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Detection and treatment of congenital

Annette Grters and Heiko Krude
Abstract | Congenital hypothyroidism is the most frequent endocrine disorder in neonates. Controversy
exists regarding the necessity to adjust current screening programs to also diagnose patients with central
hypothyroidism or those with mild forms of congenital hypothyroidism, who have high TSH levels but normal
T4 and normal T3 levels (also known as subclinical hypothyroidism). Thyroid hormone replacement should
start as soon as the diagnosis is confirmed by measurement of elevated TSH and low serum thyroid
hormone levels. Further diagnostic approaches, such as ultrasonography, scintigraphy and measurement
of thyroglobulin levels, to determine the subtype of congenital hypothyroidism, should not delay initiation of
treatment. Recommendations regarding the initial dosage of levothyroxine vary considerably, and no general
accepted guideline exists with regards to initial dosage or optimal time point for dose adjustment according to
biochemical parameters. More than 30years after the introduction of the first neonatal screening programs,
mental retardation can be prevented in the majority of children (>90%) with congenital hypothyroidism if therapy
is commenced within the first 2weeks of life, making neonate screening for this disorder the most successful
population-based screening test in pediatrics.
Grters, A. & Krude, H. Nat. Rev. Endocrinol. 8, 104113 (2012); published online 18 October 2011; doi:10.1038/nrendo.2011.160

The term congenital hypothyroidism was introduced of thyroid hormone synthesis, which occurs in most cases
more than 60years ago when Radwin et al. first described as an autosomal recessive trait of inheritance. Secondary
children with hypothyroid-associated features of severe congenital hypothyroidism, also termed central congeni-
intellectual disability and growth retardation.1 Today, tal hypothyroidism, is caused by deficiencies in TSH, for
this definition of congenital hypothyroidism has to be example, in patients with pituitary insufficiency or struc-
revisited, as the diagnosis of the disease is made before tural abnormalities of the pituitary gland orhypothalamus.
the onset of severe clinical symptoms, on the basis of Over time, TSH cut-off levels used in confirmatory
biochemical measurement of TSH and thyroid hormone diagnoses have been lowered, leading to the diagnosis of
levels alone.2,3 congenital hypothyroidism in patients who exhibit ele
Primary congenital hypothyroidism, the most common vated TSH levels without decreased peripheral thyroid
form of congenital hypothyroidism, occurs as a result of hormone concentrations or clinical symptoms. This mild
developmental defects of the thyroid gland, known as form of congenital hypothyroidism occurs as the result
thyroid agenesis or dysgenesis, or is due to disruptions of either a transient or permanent rise in TSH levels and
in thyroid hormone biosynthesis, also known as thyroid has been named subclinical hypothyroidism. However,
dyshormonogenesis. In the majority (80%) of cases, a struc- given that this condition does not reflect a true state of
tural defect of the thyroid gland is present: an ectopic gland hypothyroidism, nor causes an obvious developmental
in a cranial, sometimes lingual, position; thyroid gland defect, this form would be more accurately labeled as
hypoplasia; or the complete absence of thyroid tissue.46 hyperthyrotropinemia.
Minor variants of thyroid dysgenesis include the absence The purpose of this Review is to summarize the current
of the thyroid isthmus or a lack of onein most cases the knowledge on the etiology underlying thyroid dysgenesis
leftlobe of the thyroid. This thyroid hemiagenesis can and dyshormogenesis and to provide an update on the evi-
Institute of be found with a frequency of 1 in 1,0002,000 individuals dence concerning the diagnosis and treatment of patients
Experimental Pediatric
Endocrinology, Charit without a pre-existing diagnosis of hypothyroidism;7 its with congenital hypothyroidism.
Universittsmedizin finding in children with neonatally elevated levels of TSH,
therefore, does not confirm the diagnosis of congenital Neonatal screening
D13353 Berlin, hypothyroidism. In the remaining 20% of children with Klein and co-workers first showed that the IQ of a child
Germany (A. Grters, congenital hypothyroidism, a normal or enlarged thyroid with congenital hypothyroidism dramatically depends
can be identified. These children are affected by a defect on the time of clinical diagnosis and initiation of replace-
Correspondence to: ment therapy.8 Only diagnosis and treatment before the
A. Grters
annette.grueters@ Competing interests age of 3months enables normal mental development, The authors declare no competing interests. an observation that led the researchers to propose the

