南京地区1998-2009年新生儿先天性甲状腺功能减低症筛查及治疗随访结果分析

目的 总结并分析1998年1月- 2009年12月南京地区新生儿先天性甲状腺功能减低症(CH)的筛查结果.方法 采集出生72 h新生儿442 454例的足跟血滴于滤纸上,采用时间分辨免疫法测定滤纸血斑促甲状腺激素(TSH),阳性者召回进一步测定静脉血TSH、三碘甲状腺原氨酸(T3)、四碘甲状腺原氨酸(T4)、游离T3(FT3)、游离T4(FT4)以明确诊断.确诊者立即开始予左旋甲状腺素片(4.3～12.0μg·kg-1·d-1)替代治疗,定期监测其甲状腺功能,测量其身高、体质量,其中68例患儿子智力测试,以评估疗效.结果 12 a共筛查442 454人,确诊CH 183例,发病率为0.41‰,对117例进行随访.初始治疗时间的中位数为18 d(7～67d),初始左旋甲状腺素的平均剂量为7.35 μg·kg-1·d-1.CH患儿的身高、体质量结果基本达到正常参照标准.盖泽尔婴幼儿发展量表(GESELL)测试结果显示1例智能发育落后,8例智能发育迟缓.T4、FT4的治疗前水平与患儿的GESELL测试总分、适应性及精细运动均呈正相关(Pa＜0.05).结论 经筛查确诊的CH患儿,应尽可能早地进行激素替代治疗,可有效改善其预后.因此新生儿筛查及随访治疗工作值得推广和完善.     

Thyroid function in children with Down's syndrome]

The aim of the present study was to evaluate thyroid function in 45 Down's syndrome patients in order to verify the hypothesis of an increased risk of thyroid disorders associated with trisomy 21. A patient with subclinical hypothyroidism (TSH 16.6 microU/ml; T4 6.4 micrograms/dl) was diagnosed in a group of 28 subjects with Down's syndrome studied at a mean age of 6 years and 5 months using T3, T4, FT3, FT4, TSH assays and clinical examination. T4 and TSH values were also measured in 10 of these children at the neonatal screening. One infant presented transient neonatal hyperthyrotropinemia but later became euthyroid. The analysis of thyroid hormone values at the neonatal screening of other 17 subjects with Down's syndrome did not reveal other cases with thyroid function disorders. The results of this study highlight that altered thyroid functions are evident in children with trisomy 21 associated with heart anomalies. A careful clinico-endocrinological follow-up of patients with Down's syndrome is recommended in order to ensure an early diagnosis of thyroid function disorders and/or autoimmune diseases which might complicate the evolution of trisomy and negatively affect outcome.     

Thyroid dysfunction in Down's syndrome and screening for hypothyroidism in children and adolescents using capillary TSH measurement

Thyroid dysfunction is more common in individuals with Down's syndrome (DS) than in the general population, whose clinical features can mask the presenting signs and symptoms of hypothyroidism. Biochemical screening is necessary; however, venepuncture may be difficult. AIMS: To assess the prevalence of thyroid dysfunction in children and adolescents with DS and the feasibility of screening for hypothyroidism using capillary dried blood spot thyroid stimulating hormone (TSH) from infancy. METHODS: 394 children (217 boys, 177 girls) were clinically assessed for thyroid dysfunction and 305 children (aged 4 months to 18.9 years) were screened for hypothyroidism by capillary whole blood TSH sample. RESULTS: Thyroid dysfunction was detected in 4.6%, with 50% unscreened since neonatal screening. Parents reported minimal distress by fingerprick screening. CONCLUSION: DS is associated with an increased prevalence of thyroid dysfunction, particularly in preschool children. Biochemical screening is essential and capillary whole blood TSH sampling for hypothyroidism is feasible, less invasive and acceptable.     

Three-year follow-up of borderline congenital hypothyroidism

The purpose of this study was to determine whether children with borderline hypothyroidism in the neonatal period had persistent hypothyroidism after 3 years of levothyroxine replacement therapy. Fourteen term infants with slightly abnormal newborn screening results (thyroxine <10th percentile, thyroid stimulating hormone ?TSH <40 microU/mL) were identified. The subsequent serum confirmatory TSH results of 12 subjects were modestly elevated (5.3 to 18.8 microU/mL, normal 0.6 to 4.6), whereas 2 subjects who had borderline confirmatory TSH (4.6 and 4.7 microU/mL) had abnormal TSH responses to thyrotropin releasing hormone testing. After 3 years of therapy, levothyroxine was discontinued in 13 patients, and repeat thyroid function tests were obtained 1 month later. Levothyroxine was not discontinued in one patient because he had an elevated random TSH (10 microU/mL) while receiving therapy. At 3 years of age, 13 patients had persistently abnormal thyroid function tests (TSH >4.6 microU/mL or a thyroid releasing hormone test result consistent with primary hypothyroidism), and levothyroxine was reinitiated. Only one patient had normal thyroid function studies. Although prospective studies are still lacking, we recommend levothyroxine replacement in newborns with borderline hypothyroidism.     

