Author Stephen LaFranchi, MD Section Editor Mitchell Geffner, MD
4/8/2015 Clinical features and detection of congenital hypothyroidism Official reprint from UpToDate® www.uptodate.com ©2015 UpToDate® Clinical features and detection of congenital hypothyroidism Author Stephen LaFranchi, MD Section Editor Mitchell Geffner, MD Deputy Editor Alison G Hoppin, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2015. | This topic last updated: Feb 24, 2015. INTRODUCTION — Congenital hypothyroidism, occurring in approximately 1:2000 to 1:4000 newborns, is one of the most common preventable causes of intellectual disability (mental retardation). There is an inverse relationship between age at clinical diagnosis and treatment initiation and intelligence quotient (IQ) later in life, so that the longer the condition goes undetected, the lower the IQ [1]. (See "Intellectual disability (mental retardation) in children: Definition; diagnosis; and assessment of needs".) Most newborn babies with congenital hypothyroidism have few or no clinical manifestations of thyroid hormone deficiency, and the majority of cases are sporadic. As a result, it is not possible to predict which infants are likely to be affected. For these reasons, newborn screening programs in which either thyroxine (T4) or thyrotropin (TSH) are measured in heelstick blood specimens were developed in the mid1970s to detect this condition as early as possible [2]. These screening efforts have been largely successful, but more severely affected infants may still have a slightly reduced IQ and other neurologic deficits despite prompt diagnosis and initiation of therapy. This topic will review the epidemiology, causes, clinical manifestations, and diagnosis of congenital hypothyroidism, and its detection by newborn screening. Treatment and prognosis of this disorder are discussed separately. (See "Treatment and prognosis of congenital hypothyroidism".) EPIDEMIOLOGY — Data obtained from national and regional screening programs indicate that the incidence of congenital hypothyroidism varies globally. The incidence varies by geographic location and by ethnicity, as illustrated by the following studies: ● In a study over a 20year period (1981 to 2002) from a French screening program, the incidence of permanent congenital hypothyroidism was 1:4000 [3]. ● In a study in the Greek Cypriot population over an 11year period (1990 to 2000), the incidence of permanent congenital hypothyroidism was 1:1800. Hypothyroidism was initially detected by an elevated TSH value obtained between 3 to 6 days of age [4]. ● A summary of all screening programs in the United States found that the incidence of congenital hypothyroidism increased from 1:4094 in 1987 to 1:2372 in 2002 [5]. The reason for the increased incidence is not clear. It is possible that changes in testing cutoffs have led to detection of milder cases. In addition, there is some variation in the incidence among different racial and ethnic groups, and the mix of these groups has changed. A review of the New York program during the years 2000 to 2003 showed that the incidence of congenital hypothyroidism was somewhat lower in white (1:1815) and black infants (1:1902), as compared to Hispanic (1:1559) and Asian infants (1:1016); the overall incidence of congenital hypothyroidism was 1:1601 [5]. In addition, the incidence was nearly double in twin births (1:876) as compared to singletons (1:1765), and even higher in multiple births (1:575). The incidence was higher in preterm infants (<1500 gm; 1:1396) than term infants (>2500 gm 1:1843). Older mothers (>39 years of age) had a higher incidence (1:1328) than younger mothers (<20 years; 1:1703). Nearly all screening programs report a female preponderance, approaching a 2:1 female to male ratio. A report from Quebec shows that this female preponderance occurs mostly with thyroid ectopy, and less so with agenesis [6]. Another study from Quebec found that thyroid dysgenesis was more prevalent in white than in black infants, whereas dyshormonogenesis occurred equally in these racial groups [7]. (See 'Thyroid dysgenesis' below.) http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 1/19 4/8/2015 Clinical features and detection of congenital hypothyroidism ETIOLOGY — Approximately 85 percent of permanent cases of congenital hypothyroidism are sporadic (most caused by thyroid dysgenesis) and 15 percent are hereditary (most caused by one of the inborn errors of thyroid hormone synthesis) (table 1). As noted above, the apparent increasing incidence of congenital hypothyroidism is likely due to the detection of milder cases, including cases of subclinical hypothyroidism and transient hypothyroidism. In a study from Japan, patients with hypothyroidism detected by newborn screening were reevaluated at ages 5 to 19 years. Among the cases with overt hypothyroidism, 73 percent were caused by thyroid dysgenesis, whereas of cases of subclinical hypothyroidism, only 36 percent were caused by thyroid dysgenesis [8]. In addition, some of these disorders may present after the neonatal period and are sometimes called “late onset congenital hypothyroidism”. Lateonset disease is most often caused by one of the inborn errors of thyroxine synthesis or an ectopic thyroid gland. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Lateonset congenital hypothyroidism' and 'Disorders of thyroid hormone synthesis and secretion' below and 'Defects in thyroid hormone transport' below.) Thyroid dysgenesis — The most common cause of congenital hypothyroidism is some form of thyroid dysgenesis, (eg, agenesis, hypoplasia, or ectopy). Thyroid ectopy accounts for twothirds of the cases worldwide [9]. In a study of 230 infants with permanent primary hypothyroidism, representing 90 percent of all infants identified by newborn screening in Quebec from 1988 to 1997, 61 percent had ectopic thyroid tissue, 16 percent had thyroid agenesis, 4 percent had a normalsized thyroid and 18 percent had a goiter, as determined by radionuclide imaging [10]. More girls than boys had thyroid ectopy (104 versus 37), but there were similar numbers of girls and boys in other groups. Among these infants, 5 percent had other congenital abnormalities, mostly cardiac septal defects. (See 'Congenital malformations' below.) Although most cases of thyroid dysgenesis are sporadic, there is evidence of a familial/genetic component in some patients. ● In a study of 2472 patients with congenital hypothyroidism resulting from thyroid dysgenesis (identified by newborn screening in France between 1980 and 1998), 48 (2 percent) of cases appeared to be familial [11,12]. The distribution of various causes of hypothyroidism in both the sporadic and familial groups was similar to that in the Quebec study. ● Further evidence of a genetic component comes from a study of 84 children with congenital hypothyroidism, whose firstdegree relatives were more likely to have asymptomatic thyroid developmental abnormalities than controls (21.4 and 0.9 percent, respectively) [13]. This suggests there is a common genetic component of congenital hypothyroidism with heterogeneous phenotypes. However, there was discordance for thyroid dysgenesis in all monozygotic twins (five pairs) and dizygotic twins (seven pairs) in both the Quebec and Brussels screening