This document discusses congenital hypothyroidism, including its causes, genetic factors, and newborn screening. The majority of cases are caused by thyroid dysgenesis, with the thyroid gland absent, located abnormally, or hypoplastic. Rarer causes include dyshormonogenesis and central hypothyroidism. Genetic testing should be considered for specific clinical manifestations or a familial history. Newborn screening primarily uses TSH testing, with a recall threshold of >20 mIU/L, though primary T4 testing with backup TSH is also used. Early treatment is important to prevent intellectual disability.

1. DR LAVANYA BONNY
SR, DEPT OF ENDOCRINOLOGY
ST JOHNS MEDICAL COLLEGE
BANGALORE

2.  The term ‘congenital hypothyroidism’ was introduced more than 60 years ago
 Radwin et al. described children with hypothyroid-associated features of severe
intellectual disability and growth retardation
 most frequent endocrine-metabolic disease in infancy
 incidence - 1/3000 to 4000 newborns

3.  80% to 85% - THYROID DYSGENESIS
 due to alterations occurring during the gland organogenesis
 resulting either in a thyroid that is absent (thyroid agenesis or athyreosis)
 or hypoplastic (thyroid hypoplasia)
 or located in an unusual position (thyroid ectopy)
 Usually sporadic, genetic in 5%

4.  15 %- THYROID DYSHORMONOGENESIS
 caused by inborn errors in the molecular steps required for the biosynthesis of
thyroid hormones
 characterized by enlargement of the gland (goiter), presumably due to elevated TSH
levels.
 AR inheritance

5.  RARELY - central origin
 due to hypothalamic and/or pituitary diseases
 reduced production and/or effect of either TRH or TSH

6.  terminal differentiation of the thyroid follicular cells occurs when migration is
complete (by 10–12 weeks).
 Specific proteins essential for thyroid hormone biosynthesis and secretion appear
progressively:
 TG (10–11 weeks), thyroid peroxidase, NIS (12–13 weeks), thyrotropin receptor,
thyroid oxidases, and pendrin

7.  TH concentrations are low in the fetus during the first half of pregnancy.
 During this time, the fetus is entirely dependent on maternal TH
 HPT axis is functional at midgestation.
 Thyrotropin is detectable in fetal serum as early as the 12th week and increases
from the 18th week until term

8.  The absence of thyroid follicular cells is called athyreosis or agenesis of the thyroid
 agenesis - absence of the gland due to a defective initiation of thyroid
morphogenesis
 athyreosis - disappearance of the thyroid gland following any step after the thyroid
anlage specification.
 Athyreosis accounts for 22% to 44% of cases of permanent CH

10.  ATHYREOSIS
 the absence of thyroid was reported in patients with CH associated with
 FOXE1 gene defects (Bamforth-Lazarus syndrome)
 PAX8
 in one patient with NKX2-1 mutation
 in three patients with NKX2-5 mutation.

11.  ECTOPIC THYROID
 due to a failure in the descent of the developing thyroid from the thyroid anlage
region to its definitive location in front of the trachea
 in any location along the path of migration from the foramen caecum to the
mediastinum.
 more than 50% of TD cases are associated with an ectopic thyroid

12.  ECTOPIC THYROID
 however, genetic alterations have been reported only in few patients with thyroid
ectopy.
 only one mutation in PAX8 and three mutations in the NKX2-5 gene have been
associated with the human ectopic thyroid

13.  HYPOPLASIA
 in 24% to 36% of cases of CH
 genetically heterogeneous dysgenesis
 mutations in the NKX2-1, PAX8, or TSHR gene have been reported

14.  HEMIAGENESIS
 dysgenesis in which one thyroid lobe fails to develop.
 prevalence ranges from 0.05% to 0.2% in healthy children, with the absence of the
left lobe in almost all the cases.
 In these subjects, TFT is normal

15.  HEMIAGENESIS
 candidate genes responsible for the hemiagenesis of the thyroid gland have not yet
been described
 In humans, thyroid hemiagenesis has been reported in two patients carrying the
NKX2-1 mutation

16.  Due to the low frequency of mutations in patients with thyroid dysgenesis,
 genetic testing should be initiated only in those patients with either a suggestive
clinical manifestation (FOXE1, NKX2-1 and NKX2-5 gene mutations) or with a familial
occurrence of thyroid dysgenesis (PAX8 and TSHR gene mutations).