Neonatal screening for hypothyroidism in Greece

One year's experience in screening for congenital hypothyroidism in Greece is reported. Thyroidstimulating hormone (TSH) determination by a radioimmunoassay on dried blood spots was selected as the screening method. During the first year of screening 75,879 newborn infants were tested from Guthrie blood spots taken on the 5th day of life. Eighteen cases of primary congenital hypothyroidism with serum TSH levels over 100 IU/ml were detected, giving an incidence of 1:4200. One case had already been diagnosed clinically. Replacement treatment was started between the 22nd and the 50th days of life.     

Dopamine suppresses thyroid-stimulating hormone secretion in neonatal hypothyroidism

The infusion of dopamine, a hypophysiotropic catecholamine, which inhibits release of thyroid stimulating hormone (TSH), is the inotropic therapy of first choice in neonatal intensive care. Newborns with primary hypothyroidism are at increased risk of cardiocirculatory morbidity and are screened by measuring serum TSH concentrations. In an infant with both congenital heart disease and neonatal hypothyroidism, withdrawal of dopamine infusion was documented to evoke a doubling of serum TSH levels within 40 min, a finding suggestive of an inhibitory effect of dopamine administration on neonatal TSH hypersecretion. As a result, dopamine therapy may be a pitfall in TSH screening for neonatal 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.     

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.     

Newborn screening for congenital hypothyroidism

Most neonates born with congenital hypothyroidism (CH) have normal appearance and no detectable physical signs. Hypothyroidism in the newborn period is almost always overlooked and delayed diagnosis leads to the most severe outcome of CH, mental retardation, emphasizing the importance of neonatal screening. Blood spot T4 or TSH or both can be used in neonatal screening for CH. The latter, which is more sensitive, is not cost effective, so the first two are used in different programs in the world. TSH screening was shown to be more specific in the diagnosis of CH; T4 screening is more sensitive in detecting newborns especially with rare hypothalamic-pituitary hypothyroidism, but less specific with a high frequency of false positives mainly in low birth weight and premature infants. The time at which the sample is taken may vary between centers, with the majority taking blood from a heel prick after 24 hours of age to minimize the false positive high TSH due to the physiological neonatal TSH surge that elevates TSH levels and causes dynamic T4 and T3 changes in the first 1 or 2 days after birth. Early discharge of mothers postpartum has increased the ratio of false positive TSH elevations. Although transient hypothyroidism may occur frequently, all suspected infants should be treated as having CH for the first 3 years of life, taking into account the risks of mental retardation. A reevaluation after 3 years is needed in such patients. The goal of initial therapy in CH is to minimize neonatal central nervous system exposure to hypothyroidism by normalizing thyroid function, as reflected by T4 and TSH levels, as rapidly as possible. Iodine deficiency is the most important cause of CH worldwide. Iodine is essential for thyroid hormone synthesis and is present in soil, water and air. Prevention of iodine deficiency can be by iodized salt, iodized oil, iodized bread or iodine tablets.     

Maternal TSH-receptor antibodies and TSH antibodies in screening for congenital hypothyroidism

Serum samples from 30 mothers who had given birth to at least one child with a positive neonatal thyrotropin (TSH) screening test were analysed for TSH-receptor antibodies. One mother with hypothyroidism after thyroiditis who had two sons who had had transient congenital hypothyroidism, showed significantly elevated concentrations of TSH receptor blocking IgG antibodies in her serum. The three daughters of another mother had neonatal hyperthyrotropinaemia but normal thyroid hormone levels. This woman had elevated serum levels of TSH but was clinically and biochemically euthyroid. The apparent hyperthyrotropinaemia in this family was due to an artifact in the TSH radioimmunoassay caused by maternal anti-TSH IgG antibodies. It is obvious that placental transfer of maternal IgG antibodies to the thyroid TSH receptor is one cause of transient congenital hypothyroidism. Likewise, maternal IgG directed against TSH interferes with radioimmunoassays of TSH and the results may be falsely interpreted as hyperthyrotropinaemia. It is concluded that in neonatal hyperthyrotropinaemia analysis of the mother's serum is indicated, and that maternal TSH receptor blocking antibodies must be considered as a cause of congenital hypothyroidism, especially if the mother has a history of thyroid dysfunction.     