centers [14]. ● Rare cases of thyroid dysgenesis have been associated with lossoffunction mutations in PAX8, thyroid transcription factor2 (TTF2, also called FOXE1), and transcription factors NKX2.1 (formerly called TTF1) and NKX2.5 [1519]. Mutations in these genes may be associated with congenital anomalies of other tissues. A heterozygous mutation in PAX8 was associated with congenital hypothyroidism and anomalies of the urogenital tract (horseshoe kidney, ureterocele, undescended testes, and hydrocele) [18]. A homozygous missense mutation in TTF2 resulted not only in thyroid agenesis, but cleft palate in two male siblings [19]. Not all TTF2 mutations are associated with thyroid agenesis, as shown by a case report of a patient with congenital hypothyroidism and a TTF2 mutation, associated with cleft palate, spiky hair, and bilateral choanal atresia [20]. Thyroid scan showed thyroid tissue in a eutopic location. NKX2.1 is expressed in both the thyroid and central nervous system. Mutations in NKX2.1 have been reported to result in congenital hypothyroidism with persistent neurologic problems, including ataxia, despite early thyroid hormone treatment [16]. ● Infants with trisomy 21 (Down syndrome) have a higher incidence of hypothyroidism detected by newborn screening programs. Whereas older children with trisomy 21 have autoimmune thyroid disease, the http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 2/19 4/8/2015 Clinical features and detection of congenital hypothyroidism hypothyroidism seen in neonates is not associated with antithyroid antibodies [21]. There is speculation that the extra chromosome 21 results in genomic dosage imbalance of dosagesensitive genes interfering with thyroid hormone production. Resistance to TSH — Mutations in the TSH receptor will present as primary hypothyroidism, with an elevated serum TSH and low T4 level. Such defects are increasingly recognized [22]. In a report from Japan, TSH receptor mutations were present in 4.3 percent of patients with congenital hypothyroidism (1:118,000 of the general population) [23]. In a report from Great Britain, TSH receptor mutations were identified in 5 percent of children with congenital nongoitrous hypothyroidism born to consanguineous families [24]. In addition, some forms of pseudohypoparathyroidism include congenital hypothyroidism. This is a result of Gprotein alpha subunit (GNAS) gene mutations that interfere with both PTH and TSH signaling [25]. A complex phenotype of congenital hypothyroidism and pseudohypoparathyroidism has been described in the presence of a combination of inactivating mutations of the TSH receptor and mutations of the downstream G protein (GNAS) [26]. (See "Resistance to thyrotropin and thyrotropinreleasing hormone", section on 'Resistance to TSH (RTSH)'.) Disorders of thyroid hormone synthesis and secretion — Hereditary defects in virtually all steps in thyroid hormone biosynthesis and secretion have been described; all are characterized by autosomal recessive inheritance. Among them, the most common is a defect in thyroid peroxidase activity that results in impaired iodide oxidation and organification [27], and may be associated with sensoryneural hearing loss (Pendred syndrome) (figure 1). (See "Congenital and acquired goiter in children", section on 'Inborn errors of thyroid hormone production'.) Other less common defects include: ● Defects in iodide transport, caused by a mutation in the sodium/iodide symporter gene [28]. ● Defects in the generation of hydrogen peroxide, a substrate for thyroid peroxidase in the oxidation of iodide, caused by mutations in the dual oxidase 2 gene (DUOX2, formerly called thyroid oxidase 2, THOX2) [2931], or the related gene, dual oxidase maturation factor 2 (DUOXA2) [32]. ● Production of abnormal thyroglobulin molecules, caused by mutations in the thyroglobulin gene [33]. ● Iodotyrosine deiodinase deficiency, due to homozygous mutations of the DEHAL1 gene [34]. Altogether, these disorders account for approximately 15 percent of cases of congenital hypothyroidism. (See "Thyroid hormone synthesis and physiology".) Defects in thyroid hormone transport — Passage of thyroid hormone into the cell is facilitated by plasma membrane transporters. A mutation in one such transporter gene, monocarboxylate transporter 8 (MCT8), located on the X chromosome, has been reported in more than 100 individuals with Xlinked mental retardation. The defective transporter appears to impair passage of T3 into neurons; this syndrome is characterized by elevated serum T3 levels and psychomotor retardation [35]. This disorder is discussed in detail in a separate topic review. (See "Impaired sensitivity to thyroid hormone", section on 'Thyroid hormone cell membrane transport defect'.) Defects in thyroid hormone metabolism — Inherited defects in thyroid hormone metabolism involve the gene for selenocysteine insertion sequencebinding protein 2 (SECISBP2). In theory, mutations in this gene could cause congenital hypothyroidism, but to date there are only reports in children (with short stature and delayed bone age) and adults. (See "Impaired sensitivity to thyroid hormone", section on 'Thyroid hormone metabolism defect'.) Resistance to thyroid hormone — Resistance to thyroid hormone is caused by mutations in thyroid hormone receptors (primarily the TH receptor beta gene). The incidence is approximately 1:40,000. It is characterized by high serum T4, free T4, T3, and free T3 levels with normal or slightly elevated serum TSH levels. Rarely, patients with high TSH levels may be detected by newborn screening programs. Patients generally do not have clinical manifestations of hyperthyroidism, and, for most, no treatment is indicated. (See "Impaired sensitivity to thyroid hormone", section on 'Resistance to thyroid hormone (RTH beta and nonTRRTH)'.) http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 3/19 4/8/2015 Clinical features and detection of congenital hypothyroidism Central hypothyroidism — Infants with central (hypothalamic or pituitary) hypothyroidism are detected by screening programs that employ the initial T4/followup TSH approach. Programs based only on TSH screening alone will not identify these infants. Central hypothyroidism occurs in 1:25,000 to 1:100,000 newborns [36]. It may be associated with other congenital syndromes, particularly midline defects such as septooptic dysplasia or mid line cleft lip and palate defects, and may follow birth trauma or asphyxia. Rare genetic causes result from mutations in the genes for the thyrotropinreleasing hormone receptor [37], or for TSH [38,39]. (See 'Newborn screening programs' below and "Resistance to thyrotropin and thyrotropinreleasing hormone".) Most infants with central hypothyroidism, except those with mutations in the genes for TSH, TRH, or TRH receptors, have other pituitary hormone deficiencies. Some cases of central hypothyroidism are present in infants with congenital hypopituitarism caused by mutations in transcription factors involved with pituitary development. A mutation in POU1F1 caused central hypothyroidism in a mother and her infant [40]. In a large prospective study, all infants with delayed TSH response to TRH had multiple pituitary hormone deficiencies [41]. The presence of another hormone deficiency should