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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 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 • 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