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

4. Thyroid Migration

6. The Thyroid gland

7. Thyroid Hormone Biochemistry

8. Production of thyroid hormones

9. 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

10. 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

11. 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

12. 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

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

15. 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

16. Thyroid Hormone Levels after Birth

17. Control of Thyroid Hormone Secretion

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

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

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

21. 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

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

23. Congenital Hypothyroidism Etiology ectopic gland42-48% athyreosis29-35% dyshormonogenesis 22-25% all others < 0.1%

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

25. Lingual thyroid

26. Radionuclide scan (Tc99) of thyroid

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

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

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

30. Congenital Hypothyroidism - Untreated

31. 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

32. Heel-prick method for screening

33. Guthrie paper

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

35. 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 2 nd /3 rd hypothyroidism

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

37. Addition of T3 treatment

38. Strich D, Neogolni L, Gillis D, JPE&M,2013

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