be particularly suspected in infants with hypoglycemia or micropenis [36]. (See "Approach to hypoglycemia in infants and children".) Congenital central hypothyroidism also can be caused by insufficient treatment of maternal hyperthyroidism during pregnancy [42,43]. Congenital central hypothyroidism may persist beyond 6 months of age especially when maternal thyrotoxicosis occurred before 32 weeks gestation [43]. One study suggests that some of these infants also may have primary hypothyroidism with thyroid "disintegration", possibly because insufficient TSH during the period of maternal hyperthyroidism inhibited the normal growth and development of the fetal thyroid [44]. Transient congenital hypothyroidism — Transient congenital hypothyroidism is more common in Europe than in North America. In a 20year study from a French newborn screening program, congenital hypothyroidism was transient in 40 percent of patients [3]. The causes of transient hypothyroidism in newborn infants are: ● Iodine deficiency — Iodine deficiency, particularly in preterm infants, accounts for many cases in Europe, where maternal dietary iodine intake is less than in the United States [45]. ● Transfer of blocking antibodies or antithyroid drugs — Transplacental transfer of TSHreceptor blocking antibodies (TRBAb) can occur in infants of mothers with autoimmune thyroid disease [46]. Such a diagnosis should also be considered if more than one infant born to the same mother (in the same or multiple pregnancies) is identified as having primary hypothyroidism by newborn screening. Studies using newborn screening specimens show TRBAb in approximately 1:100,000 newborns [47]. This form of hypothyroidism usually subsides in one to three months as the maternal antibodies are cleared [48,49]. ● Antithyroid drugs — Antithyroid drugs given to mothers with hyperthyroidism also can cross the placenta. These drugs are cleared in days; as a result, many of these infants are euthyroid when restudied a few weeks after delivery. ● Iodine exposure — Exposure of the fetus or newborn to high doses of iodine can cause hypothyroidism. This can occur in infants of mothers with cardiac arrhythmias treated with amiodarone [50], when iodine containing antiseptic compounds are used in mothers or infants, or after amniofetography with a radiographic contrast agent [51,52]. Populations at risk include infants born prematurely and in preterm or term infants with congenital heart defects, due to exposure to iodine through the skin and/or in contrast media used for cardiac catheterization [5355]. Ingestion of excessive iodine from nutritional supplements during pregnancy also is reported to cause transient congenital hypothyroidism [56]. The risk of hypothyroidism appears to be related to the type and duration of iodine exposure. Transient exposure of pregnant women to an iodinated contrast agent for computerized tomography (CT) study appears to have no effect on neonatal thyroid function [57,58]. (See "Iodineinduced thyroid dysfunction" and "Diagnostic imaging procedures during pregnancy", section on 'Iodinated contrast materials'.) ● Large hepatic hemangiomas — Large hepatic hemangiomas, present from birth, may produce increased levels of type 3 deiodinase, resulting in "consumptive hypothyroidism". A case report describes an infant with http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 4/19 4/8/2015 Clinical features and detection of congenital hypothyroidism a massive hepatic hemangioendothelioma that caused hypothyroidism, discovered at eight weeks of age [59]. Large doses of thyroid hormone were required to normalize serum TSH. The hypothyroidism resolved by 16 months of age, as the hemangioendothelioma regressed. ● Mutations in the dual oxidase (DUOX1 and DUOX2) gene — The dual oxidase genes are involved in the generation of hydrogen peroxide, required by thyroid peroxidase in the synthesis of thyroid hormone. Biallelic lossoffunction mutations in DUOX2 and monoallelic lossoffunction mutations in DUOXA1 genes are rare causes of transient congenital hypothyroidism [60,61]. Mutations in the related gene DUOXA2 also are reported to cause a more permanent, albeit mild, form of congenital hypothyroidism, as discussed above. (See 'Disorders of thyroid hormone synthesis and secretion' above.) CLINICAL MANIFESTATIONS — The vast majority (more than 95 percent) of infants with congenital hypothyroidism have few if any clinical manifestations of hypothyroidism at birth [62]. This is because some maternal T4 crosses the placenta, so that even in infants who cannot make any thyroid hormone, umbilical cord serum T4 concentrations are about 25 to 50 percent of those of normal infants [63]. In addition, many infants with congenital hypothyroidism have some, albeit inadequate, functioning thyroid tissue. Despite these mitigating influences, congenital hypothyroidism may have subtle effects in utero. One report described reduced variability in fetal heart rate tracings in nearly 50 percent of infants with congenital hypothyroidism [64]. Birth length and weight typically are within the normal range although birth weight can be increased [65]; head circumference also may be increased. The knee epiphyses often lack calcification, and this is more likely to occur in males than females (40 versus 28 percent, respectively) [66]. Many infants are born in regions of the world that lack newborn screening programs. Symptoms and signs that develop in these infants include lethargy, hoarse cry, feeding problems, often needing to be awakened to nurse, constipation, macroglossia, umbilical hernia, large fontanels, hypotonia, dry skin, hypothermia, and prolonged jaundice [67]. A few newborn infants with thyroid dyshormonogenesis have a palpable goiter, but it usually appears later. Congenital malformations — Congenital hypothyroidism appears to be associated with an increased risk of additional congenital malformations affecting the heart, kidneys, urinary tract, gastrointestinal and skeletal systems [6872]. As an example, in a populationbased study of 1420 infants with congenital hypothyroidism, the prevalence of other congenital malformations (mostly cardiac) was fourfold higher (8.4 percent) than in the control infant population (1 to 2 percent) [68]. In the New York State Congenital Malformation Registry (980 children), there was an increased risk of renal and urologic abnormalities (Odds Ratio 13.2) [72]. Infants with congenital hypothyroidism and cleft palate may have a TTF2 (FOXE1) gene mutation [19]. Infants with persistent neurologic problems, including ataxia, are suspect for a NKX2.1 gene mutation [16]. NEWBORN SCREENING PROGRAMS — Screening of all newborns is now routine in all 50 states of the United States, and in Canada, Europe, Israel, Japan, Australia and New Zealand; screening programs are under development in Eastern Europe, South America, Asia, and Africa. In the United States, more than 4 million infants are screened annually, leading to the detection of 1800 infants per year with congenital hypothyroidism. Out of a worldwide birth population of approximately 130 million infants annually, it is estimated that 25 to 30 million infants (20 to 25 percent) are screened and 8,000 to 10,000 infants with hypothyroidism are detected annually. Blood for screening