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.     

Tc]-99m thyroid scintigraphy in congenital hypothyroidism screening program

The aetiology of congenital hypothyroidism (CH) may be important in determining disease severity, outcome and treatment schedules because athyroid patients need higher treatment doses and close monitoring particularly early in life. The aim of this study was to evaluate thyroid scintigraphy (TS) findings in infants with CH and to determine the relationship of serum TSH and T4 values with thyroid agenesia, in an attempt to identify factors that may detect thyroid agenesia before treatment. Since August 2002 to April 2005, screening program for CH was carried out in the Isfahan University of Medical Sciences and Health Services, Isfahan, Iran. Screening was performed by measuring both the serums T4 and TSH concentration at day 3-7 of birth. Full-term newborns were recalled based on a serum TSH >20 mIU/l or serum T4 < 6.5 microg/dl and premature newborns based on T4 level by weight and TSH level by age. After repeating the laboratory test and clinical evaluation, Tc-99m TS was recommended for all infants with suspected CH before thyroxin replacement therapy. On the basis of Tc-99m TS, the thyroid gland was classified as normal scan, ectopic, goiter and athyrosis. TS results were compared with serum T4 and TSH levels. Of 93 381 newborns screened over a period of nearly 3 years, 262 neonates were found to have CH. The overall incidence of CH was 1 : 357 live births with a female/male ratio (F/M) of 1.4/1. Thyroid scan was performed on 116 (54%) of the infants with CH; of them, 33 cases (28.4%) were athyrotic (F/M = 0.8/1) while seven infants (6%) had ectopic thyroid (F/M = 1.3/1) and 76 cases (65.6%) had a normal thyroid scan (F/M = 1.5/1). Infants with the absence of thyroid in TS had significantly higher TSH value in comparison with those with ectopic or normal TS (116.3 +/- 109.64 vs. 108.10 +/- 62.92 or 55.35 +/- 48.26 mIU/l, respectively, P < 0.0001). Although not statistically different, the mean T4 level was higher in normal TS group than in ectopic and athyrotic groups (8.03 +/- 3.48 vs. 6.36 +/- 5.57 or 5.04 +/- 3 microg/dl, respectively, P = 0.09). We conclude that Tc-99m TS is a useful diagnostic tool for the initial investigation of suspected CH and considering the correlation of TS results with blood TSH levels, proper management and close monitoring of hypothyroid infants with severe hormonal alterations is necessary for the detection of thyroid agenesia.     

Raised serum TSH in hypothyroidism.

It is desirable to detect early hypothyroidism of the mildest degree even before conventional tests of thyroid function become abnormal. Serum TSH levels (normal: undetectable to 4 muU/ml) rise in patients with mild hypothyroidism long before serum T4 and T3 levels fall. In the patient described the serum TSH level was 310 muU/ml, while other tests of thyroid function gave normal results. After treatment with thyroxine, serum TSH returned to normal. It should now be accepted that patients with mild hypothyroidism have a raised serum TSH and that thyroid insufficiency can be confidently excluded if the serum TSH concentration is normal. It is thus important to assay serum TSH when suspicion of hypothyroidism is aroused.     

A high prevalence of consanguineous and severe congenital hypothyroidism in an Iranian population

To determine the incidence of permanent congenital hypothyroidism (CH) in Tehran and Damavand, cord blood spots were collected from February 1998-August 2002 and infants with TSH > or =20 mU/l were recalled. CH was confirmed in neonates (aged > or =7 days) with serum TSH >10 mU/l and T4 <84 nmol/l. Cases were followed up until September 2003. Dysgenesis was detected by thyroid imaging. In eutopic cases, serum TSH and T4 measurements following levothyroxine discontinuation (2-3 years of age) confirmed dyshormonogenesis and transient CH. Of 35,067 neonates, 373 (1.06%) were recalled and 25 (1:1,403 births) had permanent CH (six had transient CH and four remain unknown). Dysgenesis was detected in 18 (1:1,948 births) and dyshormonogenesis in seven (1:5,010 births) infants. Parental consanguinity was present in 10 (55.6%) dysgenetic, three (42.9%) dyshormonogenetic, and overall 6,648 (28.6%) of 23,227 screened infants. Odds ratio (95%CI(OR)) of consanguinity in permanent CH and dysgenesis was 2.75 (1.17-6.47) and 3.74 (1.33-10.52), respectively. The high prevalence of parental consanguinity in infants with permanent CH warrants genetic assessment.     

