3. DEFINITION
• Congenital hypothyroidism is inadequate thyroid hormone
production in newborn infants. It can occur because of an
anatomic defect in the gland, an inborn error of thyroid
metabolism, or iodine deficiency.
An infant with cretinism. Note the hypotonic posture, coarse
facial features, and umbilical hernia.
5. The gland descends to
its definitive position in
the anterior lower neck
by the end of the first
trimester.
Embryogenesis begins
on the floor of the
primitive oral cavity.
5
6. 6
• Hypothalamic-pituitary-thyroid axis becomes functional
in 2nd trimester
Thyrotropin-releasing
hormone (TRH), a
tripeptide synthesized
in the hypothalamus,
stimulates the release
of pituitary thyroid-
stimulating hormone
(TSH).
8. Neonatal physiology
• 30 minutes after delivery- an abrupt 3 to 6-fold
increase in circulating T3 and T4 level ,
coincident with increase of serum TSH
concentration.
• TSH surge -stimulation of the neonatal thyroid
gland, hence increase circulating TH.
• However, the TSH surge is short lived, and
TSH hormone will decline after 72-96 hour of
life due to feedback inhibition by T4 either the
hypothalamic or the pituitary level(or both).
9. • preterm infant-TSH surge is less marked, and the
T4 and T3 responses are blunted.
• <31 weeks’ gestation no surge seen and, instead
T4 fall for 7 to 10 days.
Neonatal physiology contd…
10. Normal level of thyroid hormones
Age TSH (mIU/L) Free T4 (pmol/L)
Birth-D3 OL <21 26-65
D4-D30 0.51-10.8 12-30
D31-1yr 0.39-7 9-16.1
≥ 1 yr 0.4-6 13.2-22.2
10
11. Functions of thyroid hormones
Target tissue Mechanism
Nervous system Promote normal brain development
Heart • Increase number, affinity of beta adrenergic receptors
• Enhance responses to circulating catecholamine
Muscle Increase protein breakdown
Bone Promote normal growth and skeletal development
Gut Associated with carbohydrate absorption
Adipose tissue Stimulate lipolysis
Lipoprotein Stimulate formation of LDL receptors
Other • Stimulate oxygen consumption by metabolically active tissues
• Increase metabolic rates
• Promote development of reproductive system
• Maturation of fetal lungs
11
12. INCIDENCE
• Incidence of congenital hypothyroidism
worldwide is 1:2500 - 4000 live births
• In Malaysia, it is reported as 1:3666
• It is the commonest preventable cause of
mental retardation in children
13. Screening
• Well established in developed countries
• Malaysia - Started in october 1998 by Ministry of health
• In kelantan – May 1999 (HRPZ2)
• Why screening
• Cannot be detected at birth
• Most common cause of mental retardation
• Late presentation 2-6 months
14. Malaysian’s strategy
• Cord Blood TSH level is measured primarily
supplemented by T4 for determination of borderline TSH
level
• Infants with elevated TSH values & with borderline TSH
and low T4 are recalled for re-testing
15. Why Cord Blood TSH?
• Much higher coverage for infants
• Can be done together with established newborn cord
blood screening for G6PD deficiency.
• Cord blood sample is simple, non invasive and offers the
earliest postnatal diagnosis and treatment.
16. • Missed, insufficient, clotted, BBA cases
should be taken only after the 3rd day of life (4th day)
-to avoid the TSH surge that occur from ½ H of life to
about 72 H of life.
20. 1.Thyroid dysgenesis
• 85% of cases.
• aplasia, hypoplasia, and dysplasia;
• thyroid dysgenesis -genetic abnormality in one of
the transcription factors necessary for thyroid gland
development
• no goitre
• low total and free T4 levels, elevated TSH, and
• normal TBG.
• Thyroglobulin (TG) -low in aplasia and hypoplasia
• Confirmed absence by USG and/or thyroid
scintiscanning with radioactive iodine (RAI) or
pertechnetate (99mTc)
21. 2.Defects in thyroid hormone synthesis and secretion
(Thyroid dyshormonogenesis)
• 10% to 15%
• 25% recurrence risk -siblings.
• synthetic defect is abnormal thyroid peroxidase activity
• Pendred syndrome –goiter +sensorineural deafness
• Goiter present.