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introduction of screening programs. Neonatal screening Key points

for congenital hypothyroidism became a feasible option
Neonatal screening for primary congenital hypothyroidism is an efficient tool for
only after the development of specific, robust and sensitive the secondary prevention of severe mental retardation
radioimmunoassays for TSH and T4.9 Subsequently, the
Diagnosis of primary congenital hypothyroidism is based on detection of an
results of two pilot screening programs were published in increased TSH concentration in the presence of low T4 levels in serum
the early 1970s.10,11
The differential diagnosis of congenital hypothyroidism includes defects of
Owing to the transient rise of TSH in the first 48h after thyroid hormone synthesis in patients with a normal thyroid gland or goiter and
birth,12 either cord blood samples or dried blood spots several diseases arising from thyroid transcription factor defects in patients
taken from heel pricks after the third day of life were used with thyroid dysgenesis
to measure either TSH alone (Europe and Japan)3 or T4 Although evidence for particular treatment modalities was not generated in
followed by TSH in neonates with a T4 concentration prospective controlled studies, an initial daily dose of >10g levothyroxine
below the 10th percentile (North America).2 Both strat per kg of body weight is recommended to treat congenital hypothyroidism
egies aimed to identify children with primary congeni
tal hypothyroidism but not those with central congenital
hypothyroidism. The results of these first screening pro- a Athyrosis Ectopy Hypoplasia
grams were encouraging and confirmed that early diagno-
sis and treatment can offer a normal intellectual outcome
in a disease that was historically thought to result in severe
mental retardation.2,3
The incidence of congenital hypothyroidism that was
observed in the first screening programs was similar, with
a rate of 1 in 3,0004,000, which was twofold higher than
the incidence calculated by clinical diagnosis in the pre-
screening era.1317 Further neonatal screening programs b Day 10 Day 12 Day 13 Day 15
have confirmed an incidence of 1 in 3,500 in a wide range
of different geographic and ethnic populations.18 Two
exceptions in US screening programs refer to Hispanic
neonates, who exhibit an increased incidence of 1 in
2,000, and to neonates of African American origin, who
show a reduced incidence of 1 in 10,000.19 Interestingly,
a female preponderance was observed in all screening
cohorts, similar to that seen in cohorts studied before the
introduction of screening.20
Over the past four decades, increasing overall incidence
rates have been observed in the USA, without an obvious
Transcription factor genes expressed: PAX8, NKX2-1, FOXE1, NKX2-5
identifiable reason. Several factors haven been proposed
to underlie this increase: the diagnosis of more subtle cases Functional genes:
of congenital hypothyroidism due to lower TSH cut-off
levels; the increasing number of preterm children, who can Figure 1 | Congenital hypothyroidism due to thyroid dysgenesis. a | The three
be affected by a transient rise in TSH levels; and a change different forms of thyroid dysgenesis are shown: complete absence of the thyroid
in study populations, with a higher proportion of neonates gland, ectopic gland and thyroid hypoplasia. The first and second images were
with a Hispanic background.21 obtained by scintigraphy, the third by ultrasonography. b | Different steps of the
embryonic development of the thyroid gland in mice embryos, as shown in 3D
reconstructions. Green marks the endodermal pharynx from which the thyroid
primordium (in gray) is budding at day10 of mouse development. The thyroid bud
Insights into the pathogenesis of congenital hypo keeps in contact with the arteries of the heart outflow tract (in red) until later
thyroidism have revealed that genetic causes are detect- stages, when the aortic arch develops further caudally into the mediastinum. The
able not only in patients with dyshormonogenesis, but thyroid migrates back cranially and by lateralization builds the final lateral
also in individual patients with developmental defects functional lobes of the gland at day15, which corresponds to week12 of human
of the thyroid, which were previously regarded to have development. During these different steps of embryogenesis, several
a noninherited sporadic disorder.22 However, although transcription-factor-encoding genes are continuously expressed, whereas the
molecular genetic testing can clarify the cause of dys TSHR gene, as the other functional genes important for thyroid hormone synthesis,
is only expressed during late stages of fetal development.
hormonogenesis in the majority of patients, the molecular
basis of congenital hypothyroidism in those with thyroid
dysgenesis remains predominantly unknown. Only few hypothyroidism with normal localization of the thyroid
familial cases of thyroid dysgenesis have been reported gland or a goiter can reflect a recessively inherited defect
to date,23 and discordance is found even between mono of thyroid hormone synthesis (Figure2). These rare muta-
zygotic twins.24 Nevertheless, in single cases of thyroid tions have clinical relevance, as they enable clinicians to
dysgenesis, inactivating mutations in transcription-factor- provide genetic counseling, as well as adequate treatment
encoding genes expressed during thyroid organogenesis and follow-up, for example because affected patients
have been identified (Figure1).22 In addition, congenital with thyroid dysgenesis can manifest with more complex