is collected onto filter paper cards after heel prick, usually two to five days after birth [73,74]. Some programs also routinely obtain a second specimen between two and six weeks after birth [36]. The cards are then sent to a centralized laboratory for testing. Three major screening strategies have evolved: ● Initial blood T4 assay, with followup TSH assay if the blood T4 value is below a certain concentration (usually less than the 10th percentile) ● Initial blood TSH assay http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 5/19 4/8/2015 Clinical features and detection of congenital hypothyroidism ● Simultaneous T4 and TSH assay Most programs in the United States started with the initial T4/followup TSH testing approach, but many have switched to initial TSH testing. Either approach detects the majority of infants with congenital primary hypothyroidism, and each has its advantages. Infants with a delayed rise in blood TSH concentration [75] and those with central hypothyroidism most commonly are detected by the initial T4/followup TSH assay method [36,76], whereas infants with subclinical hypothyroidism (high blood TSH, normal blood T4) most commonly are detected by TSH testing. A retrospective study from a program that employs simultaneous measurement of T4 and TSH reported that only 19 percent of infants subsequently diagnosed with central hypothyroidism had a newborn screening result of T4 <5 mcg/dL [77]. Thus, the majority of infants with central hypothyroidism will not be detected even by this screening approach, because their T4 level is above the screening cutoff. Thus, it is important to refer and evaluate infants who have clinical features suggestive of congenital hypopituitarism; clinicians should not be falsely reassured by a normal screening T4 result. Infants with blood TSH values above certain levels, usually 15 mU/L (serum TSH >30 mU/L), are recalled for clinical evaluation and serum testing, which occurs between 1 and 3 weeks of age in wellrun programs. Using this screening technique, 0.1 percent of infants in the population are recalled for further testing, and about half of these are diagnosed with hypothyroidism. Thus, two infants are recalled for each infant who is ultimately diagnosed with congenital hypothyroidism. Programs that recall infants only on the basis of low blood T4 values have recall rates of approximately 0.3 percent. Screening with multiple tests (eg, T4 and TSH, or T4 and TSH and thyroxinebinding globulin [TBG]) has been suggested as a way to improve detection of both primary and central hypothyroidism [78]. However, the improved detection rate is associated with an increased number of false positive screens. False positive screens may lead to unnecessary parental anxiety as well as a potential rise in overall costs because of unnecessary recall of patients and need for further testing. It is possible that a "false positive" screen (mildly elevated screening TSH result, but normal serum TSH level) is associated with an increased risk for mild thyroid disease. One study found that of 44 children with false positive screens due to hyperthyrotropinemia, 14 (32 percent) had subclinical hypothyroidism at age eight [79]. The TSH elevation at eight years was mild (4.1 to 8.2 mU/L). DIAGNOSTIC STUDIES — Infants with abnormal screening results are recalled for further testing. At recall, the infant should be examined and a blood sample obtained by venipuncture to confirm the diagnosis of hypothyroidism (algorithm 1) [74]. If the diagnosis of hypothyroidism is confirmed, other studies (such as thyroid radionuclide uptake and imaging, ultrasonography, serum thyroglobulin, tests for thyroid autoantibodies, or urinary iodine excretion) may be performed to identify the cause. In the majority of cases, the decision to start thyroid hormone treatment is based on thyroid function test results. Thus, we consider additional diagnostic studies to identify a cause to be optional. There are some circumstances, discussed below, where these diagnostic tests do influence the treatment decision. Serum tests of thyroid function — Results of serum tests of thyroid function can be interpreted as follows: ● Primary hypothyroidism – The findings of low serum T4 or free T4 and high serum TSH values confirm the diagnosis of primary hypothyroidism, and treatment is indicated, beginning immediately [74]. TSH >10 mU/L is definitively elevated in infants after one week of age. (See "Treatment and prognosis of congenital hypothyroidism".) One must keep in mind that serum T4 concentrations are higher in the first few weeks of life in normal infants than in adults because of the surge in TSH secretion that occurs soon after birth (figure 2). (See "Thyroid physiology and screening in preterm infants".) http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 6/19 4/8/2015 Clinical features and detection of congenital hypothyroidism • Serum TSH concentrations rise abruptly to 60 to 80 mU/L at birth. The serum TSH concentration then decreases rapidly to about 20 mU/L 24 hours after delivery, and then more slowly to 6 to 10 mU/L at one week of age. • Between one and four days of life, the normal range for serum total T4 concentrations is about 10 to 22 mcg/dL (129 to 283 nmol/L) and the normal range for serum free T4 concentrations is about 2 to 5 ng/dL (25 to 64 pmol/L). • After four weeks of life, the normal range for serum total T4 concentrations is 7 to 16 mcg/dL (90 to 206 nmol/L) and the normal range for serum free T4 concentrations is 0.8 to 2.0 ng/dL (10 to 26 pmol/L). ● Subclinical hypothyroidism – A normal serum total or free T4 concentration and a high serum TSH concentration define subclinical hypothyroidism. In cases where the serum TSH is marginally elevated (eg, 6 to 10 mU/L), one option is to monitor carefully, repeating a serum TSH and free T4 in a week. Some infants will normalize TSH without treatment using this approach. However, if the serum TSH does not normalize by four to six weeks of age, we recommend starting thyroid hormone treatment, because the development of the central nervous system is critically dependent on adequate amounts of T4. (See "Treatment and prognosis of congenital hypothyroidism".) ● Central hypothyroidism – In those programs that follow up with infants with low blood T4 screening results alone, low serum total or free T4 concentrations in the presence of low or normal serum TSH concentrations indicate the presence of central hypothyroidism. Rare infants who are ultimately proven to have primary hypothyroidism also may have low serum total or free T4 and TSH values when recalled, because the expected rise in serum TSH is delayed [80]. Infants with either of these findings should be treated. Premature infants and infants with nonthyroidal illness also may have low serum total and free T4 and normal serum TSH concentrations [81]. We do not recommend treatment for these infants unless there is other evidence of hypothalamic or pituitary disease. (See "Thyroid physiology and screening in preterm infants", section on 'Preterm infants and nonthyroidal illness'.) The combination of a low serum total T4 concentration and normal serum free T4 and TSH concentrations indicates the presence of thyroxinebinding globulin (TBG) deficiency, an Xlinked recessive