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.     

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.     

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.     

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.     

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。     

Agenesis of the internal carotid artery and congenital pituitary hypoplasia: proposal of a cause of congenital hypopituitarism

We describe a patient with microphallus without pigmentation and multiple pituitary hormone deficiencies. The left internal carotid artery and carotid canal were absent and the pituitary gland and sella turcica showed hypoplasia on MRI and magnetic resonance angiography. The internal carotid artery develops in the 4th embryonic week, while the pituitary primordium develops in the 3rd to 4th week. This suggests a possible relationship between internal carotid artery and congenital hypopituitarism. However, there is bilateral blood supply to the hypophysis via the superior and inferior hypophysial arteries, so it is unknown why pituitary hypoplasia may arise from blocking the unilateral blood supply. Conclusion:disruption of internal carotid artery perfusion may lead to pituitary hypoplasia with congenital hypopituitarism as a new disease entity in humans.Abbreviations AICA agenesis of the internal carotid artery - CNPAS congenital nasal pyriform aperture stenosis - CPH congenital pituitary hypoplasia - SMCI solitary maxillary central incisor     

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.     

Congenital hypothyroidism, seasonality and consanguinity in the West Midlands, England

Seasonal variation in the incidence of congenital hypothyroidism (CHT) is reported by some centres. Also, the incidence of CHT varies with ethnic origin. We report our experience in the West Midlands, England. The overall incidence of CHT among 1128 632 neonates screened over 16 years in the West Midlands was 1:2924 live births, but was increased (1:2323; p<0.05) between October and December. In the city of Birmingham between 1981 and 1991, the incidence of CHT was 1:781, 1:5540 and 1:2257 in Pakistani, Indian and North-West European children, respectively; no cases were seen in those from other ethnic groups. Consanguinity among those of Pakistani descent could account for the increased incidence within this population. Identification of the cause of seasonal variation may aid development of preventative strategies.     

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.     

Serum lipoproteins and apolipoprotein E in infants with congenital hypothyroidism

BACKGROUND: Hypothyroid adults have a high risk of atherosclerosis, secondary to increased levels of various cholesterol fractions, particularly low-density lipoprotein cholesterol (LDL-C). We investigated the existence of a correlation between thyroid hormone deficiency and serum lipoproteins and a possible effect of different apolipoprotein E (apoE) phenotypes on lipoprotein levels in 75 infants with hypothyroidism. METHODS: Seventy-three of the 75 infants had congenital hypothyroidism. At the age of one month, prior to the initiation of thyroid hormone substitution therapy, thyroid-stimulating hormone (TSH), thyroid hormones and lipid profile parameters were determined. Subsequently, apoE phenotyping in all patients was performed by isoelectric focusing followed by immunoblotting. RESULTS: Significant negative correlations were identified between triiodothyronine (T3) and LDL-C and total cholesterol (TC) levels and between thyroxine (T4) and TC levels. There were no correlations between TSH and free (F)T4 and lipid profile parameters. Although infants carrying at least one E4 allele had higher LDL-C (as well as TC and triglyceride) levels than those carrying at least one E2 allele, these differences were not statistically significant. No significant differences in thyroid hormones were noted in E4 allele carriers in comparison with other patients. CONCLUSIONS: The observed lack of a significant correlation between thyroid hormones (except T3), apoE phenotypes and lipoprotein levels suggests that, early in infancy, other factors may play a more important role in determining lipoprotein levels.     

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.     