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The majority of patients with mutations of the NKX21
gene present with either mild or severe congenital hypo
Hypothalamus thyroidism in association with variable pulmonary symp-
toms, as well as neurological alterations, such as severe
choreoathetosis, ataxia and other movement disorders.32,33
Thyroid NIS This particular association of symptoms results from
follicle the multiple roles of the NKX21 transcription factor in the
I development and function of different organ systems, that
Pendrin TRHR is, the CNS, lung and thyroid. The phenotype of NKX21-
deficient patients is variable, with no direct correlation of
TSH disease severity between these organ systems. Neonates
H2O2 I and infants have died due to severe pulmonary insuffi-
DUOX1/2 TSHR Pituitary ciency despite only mild hypothyroidism,34,35 whereas other
patients have severe motor defects but completely normal
I thyroid function and no pulmonary symptoms. Sequencing
of the NKX21 gene is recommended in neonates with ele-
vated TSH levels and severe pulmonary complications or
HO O in children with congenital hypothyroidism and unfavor
able motor development despite adequate treatment. In
I I T4 the first year of life, muscular hypotonia occurs, which is
followed by the more specific movement defect of chorea
Figure 2 | Thyroid hormone synthesis. The several levels of thyroid regulation by TRH
and TSH as well as the functional steps of thyroid hormone production are shown. (involuntary, irregular migrating contractions of the limbs)
The key elements of thyroid hormone production are: transport of iodine through the or athetosis (involuntary, convoluted writhing and twist-
thyroid cell into the thyroid follicular lumen; iodination of tyrosine rings of the matrix ing movements of the fingers, arms, legs and neck) during
protein thyroglobulin in the follicular lumen by TPO and H2O2 generated by the DUOX further motor development. During adolescence, the
enzymatic system; joining of two iodinated tyrosine residues of thyroglobulin into movement disorder does not deteriorate, and an improve-
the mature T4 molecule by TPO; transport of T4 through the thyroid cells into the ment of chorea was observed in some adult patients.36
circulation, most likely via T4 transporter molecules, which are not yet defined in
Genetic counseling is based on the autosomal dominant
detail. The whole process is activated by TSH, which is secreted from the pituitary
gland under control of TRH, in response to thyroid hormone level. Abbreviations:
inheritance; however, the relevance of counseling is very
DUOX, dual oxidase; NIS, sodium-iodide symporter; Tg, thyroglobulin; TPO, thyroid limited due to the variable penetrance of NKX21 gene
peroxidase; TRH, thyroid-releasing hormone; TSHR, TSH receptor. mutations within the three affected organ systems.

comorbidities. Nevertheless, in some patients with well- A very rare variant of congenital hypothyroidism due
defined genetic defects, such as Down syndrome25 or to mutations in the NKX25 gene was described in four
WilliamsBeuren syndrome,26 the molecular basis of patients, of whom one was affected by an associated heart
the usually mild forms of congenital hypothyroidism or defect. Although heart defects account for 50% of all
hyperthyrotropinemia remains to be identified. associated malformations in congenital hypothyroidism,
only this one NKX25 mutation has been reported to date.37
Mutations causing thyroid dysgenesis
Due to the low frequency of mutations in patients with PAX8
thyroid dysgenesis,27,28 genetic testing should be initiated Another example of a thyroid transcription factor defect
only in those patients with either a suggestive clinical that affects thyroid function and development is the
manifestation (FOXE1, NKX21 and NKX25 gene muta- PAX8 gene mutation.38 This defect in thyroid dysgenesis
tions) or with a familial occurrence of thyroid dysgenesis leads to a variable and potentially asymmetric hypoplasia
(PAX8 and TSHR gene mutations). of the thyroid gland. Hypothyroidism can be mild, and
some patients manifest an elevation of TSH levels only
FOXE1 later during childhood, thereby escaping the diagnosis by
At birth, the clinical diagnosis of a child with congenital neonatal screening.38 In addition to thyroid dysgenesis,
hypothyroidism and thyroid dysgenesis associated with PAX8 gene mutations can also lead to unilateral kidney
cleft palate and striking spiky hairs should suggest the agenesis. Patients with a PAX8 mutation should, therefore,
diagnosis of the BamforthLazarus syndrome,29 which is undergo renal ultrasound investigation.39 Although PAX8
caused by a mutation in the transcription-factor-encoding is also expressed in the brain and the ear anlage, no further
gene FOXE1.30,31 These children have an unfavorable cog- defect or clinical symptom of the CNS has been described
nitive outcome despite adequate treatment of congenital in PAX8-deficient patients.40
hypothyroidism owing to the additional role of FOXE1
in the development of the central nervous system (CNS). TSHR
This prognosis, as well as the autosomal recessive mode Even before the description of thyroid dysgenesis caused by
of inheritance, should be addressed in genetic counseling. transcription factor defects, inactivating mutations of the

