编码区突变研究。提取患儿外周血全基因组DNA，PCR扩增TUBB1基因全编码区，对扩增产物进行Sanger测序，并进行生物信息学分析。结果 289例CH伴TD患儿中发现4例（1.4%） TUBB1基因存在c.952C > T （p.R318W）杂合变异，导致TUBB1蛋白第318位色氨酸变成精氨酸，根据美国医学遗传学与基因组学学会遗传变异分类标准与指南，该变异评级为"可能致病的"。结论 在山东地区CH伴TD患儿中发现了新的TUBB1基因变异，提示TUBB1基因可能是CH伴TD的候选致病基因。     

先天性甲状腺功能减低症35例甲状腺过氧化物酶基因突变检测

目的 检测35例先天性甲状腺功能减低症(CH)患儿甲状腺过氧化物酶(TPO)基因突变.方法 抽取35例先天性甲状腺功能减低症患儿外周血并提取DNA,用PCR扩增患儿TPO基因所有17个外显子、外显子-内含子交界区以及3'端和5'端非翻译区,用DNA测序技术和限制性内切酶检测基因突变,并对发现突变的CH患儿父母进行对照分析.结果 5例CH患儿存在TPO基因突变:1例为c.961A＞G和c.2422delT突变复合杂合子,1例为c.2268insT和c.1477G＞A突变复合杂合子,3例为c.2268insT突变纯合子.其中c.961 A＞G[p.Thr321 Ala]为未见文献报道的突变.结论 在35例先天性甲状腺功能减低症检测到4种TPO基因突变.

Abstract：

Objective To identify thyroid peroxidase (TPO) gene mutations in 35 patients with congenital hypothyroidism. Method Genomic DNA was isolated from peripheral blood samples of 35 patients with congenital hypothyroidism. All of the 17 exons and flanking introns of TPO gene were amplified by PCR, then the PCR products were sequenced bi-directionally and were analyzed by restriction endonucleases. Result One patient had compound heterozygous mutations c. 961A ＞ G/c. 2422delT, one was c. 2268insT/c. 1477G ＞ A, and three was homozygous mutation c. 2268insT. The TPO gene mutation c.961A ＞ G [p. Thr321Ala] was one novel mutation. Conclusion High frequency mutation in TPO gene was detected in patients with congenital hypothyroidism.     

替代治疗后先天性甲状腺功能减低症患儿的气质特征初步探讨

目的探讨替代治疗后先天性甲状腺功能减低症患儿的气质特征。方法2004—2005年采用中国婴儿气质量表对在深圳市妇幼保健院确诊的25例替代治疗后先天性甲状腺功能减低症患儿和145例正常儿童进行测查。结果先天性甲状腺功能减低症患儿组D型、S型和中间型比例较多,与对照组间差异有显著性。在活动水平、节律性、适应性、持久性、注意分散、反应阈6个维度的得分上与对照组比较差异存在显著性。结论替代治疗后先天性甲状腺功能减低症患儿的气质有其独特性,其气质类型比正常儿童消极,应针对患儿的气质特点进行综合治疗。     

Higher incidence of thyroid agenesis in Mexican newborns with congenital hypothyroidism associated with birth defects

Background

Congenital hypothyroidism (CH) is the most common endocrine system disorder in newborns. Ectopic thyroid and agenesis are the most frequent thyroid structural malformations. Several reports have shown that CH is associated with birth defects (BD) ranging from congenital heart disease to ocular and gastrointestinal anomalies.

Aims

We investigated how many and what types of BD were associated with CH in Mexican children.

Study design

Cross-sectional study conducted in patients with confirmed CH.

Setting

Highly specialized government pediatric center in Mexico City.

Subjects

We included 212 patients with permanent CH identified by newborn screening.

Results

We found that 24% of patients with CH also had BD, and that there was a higher prevalence of thyroid agenesis in the group of patients with CH associated with BD (CH + BD) versus the isolated CH group (p = 0.007). There were more females than males in both groups. The most common BD were congenital heart diseases, especially those of the atrial septum, followed by patent ductus arteriosus, found as a single malformation or as part of a complex congenital heart disease. In this study, we found Hirschsprung disease, Beckwith-Wiedemann syndrome, Pierre Robin sequence, Albright's osteodystrophy, VATER association, and frontonasal dysplasia associated with CH.