High prevalence of congenital hypothyroidism in the Greek Cypriot population: results of the neonatal screening program 1990-2000

OBJECTIVE: To evaluate the results of the screening program for congenital hypothyroidism (CH) in the Greek Cypriot population. CHILDREN AND METHODS: During 1990-2000, 109,532 neonates were screened by TSH determination. Permanent CH was proven with biochemical findings after discontinuation of treatment for scintigraphy at the age of 3 years. RESULTS: Permanent CH was diagnosed in 61 infants, incidence 1/1800, with female/male ratio 2.05/1. The most common clinical findings were omphalocele (61%), large anterior fontanelles (49%) and edema of the eyelids (34%). The more delayed the bone maturation, the lower were initial T4 levels (p = 0.005). Bone maturation tended to be more advanced in thyroid hypoplasia and more delayed in thyroid agenesis (p = 0.049). Scintigraphy of the thyroid with TC99 revealed ectopia in 38%, thyroid agenesis in 36%, thyroid hypoplasia in 24% and dyshormonogenesis in 1.7%. Children with transient CH had significantly lower T4 and higher TSH values initially compared to those with permanent CH after birth; initial TSH level, however, failed to predict the nature of CH. Children with transient CH required less thyroxine dosage to maintain normal thyroid hormone levels and they had a normal thyroid gland on scintigraphy. The TSH level was normalized before the age of 2 months with a starting L-thyroxine dose of 10 microg/kg/daily. CONCLUSIONS: The incidence of primary CH in Greek Cypriots is 1/1800 live births. The most common etiology is thyroid dysgenesis. Initial T4 levels correlated with the degree of skeletal maturation and the etiology. Initial TSH level, although lower in children with transient CH, could not predict the nature of CH.     

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.     

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.     

Increased incidence of congenital hypothyroidism due to iodine deficiency

BACKGROUND: The incidence of congenital hypothyroidism (CH) is expected to be elevated in iodine-deficient areas. In this study, the authors aimed to determine the incidence of transient and permanent CH in a large city which is known to be in the zone of moderate iodine deficiency. METHODS: Newborn babies in Bursa, Turkey, were screened by measurement of serum thyroid-stimulating hormone (TSH) obtained by heel prick. The babies who had a serum TSH >20 mIU/L were recalled for measurement of T4 and TSH in venous serum. RESULTS: A total of 11 770 newborns were screened over a period of 9 years. The incidence of CH was found to be 1/840. However, after excluding the transient cases, permanent CH was diagnosed in 1/2354. It was impossible to distinguish transient patients from permanent CH by initial laboratory tests (P > 0.05). The estimated power of the study in determining the incidence of CH in the population was 90% (P < 0.05). CONCLUSION: The authors conclude that the incidence of CH is very high in their population which warrants a country-wide neonatal screening program. Since transient cases cannot be distinguished and untreated transient hypothyroidism may also cause mental retardation, treatment must be started as early as possible with frequent monitoring to optimize the outcome and identify the transient patients.     

Congenital hypothyroidism with delayed rise in serum TSH missed on newborn screening

We report on a female patient with congenital hypothyroidism (CH) missed on a newborn screening test. She is now 10 years old with retarded development. The patient was born premature at 34 weeks of gestation with birth-weight of 1515 g, and was judged to be normal in the screening programme of Niigata Prefecture. However, she gradually suffered from poor weight gain and retarded development with stridor at breathing. Serum thyroid stimulating hormone (TSH) levels were rechecked and showed high values with normal T3 and T4 levels. She was referred to our hospital at the age of 13 months. She was diagnosed as having CH (ectopic thyroid) with a delayed rise in blood TSH concentration, probably due to the prematurity of the hypothalamic-pituitary-thyroid axis. l -thyroxine therapy brought a decline in TSH levels with partial improvement of her symptoms. Regardless of the result of newborn screening, infants with elevated serum TSH levels should be carefully examined for possible CH, even when T3, T4 and free T4 values are in the normal range.     

Recovery Period of Hypersecretion of Thyroid-Stimulating Hormone in Patients with Congenital Hypothyroidism Treated with Thyroid Hormone

The recovery periods of serum thyroid stimulating hormone (TSH) were studied in patients with congenital hypothyroidism found on neonatal screening. L-T4 was administered at 37.8 ± 15.1 days of age (M ± SD), and serum T4, T3, and TSH concentrations were measured. After L-T4 therapy with 10 µg/kg, the serum TSH levels decreased to below 10 µU/ml in five patients within a week, and in another two patients, within two weeks, and in the total number of 12 patients out of 15 (80%), by one month. These results suggest that the recovery of serum TSH occurs rapidly in hypothyroid infants. Thus, the serum TSH concentration may be a good measurement for assessing the adequacy of thyroid hormone therapy from early infancy in patients with congenital hypothyroidism.     