disorder that occurs in approximately 1:4000 newborns, predominantly males [82]. These infants are euthyroid and do not require treatment. Thyroid imaging — Thyroid ultrasonography or radionuclide uptake measurements and imaging (“scan”) provide information about the underlying etiology, eg, thyroid dysgenesis or one of the types of dyshormonogenesis [83,84]. We do not recommend either test routinely, because for most cases the results do not alter management. However, the tests may provide useful information in infants with the following characteristics: ● Infants with minor abnormalities in thyroid function, in whom it is not clear whether thyroid hormone treatment is indicated (eg, TSH 5 to 10 mU/L, with free T4 in the normal reference range for age). In such an infant, the finding of ectopically located thyroid tissue would support a diagnosis of hypothyroidism. ● Infants with a small goiter in whom an enzymatic defect in T4 synthesis is suspected; most of these infants have normal or high uptake values in normally located if not enlarged thyroid glands. As these defects are hereditary (autosomal recessive), this finding allows counseling about risk in future children. ● Infants suspected of having transient hypothyroidism. The presence of reduced radionuclide uptake in normally located thyroid tissue supports a diagnosis of mild, possibly transient hypothyroidism. Cases of transient hypothyroidism due to transplacental passage of maternal TSHreceptor blocking antibodies (TRB Ab) typically do not have radionuclide uptake or image on scanning, but on ultrasonography a normal thyroid gland may be visualized. (See 'Transient congenital hypothyroidism' above.) Thyroid ultrasonography and color flow Doppler — If the clinician chooses to do thyroid imaging, we http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 7/19 4/8/2015 Clinical features and detection of congenital hypothyroidism recommend starting with ultrasound. If an ectopic thyroid gland is identified by ultrasound, radionuclide imaging will not be necessary, thus avoiding radiation exposure and expense. However, ultrasound is not as reliable as radionuclide imaging in identifying cases of thyroid dysgenesis [85]. In studies comparing the two procedures, some infants had ectopic thyroid tissue detected by radionuclide imaging, but the ultrasound images revealed either no thyroid tissue or thyroid hypoplasia; in some of the other infants, radionuclide imaging revealed thyroid agenesis or hypoplasia but the ultrasound images were normal [86,87]. Color flow Doppler ultrasonography may be superior to gray scale ultrasonography. It detected ectopic thyroid tissue in 90 percent of infants with congenital hypothyroidism and ectopic tissue detected on radionucleotide imaging [88]. Thyroid radionucleotide uptake and scan — If the ultrasound study does not detect ectopic thyroid tissue, then a thyroid radionuclide uptake scan may help to identify cases of thyroid dysgenesis. Either 99mpertechnetate or 123Iiodine should be used, instead of 131Iiodine, because the radiation doses are much lower. 99m pertechnetate is more readily available and allows a good scan picture, but because it is not organified, there is no measure of uptake. 123I must be specially ordered, due to its short halflife, but it will provide both a scan and a measure of uptake. A large gland in a normal location typically is seen with one of the enzymatic defects. A positive perchlorate discharge test is compatible with an organification defect [89]. Serum thyroglobulin concentration — Measurement of serum thyroglobulin has been advocated as a means to distinguish among the causes of congenital hypothyroidism. One study reported low serum thyroglobulin concentrations in infants with thyroid agenesis (mean 12 ng/mL, range 2 to 54 ng/mL), intermediate concentrations in those with ectopic thyroid tissue (92 ng/mL, range 11 to 231 ng/mL), and high concentrations in those with goiters (226 ng/mL, range 3 to 425 ng/mL); the normal range was 20 to 80 ng/mL [83]. Given the degree of overlap among these groups, we do not think that measurement of serum thyroglobulin can substitute for radionuclide imaging, and do not recommend it except in puzzling cases. Urinary iodine concentration — If there is a history of iodine exposure, or if the infant is born in an area of endemic goiter, measurement of urinary iodine can confirm an excess (or deficient) state. Usually, however, this information can be obtained by history. In infants thought to have iodineinduced hypothyroidism, any continuing iodine exposure should be discontinued and T4 therapy given for several months and then gradually withdrawn. INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easytoread materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want indepth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.) ● Basics topics (see "Patient information: Congenital hypothyroidism (The Basics)") SUMMARY AND RECOMMENDATIONS — Congenital hypothyroidism occurs in approximately 1:2000 to 1:4000 newborns and is one of the most common preventable causes of intellectual disability (mental retardation). Newborn screening programs allow for early identification and treatment of affected infants to minimize complications. ● Approximately 85 percent of permanent cases of congenital hypothyroidism are sporadic, and most of these are caused by thyroid dysgenesis. The remaining 15 percent are hereditary, and may present during or after the neonatal period (table 1). (See 'Thyroid dysgenesis' above and 'Disorders of thyroid hormone synthesis and secretion' above.) http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 8/19 4/8/2015 Clinical features and detection of congenital hypothyroidism ● Because some maternal thyroid hormone crosses the placenta, and because commonly there is some residual thyroid function in the neonate, the vast majority (more than 95 percent) of infants with congenital hypothyroidism are asymptomatic at birth. Rarely, newborns with congenital hypothyroidism present with lethargy, hoarse cry, feeding problems, often needing to be awakened to nurse, constipation, macroglossia, umbilical hernia, large fontanels, hypotonia, dry skin, hypothermia, and prolonged jaundice. (See 'Clinical manifestations' above.) ● Newborn screening programs use one of the following strategies, each of which detects the majority of infants with congenital hypothyroidism: • Initial blood T4 assay, with followup TSH assay if the blood T4 value is below a certain concentration – This strategy detects infants with a delayed rise in blood TSH concentration and those with central hypothyroidism, but not those with subclinical primary hypothyroidism. • Initial blood TSH assay – This strategy detects infants with subclinical hypothyroidism, but not those with central hypothyroidism. • Simultaneous T4 and TSH assay – This strategy has the potential to detect all the thyroid disorders described with the above two screening approaches. ● Infants with abnormal screening results are recalled for further testing. At recall, the infant should be examined and a blood sample obtained by venipuncture to confirm the diagnosis of hypothyroidism (algorithm 1). Agespecific norms must be used for interpretation, because T4 concentrations are