Conclusions

In this study population, there was a high prevalence of BD in patients with permanent CH. Thyroid agenesis was the main etiological cause of CH in patients with associated congenital malformations. The high prevalence of CH + BD underlines the need for a comprehensive clinical diagnostic approach of the patients with CH.     

Clinical and morphological characteristics of ectopic thyroid gland in children: A series of 24 patients from Northwest India

Background

Most adults with ectopic thyroid gland (ETG) are asymptomatic at the time of detection of ETG. Unlike adults, the clinical and morphological spectrum of ETG in children remains less characterized.

Significance of elevated serum thyrotropin during treatment of congenital hypothyroidism

Serum thyrotropin concentrations are frequently elevated during treatment of children with congenital hypothyroidism. It is unclear if elevated thyrotropin during early treatment indicates non-optimal treatment. In a cohort of 49 children with congenital hypothyroidism, we studied the decline in serum thyrotropin concentration after initiating L-thyroxine treatment, the relationship between elevated thyrotropin and treatment variables, and non-compliance with the treatment as a possible cause of elevated thyrotropin. The initial mean dose of thyroxine was 8.5 (SD 3.3) μg/kg body weight/day: 71 % of the serum samples obtained 15-21 days after the start of treatment had serum thyrotropin concentrations < 10 mU/1. Six children had no samples with serum thyrotropin < 10 mU/1 during the first 3 months of treatment. These children had a lower thyroxine dose prescribed, and serum thyrotropin was normalized when the dose was sufficiently increased. During treatment, from 6 weeks of age, serum thyrotropin > 10 mU/1 was related to a lower dose of thyroxine and lower serum thyroxine, and was not due to non-compliance with treatment.     

Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine

The optimal strategy in neonatal screening for congenital hypothyroidism is still a subject of controversy. In Kanagawa Prefecture in Japan, simultaneous thyroid-stimulating hormone (TSH) and T4/fT4 determination has been used, while the results of our program may provide valuable information. Cumulative findings were analysed to determine the type and frequency of thyroid disorders in infants detected by simultaneous TSH and T4/fT4 determination, and the TSH and T4/fT4 screening strategy was validated. A total of 1284130 neonates were screened between October 1979 and September 1997 and infants followed because of low T4/fT4 without elevated TSH (T4 < 51.5 nmol/L or fT4 < 9 pmol/L and TSH < 15 mU/L) were retrospectively analysed. The first survey was carried out within 6 mo of birth and the second in 1998; 258 infants were diagnosed with congenital hypothyroidism at the first medical evaluation, 15 of them with hypothalamo-pituitary hypothyroidism. However, in the second survey, only 8 children were confirmed as having hypothalamo-pituitary hypothyroidism, therefore the incidence detected by the present strategy was 1/160516. Of 8 children with hypothalamo-pituitary hypothyroidism, mental retardation was prevented in 3 owing to early treatment. CONCLUSIONS: Simultaneous measurement of TSH and T4/fT4 is a useful strategy for detecting hypothalamo-pituitary hypothyroidism, but more studies are needed to show the cost-benefits of using this strategy.     

新生儿先天性甲状腺功能减低症危险因素的Meta分析

目的 探讨新生儿先天性甲状腺功能减低症(congenital hypothyroidism,CH)的危险因素,为CH的预防提供参考依据.方法 系统收集中国生物医学文献数据库、中国知网、维普中文期刊数据库、万方数据库、PubMed、Web of Science、Embase、SpringerLink、Elsevier/S...     

北京市20年新生儿疾病筛查回顾性分析

目的分析北京市1989—2009年新生儿先天性甲状腺功能减退症（CH）和苯丙酮尿症（PKU）的筛查结果,为进一步提高新生儿疾病筛查的管理水平及干预措施提供依据。方法 采集出生72h后、正常哺乳的新生儿足跟血于特定滤纸上,进行CH及PKU筛查。PKU筛查检测指标为血苯丙氨酸（Phe）浓度,分别采用细菌抑制法（1989—2003年）和荧光法（2004—2009年）;CH筛查检测指标为血促甲状腺激素（TSH）水平,分别采用放免法（1989—2003年）及时间分辨荧光免疫分析法（DELFIA）（2003—2009年）。结果 1989—2009年,北京市共筛查新生儿1745998名,筛查率由1989年的14.01%提高到2009年98.16%,可疑患儿复诊率由1991年的65.85%提高到2009年的92.18%,共确诊CH482例,发病率1：3622;PKU192例,发病率1：9094。结论 新生儿疾病筛查是包括管理、筛查、随访、诊治、评估、教育等多个环节的系统服务工程,各部门的协调配合是提高筛查管理质量的有效措施,完善的新生儿疾病筛查工作可有效降低残疾儿的发生。     