17.  FOXE 1
 child with congenital hypothyroidism and thyroid dysgenesis associated with cleft
palate and striking spiky hairs should suggest the diagnosis of the Bamforth–Lazarus
syndrome
 Also have choanal atresia
 unfavorable cognitive outcome despite adequate treatment of congenital
hypothyroidism owing to the additional role of FOXE1 in the CNS dvpt

18.  FOXE 1

19.  NKX2-1
 present with either mild or severe congenital hypothyroidism
 A/w variable pulmonary symptoms, as well as neurological alterations, such as
severe choreoathetosis, ataxia and other movement disorders.
 results from the multiple roles of NKX2-1 in the development of CNS, lung and
thyroid

20.  NKX2-1
 AD with variable penetrance
 In the first year of life, muscular hypotonia occurs, which is followed by the more
specific movement defect of chorea or athetosis during further motor development.
 During adolescence, the movement disorder does not deteriorate, and an
improvement of chorea was observed in some adult patients

21.  NKX2-5
 described in four patients, of whom one was affected by an associated heart defect.

22.  PAX8
 variable and potentially asymmetric hypoplasia of the thyroid gland.
 Hypothyroidism can be mild, and some patients manifest an elevation of TSH levels
only later during childhood
 can also lead to unilateral kidney agenesis.
 Patients with a PAX8 mutation should undergo renal USG

23.  TSHR
 TSHR is expressed only late during fetal development
 homozygous or compound heterozygous inactivating mutations lead to hypoplasia
and not to an ectopic gland or agenesis of the gland.
 A less severe inactivation of the TSH receptor can also result in mildly elevated TSH
levels with normal T4 levels

24.  NIS
 member of the sodium/solute symporter family that actively transports iodide
across the membrane of the thyroid follicular cells.
 Also expressed in salivary glands, gastric mucosa, small intestinal mucosa, lacrimal
gland, nasopharynx, thymus, skin, lung tissue, choroid plexus, ciliary body, uterus,
lactating mammary tissue and mammary carcinoma cells, and placenta.
 Only in thyroid cells is iodide transport regulated by TSH.

25.  NIS
 AR inheritance
 In the neonatal period, infants with iodide transport defects are found to have a
normal-size or slightly enlarged thyroid gland by USG and elevated serum TG levels.
 Radioactive iodide uptake is absent.
 Measurement of the saliva-to-plasma 123I ratio is around one.

26.  NIS
 The degree of hypothyroidism is variable and ranges from mild to severe, possibly
depending on the amount of iodide in the diet.
 children are severely hypothyroid if maintained with a normal iodine diet
 addition of high amount of iodide to the diet tends to compensate the iodide
transport failure.

27.  TPO
 The most frequent cause of dyshormonogenesis is thyroperoxidase (TPO) deficiency.
 leads to severe hypothyroidism with a large goiter.

28.  TPO
 Iodine organification defects can be quantified as total or partial:
 total iodide organification defects - discharge of more than 90% of the radioiodide
taken up by the gland within 1 hour after administration of sodium perchlorate,
usually given 2 hours after radioiodide.
 A total disappearance of the thyroid image is also observed.
 Partial defects - discharge of 20% to 90% of the accumulated radioiodine

29.  TG
 moderately to severely hypothyroid.
 plasma thyroglobulin concentration is low, especially in relation to TSH, and does
not change after T4 treatment or injection of TSH.

30.  DUOX1 AND DUOX2
 The generation of H2O2 is a crucial step in thyroid hormonogenesis
 DUOX1 and DUOX2 are glycoproteins with seven putative transmembrane domains.
 Their function remained unclear until DUOXA2, was identified, which allows the
transition of DUOX2 from the ER to the Golgi.