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TSH receptor 41 were found to result in congenital hypo difficulty, lethargy, constipation, macroglossia, hypo
thyroidism and thyroid dysgenesis with autosomal recessive thermia, edema, wide posterior fontanel, umbilical hernia
inheritance. Because the encoding gene, TSHR, is expressed and the so-called hypothyroid facial appearance.13 If con-
only late during fetal development, homozygous or com- genital hypothyroidism remains untreated, the clinical
pound heterozygous inactivating mutations lead to hypo symptoms become evident in the second half of the first
plasia and not to an ectopic gland or agenesis of the gland. year of life, with growth retardation and a delay in motor
A less severe inactivation of the TSH receptor can also result development. In addition to the delay in the development
in mildly elevated TSH levels with normal T4 levels.42 of motor skills, intellectual disability is the most impor-
tant and devastating clinical symptom of congenital
Mutations causing thyroid dyshormonogenesis hypothyroidism, as it is not reversible.
Each step of the complex process of thyroid hormone syn- Almost 10% of neonates with congenital hypothyroidism
thesis, including iodine transport into the thyroid follicle are affected by additional congenital malformations.52
(via the sodium-iodide symporter NIS and the sodium- Congenital heart defects are the most common, affect-
independent chloride/iodide transporter pendrin43) and ing 50% of patients. Congenital hypothyroidism can also
iodine incorporation into the nascent thyroid hormone occur as one obligatory feature of rare genetic syndromes,
(via the enzymes thyroid peroxidase [TPO],44 dual oxi- such as the BamforthLazarus syndrome,29 and is more
dases [DUOX]45 and the matrix protein thyroglobulin46) frequent in children with Down syndrome53 and pseudo-
can be affected (Figure2). hypoparathyroidism type1a.54 Clinical symptoms of an
underlying syndrome can precede the diagnosis of con-
TPO and TG genital hypothyroidism, especially in patients with the
Since the first description of an inactivating mutation in BamforthLazarus syndrome, in whom cleft palate and
the TPO gene in 1992,47 it was shown that in most chil- spiky hairs are present at birth. Mild congenital hypo-
dren with thyroid dyshormogenesis, a molecular inherited thyroidism or elevated TSH levels are more frequent in
defect of thyroid hormone synthesis can be diagnosed. The patients with WilliamsBeuren syndrome26 and in those
partial or complete loss of activity of TPO or thyroglobulin with pseudohypoparathyroidism type1a.54
(encoded by the TG gene) leads to severe hypothyroidism
with a large goiter. Cases missed by screening
Variants of congenital hypothyroidism that are charac
SLC26A4 terized by an inappropriate low TSH level, such as central
The SLC26A4 gene encodes pendrin, a protein expressed and preterm congenital hypothyroidism, cannot be diag-
in follicular cells and in cells of the inner ear that transports nosed with TSH-based screening strategies. Because
iodine into the thyroid follicle. In children with mutations free T4 measurement in dried blood spots has not been
in this gene, an associated hearing loss can be present and established with sufficient sensitivity and specificity so far,
might help to focus the molecular genetic diagnosis.48 indirect strategies were developed to diagnose these dis
ease variants. In the Netherlands, an elaborated approach
DUOX combines the screening of total T4 with measurement of
In contrast to the effects of insufficient or absent TPO TSH and thyroxine-binding globulin as a surrogate for the
or thyroglobulin activity, defects in the H2O2-generating free T4 fraction.55 The results of this program clearly show
oxidase system (DUOX2, DUOX2a) are more subtle and that, in addition to primary congenital hypothyroidism,
can appear as a transient, mild TSH elevation,49 pos- almost all cases of central congenital hypothyroidism can
sibly due to the redundancy of different proteins in the be detected, with an incidence rate of 1 in 21,000, which
oxidasesystem. is close to the rate of 1 in 19,000 calculated based on the
clinical diagnosis of central congenital hypothyroidism.56
GNAS Due to the immature hypothalamicpituitarythyroid
Combined central and primary congenital hypothyroidism axis in preterm neonates,57 some preterm children with
can result from mutations in the GNAS gene, which cause hypothyroidism exhibit a late rise of TSH levels and might,
pseudohypoparathyroidism type1a.50 The underlying therefore, be missed with TSH-based screening programs.
gene defect affects the function of the Gprotein, which Moreover, dopamine, which is frequently used in the
is crucial for TRH as well as TSH receptor signaling, treatment of ill premature neonates, can attenuate TSH
leading to only mildly elevated TSH levels.51 Features that release.58 Although these occurrences are rare,59 single case
are clinically suggestive of this form of congenital hyper- reports of prematurely born patients with undiagnosed
thyroidism are the associated findings of short digits and congenital hypothyroidism have led to the important
short stature and mental retardation despite adequate recommendation to re-screen neonates born preterm
levothyroxine treatment. before discharge from the hospital, especially those in
intensive care units who received dopamin.60
Clinical diagnosis
Signs and symptoms Confirmatory diagnosis
Clinical symptoms of congenital hypothyroidism detec Biochemical measurements
ted by screening in neonates are usually subtle and Once a child has a conspicuous result in the neo
nonspecific. They include long-term jaundice, feeding natal screeni ng, the definite diagnosis of congenital