Transient secondary hypothyroidism and thyroxine binding globulin deficiency in leukemic children during polychemotherapy: An effect of L-asparaginase

Recently it has been observed that L-asparaginase causes transient thyroxine binding globulin (TBG) deficiency in adults. In the present study we investigated the influence of L-asparaginase on the pituitary-thyroid axis and on the synthesis of TBG. 14 children with acute lymphoblastic leukemia were treated with a combination of L-asparaginase, vincristine, prednisone and daunomycin for remission induction. Thyroid function was monitored by measuring total T₄, free T₄, total T₃, TSH and TBG with specific radioimmunoassays before, during and after treatment. Within 3 weeks of L-asparaginase therapy total T₄ fell significantly from 10.7±1.6 to 2.9±1.8 g/100 ml, free T₄ from 1.77±0.4 to 0.94±0.35 ng/100 ml, total T₃ from 0.99±0.23 to 0.35±0.2 ng/ml and TBG from 29.4±3.6 to 8.0±3.8 g/ml. Basal TSH values tinuation of L-asparaginase, but following further treatment with other antileukemic agents, all values became normal within 2–4 weeks. In 6 patients with hypothyroid free T₄ values TRH induced TSH release was totally blocked during L-asparaginase therapy. Our data clearly demonstrated that L-asparaginase caused a transient TBG deficiency. Total T₄ and T₃ were in the hypothyroid range because of low TBG concentrations. In addition to TBG deficiency transient, secondary hypothyroidism occurred in approximately 40–50% of all patients treated with L-asparaginase. These alterations were most likely caused by drug induced inhibition of protein synthesis. Under certain circumstances thyroid hormone replacement might be life-saving in severely ill patients suffering from transient, drug induced hypothyroidism.Presented in part at the 19th Meeting of the European Society for Pediatric Endocrinology, August 31–September 3, 1980, Bergamo/Italy     

Intellectual outcome, motor skills and BMI of children with congenital hypothyroidism: a population-based study

AIM: To evaluate intellectual outcome, motor skills and anthropometric data of children with congenital hypothyroidism (CH). METHODS: Children with permanent CH who were born in 1999 in Bavaria were eligible for this prospective, population-based study. Cognitive performance was evaluated by the Kaufman Assessment Battery for Children and motor skills were assessed by the motor test, Motoriktest für vier-bis sechsjahrige Kinder (MOT) 4-6. RESULTS: Eighteen of 21 eligible children participated (86%). Median age of the children was 5.5 years (range 4.9-5.8). Treatment with levothyroxine was started after a median of 7.2 days (range 4-15) with a median dose of 12.0 microg/kg (range 7.2-17.0). Mean intelligence quotient (IQ) of the children was 100.4 (standard deviation [SD] 10.1): no children had IQ values below the normal range. Reactivity and speed of movement were significantly reduced in children with CH. Children with an initial thyroid-stimulating hormone (TSH) value of >200 mU/L performed significantly worse than children with TSH value of 相似文献   

早期治疗对先天性甲状腺功能减低症患儿智力及体格发育的影响

目的：比较治疗开始时间不同的先天性甲状腺功能减低症（congenital hypothyroidism, CH）患儿治疗后智力发育、体格发育水平的不同,以寻求改善患儿预后的最佳治疗时间。方法：对2008年9月至2011年9月经新生儿疾病筛查确诊为CH,并在出生后3个月内开始应用甲状腺激素治疗的CH患儿49名,按开始治疗时间分为两组：生后1个月内治疗组（n=26）及1～3个月治疗组（n=23）。分别于6个月、1岁、2岁时,检测两组患儿体格发育情况,应用Gessell 发育量表评估智力发育商（DQ）及采用免疫荧光法测定甲状腺功能。结果：两组经甲状腺激素长期治疗,6个月、1岁、2岁时游离三碘甲状腺原氨酸（FT3）、游离甲状腺素（FT4）及促甲状腺素（TSH）水平差异无统计学意义（P>0.05）,但1个月内治疗组患儿的身长、体重均明显高于1～3个月治疗组,差异有统计学意义（P0.05）。结论：CH开始治疗时间影响患儿智力发育和体格发育;生后1个月内开始治疗者,智力及体格发育优于1～3个月开始治疗者。     

Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine

Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.     

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.     

Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine.

Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.