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.     

Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program

We examined the results of the Northwest Regional Screening Program (NWRSP) over its first 10 years to determine whether the detection of hypopituitary hypothyroidism is a justified advantage of the primary thyroxine (T4)-supplemental thyroid-stimulating hormone (TSH) screening strategy, and to determine whether all such infants will be detected by this screening approach. Between May 1975 and May 1985, the NWRSP screened 850,431 infants, detecting 192 infants with primary hypothyroidism (1:4429) and eight with hypopituitary hypothyroidism (1:106,304). In 11 additional infants, TSH deficiency, not detected by the screening program, was diagnosed on recognition of clinical features over the same period. Thyroid hormone treatment was begun in seven of the 11 infants prior to obtaining the screening sample results because of clinical symptoms of hypopituitarism, including hypoglycemia, persistent jaundice, microgenitalia, diabetes insipidus, midface hypoplasia, cleft lip or palate, or abnormalities of vision. The other four infants were not detected despite clinical features of hypopituitarism (in retrospect) and low serum T4 with TSH concentration below assay sensitivity on at least one screening sample. The most accurate assessment of total cases comes from Oregon, where all cases of congenital hypopituitarism are referred to our center; we estimate a frequency of 1:29,000. In our experience, a combination of newborn T4-supplemental TSH screening measurements and recognition of clinical features of hypopituitarism is the optimal strategy for detecting infants with congenital hypopituitary hypothyroidism.     

Thyroid dysfunction in children with Down's syndrome

Thyroid function tests were carried out on 320 children with Down's syndrome aged between 5 d and 10 y. Thyroid function was normal in 230 patients (71.9%) and abnormal in 90 (28.1%). Six patients (1.8%) had primary congenital hypothyroidism, one patient had acquired hypothyroidism and two had transient hyperthyrotropinaemia of the newborn. Sixteen of the remaining 81 patients (25.3%) had compensated hypothyroidism with increased thyroid-stimulating hormone (TSH) levels (11-20 mU l -1 ). Their T 4 levels were found to be either normal or close to the lower limit of normal. These cases were started on thyroxine therapy. Sixty-five of the 81 patients had a mild compensated hypothyroidism with mild TSH elevation (6-10 mU l -1 ). None of the patients had hyperthyroidism. The antithyroid antibodies were positive in the acquired hypothyroidism case.

Conclusion: The prevalence of congenital hypothyroidism was 1.8% in children with Down's syndrome while 25.3% of them had compensated hypothyroidism. It is suggested that Down's syndrome patients with normal thyroid functions and those with compensated hypothyroidism should be followed annually and every 3 mo, respectively. Besides congenital hypothyroidism cases, those with TSH levels between 11 and 20 mU l -1 may benefit from treatment with low-dose thyroxine.     

Congenital hypothyroidism

Congenital hypothyroidism is one of the most common diseases in paediatric endocrinology. Thyroid hormones are essential in brain development, which takes place during foetal life and early postnatal life up to the 2nd year of age. The main etiologic factors of congenital hypothyroidism are anomalies of development, function and regulation of the thyroid gland. Clinical signs of thyroid hormone deficiency in infants are non-specific. Early diagnosis is based on newborn screening for congenital hypothyroidism, which was started in Poland in 1977. Treatment within the first days of life with appropriate dosage of thyroxine prevents mental retardation. This paper summarises current knowledge on congenital hypothyroidism in children.     