先天性甲状腺功能减退症新生儿心电图改变的意义

目的评价先天性甲状腺功能减退症(CH)新生儿的心电图(ECG)改变,及与血清甲状腺激素(TH)水平的相关性,探讨TH减少对新生儿心脏电生理活动的影响。方法对50例CH新生儿(日龄17～28d)和35例健康新生儿(健康对照组)进行常规十二导联ECG检查,分别检测心率(HR)、PR间期(PR)、QT间期(QT)、QRS波电轴(QRSa)、QRS波时限(QRS)、校正QT间期(QTC)等,同时用化学发光法测定血清游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、总三碘甲状腺原氨酸(TT3)、总甲状腺素(TT4)和促甲状腺素(FSH)水平,对心电图指标和血TH水平行相关性分析。结果与健康对照组相比,CH组血清FT3、FT4、TT3、TT4水平显著降低,TSH水平显著升高(Pa<0.001);CH组HR显著低于健康对照组,PR及QT较健康对照组显著延长(Pa<0.05),但二组QRSa、QRS及QTC差异均无统计学意义(Pa>0.05)。HR与FT3、FT4呈显著正相关,与TSH呈显著负相关(Pa<0.05);PR间期与FT3、FT4、TT4呈显著负相关,与TSH呈显著正相关(Pa<0.05);但QT、QRS、QRSa及QTC与血TH水平均无明显相关(Pa>0.05)。结论CH可对新生儿窦房结起搏产生显著影响,引起心脏自律性改变,而心肌动作电位、房室传导等电生理活动则尚未受影响。     

Influence of Mode of Delivery on Fetal Pituitary-Thyroid Axis

We measured the cord serum levels of thyroid-stimulating hormone (TSH), thyroxine (T4) and triiodothyronine (T3) in 922 neonates delivered by mothers who had no thyroid disorders. The T4 and T3 levels increased progressively from the 27th to the 40th week of gestation. However, the TSH levels varied widely and had no correlation with gestational age, because they were affected by the mode of delivery. The mean cord serum TSH level in neonates delivered by vacuum extraction was 16.3 ±10.0 µUml (n = 30), which was significantly higher than the level following normal vaginal delivery (9.5 ± 6.0 µ U/ml, n = 622) (p < 0.005). The mean cord serum TSH level following elective caesarean section was 6.5 ± 3.1 µ U/ml (n = 79), and this was significantly lower than after normal vaginal delivery (p< 0.005). TSH levels in high-risk neonates were significantly higher than in neonates without risk factors. A significant positive correlation was found between the duration of the second stage of labor and the cord serum TSH level (r = 0.45, n = 412, p<0.01). However, there was no correlation between the cord serum TSH level and the congenital hypothyroidism screening TSH level (r = 0.01, n = 468). We conclude that the cord serum TSH level reflects delivery stress and that an elevated level does not influence the congenital hypothyroidism screening TSH test in which blood is obtained at five days of life.     

先天性甲状腺功能减低症筛查及治疗效果分析

目的了解先天性甲状腺功能减低症(CH)的筛查及替代治疗结果。方法回顾性分析2003年7月—2015年7月采用时间分辨荧光免疫法测定新生儿促甲状腺激素(TSH)水平筛查CH的资料;阳性召回的可疑患儿采用化学免疫发光法测定血清甲状腺功能,确诊者予左旋甲状腺素钠替代治疗并定期随访。结果 12年来共筛查新生儿1 228 289例,确诊950例,CH发病率1/1 293。接受正规治疗、随访满2年及以上的635例CH患儿中,488例(76.85%)为永久性CH,147例(23.15%)为暂时性CH。CH患儿随访至1岁和3岁时,体格生长和发育商(DQ)无异常。结论新生儿筛查可早期诊断CH,早期实施替代治疗。     

Persistently raised thyroid stimulating hormone in adequately treated congenital hypothyroidism on long-term follow-up

AIM: To determine the percentage of patients with inappropriate secretion of TSH (ISTSH) in a large cohort of patients with congenital hypothyroidism (CH), and to examine a probable influence of the pretreatment T4 or TSH levels and the etiology of CH on ISTSH by describing the clinical features of these patients. PATIENTS AND METHODS: We retrospectively examined the records, including anthropometric data, clinical findings, and thyroid function tests (TFT), of 500 children diagnosed with CH. Inclusion criteria of ISTSH were appropriate doses of L-T4, improvement of clinical findings, normalization of serum total T4 levels and persistently high TSH concentrations. A group of patients who demonstrated adequate suppression of TSH (<6 mU/l) with therapy among 500 CH patients were chosen randomly as a control group. Both groups were compared with regard to the etiology of CH, and TFT at baseline and during the treatment period. RESULTS: Overall, 27 (5.4%) out of the 500 patients with CH had ISTSH. Nine patients (1.8%) with ISTHS did not show TSH normalization during the follow-up period. Four out of 27 patients with ISTSH had organic lesions (three empty sella, one corpus callosum agenesis) on cranial imaging. No statistically significant difference was found between the groups for etiological classification. The pretreatment T4 and TSH levels in ISTHS and control groups were not significantly different. CONCLUSIONS: Our results suggest that a minority (5.4%) of adequately treated children with CH have persistently raised TSH levels. The delay in normalization of TSH is not related to pretreatment T4 and TSH values or the etiology of CH.     