Manifestations of congenital hypothyroidism during the 1st week of life

Congenital hypothyroidism (CHT) produces few and vague clinical signs during the first few weeks of life, when it is still possible to prevent irreparable brain damage. In the Finnish national screening programme for CHT, treatment is started at a median age of 6 days. According to multiple logistic regression analysis based on 102 cases, the main manifestations of CHT at this age are retardation of skeletal maturation and growth in lenght, icterus, large tongue, abdominal distension, skin mottling, muscle hypotonia and probably increased head size. The presence of other signs did not increase the probability of CHT. All signs are non-specific and some of the hypothyroid infants did not have any of them. Control of other confusing perinatal problems improved the diagnostic scoring but this did not increase the accuracy of prediction acceptably.Abbreviations T4 thyroxine - TSH thyroid stimulating hormone - CHT congenital hypothyroidism - FEH height of distal femoral epiphyses     

先天性甲状腺功能减退症患儿GNAS和THRA基因突变分析

目的 对70例先天性甲状腺功能减退症（CH）患儿的刺激性G蛋白α亚基（GNAS）基因和甲状腺素受体α（THRA）基因进行二代测序分析,并初步探讨GNAS和THRA基因突变型与CH患儿的临床表现型之间的关系。方法 选取70例通过新生儿筛查确诊为CH的患儿,采集外周血并进行DNA样本提取,利用二代测序技术对GNAS和THRA基因进行突变筛查,利用生物信息学软件分析基因突变的致病性。结果 70例CH患儿中,3例患儿（4%）检出9种GNAS基因的错义突变（包括3种已知基因突变和6种新突变）,4例患儿检出同1种THRA基因多态c.508A > G（p.I170V）。经过生物信息学软件预测和ACMG/AMP指南分析发现2种GNAS基因突变[c.301C > T（p.R101C）、c.334G > A（p.E112K）]致病的可能性大。3例携带GNAS基因突变的患儿存在不同程度的甲状腺功能低下表现。结论 GNAS基因突变与CH的发病有关,患儿的临床表现存在较大的异质性;THRA基因突变可能与CH的发病无相关性。     

Influence of severity of congenital hypothyroidism and adequacy of treatment on school achievement in young adolescents: a population-based cohort study

AIM: To evaluate whether precociously treated subjects with congenital hypothyroidism (CH) are at risk of poor school performance in early adolescence, and to investigate which factors affect their school achievement. METHODS: All children treated early for congenital hypothyroidism and born in France during the first 7 y (1979-1985) of the national screening program for congenital hypothyroidism were selected for the study. School performance during childhood, assessed according to age at entry into the first grade of secondary school, was evaluated as normal (usually 11 y of age) vs late entry (> or = 12 y). The national register of children with congenital hypothyroidism enabled a comparison to be made with data from the national population for the same school years. RESULTS: School achievement was similar among the 682 patients with CH and in the national population. After an adjustment for the sex and socioprofessional category of the parents, the severity of CH as assessed by the type (athyreosis. the most severe vs other types), the initial low serum T4 levels (< or = 53 nmol/L vs >53 nmol/L), and the profound bone maturation delay (absence vs presence of the two knee epiphyseal ossification centres at diagnosis), initially low L-thyroxine dosage (below vs > or = 7 microg/kg/day), the absence of near normalization of thyroid hormone levels after 15 d of treatment and poor adequacy of treatment throughout childhood were associated with an increased risk of school delay. School achievement was unaffected by the age at start of treatment (mean age = 22.8 +/- 6.8 d). In a multivariate logistic regression analysis, recurrent episodes of insufficiently suppressed TSH levels (> or = 15 mUi/L at least four times during follow-up from the age of 6 mo onwards) were the most important variable associated with school delay. CONCLUSION: Careful follow-up of the adequacy of treatment is required throughout childhood, to reduce the risk of school delay.     