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Positive screening result

Serum TSH, total T4/free T4

Normal TSH, normal T4 High TSH, normal T4

No further diagnostic test Repeat TSH after 1 week High TSH and low T4:
confirmed congenital
Normal TSH, normal T4 TSH constantly high, TSH increasing while T4
normal T4 still normal:
congenital hypothyroidism
is probable

hypothyroidism Positive
Maternal autoimmune/ Thyroid normal/
iodine deficiency history? goiter
TPO, TG, etc. genes Negative Ultrasonography
and thyroglobulin
or scintigraphy
FOXE1 gene Cleft palate, Associated symptoms? Dysgenesis
spiky hairs

Muscle hypotonia,
NKX2-1 gene
pulmonary symptoms

PAX8 gene Renal malformations

NKX2-5 gene Heart defect

Figure 3 | Diagnostic algorithm for the detection of primary congenital hypothyroidism. Although evidence for the alternative
steps of the diagnostic procedure in the confirmation and differential diagnostic of congenital hypothyroidism is limited, the
algorithm is based on available guidelines and personal experience of the authors.

ypothyroidism depends on a so-called confirmatory

h gland, an elevated but not further increasing TSH level
diagnosis (Figure3). To avoid misdiagnosis owing to a is a good marker indicating an individual steady-state of
transient TSH surge or a sample error, serum measure sufficient T4. Treatment, therefore, does not need to be
ment of TSH, T4either total or free T4and T3 is neces initiated as long as the serum T4 is within the normal,
sary before treatment can be initiated. In neonates with age-adjusted range and the TSH concentration does not
elevated serum TSH and low thyroid hormone levels, further increase in repeated serum controls.
the diagnosis of congenital hypothyroidism is con A stable, elevated TSH level with normal T4 concentra-
sidered to be confirmed; thyroid imaging and testing tion is present in at least 3% of the healthy child popu
for maternal thyroid antibodies is then recommended lation, given that the upper normal TSH level is defined by
to more precisely define subgroups of congenital statistical means of +2SD when measuring normal control
hypothyroidism.61,62 populations. Longitudinal measurements in large cohorts
In patients with confirmed severe congenital hypo revealed that a TSH level <7.5 mU/l will not further
thyroidism, serum levels of TSH >50mU/l and low T4 or increase over time.64 This normal, elevated TSH level,
free T4 levels are present, whereas T3 values are in the lower therefore, probably reflects an inborn variant of the indivi
normal range in most cases. More difficult to interpret are dual set-point of the hypothalamuspituitarythyroid axis
those values that reflect mild congenital hypothyroidism, and does not represent imminent pathology.
with TSH levels <50mU/l and normal or borderline T4
(or free T4) concentration. Because signs and symptoms Imaging
of congenital hypothyroidism are related to decreased As part of the confirmatory diagnosis, imaging can be
thyroid hormone levels and not to elevated TSH levels, it employed in neonates with biochemically proven congeni-
is necessary to assess whether a child is deprived of thyroid tal hypothyroidism to define the subgroup of hypothyroid
hormone or not. Interindividual T4 levels vary enor- pathology (thyroid dysgenesis versus dyshormonogenesis).
mously, and the normal range of T4 and free T4 can differ The technique used for imaging differs between centers
by 100% (Table1).63 In addition, neonatal T4 levels change and depends mostly on local experience and availability.
rapidly in the first days of life, and the almost twofold The less invasive ultrasonography technique is sufficient
higher levels in the first week of life need to be considered to separate a structural defect from a normal or enlarged
in the assessment.63 In a child with a functioning pituitary gland,5 whereas only the more invasive s cintigraphy