• Total and free T4 levels are low, TSH is elevated,
• TBG is normal.
• serum TG, low in TG synthetic defects and high in other
thyroid hormone synthetic defects.
• Imaging reveals a normally placed thyroid gland
22. • other signs of pituitary dysfunction, -hypoglycemia,
microphallus, and midline facial abnormalities.
• Septo-optic dysplasia -important cause of central
hypothyroidism.
• Goiter is not present.
• Total and free T4 are low, TSH is low or inappropriately
normal,
• TBG is normal.
• If central hypothyroidism is suspected, cortisol and
growth hormone measured and (MRI) scan done to
visualize the hypothalamus and pituitary gland
4.Central (hypothalamic–pituitary)
hypothyroidism
23. 5. Transient hypothyroidism
• This accounts for 10% of cases and is usually related to
either maternal medications, eg carbimazole, or to
maternal antibodies.
• Maternal antithyroid drugs can cause decreased neonatal
thyroid hormone synthesis which lasts for a few days to
two weeks after birth.
• Maternal antithyroid antibodies can cross the placenta
and block the TSH receptor in the neonatal thyroid. This
effect can last up to 3 to 6 months after birth as maternal
antibody levels fall
24. Clinical diagnosis
• Most infants are asymptomatic at birth.
• Most infants with the disease have no obvious clinical
manifestations at birth, therefore neonatal screening of thyroid
function should be performed on all newborns.
Subtle clinical features occurred during early weeks of life:
• Prolonged neonatal jaundice
• Constipation
• A quiet baby
• Enlarged fontanelle
• Respiratory distress with feeding
• Dry skin
• Absence of one or both epiphyses on X-ray of left knee
(lateral view).
25. The infant on the left with CH demonstrate absence of the distal femoral and
proximal tibial epiphyses, while in normal infant on the right the distal femoral
epiphysis is present.
26. • If left untreated, overt clinical signs will appear by 3 - 6
months:
• coarse facies
• dry skin
• Macroglossia
• hoarse cry
• umbilical hernia
• Lethargy
• slow movement
• Hypotonia
• delayed developmental milestones.
28. • Infant with congenital hypothyroidism. A - 3 month old infant with
untreated CH; picture demonstrates hypotonic posture, myxedematous
facies, macroglossia, and umbilical hernia. B - Same infant, close up of face,
showing myxedematous facies, macroglossia, and skin mottling. C - Same
infant, close up showing abdominal distension and umbilical hernia.
29.
30. TREATMENT
• Timing: Should begin immediately after diagnosis is
established. If features of hypothyroidism are present,
treatment is started urgently.
• Duration: Treatment is life long except in children
suspected of having transient hypothyroidism where re-
evaluation is done at 3 years of age.
31. • Preparation: There are currently no approved liquid
preparations.
• Only L-thyroxine tablets should be used. The L-
thyroxine tablet should be crushed, mixed with
breast milk, formula, or water and fed to the
infant.
• Tablets should not be mixed with soy formulas
or any preparation containingiron (formulas or
vitamins), both of which reduce the absorption
of T4.
32.
33. GOALS OF THERAPY
• To restore the euthyroid state by maintaining a normal
serum FT4 level at the upper half of the normal age-
related reference range. Ideally, serum TSH levels should
be between 0.5-2.0 mU/L.
• Serum FT4 level usually normalise within 1-2 weeks, and
then TSH usually become normal after 1 month of
treatment.
• Some infants continue to have high serum TSH
concentration (10 - 20 mU/L) despite normal serum FT4
values due to resetting of the pituitary-thyroid feedback
threshold. However, compliance to medication has to be
reassessed and emphasised.
34.
35. FOLLOW UP
• Monitor growth parameters and developmental assessment.
• The recommended measurements of serum FT4 and TSH by
American Academy of Pediatrics are according to the following
schedules: -
• At 2 and 4 weeks after initiation of T4 treatment.
• Every 1 to 2 months during the first 6 months of life.
• Every 3 to 4 months between 6 months and 3 years of age.
• Every 6 to 12 months thereafter until growth is completed.
• After 4 weeks if medication is adjusted.
• At more frequent interval when compliance is questioned or
abnormal values are obtained.
• Ongoing counseling of parents is important because of the
serious consequences of poor compliance.
