congenital hypothyroidism thyroid gland embryology thyroid hormone synthesis feedback mechanisms...

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 palatePark 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 HypothyroidismManifestations

• 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

• 10-15 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 rise2nd/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

• Worse if athyreosis (in utero hypothy)

• Worse if mother hypothyroid

• Usually normal intelligence if RX early

• Significant mental impairment in

screened false negatives

Prognosis