Dopamine infusion and hypothyroxinaemia in very low birth weight preterm infants

The purpose of this study was to assess the relationship between transient hypothyroxinaemia of prematurity (THOP) in very low birth weight newborns and dopamine administration. A total of 172 newborns was enrolled in a prospective observational study and divided into three groups: group A included newborns who were never treated with dopamine; group B were infants in whom dopamine treatment was discontinued for at least 6 h before the congenital hypothyroidism screening and group C included infants who were given dopamine during the screening. Among those newborns given dopamine, the THOP incidence was higher (11.6% in group A; 53.8% in group B; 89.3% in group C), and the vales of TSH (1.67±2.32 µU/ml in group A; 1.29±1.74 µU/ml in group B; 0.89±1.34 µU/ml in group C) and thyroxine (6.1±2.2 µg/dl in group A; 3.9±1.9 µg/dl in group B; 2.4±1.4 µg/dl in group C) were significantly lower. These differences were further confirmed even after gestational age stratification and mathematical correction for differences in clinical conditions. The effects of dopamine appear to be dose-dependant. Conclusion:even if it cannot be excluded that reduced thyroid stimulating hormone and thyroxine concentrations are caused by non-thyroidal illness, the results suggest that the infusion of dopamine reduces the thyroid stimulating hormone and thyroxine levels in very low birth weight newborns.Abbreviations CHT congenital hypothyroidism - ESS euthyroid sick syndrome - GA gestational age - iRDS infantile respiratory distress syndrome - THOP transient hypothyroxinaemia of prematurity - VLBW very low birth weight     

Unawareness of the effects of soy intake on the management of congenital hypothyroidism

It has been established that soy products can interfere with thyroid hormone absorption resulting in continued hypothyroidism in individuals receiving recommended levothyroxine replacement. It has also been reported that achievement of euthyroidism in hypothyroid patients using soy products requires increased doses of levothyroxine. We have observed 2 patients with congenital hypothyroidism who continued to manifest clinical hypothyroidism while receiving recommended doses of hormone and ingesting soy products. The first patient was diagnosed by newborn screening (thyroid-stimulating hormone [TSH] =169 μIU/mL) and treated with 50 μg of levothyroxine since 6 days of age while simultaneously starting soy formula. At 3 weeks of age, she was clinically and biochemically hypothyroid (thyroxine = 4.0 μg/dL, TSH = 216 μIU/mL). We stopped her soy formula and decreased her levothyroxine dose. Three weeks later signs of hypothyroidism were resolving, and, by 10 weeks of age, she was clinically and biochemically euthyroid. Another patient was diagnosed by newborn screening, received levothyroxine, and did well. She was lost to us for 2 years. During this interval she began consuming soy milk and became profoundly hypothyroid (free thyroxine <0.4 ng/dL, TSH = 248 μIU/mL), even though the primary care physician had increased her levothyroxine dose to 112 μg/day. She was switched to cow milk, and her thyroid function slowly normalized with decreasing doses of levothyroxine. These 2 patients reinforce the importance of remembering that soy products interfere with levothyroxine absorption and can endanger infants and young children with congenital hypothyroidism who are at risk for developmental and growth delay.     

Combined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning.

BACKGROUND: Thyroid imaging is helpful in confirming the diagnosis of congenital hypothyroidism and in establishing the aetiology. Although isotope scanning is the standard method of imaging, ultrasound assessment may be complementary. AIM: To determine the strengths and weaknesses of thyroid ultrasound and isotope scanning in neonates with thyroid stimulating hormone (TSH) elevation. METHODS: Babies from the West of Scotland with raised capillary TSH (>15 mU/l) on neonatal screening between January 1999 and 2004 were recruited. Thyroid dimensions were measured using ultrasonography, and volumes were calculated. Isotope scanning was carried out with a pinhole collimator after an intravenous injection of 99m-technetium pertechnetate. RESULTS: 40 infants (29 female) underwent scanning at a median of 17 days (range 12 days to 15 months). The final diagnosis was athyreosis (n = 11), ectopia (n = 12), hypoplasia (n = 8; 3 cases of hemi-agenesis), dyshormonogenesis (n = 5), transient hypothyroidism (n = 2), transient hyperthyrotropinaemia (n = 1) and uncertain status with gland in situ (n = 1). 6 infants had discordant scans with no isotope uptake but visualisation of thyroid tissue on ultrasound. This was attributed to TSH suppression from thyroxine (n = 3); maternal blocking antibodies (n = 1); cystic degeneration of the thyroid (n = 1); and possible TSH receptor defect (n = 1). CONCLUSIONS: Isotope scanning was superior to ultrasound in the detection of ectopic tissue. However, ultrasound detected tissue that was not visualised on isotope scanning, and showed abnormalities of thyroid volume and morphology. We would therefore advocate dual scanning in newborns with TSH elevation as each modality provides different information.     