31.  DUOX1 AND DUOX2
 In order to produce congenital permanent hypothyroidism, a severe alteration of
both alleles of DUOX2 gene is required.
 Commonly, a less severe mutation- more subtle and can appear as a transient, mild
TSH elevation

32.  PENDRIN
 SLC26A4 gene encodes pendrin
 moderately enlarged thyroid gland, are usually euthyroid
 subclinically hypothyroid with goiter, and show moderate-to-severe SNHL (due to a
cochlear defect)

33.  PENDRIN
 Discharge of radioiodide after administration of sodium perchlorate is moderately
increased (>20%).
 The Pendrin has been localized into the apical membrane of the thyroid follicular
cell

34.  DEHAL1
 Gene responsible for deiodination of MIT and DIT
 AR or AD with incomplete penetration
 patients were hypothyroid and goitrous with a high phenotypic variability

35.  GNAS
 Combined central and primary congenital hypothyroidism can result from mutations
in the GNAS gene
 cause pseudohypoparathyroidism type 1a
 affects the function of the G-protein α, which is crucial for TRH as well as TSH
receptor signaling, leading to only mildly elevated TSH levels

36.  GNAS
 Gsα is involved in the stimulatory pathways of TSH and TRH as well as of other
hormones binding to a Gsα-coupled receptor (e.g., PTH, GnRH, FSH, LH).
 associated findings of short digits and short stature and mental retardation despite
adequate levothyroxine treatment.

37.  may be due to alterations in the TSH stimulation pathway, due to unresponsive TSHR
or mutation in the modulating proteins downstream in the signaling pathway, such
as G proteins, adenylate cyclase, or the various kinases.
 To date, only defects in the TSHR and GSα have been described.

38.  1 in 50,000 newborns
 generally associated with alterations in hypothalamus or pituitary development.
 mildly to moderately hypothyroid.
 The accompanying pituitary hormonal deficiencies, especially the lack of cortisol,
may be responsible for high morbidity and mortality
 PIT1 and PRPO1, HESX1, LHX3, LHX4 and SOX3

39.  Defects in Transmembrane Transport of Thyroid Hormone
 Target tissues need to convert T4 into T3 by outer ring deiodination (ORD).
 Alternatively, T4 is metabolized by inner ring deiodination (IRD) to inactive Rt3
 by the same reaction, T3 is inactivated to T2.
 T2 is also produced by ORD from rT3.
 Three iodothyronine deiodinases (D1 to D3) are involved in these reactions

40.  MCT8 - Allan-Herndon-Dudley syndrome
 X linked
 Gene - SCL16A2
 Inactivating mutations of the MCT8 gene - severe X-linked form of mental
retardation and alterations in thyroid hormone levels.
 The neurologic phenotype includes central hypotonia with poor head control;
peripheral hypotonia, which evolves into spastic quadriplegia; inability to sit, stand,
or walk

43.  most infants with CH appear normal at birth, because of the protective effects of a
substantial maternal-fetal transfer of T4
 There is also increased intracerebral conversion of T4 to T3, resulting in greater
local availability of T3 despite its low serum concentration.
 The cerebral damage is mainly due to lack of TH after birth

44.  IN NEONATES
 long-term jaundice, feeding difficulty, lethargy, constipation, macroglossia,
hypothermia, edema, wide posterior fontanel, umbilical hernia and ‘hypothyroid
facial appearance’.
 If untreated, the clinical symptoms become evident in the second half of the first
year of life, with growth retardation and a delay in motor development.
 intellectual disability is not reversible

45.  Almost 10% of neonates - additional congenital malformations.
 Congenital heart defects are the most common, affecting 50% of patients.
 Congenital hypothyroidism is more frequent in children with Down syndrome and
pseudohypoparathyroidism type 1a

48.  Pilot screening programs for CH were developed in Quebec and Pittsburgh in early
1970s
 In India, the first NBS programme for CH was at BJ Wadia Hospital, Mumbai in 1982
using cord blood TSH and subsequently in 1984 using postnatal DBS T4

49.  The TSH surge starts 30 min after birth (T4 some hours later), is most marked for
the next 24 h, but may persist for 48 to 72 h.
 Thus, cord blood is largely spared of the neonatal surge
 If the screen sample is taken during the surge, a false positive result will follow.
 screen sample should therefore be taken either from the cord (placental end,
immediately after delivery) or postnatally after 72 h of life.
 If the hospital stay is shorter, it may be taken after 48 h of life