先天性甲状腺功能减退症新生大鼠大脑蛋白质差异表达的研究

目的 应用蛋白质组学方法筛选新生先天性甲状腺功能减退症大鼠大脑差异表达蛋白质,为阐明CH致脑发育障碍发病机制提供有价值的线索.方法 制作CH仔鼠动物模型,于出生时称重后处死仔鼠,取大脑,提取大脑皮质总蛋白,Bradford法检测蛋白质浓度.应用双向电泳(2-DE)技术分析新生正常仔鼠与CH仔鼠大脑蛋白质差异表达情况.选择重复性、分辨率好且表达差异明显的蛋白质点进行质谱分析.RIA法检测各组大鼠血清FT3、FT4水平.结果 新生甲减组仔鼠体重、FT3、FT4水平均低于正常组仔鼠(t体重=-8.07,tFT3=5.39,tFT4=7.62,P＜0.01).建立了较稳定的正常与CH仔鼠大脑2-DE图谱,筛选出7个重复性、分辨率好且表达差异明显的蛋白质点进行质谱分析.MALDI-TOF-MS质谱分析鉴定了相关的7个差异表达蛋白,包括塌陷反应介导蛋白2、肌动蛋白相关蛋白2/3复合物第5亚单位、泛素结合酶E2-25K、ATP合酶D亚单位、Cu-Zn超氧化物歧化酶、突触核蛋白α、核苷二磷酸激酶.结论 神经元突触形成异常、ROS产生异常增多、细胞凋亡等多条途径可能参与了CH致脑发育障碍,本研究为探讨CH致脑发育障碍机制提供了重要线索.

Abstract：

Objective To screen differentially expressed brain proteins with proteomic method in cerebral cortex of neonatal rats with congenital hypothyroidism. Method From the 13th day of gestation,pregnant Wistar rats from the experimental group were given intragastrically with 2. 5 ml of 1%propylthiouracil daily. Cerebral cortex specimens were collected from the control and hypothyroidism neonatal rats. Two-directional electrophoresis (2-DE) was applied to analyze protein expression diversities between the euthyroid and hypothyroidism neonatal rat cerebral cortex. Protein spots with significantly different expression were screened and identified by mass spectrometry. Radioimmunoassay (RIA) was used to analyze serum FT3 , FT4 levels of each groups. Result The body weight of hypothyroid neonatal rats were lower than those in the corresponding control group (t = -8.07, P ＜0. 01 ). The FT3 levels of hypothyroid neonatal rats were lower than those in the corresponding control group ( t = 5. 39, P ＜ 0. 01 ). The FT4 levels of hypothyroid neonatal rats were lower than those in the corresponding control group (t = 7.62, P ＜ 0. 01 ).Stable 2-DE maps of normal and CH neonatal rat were constantly obtained. The maps were analyzed by software. Seven protein spots with high reproducibility, high resolution and significantly different expression were chosen and identified by mass spectrometry, including collapsing response mediator protein 2, actin related protein 2/3 complex subunit 5, ubiquitin-conjugating enzyme E2-25K, ATP synthase subunit d, CuZn superoxide dismutase, synuclein alpha, and nucleoside diphosphate kinase. Conclusion The value of this research is demonstrated here by the identification of several proteins known to be associated with nerve synapse structures formation, cell survival, metabolism, cell signal transduction, neural differentiation and nerve growth in the central nervous system. Furthermore this study identified several proteins except for collapsing response mediator protein 2 and Cu-Zn superoxide dismutase that have not previously been described in the literature and which may play an important role as either sensitive biomarkers of brain dysfunction caused by congenital hypothyroidism. In congenital hypothyroidism, brain development retardation may be related with some important processes, including abnomal synaptic formation, excess ROS production and apoptosis. The above-mentioned proteins may play critical roles in the processes, which provide valuable clues to clarify the pathogenesis of brain developmental disorders induced by congenital hypothyroidism.     