Maternal TSH-Receptor Antibodies and TSH Antibodies in Screening for Congenital Hypothyroidism

ABSTRACT. Serum samples from 30 mothers who had given birth to at least one child with a positive neonatal thyrotropin (TSH) screening test were analysed for TSH-receptor antibodies. One mother with hypothyroidism after thyroiditis who had two sons who had had transient congenital hypothyroidism, showed significantly elevated concentrations of TSH receptor blocking IgG antibodies in her serum. The three daughters of another mother had neonatal hyper-thyrotropinaemia but normal thyroid hormone levels. This woman had elevated serum levels of TSH but was clinically and biochemically euthyroid. The apparent hyperthyrotropinaemia in this family was due to an artifact in the TSH radioimmunoassay caused by maternal anti-TSH IgG antibodies. It is obvious that placental transfer of maternal IgG antibodies to the thyroid TSH receptor is one cause of transient congenital hypothyroidism. Likewise, maternal IgG directed against TSH interferes with radioimmunoassays of TSH and the results may be falsely interpreted as hyperthyrotropinaemia. It is concluded that in neonatal hyperthyrotropinaemia analysis of the mother's serum is indicated, and that maternal TSH receptor blocking antibodies must be considered as a cause of congenital hypothyroidism, especially if the mother has a history of thyroid dysfunction.     

Update of newborn screening and therapy for congenital hypothyroidism

Unrecognized congenital hypothyroidism leads to mental retardation. Newborn screening and thyroid therapy started within 2 weeks of age can normalize cognitive development. The primary thyroid-stimulating hormone screening has become standard in many parts of the world. However, newborn thyroid screening is not yet universal in some countries. Initial dosage of 10 to 15 microg/kg levothyroxine is recommended. The goals of thyroid hormone therapy should be to maintain frequent evaluations of total thyroxine or free thyroxine in the upper half of the reference range during the first 3 years of life and to normalize the serum thyroid-stimulating hormone concentration to ensure optimal thyroid hormone dosage and compliance. Improvements in screening and therapy have led to improved developmental outcomes in adults with congenital hypothyroidism who are now in their 20s and 30s. Thyroid hormone regimens used today are more aggressive in targeting early correction of thyroid-stimulating hormone than were those used 20 or even 10 years ago. Thus, newborn infants with congenital hypothyroidism today may have an even better intellectual and neurologic prognosis. Efforts are ongoing to establish the optimal therapy that leads to maximum potential for normal development for infants with congenital hypothyroidism. Remaining controversy centers on infants whose abnormality in neonatal thyroid function is transient or mild and on optimal care of very low birth weight or preterm infants. Of note, thyroid-stimulating hormone is not elevated in central hypothyroidism. An algorithm is proposed for diagnosis and management. Physicians must not relinquish their clinical judgment and experience in the face of normal newborn thyroid test results. Hypothyroidism can be acquired after the newborn screening. When clinical symptoms and signs suggest hypothyroidism, regardless of newborn screening results, serum free thyroxine and thyroid-stimulating hormone determinations should be performed.     

Neonatal hypothyroidism detected by the Northwest Regional Screening Program.

The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in Oregon, Montana, Alaska, and Idaho (combined birthrate of 69,000/ yr) was added to our ongoing screening program in 1975. The program utilizes dried blood filter paper specimens collected routinely in the first few days of life in all four states and again at about 6 weeks of age in Oregon only. The screening test consist of an initial thyroxine (T4) measurement; a thyroid-stimulating hormore (TSH) determination is performed on those specimens with T4 concentrations in the lowest 3% group. Serum samples obtained by venipuncture are requested for confirmation of the diagnosis. In the first two years of the program, 25 infants with primary hypothyroidism were detected amont 110,667 infants screened, a frequency of 1:4,430. Fourteen cases of thyroxine-binding globulin deficiency were also detected, a frequency of 1:7,900. Using the T4 followed by TSH testing approach, the frequency of request for repeat specimens was 0.4% in Oregon and 0.05% in the other states. The cost per specimen was $1.96. The majority of infants lacked clinical signs or symptoms of hypothyroidism; only one infant was clinically suspected of having hypothyroidism prior to detection. The most common neonatal symptoms were constipation, lethargy, and prolonged jaundice, while the most common physical signs were hypotonia, umbilical hernia, and large fontanels. Thyroid scans showed the most common etiology to be thyroid aplasia, followed by an ectopic gland, hypoplasia, and goiter. Serum T4 concentrations were lowest in those infants with aplasia, intermediate in infants with an ectopic gland or hypoplasia, and normal in the infant with the goiter. Neonatal hypothyroidism varies in degree and has several different causes; the capacity to secrete thyroid hormone, the duration before hypothyroidism becomes clinically manifest, and possibly the eventual prognosis for intellectual function depend on the nature of the underlying cause. While the mean age at treatment was 59 days, the goal of diagnosing congenital hypothyroidism and treating affected infants by 1 month of age seems realistic.     

