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Congenital Hypothyroidism
• Thyroid gland embryology
• Thyroid hormone synthesis
• Feedback mechanisms
• In-utero + neonatal dynamics
• Etiology
• Manifestations
• Treatment
• Prognosis
Thyroid Embryology
Median anlage – pharyngeal floor
Lateral anlagae 4th pharyngeal pouch
Fusion of both parts
Migration to anterior neck (by ED50)
Thyroid transcription factors:
TTF-1, TTF-2, PAX-8
Responsible for less than 10% of CH
Thyroid Migration
The Thyroid gland
Thyroid Hormone Biochemistry
Production of thyroid hormones
Thyroid Hormone Synthesis
• Iodide trapping
• Synthesis of thyroglobulin
• Organification of iodotyrosine
• Coupling, storage of T3 and T4 in colloid
• Endocytosis of colloid droplets
• Hydrolysis of TG to MIT, DIT, T3 and T4
• Secretion and circulation
• Deiodination of MIT and DIT, Iodine recycling
Protein binding, receptor affinity
• Binding proteins TBG, Albumin and Prealbumin
• Free T4 – normal serum levels -10-20pmol/l
• Free T3 - normal serum levels -3-7 pmol/l
• T3 affinity to TR - X10 T4 affinity
• T3
most active thyroid hormone
Monodeiodinases
• MDI - T4 to T3 in peripheral tissues
• MDII - T4 to T3 in brain, pituitary
• MDIII - T4 to rT3 - many tissues,
abundant in fetus and placenta
• 80% of T3 - from peripheral conversion
Allan-Herndon-Dudley syndrome
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Described -1944, molecular description- 2003
Muscle hypotonia and hypoplasia
Intellectual impairment
Caused by mutation in SLC16A2/MCT8
Lack of T3 transport to the brain
Normal T4 transport
---The brain needs T3
Allan-Herndon-Dudley syndrome IQ in 26 patients
Fetal and newborn thyroid function
• Fetal pituitary and thyroid - 10-12 wks.
relatively inactive
• From midgestation increased TSH and T4
• T3 low throughout gestation (low MDI)
• rT3 - high by 20-24 wks (high MDIII),
declines after birth at 2-3 wks to adult levels
• After delivery - TSH, T4 and T3 surges
Thyroid Hormone Levels after Birth
Control of Thyroid Hormone Secretion
Thyroid Hormone Effects
• Brain development in infancy
• Somatic growth and development
• Thermogenesis
• Adrenergic effects
Transient dysfunction - preterm
• Transient hypothyroxinemia
- in 50% before 30 wks.
- normal TRH response
- hypothalamic immaturity
Transient dysfunction – preterm (2)
Transient primary hypothyroidism
- normal TSH and T4 at birth
- later T4 decreases and TSH increases
- causes - Iod. deficiency, Iod. solutions
Transient dysfunction – preterm (3)
• Low T3
- Delayed, reduced TSH and T4 surge
- Delayed T3 increase
- Severe cases - also low T4 and TSH
Etiology: inhibition of MDI by undernutrition, hypoxia, hypoglycemia,
sepsis, hypocalcemia, birth trauma
Congenital Hypothyroidism
• Incidence
• Worldwide 1:4,000-1:3,000
• F>M - 2:1
Congenital Hypothyroidism
•
Etiology
• ectopic gland
42-48%
• athyreosis
29-35%
• dyshormonogenesis 22-25%
• all others
< 0.1%
TTF-2 mutation
Spiky hair, hypertelorism, micrognathia, cleft palate
Park SM, Chatterjee VK. J Med Genet 2005;42:379-89
Lingual thyroid
Radionuclide scan (Tc99) of thyroid
Congenital Hypothyroidism
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Other causes
• maternal iodine deficiency (“endemic”)
•TRH/TSH deficiency
- isolated : familial, sporadic
- in panhypopituitarism
•Thyroid hormone resistance
Congenital Hypothyroidism
Manifestations
• Few in 1st 6-12 wks.
• Early - prolonged jaundice
- poor feeding
- transient hypothermia
- large post. fontanelle
Congenital Hypothyroidism
Late Manifestations
• Thickened tongue
• Hoarse cry
• Hypotonia
• “Potbelly”
• Constipation
• Bradycardia,
• Low BP
• MENTAL RETARDATION
Congenital Hypothyroidism - Untreated
Congenital Hypothyroidism
- screening
• Logic - prevention of retardation
• Method
- whole blood, filter paper,
- 3rd day of life
- logistics of reporting
• In Israel - first T4, if low – TSH
(except for preterm)
• USA - first TSH, if high - T4
Heel-prick method for screening
Guthrie paper
Congenital Hypothyroidism
What to do with +ve screen?
• Repeat tests and start treatment
• Thyroid imaging scan
• 10-15 mg/kg l-thyroxine
• assure compliance
Shortcomings of screening methods
 Primary T4 screen
False positives – TBG deficiency
False negatives – early test, T4 can be normal
 Primary TSH screen
False positives – early test, delayed decline
False negatives –
delayed TSH rise
2nd/3rd hypothyroidism
Follow-up
• Serum levels of TSH FT4 and T3 (or FT3)
• Growth
• Bone Age
• Note compliance before adjusting dose
Addition of T3 treatment
Addition of T3 treatment
Strich D, Neogolni L, Gillis D, JPE&M ,2013
Prognosis
• Worse if athyreosis (in utero hypothy)
• Worse if mother hypothyroid
• Usually normal intelligence if RX early
• Significant mental impairment in
screened false negatives