Congenital hypothyroidism and partial thyroid hormone unresponsiveness of the pituitary in a patient with congenital thyroxine binding albumin elevation

We describe a girl who presented at the age of 6 weeks with cardiogenic shock due to congenital hypothyroidism (serum thyroxine (T4) <12 nmol/l). Thyroxine replacement therapy was instituted. In spite of high total serum T4 levels, thyroid stimulating hormone (TSH) serum values remained elevated. The raised serum T4 levels were the result of congenital elevation of thyroid binding albumin (TBA). Toxic doses of both T4 and triiodothyronine (T3) normalized the elevated TSH levels indicating that the pituitary is responsive to thyroid hormone, albeit at a higher threshold. In patients with congenital TBA elevation and an altered T4 pituitary response requiring thyroid replacement therapy, the measurement of serum free T4 levels is the parameter of choice to monitor treatment.     

云南省部分地区新生儿先天性甲状腺功能减低症筛查结果分析

目的 总结并分析云南省部分州市先天性甲状腺功能减低症(CH)的筛查结果.方法 对2012 年7 月至2014 年4 月在云南省昭通市、曲靖市、丽江市和迪庆藏族自治州四地出生的活产婴儿236 218 例进行CH 筛查,其中男121 463 例,女114 755 例.初筛足跟血促甲状腺激素(TSH)≥ 8 μIU/L 者原血片重新复查,复查后仍为阳性者召回进一步测定静脉血TSH 和游离甲状腺素(FT4)以明确诊断.结果 236 218 名新生儿中,血片合格率为96.67%,不合格血片补采率为81.75%,初筛阳性召回率为73.02%.确诊CH 66 例,其中男性36 例,女性30 例(P>0.05).CH 发病率为1: 3 579,显著低于全国平均发病水平(1/2 034,P<0.01).患儿出生胎龄多为37~42 周,>42 周者只占3%;大部分患儿出生体重在正常范围;出生身长<50 cm 者占32%.结论 云南地区CH 发病率低于全国平均水平;CH 患儿临床特征无特异性;云南地区新生儿疾病筛查工作质量还需要进一步提高.     

Incidence of febrile convulsions in children with congenital hypothyroidism

Brain excitability has been inconsistently reported to be increased both in hypo- and hyperthyroidism, but there have been few studies on the effects of thyroid hormones on brain excitability in children. With this in mind, we investigated the incidence of febrile convulsions (FCs) among patients with congenital hypothyroidism, who have been taking L - thyroxine since the age of 1 month. The incidence of FCs among congenital hypothyroid patients was 1.6% (1/63) which was significantly low ( p < 0:05) compared with that of normal control children who visited our hospitals as outpatients (28/341, 8.2%) and that of others (322/3301, 9.8%) investigated 33 years ago in the same area. The incidence of FC among siblings of the 63 patients (7/74, 9.5%) was not statistically different from the controls. At least 8 of the 126 parents (6.4%) had experienced FC, however, only one child was affected in the 8 families. In conclusion, it seems likely that patients with congenital hypothyroidism on regular L -T4 replacement are less prone to experience FC. More studies on the incidence of convulsive disorders in children with thyroid diseases are needed to clarify the effects of thyroid hormones on brain excitability.     

先天性甲状腺功能减低症患儿DUOXA2基因突变研究

目的 探讨广州地区先天性甲状腺功能减低症(CH)患儿DUOXA2基因突变特点及其基因型与表型的关系。方法 采用PCR及直接测序法,对2011年至2012年出生、广州市新生儿筛查中心诊断并排除DUOX2基因突变的20例疑似甲状腺激素合成障碍的CH患者进行DUOXA2基因突变分析。结果 20例CH患者中2例为p.Y246X/p.Y246X纯合突变;4例为单等位基因杂合突变:分别为已知致病突变c.413-414ins A携带者2例,p.Y246X携带者1例,新突变p.G79R携带者1例。2~3岁再评估时显示,2例p.Y246X/p.Y246X纯合突变者分别表现为暂时性CH及轻度永久性CH;4例单等位基因突变者,除1例p.Y246X携带者表现为典型永久性CH外,其余3例携带者均为暂时性CH。结论 DUOXA2基因突变是广州地区疑似甲状腺激素合成障碍性CH患儿较常见的分子发病基础,多数表现为暂时性CH,未发现DUOXA2基因型与表型的关系。新突变p.G79R为致病性突变的可能性大。