Alterations of neonatal thyroid function

Grüters A, Krude H, Biebermann H, Liesenkötter KP, Schöneberg T, Gudermann T. Alterations of neonatal thyroid function. Acta Pædiatr 1999; Suppl 428: 17–22. Stockholm. ISSN 0803–5326
Recent progress has been made in understanding the pathogenesis of neonatal thyroid disorders. Autosomal recessive inheritance of mutations of the thyroid peroxidase and thyroglobulin genes has been described in some patients with congenital hypothyroidism (CH) and a family history of CH. Autosomal recessive inheritance of mutations of the thyrotrophin (TSH) receptor gene has also been reported in patients with CH and thyroid hypoplasia, and autosomal dominant mutations of the PAX8 gene have been described in patients with different forms of thyroid dysgenesis. These discoveries are important for patients with CH diagnosed by neonatal screening, as these patients will have normal fertility. The molecular genetic analysis of mutations of the TSH gene in patients with familial and sporadic cases of isolated central CH, who are missed by TSH screening programmes, now enables rapid diagnosis and appropriate therapy in the neonate. In newborn infants with severe non-autoimmune hyperthyroidism, autosomal dominant gain-of-function mutations in the TSH receptor gene have been demonstrated. In these patients, molecular genetic studies are extremely helpful in therapeutic decision making, as early thyroid ablation is the only effective treatment that avoids the sequelae of long-term hyperthyroidism. Molecular genetic studies are therefore useful in the diagnostic work-up of neonatal thyroid alterations. □ Congenital hypothyroidism, molecular pathogenesis, neonatal hyperthyroidism     

Subclinical hypothyroidism in in vitro fertilization babies

Aim: Assisted reproduction technology is used widely all over the world. There is a great concern about the morbidity of in vitro fertilization (IVF) babies, but investigations are mostly related to mechanical conditions that are attributed to multiparity. This paper aimed to investigate the effect of IVF on thyroid functions in newborns. Methods: A total of 98 healthy, term IVF newborns were evaluated between postnatal 2–4 weeks of age by screening of thyroid functions between July 2006 and April 2008. Ten subjects were assessed as a study group whose thyroid‐stimulating hormone (TSH) levels were higher than 6.5 mU/L. Control group consisted of randomly selected 10 naturally conceived infants with hyperthyrotropinemia (whose TSH levels were higher than 6.5 mU/L but under 15 mU/L) with the same age. All children were thoroughly examined, and serum fT4, TSH, anti‐thyroid peroxidase and anti‐thyroglobulin antibodies were measured, and a thyrotropin‐releasing hormone (TRH) test was performed in all subjects in both groups. Results: Euthyroid hyperthyrotropinemia was diagnosed in approximately 10% of IVF babies. Exaggerated TSH levels to TRH were obtained in all IVF babies (subclinical hypothyroidism) but in none of the controls. A significant difference was noted in the concentration of TSH at the 20th min between the two groups (p < 0.001). Besides, sustained and delayed TSH responses were observed in IVF babies. Neonatal screening tests were negative in both of the groups. Conclusion: In IVF babies, despite normal neonatal screening tests, subclinical hypothyroidism might be observed that suggests the need for screening in this respect.     