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Table1 | Final IQ outcome* in children with congenital hypothyroidism treated with levothyroxine
Study n (patients/controls) Duration Start of Levothyroxine dose Full-scale IQ Full-scale IQ
(years) treatment (g/kg daily) controls CH patients
(days of life)
Oerbeck etal.79 49/41 (siblings) 20 24.4 8.4 111.4 102.4
Rovet etal.78 42/42 (siblings) 69 12.8 (7.618) 3.212.3 108.9 102.7
Dimitropoulos 63/175 14 9 (518) 14.7 (9.923.6) 111.4 101.7
etal.84 (normal control group)
*Measured with the Wechsler intelligence scale. Abbreviation: CH, congenital hypothyroidism.

either with radioactive iodine or technetium, performed Treatment

when TSH concentration is still highenables an exact In principle, successful treatment is achieved by applica-
localization of an ectopic, lingual thyroid gland.65 tion of a single oral levothyroxine dose in the morning.
To further increase the specificity in discerning sub- The choice of levothyroxine rather than liothyronine
groups of congenital hypothyroidism, thyroglobulin can be or a combination of the two is reasonable, because the
measured as a thyroid-tissue-specific marker. The discrimi biologically active liothyronine is generated by local
nation of goiter versus athyrosis (lack of the thyroid gland) expression of deiodinases, especially in the brain and
can easily be achieved in children by combining measure- other target tissues.71 In addition, studies have shown
ment of thyroglobulin levels and ultrasonography. How that treatment with liothyronine is not superior in terms
ever, the more subtle differentiation of apparent athyrosis of final cognitive outcome.72 In most countries, levo
from an ectopic thyroid glandalthough possible in most thyroxine for oral application is only licensed as a tablet.
cases of complete absence of thyroglobulinremains dif- In Europe, liquid preparations with a concentration of 5g
ficult in some children, owing to the individual overlap per drop are licensed, which allows smaller intervals of
of thyroglobulin levels in these conditions.66 Nevertheless, doseadjustment.73
as the demonstration of an ectopic gland versus athyrosis Resorption of oral levothyroxine is excellent, and dif-
does not change the indication for or dose of levothyroxine, ferences in individual kinetics that might exist are over-
several pediatric centers regard ultrasonography combined come by dose adjustment according to actual TSH levels.
with measurement of thyroglobulin levels to be sufficient However, soy milk has been shown to interfere markedly
and do not perform scintigraphy. with the resorption of levothyroxine to the extent that
Imaging should not delay the initiation of therapy, the drugs dose has to be increased after consumption of
which should start as early as possible. Scintigraphy can be soy-rich foodstuffs.74
combined with a perchlorate-based protocol to measure Owing to the long half-life of levothyroxine in the cir-
the amount of organified iodine to demonstrate a defect culation, several days of administration are needed to
in thyroid hormone synthesis. However, this investigation, reach a steady-state. In addition, a preliminary report in
which is part of a scientific approach rather than clinical adult patients documented an at least equal, if not better,
routine, can be postponed until a later age, when chil- effect of levothyroxine application in the evening rather
dren will be off treatment for re-evaluation of the initial than in the morning.75 The current recommendation to
diagnosis in their third year of life. take levothyroxine in the morning might, therefore, need
revisiting; in particular situations of low compliance, the
Thyroid antibodies and iodine time point of drug administration should be adapted to
In children with confirmed biochemical hypothyroidism the individual.
and a normal thyroid gland on imaging, a further diagnos-
tic step should be performed to exclude either a maternal Dose and start of treatment
thyroid autoimmune disease or an iodine overload as a Since the first introduction of screening, the optimal start-
potential cause of transient congenital hypothyroidism. ing point and dose of levothyroxine have been discussed
Typically, maternal antibodies that can cause fetal hypo- controversially. The initial doses for neonates in the first
thyroidism block the TSH receptor, and after clearance screening programs were chosen on the basis of practica-
from the infants circulation at an age of 6months, thyroid bility (availability of tablet preparations of levothyroxine
function normalizes.67,68 The same transient course can be for adults: 25.0g, 50.0g or 37.5g as half of a 75.0g
expected in those rare cases of iodine overload that can tablet) and individual clinicians experience. In North
result from maternal disinfection with povidone iodine America, a daily dose of 25g was given,2 whereas in
before or during delivery or from a direct application of Europe several centers administered 50g per day,3 result-
this substance to the neonate during preoperative dis ing in individual doses of levothyroxine of 510g/kg
infection. The transdermal resorption of high amounts or 1020g/kg body weight, respectively. Irrespective of
of iodine leads to an inactivation of the neonatal thyroid the dose, the initial results were encouraging, given that
gland (WolffChaikoff effect) and sometimes causes a beneficial effect, with normal growth, motor develop-
severe but short-lasting hypothyroidism.69,70 Treatment of ment and IQ, was found in almost all treated children.76,77
the child is still necessary for several weeks until normal However, in two studies of young adult patients diag-
thyroid function is restored. nosed in the first screening programs in Canada and