Congenital hypothyroidism: causes for delayed initiation of treatment]

The aim of neonatal screening programs for congenital hypothyroidism is to ensure early treatment in order to prevent brain dysfunction. There are several reasons why infants are missed in the screening program. We report on three patients with congenital hypothyroidism, who had a pathological screening result and initiation of therapy was delayed. The first patient had an increased TSH level, but she was missed because of mistakes in the confirmatory serum test. During the follow-up the patient showed typical symptoms of hypothyroidism and got a thyroxine supplementation not before the age of three years. The second patient did not get a therapy before the age of six months because of the noncompliance of the parents and physicians. The third patient had a central hypothyroidism. The neonatal screening-program revealed no measurable TSH activity. Although the child had clinical signs of a severe hypothyroidism diagnosis was not made before the age of 5.5 months. Although different reasons are known for screening errors, all these 3 patients were missed because of failures in the follow-up of a pathological screening result, indicating a poor quality in the follow-up procedure.     

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.     

The influence of etiology and treatment factors on intellectual outcome in congenital hypothyroidism.

To determine the effects of hypothyroidism and hormonal patterns on outcome, we tested 65 7- to 12-year-old children with congenital hypothyroidism using standardized tests of intelligence, neuropsychological functioning, memory, and achievement. Results were analyzed by etiology, time to thyrotropin normalization, and hormone levels at testing. Children with athyreosis scored below other etiologies on visuospatial, attention, and arithmetic indices. Children whose thyroid-stimulating hormone levels normalized by 1 to 2 months of age scored higher than later normalizers on indices of visual memory, attention, and arithmetic. Normalization of thyroid-stimulating hormone by 3 months of age was associated with better memory and learning abilities than later normalization. Thyroid hormone levels at testing were correlated with indices of sensorimotor, spatial, and language abilities. Two children with persistently elevated thyrotropin levels were not adversely affected. Present findings signify the need to establish etiology, normalize thyrotropin early, and maintain hormone levels in the normal range throughout childhood in children with congenital hypothyroidism.     

Very low birth weight newborns do not need repeat screening for congenital hypothyroidism

OBJECTIVE: To determine whether repeat screening for congenital hypothyroidism is necessary in newborns weighing <1500 g (very low birth weight [VLBW]). STUDY DESIGN: All VLBW infants born in the province of Québec between October 15, 1993, and October 15, 1994, had a second filter paper sample requested at 6 weeks of age to measure thyrotropin and thyroxine, in addition to these measurements for the routine screening sample. We then conducted a survey of all 4 academic pediatric endocrinology clinics in the province, inquiring about cases of permanent primary congenital hypothyroidism (PPCH) in children born weighing <1500 g or who may have been missed by neonatal screening. RESULTS: Two specimens were obtained in 465 VLBW newborns. One case of mild transient hyperthyrotropinemia was identified. The survey identified 4 VLBW newborns with PPCH: 1 girl and 1 boy with dyshormonogenesis, 1 athyreotic girl, and 1 girl with thyroid ectopy. All 4 were detected by their initial filter paper specimens. The survey also identified 1 case of PPCH in a girl who had a normal neonatal screen and normal birth weight. CONCLUSIONS: VLBW newborns with PPCH can mount an appropriate thyrotropin response and do not need repeat screening for congenital hypothyroidism.     

Central Congenital Hypothyroidism Detected by Neonatal Screening in Sapporo, Japan (2000–2004): It’s Prevalence and Clinical Characteristics

In Sapporo, Japan, a neonatal screening program for congenital hypothyroidism (CH) has employed measurement of free thyroxine (T4) and TSH in the same filter-paper blood spot. This system has enabled us to identify primary CH and central CH during the neonatal period. The aim of this study was to clarify the prevalence and clinical characteristics of central CH. For this purpose, the screening program requested serum from infants with free T4 concentrations below the cut off value regardless of the TSH levels. Between January 2000 and December 2004, 83,232 newborns were screened and six central CH patients were detected as a result of follow-up of low free T4 and non-elevated TSH screening (1:13,872). This frequency is higher than in other studies. Four patients showed multiple pituitary hormone deficiency with pituitary malformations on magnetic resonance imaging. One patient was diagnosed as having Prader-Willie syndrome. The remaining patient was considered to have isolated central CH. Our study demonstrated that the frequency of central CH is 1:13,872. Free T4 measurement would also be advantageous in early recognition of multiple pituitary hormone deficiency.     