higher in the first few weeks of life (and TSH in the first two years of life) than in older infants or adults. (See 'Serum tests of thyroid function' above.) ● The findings of low serum T4 or free T4 and high serum TSH values confirm the diagnosis of primary hypothyroidism. A normal serum total or free T4 concentration and a high serum TSH concentration define subclinical hypothyroidism. Low serum total and free T4 concentrations in the presence of low or normal serum TSH concentrations suggest central hypothyroidism (or primary hypothyroidism with delayed rise in TSH). Infants with any of these findings should be treated. (See 'Serum tests of thyroid function' above and "Treatment and prognosis of congenital hypothyroidism".) ● Newborn screening programs increasingly are detecting neonates with borderline thyroid function. In cases where the serum TSH is marginally elevated (eg, 6 to 10 mU/L), one option is to monitor carefully, repeating a serum TSH and free T4 in a week. Some neonates will normalize TSH using this approach; such infants can be monitored without treatment. However, if the serum TSH does not normalize by four to six weeks of age, we recommend starting thyroid hormone treatment. (See 'Serum tests of thyroid function' above.) ● If the diagnosis of hypothyroidism is confirmed, other studies, such as thyroid radionuclide uptake and imaging, ultrasonography, serum thyroglobulin assay, tests for thyroid autoantibodies, or urinary iodine excretion, may be performed to identify the cause. These tests usually do not alter treatment; thus, they are considered optional, and we recommend that they be done only in special circumstances. (See 'Diagnostic studies' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Klein AH, Meltzer S, Kenny FM. Improved prognosis in congenital hypothyroidism treated before age three months. J Pediatr 1972; 81:912. 2. Dussault JH, Coulombe P, Laberge C, et al. Preliminary report on a mass screening program for neonatal hypothyroidism. J Pediatr 1975; 86:670. 3. Gaudino R, Garel C, Czernichow P, Léger J. Proportion of various types of thyroid disorders among http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=searc… 9/19 4/8/2015 Clinical features and detection of congenital hypothyroidism newborns with congenital hypothyroidism and normally located gland: a regional cohort study. Clin Endocrinol (Oxf) 2005; 62:444. 4. Skordis N, Toumba M, Savva SC, et al. High prevalence of congenital hypothyroidism in the Greek Cypriot population: results of the neonatal screening program 19902000. J Pediatr Endocrinol Metab 2005; 18:453. 5. Harris KB, Pass KA. Increase in congenital hypothyroidism in New York State and in the United States. Mol Genet Metab 2007; 91:268. 6. Eugène D, Djemli A, Van Vliet G. Sexual dimorphism of thyroid function in newborns with congenital hypothyroidism. J Clin Endocrinol Metab 2005; 90:2696. 7. StoppaVaucher S, Van Vliet G, Deladoëy J. Variation by ethnicity in the prevalence of congenital hypothyroidism due to thyroid dysgenesis. Thyroid 2011; 21:13. 8. Nagasaki K, Asami T, Ogawa Y, et al. A study of the etiology of congenital hypothyroidism in the Niigata prefecture of Japan in patients born between 1989 and 2005 and evaluated at ages 519. Thyroid 2011; 21:361. 9. Fisher DA. Second International Conference on Neonatal Thyroid Screening: progress report. J Pediatr 1983; 102:653. 10. Devos H, Rodd C, Gagné N, et al. A search for the possible molecular mechanisms of thyroid dysgenesis: sex ratios and associated malformations. J Clin Endocrinol Metab 1999; 84:2502. 11. Castanet M, Polak M, BonaïtiPellié C, et al. Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 2001; 86:2009. 12. Castanet M, Lyonnet S, BonaïtiPellié C, et al. Familial forms of thyroid dysgenesis among infants with congenital hypothyroidism. N Engl J Med 2000; 343:441. 13. Léger J, Marinovic D, Garel C, et al. Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism. J Clin Endocrinol Metab 2002; 87:575. 14. Perry R, Heinrichs C, Bourdoux P, et al. Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology. J Clin Endocrinol Metab 2002; 87:4072. 15. Vilain C, Rydlewski C, Duprez L, et al. Autosomal dominant transmission of congenital thyroid hypoplasia due to lossoffunction mutation of PAX8. J Clin Endocrinol Metab 2001; 86:234. 16. Doyle DA, Gonzalez I, Thomas B, Scavina M. Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX21. J Pediatr 2004; 145:190. 17. Narumi S, Muroya K, Asakura Y, et al. Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a populationbased cohort of Japanese patients. J Clin Endocrinol Metab 2010; 95:1981. 18. Carvalho A, Hermanns P, Rodrigues AL, et al. A new PAX8 mutation causing congenital hypothyroidism in three generations of a family is associated with abnormalities in the urogenital tract. Thyroid 2013; 23:1074. 19. Castanet M, Park SM, Smith A, et al. A novel lossoffunction mutation in TTF2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate. Hum Mol Genet 2002; 11:2051. 20. Baris I, Arisoy AE, Smith A, et al. A novel missense mutation in human TTF2 (FKHL15) gene associated with congenital hypothyroidism but not athyreosis. J Clin Endocrinol Metab 2006; 91:4183. 21. van Trotsenburg AS, Kempers MJ, Endert E, et al. Trisomy 21 causes persistent congenital hypothyroidism presumably of thyroidal origin. Thyroid 2006; 16:671. 22. Sunthornthepvarakui T, Gottschalk ME, Hayashi Y, Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropinreceptor gene. N Engl J Med 1995; 332:155. 23. Narumi S, Muroya K, Abe Y, et al. TSHR mutations as a cause of congenital hypothyroidism in Japan: a populationbased genetic epidemiology study. J Clin Endocrinol Metab 2009; 94:1317. 24. Cangul H, Morgan NV, Forman JR, et al. Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism. Clin Endocrinol (Oxf) 2010; 73:671. 25. Persani L, Gelmini G, Marelli F, et al. Syndromes of resistance to TSH. Ann Endocrinol (Paris) 2011; 72:60. 26. LadoAbeal J, CastroPiedras I, PalosPaz F, et al. A family with congenital hypothyroidism caused by a combination of lossoffunction mutations in the thyrotropin receptor and adenylate cyclasestimulating G http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 10/19 4/8/2015 Clinical features and detection of congenital hypothyroidism alphaprotein subunit genes. Thyroid 2011; 21:103. 27. Bakker B, Bikker H, Vulsma T, et al. Two decades of screening for congenital hypothyroidism in The Netherlands: TPO gene mutations in total iodide organification defects (an update). J Clin Endocrinol Metab 2000; 85:3708. 28. Pohlenz J, Rosenthal IM, Weiss RE, et al. Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3' splice site. J Clin Invest 1998; 101:1028. 29. Vigone MC, Fugazzola L, Zamproni I, et al. Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings. Hum Mutat 2005; 26:395. 30. Moreno JC, Bikker H, Kempers MJ, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 2002; 347:95. 31. Muzza M, Rabbiosi S, Vigone MC, et al. The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects. J Clin Endocrinol Metab 2014; 99:E544. 32. Zamproni I, Grasberger H, Cortinovis F, et al. Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J Clin Endocrinol Metab 2008; 93:605. 