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Norway, who were treated with an initial dose of 25g The incidence of congenital hypothyroidism increased
per day, the final full-scale IQ was in the normal range, to 1 in 1,44687 and to 1 in 1,556, respectively, using these
albeit consistently 68 points lower than that of an appro- thresholds.88 This increase was accompanied by a more
priate sibling control group.78,79 This gap was argued to than 10-fold higher rate of screening TSH reinvestiga-
potentially result from an insufficient effect of the 25g tions, for example, a recall rate that is in the range of
levothyroxine dose.80 0.10.3% of all screened neonates when the TSH cut-off
Newer, retrospective comparisons and prospective, but level is 15mU/l. The majority of children with supposed
nonrandomized, observations revealed an improved cog- congenital hypot hyroidism were shown to have per-
nitive outcome with an increased dose of levothyroxine manent elevated TSH levels (>5mU/l) at 23years of
>10g/kg body weight daily.8082 In addition, a random- age,88 which was argued to be proof of congenital hypo
ized study comparing 37.5g and 50.0g of levothyroxine thyroidism and support the need for continued treat-
revealed a better full-scale IQ in the high-dose group com- ment with levothyroxine. However, these childrenwho
pared with the low-dose group at an age of 28years.83 had hyperthyrotropinemia rather than true congenital
Together, these data clearly favor high levothyroxine doses hypothyroidismwere treated without any evidence of
(>10g/kg per day) to improve IQ outcome in children a clinically significant benefit of treatment for their cog-
with congenital hypothyroidism. However, in a cohort nitive development. Nevertheless, given the devastating
from Switzerland, a high dose of 14.9g/kg body weight effect of hypothyroidism on the neonatal development of
still resulted in a 9points-lower full-scale IQ compared the CNS and because individual patients with mild TSH
with that of a matched control group.84 To date, no signifi- elevation might have borderline T4 values,87 the tendency
cant adverse effects have been reported when children are to overtreat is easily comprehensible. Therefore, outcome
treated with high doses of levothyroxine (37.5g or 50g studies that include a substantial number of untreated chil-
per day) in all studies. dren with mild congenital hypothyroidism are urgently
Closely linked with the effect of a high versus low initial needed to better judge this particular treatment indication.
treatment dose is the question whether an early start of
treatment can further improve the IQ in patients with Follow-up and outcome
congenital hypothyroidism. Several studies compared an After initiation of therapy, the usual recommendation
early versus late start of treatment, that is, 10days versus is to monitor TSH and T4 levels at weekly intervals for
16days88 and <15days versus >21days after birth,89 which 1month, at monthly intervals for 3months, followed by
revealed a consistently better IQ in the early-treatment a continuous follow-up every 3months during the first
group. Whether an even earlier start of treatment, before 2years of life and later every 6months. Studies about
the age of 10days, will close the gap of full-scale IQ points treatment modalities during the maintenance phase
remains to be investigated. Based on currently available have been surprisingly rare so far. One study from Brazil
outcome data, which do not reach a high level of evi- reported a clinically significant effect of the number of
dence, most guidelines now recommend a high dose of follow-up appointments on final IQ outcome.90
levothyroxine of 1015g/kg body weight with the aim to Congenital hypothyroidism is a chronic disease and the
start treatment within the first 2weeks of life.62,86 outcome of the affected children depends on optimal com-
Other potential explanations for the continuously pliance of the parents and later in life of the patients them-
observed gap in full-scale IQ outcome might be that the selves. As in other chronic, inherited diseases, treatment of
fetal period of severe hypothyroidism can induce neuronal congenital hypothyroidism and patient care is a balance
damage that cannot be compensated for by postnatal treat- of avoiding fear but maintaining a good compliance at the
ment. On the other hand, the remaining IQ gap might same time. However, congenital hypothyroidism seems to
be related to the still unknown molecular pathogenesis be easily treatable compared with other metabolic, inher-
of congenital hypothyroidism. As shown for the mental ited diseases, and a tendency to follow up children with
retardation in patients with FOXE1 deficiency 31 and for congenital hypothyroidism in unspecialized pediatric
neurological defects in those with NKX21 deficiency,32 a endocrine centers exists. How these children will develop
molecular defect that results in thyroid dysgenesis might and how efficient the health-care service within this public
also interfere with normal brain development. In some medical domain actually is remains so far unknown.
cases, this mechanism might lead to an unfavorable cog- Published outcome studies of patients with congenital
nitive or neurological outcome despite screening for and hypothyroidism are generated in highly specialized and
optimal treatment of congenital hypothyroidism. Further closely interlinked research groups that have dedicated
outcome studies need to take into account probable decades of work to the diagnosis and treatment of con-
molecular mechanisms that might interfere with normal genital hypothyroidism. So far, the general fate of children
cognitive development. from a population-wide view is unknown, because only
very few health-care service studies were undertaken
Mild forms of congenital hypothyroidism with a focus on congenital hypothyroidism.91 This fact is
A current topic of discussion concerns the diagnosis surprising given that congenital hypothyroidism is one
and necessity for treatment of mild forms of congenital of the most frequent conditions among the spectrum of
hypothyroidism in children with hyperthyropinemia. rare diseases. The population-based screening programs
Several groups have now reported their experience with that are now established in a large number of countries
low TSH cut-off levels of 10mU/l87,88 and even 6mU/l.89 generate a yearly cohort of approximately 3,000 patients