36. Follow up
• Mental and cognitive function – IQ test
• Symptoms over and under treatment
• Hearing test
• Bone age – normalisation by 1-2 years
37. Re-evaluation of patients likely having
transient hypothyroidism
• This is best done at age 3 years when thyroid dependent
brain growth is completed at this age.
• Stop L-thyroxine for 4 weeks then repeat thyroid function
test: FT4, TSH.
• Imaging studies: Thyroid scan, Ultrasound of the thyroid.
• If the FT4 is low and the TSH value is elevated,
permanent hypothyroidism confirmed and life-long L-
thyroxine therapy is needed.
38. • All newborns of mothers with thyroid diseases should be
evaluated for thyroid dysfunction, followed up and treated
if necessary.
• Compulsory screening without any miss or error
• Repeat test if any doubt
• Congenital hypothyroidism – screening, treat to prevent
MR
• Patient education and compliance to treatment/follow up
Early treatment-Excellent recovery
Take Home Message
39. REFERENCES
• Paediatrics protocol 3rd edition.
• Congenital hypothyroid screening using cord blood TSH
January 1999, journal.
• Nelson paediatrics 6th edition.
Editor's Notes
Embryogenesis begins on the floor of the primitive oral cavity. The gland descends to its definitive position in the anterior lower neck by the end of the first trimester. Thyroid glands that do not reach the normal location are ectopic but may retain function; however, the glands most often become insufficient by early to mid childhood to support full thyroid secretion (a lingual or sublingual site or even tissue found in a thyroglossal duct cyst may be the only functioning thyroid gland).
Pituitary TSH is a glycoprotein that stimulates the synthesis and
Thyroid-stimulating hormone (TSH) from the pituitary gland stimulates the secretion of thyroxine (T4) and triiodothyronine (T3) from the thyroid gland. These act at the pituitary gland level to control secretion of TSH by a negative feedback mechanism. In addition, T4 is metabolized to the potent T3 within the pituitary gland by a monoiodinase. Secretion of TSH is stimulated by thyrotropin-releasing hormone (TRH) from the hypothalamus and inhibited by somatostatin. Thyroid hormone acts at the hypothalamus to stimulate secretion of somatostatin (somatostatin acts as a negative signal to the pituitary secretion of TSH). CRH, corticotropin-releasing hormone; OB-R, leptin receptor. release of thyroid hormones by the thyroid gland.
T4T3 conversion mainly occurred in liver and kidneys
The TSH surge( a response to the thermal stimuli coincident after birth)n causes marked stimulation of the neonatal thyroid gland
Serum T3 and T4 levels increase sharply and peak within 24 hours of life, followed by a slow decline
In the preterm infant, the pattern of postnatal thyroid hormone change is simi-lar to the pattern seen in the full-term infant, but the TSH surge is less marked, and the T4 and T3 responses are blunted.
In very preterm infants (<31 weeks’ gestation), no surge is seen and, instead, the circulating T4 level may fall for the first 7 to 10 days.
TH level in newborn gradually return to adult levels by approximately 1 months of age.
Thyroid dysgenesis includes aplasia, hy-poplasia, and dysplasia
thyroid dysgenesis is associated with a genetic abnormality in one of the transcription factors necessary for thyroid gland development
Defects in thyroid hormone synthesis and secretion (thyroid dyshormono-genesis) are responsible for most of the remaining 10% to 15% of permanent CH cases and generally carry a 25% recurrence risk in subsequent siblings
The most common synthetic defect is abnormal thyroid peroxidase activity, which
results in impaired oxidation and organification of iodine
Pendred syndrome is characterized by a goiter due to an underlying mild organification defect. It is an important cause of sensorineural deafness, but hypothyroidism rarely occurs in the newborn period
Affected infants may have other signs of pituitary dysfunction, such as hypoglycemia, microphallus, and midline facial abnormalities. Septo-optic dysplasia is an important cause of central hypothyroidism. Goiter is not pres-ent
If central hypothyroidism is suspected, cortisol and growth hormone levels should be measured and a magnetic resonance imaging (MRI) scan done to visualize the hypothalamus and pituitary gland
Clinical features of hypothyroidism are subtle during the early weeks of life. However, prolonged neonatal jaundice (3/3), widely opened posterior fontanelle (3/3) and dry skin (3/3) were the common features in all our cases by 2-6 weeks of life.