33. Pardo V, Rubio IG, Knobel M, et al. Phenotypic variation among four family members with congenital hypothyroidism caused by two distinct thyroglobulin gene mutations. Thyroid 2008; 18:783. 34. Moreno JC, Klootwijk W, van Toor H, et al. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Engl J Med 2008; 358:1811. 35. Friesema EC, Grueters A, Biebermann H, et al. Association between mutations in a thyroid hormone transporter and severe Xlinked psychomotor retardation. Lancet 2004; 364:1435. 36. Hanna CE, Krainz PL, Skeels MR, et al. Detection of congenital hypopituitary hypothyroidism: tenyear experience in the Northwest Regional Screening Program. J Pediatr 1986; 109:959. 37. Collu R, Tang J, Castagné J, et al. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropinreleasing hormone receptor gene. J Clin Endocrinol Metab 1997; 82:1561. 38. MedeirosNeto G, Herodotou DT, Rajan S, et al. A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene. J Clin Invest 1996; 97:1250. 39. Doeker BM, Pfäffle RW, Pohlenz J, Andler W. Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin betasubunit gene follows an autosomal recessive inheritance. J Clin Endocrinol Metab 1998; 83:1762. 40. PineTwaddell E, Romero CJ, Radovick S. Vertical transmission of hypopituitarism: critical importance of appropriate interpretation of thyroid function tests and levothyroxine therapy during pregnancy. Thyroid 2013; 23:892. 41. van Tijn DA, de Vijlder JJ, Vulsma T. Role of the thyrotropinreleasing hormone stimulation test in diagnosis of congenital central hypothyroidism in infants. J Clin Endocrinol Metab 2008; 93:410. 42. Kempers MJ, van Tijn DA, van Trotsenburg AS, et al. Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. J Clin Endocrinol Metab 2003; 88:5851. 43. Higuchi R, Miyawaki M, Kumagai T, et al. Central hypothyroidism in infants who were born to mothers with thyrotoxicosis before 32 weeks' gestation: 3 cases. Pediatrics 2005; 115:e623. 44. Kempers MJ, van Trotsenburg AS, van Rijn RR, et al. Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves' disease. J Clin Endocrinol Metab 2007; 92:2984. 45. Delange F, Dalhem A, Bourdoux P, et al. Increased risk of primary hypothyroidism in preterm infants. J Pediatr 1984; 105:462. 46. Zakarija M, McKenzie JM, Eidson MS. Transient neonatal hypothyroidism: characterization of maternal antibodies to the thyrotropin receptor. J Clin Endocrinol Metab 1990; 70:1239. 47. Brown RS, Bellisario RL, Mitchell E, et al. Detection of thyrotropin binding inhibitory activity in neonatal blood spots. J Clin Endocrinol Metab 1993; 77:1005. 48. Iseki M, Shimizu M, Oikawa T, et al. Sequential serum measurements of thyrotropin binding inhibitor immunoglobulin G in transient familial neonatal hypothyroidism. J Clin Endocrinol Metab 1983; 57:384. 49. Pacaud D, Huot C, Gattereau A, et al. Outcome in three siblings with antibodymediated transient congenital http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 11/19 4/8/2015 Clinical features and detection of congenital hypothyroidism hypothyroidism. J Pediatr 1995; 127:275. 50. Bartalena L, Bogazzi F, Braverman LE, Martino E. Effects of amiodarone administration during pregnancy on neonatal thyroid function and subsequent neurodevelopment. J Endocrinol Invest 2001; 24:116. 51. Cosman BC, Schullinger JN, Bell JJ, Regan JA. Hypothyroidism caused by topical povidoneiodine in a newborn with omphalocele. J Pediatr Surg 1988; 23:356. 52. Rodesch F, Camus M, Ermans AM, et al. Adverse effect of amniofetography on fetal thyroid function. Am J Obstet Gynecol 1976; 126:723. 53. Thaker VV, Leung AM, Braverman LE, et al. Iodineinduced hypothyroidism in fullterm infants with congenital heart disease: more common than currently appreciated? J Clin Endocrinol Metab 2014; 99:3521. 54. Linder N, Sela B, German B, et al. Iodine and hypothyroidism in neonates with congenital heart disease. Arch Dis Child Fetal Neonatal Ed 1997; 77:F239. 55. Smerdely P, Lim A, Boyages SC, et al. Topical iodinecontaining antiseptics and neonatal hypothyroidism in verylowbirthweight infants. Lancet 1989; 2:661. 56. Connelly KJ, Boston BA, Pearce EN, et al. Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion. J Pediatr 2012; 161:760. 57. Atwell TD, Lteif AN, Brown DL, et al. Neonatal thyroid function after administration of IV iodinated contrast agent to 21 pregnant patients. AJR Am J Roentgenol 2008; 191:268. 58. Bourjeily G, Chalhoub M, Phornphutkul C, et al. Neonatal thyroid function: effect of a single exposure to iodinated contrast medium in utero. Radiology 2010; 256:744. 59. Mouat F, Evans HM, Cutfield WS, et al. Massive hepatic hemangioendothelioma and consumptive hypothyroidism. J Pediatr Endocrinol Metab 2008; 21:701. 60. Maruo Y, Takahashi H, Soeda I, et al. Transient congenital hypothyroidism caused by biallelic mutations of the dual oxidase 2 gene in Japanese patients detected by a neonatal screening program. J Clin Endocrinol Metab 2008; 93:4261. 61. Hulur I, Hermanns P, Nestoris C, et al. A single copy of the recently identified dual oxidase maturation factor (DUOXA) 1 gene produces only mild transient hypothyroidism in a patient with a novel biallelic DUOXA2 mutation and monoallelic DUOXA1 deletion. J Clin Endocrinol Metab 2011; 96:E841. 62. Alm J, Hagenfeldt L, Larsson A, Lundberg K. Incidence of congenital hypothyroidism: retrospective study of neonatal laboratory screening versus clinical symptoms as indicators leading to diagnosis. Br Med J (Clin Res Ed) 1984; 289:1171. 63. Vulsma T, Gons MH, de Vijlder JJ. Maternalfetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989; 321:13. 64. Shoham I, ArichaTamir B, Weintraub AY, et al. Fetal heart rate tracing patterns associated with congenital hypothyroidism. Am J Obstet Gynecol 2009; 201:48.e1. 65. Law WY, Bradley DM, Lazarus JH, et al. Congenital hypothyroidism in Wales (19821993): demographic features, clinical presentation and effects on early neurodevelopment. Clin Endocrinol (Oxf) 1998; 48:201. 66. Van Vliet G, Larroque B, Bubuteishvili L, et al. Sexspecific impact of congenital hypothyroidism due to thyroid dysgenesis on skeletal maturation in term newborns. J Clin Endocrinol Metab 2003; 88:2009. 67. LaFranchi SH, Murphey WH, Foley TP Jr, et al. Neonatal hypothyroidism detected by the Northwest Regional Screening Program. Pediatrics 1979; 63:180. 68. Olivieri A, Stazi MA, Mastroiacovo P, et al. A populationbased study on the frequency of additional congenital malformations in infants with congenital hypothyroidism: data from the Italian Registry for Congenital Hypothyroidism (19911998). J Clin Endocrinol Metab 2002; 87:557. 69. Siebner R, Merlob P, Kaiserman I, Sack J. Congenital anomalies concomitant with persistent primary congenital hypothyroidism. Am J Med Genet 1992; 44:57. 70. Roberts HE, Moore CA, Fernhoff PM, et al. Population study of congenital hypothyroidism and associated birth defects, Atlanta, 19791992. Am J Med Genet 1997; 71:29. 71. AlJurayyan NA, AlHerbish AS, ElDesouki MI, et al. Congenital anomalies in infants with congenital hypothyroidism: is it a coincidental or an associated finding? Hum Hered 1997; 47:33. 72. Kumar J, Gordillo R, Kaskel FJ, et al. Increased prevalence of renal and urinary tract anomalies in children with congenital hypothyroidism. J Pediatr 2009; 154:263. http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 12/19 4/8/2015 Clinical features and detection of congenital hypothyroidism 73. American Academy of Pediatrics, Rose SR, Section on Endocrinology and Committee on Genetics, American Thyroid Association, et al. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 2006; 117:2290. 74. Léger J, Olivieri A, Donaldson M, et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metab 2014; 99:363. 75. Asami T, Otabe N, Wakabayashi M, et al. Congenital hypothyroidism with delayed rise in serum TSH missed on newborn screening. Acta Paediatr Jpn 1995; 37:634. 76. van Tijn DA, de Vijlder JJ, Verbeeten B Jr, et al. Neonatal detection of congenital hypothyroidism of central origin. J Clin Endocrinol Metab 2005; 90:3350. 77. Nebesio TD, McKenna MP, Nabhan ZM, Eugster EA. Newborn screening results in children with central hypothyroidism. J Pediatr 2010; 156:990. 78. Lanting CI, van Tijn DA, Loeber JG, et al. Clinical effectiveness and costeffectiveness of the use of the thyroxine/thyroxinebinding globulin ratio to detect congenital hypothyroidism of thyroidal and central origin in a neonatal screening program. Pediatrics 2005; 116:168. 79. Leonardi D, Polizzotti N, Carta A, et al. Longitudinal study of thyroid function in children with mild hyperthyrotropinemia at neonatal screening for congenital hypothyroidism. J Clin Endocrinol Metab 2008; 93:2679. 80. Larson C, Hermos R, Delaney A, et al. Risk factors associated with delayed thyrotropin elevations in congenital hypothyroidism. J Pediatr 2003; 143:587. 81. Fisher DA. Euthyroid low thyroxine (T4) and triiodothyronine (T3) states in prematures and sick neonates. Pediatr Clin North Am 1990; 37:1297. 82. Mandel S, Hanna C, Boston B, et al. Thyroxinebinding globulin deficiency detected by newborn screening. J Pediatr 1993; 122:227. 83. Muir A, Daneman D, Daneman A, Ehrlich R. Thyroid scanning, ultrasound, and serum thyroglobulin in determining the origin of congenital hypothyroidism. Am J Dis Child 1988; 142:214. 84. Schoen EJ, Clapp W, To TT, Fireman BH. The key role of newborn thyroid scintigraphy with isotopic iodide (123I) in defining and managing congenital hypothyroidism. Pediatrics 2004; 114:e683. 85. Supakul N, Delaney LR, Siddiqui AR, et al. Ultrasound for primary imaging of congenital hypothyroidism. AJR Am J Roentgenol 2012; 199:W360. 86. Takashima S, Nomura N, Tanaka H, et al. Congenital hypothyroidism: assessment with ultrasound. AJNR Am J Neuroradiol 1995; 16:1117. 87. Chang YW, Lee DH, Hong YH, et al. Congenital hypothyroidism: analysis of discordant US and scintigraphic findings. Radiology 2011; 258:872. 88. Ohnishi H, Sato H, Noda H, et al. Color Doppler ultrasonography: diagnosis of ectopic thyroid gland in patients with congenital hypothyroidism caused by thyroid dysgenesis. J Clin Endocrinol Metab 2003; 88:5145. 89. Dias VM, Campos AP, Chagas AJ, Silva RM. Congenital hypothyroidism: etiology. J Pediatr Endocrinol Metab 2010; 23:815. Topic 5836 Version 21.0 http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 13/19 4/8/2015 Clinical features and detection of congenital hypothyroidism GRAPHICS Congenital hypothyroidism or other causes of low total T4 at birth, with thyroid function test results Cause Primary hypothyroidism Serum free T4 Incidence Serum T4 Serum TSH 1:2000 to 1:4000 ↓ ↓ ↑ Thyroid dysgenesis: ectopia, aplasia, or hypoplasia 85 percent of cases ↓ ↓ ↑ Inborn errors of thyroxine synthesis (dyshormonogenesis) 15 percent of cases ↓ ↓ ↑ 1:25,000 ↓ ↓ Normal or ↓ Central hypothyroidism 1:100,000 Transient hypothyroidism Europe iodine deficiency ↓ then normalizes ↓ then normalizes ↑ then normalizes North America iodide excess and other causes ↓ then normalizes ↓ then normalizes ↑ then normalizes Maternal antibodymediated hypothyroidism 1:25,000 1:100,000 ↓ ↓ ↑ 1:4300 Normal ↓ Normal Thyroxinebinding globulin deficiency (causes low serum total T4 concentrations but not hypothyroidism) T4: thyroxine; TSH: thyroid stimulating hormone (thyrotropin). Graphic 68356 Version 7.0 http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 14/19 4/8/2015 Clinical features and detection of congenital hypothyroidism Thyroid hormone biosynthesis Thyroid hormone synthesis includes the following steps, marked by numbers in the diagram above: 1. Iodide (I – ) trapping by the thyroid follicular cells 2. Diffusion of iodide to the apex of the cells 3. Transport of iodide into the colloid 4. Oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues within thyroglobulin molecules in the colloid 5. Combination of two diiodotyrosine (DIT) molecules to form tetraiodothyronine (thyroxine, T4) or of monoiodotyrosine (MIT) with DIT to form triiodothyronine (T3) 6. Uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion of the thyroglobulin with a lysosome, and proteolysis and release of T4, T3, DIT, and MIT 7. Release of T4 and T3 into the circulation 8. Deiodination of DIT and MIT to yield tyrosine T3 is also formed from monodeiodination of T4 in the thyroid and in peripheral tissues. Illustration created by Mikael Häggström. Used under the Creative Commons CC0 1.0 Universal Public Domain Dedication. Graphic 91278 Version 1.0 http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 15/19 4/8/2015 Clinical features and detection of congenital hypothyroidism Evaluation of an infant with an abnormal screening test for hypothyroidism Graphic 73836 Version 5.0 http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 16/19 4/8/2015 Clinical features and detection of congenital hypothyroidism Thyroid physiology in the fetus and newborn Normal patterns of change for thyroidstimulating hormone (TSH), total T4, and total T3 are depicted for the fetus (beginning at 12 weeks gestation) and continuing for the first four weeks of life in the newborn. Note: To convert T3 in ng/dL to nmol/L, multiply by 0.01536. To convert T4 in mcg/dL to nmol/L, multiply by 12.87. Data from: 1. ThorpeBeeston JG, Nicolaides KH, Felton CB, et al. Maturation of the secretion of thyroid hormone and thyroidstimulating hormone in the fetus. N Engl J Med 1991; 324:532. 2. Fisher DA. Thyroid physiology in the perinatal period and during childhood. In: Werner's and Ingbar's The Thyroid, Braverman LE, Utiger RD (Eds), LippincottRaven, Philadelphia, 1996. p.974. 3. Williams FL, Simpson J, Delahunty C, et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab 2004; 89:5314. http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 17/19 4/8/2015 Clinical features and detection of congenital hypothyroidism Graphic 68673 Version 2.0 http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 18/19 4/8/2015 Clinical features and detection of congenital hypothyroidism Disclosures Disclosures: Stephen LaFranchi, MD Nothing to disclose. Mitchell Geffner, MD Grant/Research/Clinical Trial Support: Eli Lilly Inc [growth (rhGH) Ipsen [growth (rhIGFI)]; Endo Pharmaceuticals [puberty (GnRH agonist)]. Consultant/Advisory Boards: DaiichiSankyo [T2DM (colesevelam)]; Endo McGrawHill [pediatric endocrinology (textbook royalties)]. Alison G Hoppin, MD Nothing to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multilevel content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy http://www.uptodate.com/contents/clinicalfeaturesanddetectionofcongenitalhypothyroidism?topicKey=PEDS%2F5836&elapsedTimeMs=4&source=sear… 19/19
© Copyright 2024