Author Stephen LaFranchi, MD Section Editor Mitchell Geffner, MD

Transcription

4/8/2015
Clinical features and detection of congenital hypothyroidism
Official reprint from UpToDate® www.uptodate.com ©2015 UpToDate®
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.)
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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
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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)'.)
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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
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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
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● 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".)
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• 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
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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
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the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written
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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.)
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● 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.)
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Topic 5836 Version 21.0
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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
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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.
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Evaluation of an infant with an abnormal screening test for
hypothyroidism
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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.
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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.
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