51.  The ideal screening test should have high sensitivity and specificity so as not to miss
any case of CH (no false negatives)
 at the same time, should have an acceptable recall rate for confirmatory sampling
(low false positives)
 There are two main screening strategies for CH: primary T4 testing (with backup
TSH) or primary TSH testing

52.  PRIMARY T4 TESTING
 helps to identify patients with primary and secondary (central) CH.
 it misses neonates with compensated forms of CH (normal T4 with high TSH, which
is commonly seen in ectopic thyroid)
 there is a high rate of false positive results, whether done from cord blood or
postnatal day 3–5 sample
 These include infants with TBG deficiency and preterm and sick neonates

53.  PRIMARY T4 TESTING
 Hence, low T4 values must be followed by backup TSH on the same DBS
 TSH is measured in the samples with the lowest percentiles of T4 (from 3 to 20%)
 Neonates are recalled for confirmatory venous sampling if TSH is greater than the
cut-off.
 The recall rate with primary T4 testing with backup TSH is around 0.1–1%

54.  PRIMARY TSH TESTING
 more sensitive and specific for the diagnosis of primary CH compared to T4 screen
 may miss infants with delayed rise of TSH most often seen in preterm babies due to
immaturity of the HPT axis
 It also fails to detect cases of central CH

55.  PRIMARY TSH TESTING
 Measurement of TSH on DBS is done using an immunofluorescence or colorimetric
neonatal TSH kit at a centralized NBS laboratory.
 Alternatively, the serum sample analysed by ELISA or chemiluminescence methods at
routine laboratories.
 The TSH measured from a DBS is expressed in whole blood units.
 Serum units may be derived by multiplying the whole blood units value by 2.2 (to
adjust for Hct)

56.  Various cut-offs have been used in different studies across the world.
 A TSH cut-off of >20 mIU/L for recall has been shown to be associated with
reasonable specificity and recall rate
 Mildly elevated screen TSH (between 20 and 40 mIU/L) dictates recall early in the
second week of life for a repeat screening TSH

57.  However a clear-cut high screen TSH >40 mIU/L necessitates immediate recall (after
72 h of age) for a confirmatory venous sample
 In centres where the second TSH screen is done using a venous sample rather than a
heel prick DBS, both TSH and T4 may be performed on this sample
 Age-related TSH cut-off (>34 mIU/L) is suggested for screen samples taken between
24 to 48 h of age

58.  For mothers discharged within 24 h of delivery, some international programs have
used the age-related TSH cut-off of 100 mIU/L for recall.

59.  Measurement of venous serum T4/FT4 and TSH are done by chemiluminescence or
ELISA assay.
 Before 2 wk of age, venous TSH >20 mIU/L and after 2 wk of age, >10 mIU/L, is
indicative of primary CH
 Serum T4 < 10 μg/Dl (<128nmol/L) or FT4 < 1.17 ng/ dL (<15 pmol/L) is considered
low in infancy

60.  Babies with screen TSH >80 mIU/L serum units are highly likely to have low T4 or
FT4 levels
 therefore commencement of therapy is recommended as soon as the confirmatory
sample is taken, without waiting for the results unless these results are available on
the same day

61.  For mildy elevated TSH results, a repeat filter paper sample or a repeat serum
sample should be obtained as early as possible, in the second week of life
 The reason for not taking the repeat sample immediately is to allow the neonatal
factors causing a false positive result to settle down.
 If the second screen TSH is high (>20 mIU/L for age < 2 wk and >10 mIU/L for age > 2
wk), immediate confirmatory venous sample for T4/FT4 and TSH measurement
should be taken

65.  High risk neonates such as preterm, LBW (1500–2499 g), VLBW (1000–1499 g) and
sick neonates, multiple births, particularly same sex twins are at increased risk for
an inappropriate TSH level at initial screening (both false positive and false
negative)
 The postnatal TSH surge and rise in thyroid hormones seen in term infants are
attenuated owing to immaturity of the HPT axis

66.  Moreover, preterm and sick infants often have a fall in serum T4 and T3 in first week
of life, which may be due to
 poor nutrition
 decreased hepatic TBG production
 immaturity of the HPT axis
 use of iodine antisepsis
 increased tissue utilization of T4
 sick euthyroidism - resulting from associated medical problems, such as respiratory
distress syndrome or the consequences of IUGR may persist until the infant recovers
from the acute illness or gains weight

67.  preterm infants with true CH may not be able to mount an appropriate TSH response
in the first 2 wk of life due to immaturity of the HPT axis or treatment with
glucocorticoids or dopamine, leading to false negative initial screen
 A second screen done after 2 wk of age will pick up the delayed rise of TSH.