Congenital hypothyroidism. The effect of stopping treatment at 3 years of age

Fifty-six children with congenital hypothyroidism diagnosed by neonatal screening were reviewed at 3 years of age or older. The presence or absence of the thyroid gland was determined by radionuclide scanning prior to treatment in the newborn period. Thyroxine therapy was discontinued in those children who did not have anatomic defects or a secondary rise in their thyrotropin (thyroid-stimulating hormone [TSH]) level once it was suppressed by thyroid hormones. Sixteen of 17 children developed a low thyroxine and an elevated TSH level within three to six weeks. One child was not receiving thyroxine for nine months and was clinically and biochemically euthyroid. We conclude that (1) newborn thyroid scans are useful to determine the cause of hypothyroidism, (2) a secondary rise in the TSH level indicates permanent hypothyroidism, (3) only about one third of infants whose condition is diagnosed by newborn screening will qualify for a trial off therapy at 3 years of age, (4) only 1% to 2% of infants whose condition is diagnosed by newborn screening have transient hypothyroidism, and (5) a three-week period of hormone withdrawal after the age of 3 years seems adequate and safe to confirm permanent hypothyroidism.     

Determination of free thyroxine (FT4) for the detection of connatal hypothyroidism within the scope of neonatal screening

Using the reagents of a commercially available test kit (Henning, Berlin) for the determination of free thyroxin (FT4) in serum we developed a radio immuno assay procedure to measure FT4 in whole dried blood on filter paper. The inter assay coefficient of variation was 19.1%, 10.7%, and 11.0% for the hypo-, normo-or hyperthyroid range for whole blood on filter paper. The corresponding within assay values were 7.0, 10.3, and 5.3% respectively. In 15,793 samples of dried blood on filter paper which were collected on the 5th or 6th day of life for the screening of inborn errors of metabolism or hypothyroidism FT4 was measured in addition to our routine determination of thyroid stimulating hormone (TSH). The mean concentration of FT4 was 20 to 22 pg/ml. 97,8% of all results were found between 10 and 35 pg/ml. Connatal hypothyroidism was confirmed clinically in 5 children showing FT4-values of 3.5, less than 2.0, less than 2.0, 3.4, and 6.2 pg/ml. The corresponding TSH-values were greater than 224, greater than 224, 99, 203, and 129 microU/ml. To make sure that a sufficient amount of blood had been eluted from the filter paper we measured the concentration of hemoglobin as an additional parameter. Low FT4 together with low hemoglobin concentrations were obtained in 18 samples indicating that a mismeasurement of FT4 might have occurred. We suggest that the determination of TSH in doublicates, which is the routine screening procedure in West Germany might be replaced by a combined determination of FT4 and TSH.     

Genetic Analysis in Children with Transient Thyroid Dysfunction or Subclinical Hypothyroidism Detected on Neonatal Screening

About 30% of children with elevated TSH levels during neonatal screening have a transient form of disorder. On the other hand, it has been reported that subclinical hypothyroidism persists in late childhood in about 30% of children found to be false-positive during neonatal screening. The aim of this study was to determine whether transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening are influenced by genetic background. The TSH receptor (TSHR), thyroid peroxidase (TPO) and dual oxidase 2 (DUOX2) genes, for which it has been reported that heterozygous defects cause neonatal transient thyroid dysfunction, were analyzed. Nine children with transient thyroid dysfunction or subclinical hypothyroidism detected during neonatal screening were studied. One child was heterozygous for a TSHR gene mutation (R450H), and another child was heterozygous for a TPO gene mutation (P883S). No children with mutation of the DUOX2 gene were identified. Genetic background may contribute to development of transient thyroid dysfunction and subclinical hypothyroidism detected during neonatal screening.     

Frequency of congenital hypothyroidism in neonates in the Konya region, Turkey

Congenital hypothyroidism (CH) resulting from deficient production of thyroid hormone is one of the most commonly encountered diseases in pediatric endocrinology. Thyroid hormones play a crucial role in normal cerebral and growth maturation. These harmful effects on the cerebral and growth maturation can be prevented by early diagnosis and sufficient treatment in the first weeks of life. Diagnosis must be determined immediately within days after birth and effective treatment must begin. Unfortunately, despite the presence of national neonatal screening programs, CH cases are still rarely seen. In our study, it was aimed to assess the outcome of having determined an early diagnosis of CH and initiating treatment with thyroid stimulating hormone (TSH) screening test on live born babies over a period of 7 years in our hospital. With this aim, 93,897 live births were evaluated in the Doctor Faruk Sükan Obstetrics and Pediatrics Hospital between the years of 1999 and 2007. All neonates were screened with the TSH test. CH was determined in 43 (1/2183) of all cases and treatment was begun. The importance of this test was emphasized in that the test should be performed routinely on all neonates to obtain an early diagnosis and so that treatment for CH can begin.