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 pmol/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 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 wks. relatively inactive From midgestation increased TSH and T4 T3 low throughout gestation (low MDI) rT3 - high by 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 gland42-48% athyreosis29-35% 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 Repeat tests and start treatment Thyroid imaging scan mg/kg l-thyroxine assure compliance What to do with +ve screen?

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

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

Addition of T3 treatment

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

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