Thyroid function and ioduria in infants after cardiac surgery: comparison of patients with primary and delayed sternal closure.

OBJECTIVES: Thyroid hormone alterations after cardiac surgery may be aggravated by the use of iodine antiseptics. We evaluated thyroid function and ioduria in infants with delayed sternal closure (DSC) who are exposed to povidone-iodine for sternal wound protection and compared them with findings in infants after primary sternal closure. DESIGN: Prospective clinical study. SETTING: Pediatric cardiac intensive care unit. PATIENTS: Ninety-three infants after cardiac surgery using cardiopulmonary bypass, 60 of them with primary sternal closure and 33 of them with delayed sternal closure. MEASUREMENTS AND MAIN RESULTS: Thyroid hormones were studied in patients with primary sternal closure immediately after surgery, 5 days and 19 days after surgery, in patients with DSC immediately after surgery, immediately after sternal closure, and 2 wks after sternal closure. Ioduria was evaluated on the first, third, and fifth postoperative days after cardiac surgery with primary sternal closure and immediately after DSC. In both groups of patients, low total triiodothyronine, total thyroxine, thyroxine-binding globulin levels, high reverse triiodothyronine levels, and normal free triiodothyronine, free thyroxine, and thyroid-stimulating hormone levels were recorded immediately after surgery. Concentrations of total triiodothyronine and thyroid-stimulating hormone were lower in the patients with DSC. Five days after primary sternal closure and 2 wks after DSC, all thyroid hormone levels were normal for age. Ioduria after DSC was higher than ioduria after primary sternal closure. CONCLUSIONS: Patients with DSC compared with patients with primary sternal closure display more profound thyroid suppression in the immediate postoperative period. The use of povidone-iodine adhesive drapes with single povidone-iodine mediastinal irrigation in patients with DSC is associated with significant iodine absorption but no significant thyroid dysfunction.     

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.     

河南省新生儿先天性甲状腺功能低下症筛查及病因调查

目的研究河南省先天性甲状腺功能低下症（甲低,CH）的发病情况及发病原因。方法采用时间分辨免疫荧光法检测1998年1月-2004年12月河南省156家医院非选择性出生的新生儿33.8万例血促甲状腺素（TSH）水平,筛查阳性者召回,用直接化学发光免疫分析法测定其静脉血清T3、T4、TSH水平,以T3、T4低于正常、TSH水平高于正常者确诊为CH患儿,通过对CH患儿及其父母召回进行问卷调查和生长发育、智力测量及相关医学检查,寻找其发病原因及发病的高危因素。结果河南省新生儿CH筛查平均覆盖率5.93%,确诊CH 109例,发病率0.032%。CH患儿109例甲状腺部位正常,发育良好。在有高血压、糖尿病、畸形或智力低下家族史或母孕期有不良情况者中CH发病率较高。结论河南省CH患儿发病可能与甲状腺的缺如和异位无关,可能为激素的合成障碍或受体缺陷所致。     

Screening for congenital hypothyroidism with specimen collection at two time periods: results of the Northwest Regional Screening Program

To determine the benefit of collecting two routine specimens to test for congenital hypothyroidism, we examined the results of our newborn screening program during the last 9.5 years. The Northwest Regional Screening Program (NWRSP) performs a primary thyroxine test with thyroid-stimulating hormone determinations on the lowest 10% of dried blood filter paper specimens. An initial specimen is obtained in the newborn period, and a routine second specimen is collected at approximately 4 to 6 weeks of age in all infants born in Oregon and 25% of infants born in Idaho, Montana, Alaska, and Nevada. Between May 1975 and October 1984, 182 infants with primary hypothyroidism were detected from 811,917 infants screened, a prevalence rate of 1:4,461. The routine second specimen led to the diagnosis of 19 infants of 484,604 infants screened, a detection rate of 1:25,505. When infants detected by the second screen were compared with those detected by the first screen, they had higher thyroxine and lower thyroid-stimulating hormone concentrations on filter paper and serum specimens. When thyroid scanning was used, all but one infant detected by the second screen had some residual thyroid tissue, whereas 35% of infants detected by the first screen had thyroid aplasia. Skeletal maturation was more likely to be normal in infants detected by the second screen. These infants appear to have milder hypothyroidism due to a later age of onset or slower evolution of thyroid failure. At a cost of $31,881 per infant detected by the second screen, the NWRSP found it cost-effective to obtain a routine second specimen.     