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2012 Macmillan Publishers Limited. All rights reserved

with congenital hypothyroidism with the need for replace- achieved by a single, daily dose of oral levothyroxine.
ment therapy in the USA, Europe and Japan alone. The However, uncertainty and controversy remain regarding
ongoing increase in screening sensitivity due to reductions the appropriate starting dose. Despite several guidelines
in the TSH cut-off threshold will increase this number being in favor of a high dose (>10g/kg body weight
even further and will fuel the need to appropriately re- per day), the evidence level supporting this recommen-
evaluate treatment indications in children with hyper dation is still low.94 Moreover, the implementation of
thyrotropinemia. Obviously, further studies will focus on screening programs harbors the risk of overdiagnosing
these aspects of health-care research in the follow-up and and overtreating a large number of children, especially
outcome of c hildren with congenital hypothyroidism. with the current tendency to lower TSH cut-off levels.
Owing to the successful treatment of children with con- The more sensitive the screening programs, the higher
genital hypothyroidism, these individuals now reach an the risk of losing the balance between their burden and
adult age and are able to lead presumably normal lives. benefits. Further evidence is needed to justify treatment
Thus a hitherto nonexistent group of adult patients now of neonates with mild hyperthyrotropinemia as has now
requires adult health-care services that are educated about become routine in most programs with a reduced TSH
outcome, long-term needs and related organ-specific cut-off level. In addition, the development of standard-
effects in patients with developmental defects of the ized follow-up programs for adult patients with congeni-
thyroid gland treated with thyroid hormone replacement. tal hypothyroidism, who can presumably live a normal
Adult patients with congenital hypothyroidism are at risk life but are considered to be chronically ill, is a further
of obesity,92 and impaired diastolic function and increased task that needs to be addressed to optimize treatment
intima-media thickness in young adult patients with con- of congenital hypothyroidism following detection by
genital hypothyroidism diagnosed in screening programs neonatal screening.
were described in a study from Italy.93 Together, these data
clearly demonstrate the need for ongoing specialized care
Review criteria
of adult patients with congenital hypothyroidism.
Articles cited in this Review were selected on the basis
Conclusions of a search of the PubMed database. Search terms were
Neonatal screening for congenital hypothyroidism congenital hypothyroidism and outcome, treatment,
diagnosis and pathogenesis. The literature search
represents the most efficient method to prevent mental
was not limited to certain years. Only full-text papers
retardation and ensure normal IQ levels in this patient written in English were selected.
popul ation. Successful replacement therapy is easily

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