Congenital hypothyroidism in a child with unsuspected familial dysalbuminemic hyperthyroxinemia caused by a mutation (R218H) in the human albumin gene.

We found familial dysalbuminemic hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T4) and higher than normal total triiodothyronine (T3) levels. Thyroid hormone substitution began at 5 weeks of age when T4 and T3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was also present in the patient's euthyroid father and brother. Thyroid scans, serum thyroglobulin measurements, and free T4 measurements using equilibrium dialysis or 2-step immunoassay methods can identify thyroid hormone-binding protein defects and simplify the diagnosis and treatment of infants with CH.     

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     

Thyroid function abnormalities among first‐degree relatives of Iranian congenital hypothyroidism neonates

Background: Congenital hypothyroidism (CH) is a relatively common metabolic disease in neonates. Until recent years the disorder was usually regarded as occurring in a sporadic manner. Over the past few years, however, a considerable proportion of familial cases have been identified, and possible roles of autoimmune factors suggested. The aim of the present study was to evaluate abnormality of thyroid function tests in first‐degree relatives of CH neonates and compared this to the normal population. Methods: From 2002 until 2007 thyroid function tests (T4 and thyroid‐stimulating hormone [TSH]) were done in randomly selected CH and normal neonates (n= 194 and n= 350, respectively) and their first‐degree relatives. Most mothers of the CH neonates and control groups were also evaluated for thyroid peroxidase antibody (TPOAb). Results: Thyroid function test in first‐degree relative of neonates with CH (361 parents, 136 siblings) were compared with those in control groups (665 parents, 478 siblings). Abnormal thyroid function tests were found in 85 patients in the CH group versus 96 patients in the control group; hypothyroidism was found in 75 (15.1%) and 57 subjects (5%) person in the CH and control groups, respectively (P < 0.05). Positive TPO antibody was found in 22 mothers (17.3%) of CH neonates in comparison with 65 mothers (32.5%) of control groups (P < 0.05). Frequency of hyperthyroidism in parents of control group had trend to be higher than parents of CH neonates (P= 0.05) Conclusion: Familial and genetic components play a role in inheritance of CH, but maternal thyroid autoimmunity may not play an important role in the development of CH in Iran.     

Does Congenital Hypothyroidism Have Different Etiologies in Iran?

Objective

To determine the prevalence of congenital hypothyroidism (CH), permanent and transient CH.

Methods

From November 2006 to September 2007, 63031 newborns were screened by measuring serum TSH obtained by heel prick. The neonates who had a TSH≥5mU/L were recalled for measurement of serum T₄, thyroid stimulating hormone (TSH) and TSH receptor blocking antibodies (TRBAb) in venous samples. In 43 primarily diagnosed as cases of CH, treatment was discontinued at age 2–3 years for 4 weeks and T₄ and TSH were measured again. Permanent or transient CH was determined from the results of these tests and radiologic evaluation.

Findings

The incidence of congenital hypothyroidism was found to be 1:1465 with a female to male ratio of 1.19:1. The most common clinical findings were prolonged jaundice (73%), large anterior fontanel (56%) and wide posterior fontanel (55%). In 43 patients with CH, prevalence of permanent and transient form of the disorder was 53.6% and 46.4% respectively. Permanent CH was associated with higher initial TSH level than transient hypothyroidism (P<0.001). The most common etiology of permanent CH was dyshormonogenesis (57%). TRBAb was found in 6.8% of the total 43 cases.

Conclusion

Congenital hypothyroidism in Iran may have different etiologies. Due to higher rate of transient CH than other similar researches, it is reasonable to follow these patients for a longer period to rule out the possibility of permanent hypothyroidism.     

Novel TSHbeta subunit gene mutation causing congenital central hypothyroidism in a newborn male

Newborn screening programs that use only high TSH levels as a marker for hypothyroidism may overlook neonates with congenital hypothyroidism (CH) due to TSH deficiency. We sought the cause of TSH deficiency in a neonate with low levels of thyroxine and TSH. The coding region of the TSHbeta gene was amplified and its sequence examined for mutations. Two mutations in exon 3 were identified: 1) a nucleotide deletion of T410 in codon 105 resulting in a frameshift in one allele, and 2) a previously unreported nucleotide deletion of T266 in codon 57, causing a frameshift and a premature stop at codon 62 in the other allele. We describe a compound heterozygous patient with TSHbeta mutations at codons 57 and 105 that interfered with a critical disulfide bond in the TSH molecule and caused CH. State screening programs that measure both T4 and TSH levels have the potential to detect newborns with congenital central hypothyroidism.