68.  DOWNS syndrome –
 may also have mildly elevated TSH levels that can be missed by screening
 require careful followup and re-testing before 6 mo of age

69.  in instances of acute hemorrhage or hemolysis, when transfusion is warranted - may
be screened before 24–48 h of birth
 With sick infants in NICUs, screening should be performed at least by 7 d of
postnatal life
 It is suggested to do a second screening test at 2–4 wk of age for high-risk babies

71.  With confirmation of CH and treatment intiation, thyroid imaging should be done to
identify the etiology
 Imaging of the thyroid gland by either ultrasonography or nuclear imaging
(scintigraphy) or both is recommended in various guidelines

72.  SCINTIGRAPHY
 Scintigraphy may be carried out with either 10–20 MBq of 99m Tc or 1–2 MBq of 123I.
 99m Tc is more widely available, less expensive, and quicker to use than 123 I.
 However, 123 I is specifically taken up by the thyroid gland and gives a clearer scan
than 99m Tc

73.  SCINTIGRAPHY
 Scintigraphy can identify athyreosis (absence of uptake), hypoplasia of a gland in
situ (with or without hemithyroid), a normal or large gland in situ with or without
abnormally high levels of uptake, and an ectopic thyroid

74.  SCINTIGRAPHY
 Scintigraphy may show no uptake despite the presence of a eutopic thyroid gland
with
 excess iodine exposure (eg, from antiseptic preparations)
 maternal TSH receptor blocking antibodies
 TSH suppression from L-T 4 treatment
 inactivating mutations in the TSHR and NIS

75.  Scintigraphy may be done as long as the TSH is still high, i.e., safely within 7 d of
initiation of therapy
 Ultrasonography may be done weeks or even months after treatment is initiated.
 If scintigraphy was not done at the time of diagnosis, it may be done at three years
of age when permanence of CH is established prior to restarting treatment

76.  THE PERCHLORATE DISCHARGE TEST
 When the thyroid is in the normal position, a discharge of >10% of the 123 I dose
when perchlorate is administered at 2 hours indicates an organification defect

77.  USG
 can be used to investigate the absence or presence, size, echogenic texture, and
structure of a thyroid gland in situ.
 However, it cannot always detect lingual and sublingual thyroid ectopy

81.  TG
 thyroglobulin can be measured as a thyroid-tissue-specific marker.
 The discrimination of goiter versus athyrosis (lack of the thyroid gland) can easily be
achieved in children by combining measurement of thyroglobulin levels and
ultrasonography

82.  THYROID AUTOANTIBODIES
 In children with confirmed biochemical hypothyroidism and a normal thyroid gland
on imaging
 to exclude either a maternal thyroid autoimmune disease or an iodine overload as a
cause of transient congenital hypothyroidism.
 Typically, maternal antibodies that can cause fetal hypothyroidism block the TSH
receptor, and after clearance from the infant’s circulation at an age of 6 months,
thyroid function normalizes.

83.  THYROID AUTOANTIBODIES
 The same transient course can be expected in rare cases of iodine overload that can
result from maternal or fetal disinfection with povidone iodine

84.  All infants with hypothyroidism, with or without goiter, should be rendered
euthyroid as promptly as possible by replacement therapy with TH
 treatment is recommended only with LT4 as the brain converts T4 to T3 by the
locally available type 2 iodothyronine monodeiodinase enzyme.
 aim to start treatment within the first 2 weeks of life
 The goal is to normalize FT4/T4 within 2 wk and TSH within 1 mo