Neonatal screening for congenital hypothyroidism in the Federation of Bosnia and Herzegovina: eight years’ experience

This report demonstrates the prevalence of primary congenital hypothyroidism (CH) in the Federation of Bosnia and Herzegovina and summarizes the laboratory data. Neonatal thyroid-stimulating hormone (TSH) was measured in whole blood drawn between the 3rd and 5th days of life and spotted on filter paper using the fluorometric assay. Among the 87,061 neonates, 22 had CH, 13 dysgenetic forms, and nine with thyroids in situ. No differences were found between the two types in terms of TSH and total T4 concentrations. However, thyroglobulin was significantly lower in patients with dysgenetic thyroid tissue (p = 0.0023). We conclude that the prevalence of CH in the Federation of Bosnia and Herzegovina is 1:3,957 newborns.     

Transient neonatal 'athyreosis' resulting from thyrotropin-binding inhibitory immunoglobulins

Recognition of transient forms of neonatal hypothyroidism is difficult because of the urgency of thyroxine treatment. In the present report the first child born to a mother with Graves' disease developed transient hyperthyroidism during the newborn period. The mother underwent radioactive iodine treatment and was maintained euthyroid on l-thyroxine. Two subsequent children were detected by newborn thyroid screen to have low thyroxine and markedly elevated serum thyrotropin (TSH) levels. Technetium 99 metastable and iodine 123 scans at 22 days of age showed the second child to be athyreotic. The third child was not scanned. All three children were nongoitrous at birth. Patients 2 and 3 had continuous TSH suppression with thyroxine therapy for 3 and 4 years. Thyroid function measurements after discontinuation of therapy for 8 weeks were normal, and both children had normal 123I thyroid scans. The mother was found to have potent TSH-binding inhibitory immunoglobulin (TBII) levels in her serum (85.5%). A fourth child with low thyroxine and elevated TSH was born to a mother on a regimen of l-thyroxine for hypothyroidism. 99mTc scan at 26 days of age showed no thyroid tissue and was normal at 3 months. TBII activity was 35% in the maternal serum and absent in the infant's serum. The above laboratory and clinical data are compatible with the blocking nature of TBII, resulting in transient newborn hypothyroidism and an athyreotic appearance on scan. The TBII measurement can be a useful predictor of neonatal hypothyroidism as well as confirm the transient nature of the disease in newborns.     

甲状腺功能异常患儿血清瘦素水平与甲状腺激素的相关性研究

目的　研究甲状腺功能异常 [原发性甲状腺功能减退 (甲减 )和原发性甲状腺功能亢进 (甲亢 ) ]患儿血清瘦素 (leptin)水平变化 ,探讨血清瘦素与甲状腺功能的关系。方法　采用放射免疫法分别检测 2 0例甲减患儿、17例甲亢患儿和 2 5例健康儿童血清瘦素水平 ,同时采用微粒子化学发光免疫分析法检测血清游离三碘甲状腺原氨酸 (FT3 )、游离甲状腺素 (FT4)、促甲状腺素 (TSH)等指标。结果　甲低组治疗前血清瘦素水平显著低于正常对照组 (P <0 .0 0 1) ,经药物治疗甲状腺功能恢复至正常后 ,其血清瘦素浓度上升至正常水平 ;甲亢组治疗前后血清瘦素水平与正常对照组相比 ,差异无显著性 (P >0 .0 5 )。结论　甲状腺激素对血清瘦素的分泌具有促进作用     

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.