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Congenital Hypothyroidism

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

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Congenital Hypothyroidism

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  1. Congenital Hypothyroidism • Thyroid gland embryology • Thyroid hormone synthesis • Feedback mechanisms • In-utero + neonatal dynamics • Etiology • Manifestations • Treatment • Prognosis

  2. 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

  3. Thyroid Migration

  4. The Thyroid gland

  5. Thyroid Hormone Biochemistry

  6. Production of thyroid hormones

  7. 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

  8. 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

  9. 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

  10. Allan-Herndon-Dudley syndrome • 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

  11. Allan-Herndon-Dudley syndrome - IQ in 26 patients

  12. 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

  13. Thyroid Hormone Levels after Birth

  14. Control of Thyroid Hormone Secretion

  15. Thyroid Hormone Effects • Brain development in infancy • Somatic growth and development • Thermogenesis • Adrenergic effects

  16. Transient dysfunction - preterm • Transient hypothyroxinemia - in 50% before 30 wks. - normal TRH response - hypothalamic immaturity

  17. Transient dysfunction – preterm (2) • Transient primary hypothyroidism - normal TSH and T4 at birth - later T4 decreases and TSH increases - causes - Iod. deficiency, Iod. solutions

  18. 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

  19. Congenital Hypothyroidism • Incidence • Worldwide 1:4,000-1:3,000 • F>M - 2:1

  20. Congenital Hypothyroidism • Etiology • ectopic gland 42-48% • athyreosis 29-35% • dyshormonogenesis 22-25% • all others < 0.1%

  21. TTF-2 mutation Spiky hair, hypertelorism, micrognathia, cleft palate Park SM, Chatterjee VK. J Med Genet 2005;42:379-89

  22. Lingual thyroid

  23. Radionuclide scan (Tc99) of thyroid

  24. Congenital Hypothyroidism • Other causes • maternal iodine deficiency (“endemic”) • TRH/TSH deficiency - isolated : familial, sporadic - in panhypopituitarism • Thyroid hormone resistance

  25. Congenital Hypothyroidism Manifestations • Few in 1st 6-12 wks. • Early - prolonged jaundice - poor feeding - transient hypothermia - large post. fontanelle

  26. Congenital Hypothyroidism Late Manifestations • Thickened tongue • Hoarse cry • Hypotonia • “Potbelly” • Constipation • Bradycardia, • Low BP • MENTAL RETARDATION

  27. Congenital Hypothyroidism - Untreated

  28. 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

  29. Heel-prick method for screening

  30. Guthrie paper

  31. Congenital Hypothyroidism What to do with +ve screen? • Repeat tests and start treatment • Thyroid imaging scan • 10-15 mg/kg l-thyroxine • assure compliance

  32. 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

  33. Follow-up • Serum levels of TSH FT4 and T3 (or FT3) • Growth • Bone Age • Note compliance before adjusting dose

  34. Addition of T3 treatment

  35. Addition of T3 treatment Strich D, Neogolni L, Gillis D, JPE&M ,2013

  36. Prognosis • Worse if athyreosis (in utero hypothy) • Worse if mother hypothyroid • Usually normal intelligence if RX early • Significant mental impairment in • screened false negatives

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