85.  Radiograph of the knees may be obtained at diagnosis; absence of lower femoral
epiphyseal centre indicates severe CH and correlates with later intelligence and
motor score
 DOSE - 10-15 μg/kg/d should be initiated depending upon the severity of CH.
 In severe cases with very low T4, the initial dose should be on the higher side
 dose should be titrated to maintain the T4/FT4 values in the upper half of normal
range for age

88.  In tablet form.
 In neonates and infants, the tablets can be crushed and administered via a small
spoon, with suspension, if necessary, in a few milliliters of water or breast milk.
 L-T 4 can also be administered in liquid form
 But liquid preparation is not bioequivalent

89.  Can be taken in the morning or evening, either before feeding or with food
 should be administered in the same way every day.
 intake of soy, iron, and calcium at the time of L-T 4 administration should be avoide

90.  The first follow-up including TFT (FT4/ T4) should be done 2 wk after starting
treatment by which time normalization of FT4/T4 is expected.
 If the levels are low for age, a slight increase in the dose is required
 dose should not be decreased if a single value of T4 is found above the normal range
 The next test, after 1 mo, should include both T4/ FT4 and TSH; normalization of
TSH is expected by this time.

91.  The sample for thyroid function is taken before (or minimum 4 h after) ingestion of
LT4.
 Further follow-up :
 every 2 mo in early infancy till 6 mo of age
 every 3 mo during age 6 mo to 3 y
 every 3–6 mo thereafter, till growth and pubertal development is completed
 Any dose change is followed by a biochemical evaluation after 4 wk

92.  A re-evaluation of the thyroid axis is warranted at the completion of 3 y in babies
 in whom the possibility of transient CH exists such as those started on treatment
before complete evaluation, sick babies, preterms, those with a normal gland on
imaging or mild dyshormonogenesis.
 This is done by temporarily stopping LT4 for a period of 4 wk and repeating the
thyroid function tests and thyroid scan.
 Alternatively, if the permanence of CH is to be confirmed without etiological
diagnosis, the dose may be tapered by one-third for 2–3 wk and the TSH level
rechecked.

93.  If the TSH level shows a rise of >10 mIU/L, then permanence is confirmed and
treatment continued.
 If TSH level does not rise, the dose may be further tapered, stopped and then
retested.
 In those babies with proven agenesis or ectopic thyroid there is no need for
reevaluation

94.  Any etiology of CH is associated with increased risk of recurrence in the next sibling.
 Dyshormonogenesis disorders have the highest risk, being autosomal recessive in
inheritance.
 Thus, genetic counseling forms an important part of the care, in a family with a
newborn diagnosed with CH.

96.  Repeated (not just neonatal) hearing tests should be carried out before school age
and as required
 Assessing patients for evidence of visual processing problems (not just visual acuity)
is suggested
 Also recommend screening for delays in speech acquisition by the age of 3 years

97.  recommend antenatal diagnosis in
 in cases of goiter fortuitously discovered during systematic ultrasound examination
of the fetus, in relation to thyroid dyshormonogenesis
 a familial recurrence of CH due to dyshormonogenesis (25% recurrence rate)
 and known defects of genes involved in thyroid function or development with
potential germline transmission

98.  For the evaluation of fetal thyroid volume, USG should be done at 20 to 22 weeks
gestation to detect fetal thyroid hypertrophy and potential thyroid dysfunction in
the fetus.
 Goiter or an absence of thyroid tissue can also be documented by this technique.
 Measurements should be made as a function of GA

99.  Cordocentesis should be done ONLY if prenatal treatment is planned
 In a euthyroid pregnant woman, a large goiter in the fetus with progressive
hydramnios and a risk of premature labor and delivery and/or concerns about
tracheal occlusion are criteria in favor of fetal treatment in utero
 In a hypothyroid pregnant woman, the initial approach should be to treat the
pregnant woman, rather than the fetus, with L-T 4

100.  For goitrous nonimmune fetal hypothyroidism leading to hydramnios, intra-amniotic
injections of L-T 4 have been reported to decrease the size of the fetal thyroid
gland
 The expert panel proposes the use of 10 μg/kg estimated fetal weight/15 days in
the form of intra-amniotic injections
 The risks to the fetus and the psychological burden on the parents should be
factored into the risk/benefit evaluation