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Flashcards in congenital hypothyroid Deck (38):

thyroid gland develops from which embryonic lineages

follicular cells (endodermal pharynx) - produce thyroxine. parafollicular C-cells (neural crest) – produce calcitonin


1. Describe how the thyroid gland develops.

Proliferation of endodermal epithelial cells on median surface of pharyngeal floor btw 1st and 2nd arches > Intially hollow then solidifies and becomes bilobed > Connected to tongue via thyroglossal duct as it begins descent > completes descent in 7th gestational weeek


List locations of arrested thyroid migration

1. lingual - at base of tongue. 2. intralingual- inside the tongue. 3. Sublingual- below tongue in the jaw. 4. Thyroglossal cyst- in the neck at the level of the cricoid cartilage. 5. retrosternal- behind the sternum


When does thyroid hormone synthesis begin

10-12 weeks gestation- Follicular cells undergo differentiation. Thyroid begins to trap iodide


Where does iodination of thyroglobulin occur

in the colloid


compare the types of deiodinase

type I and II: convert T4 to active T3. Type III: converts T4 to inactive rT3


When is the hypothalamic-pituitary-thyroid axis functional

midgestation- HPT feedback control is evident by 25 weeks


Maternal/fetal thyroid hormone

The placenta allows passage of small quantities of maternal T4 (in athyrotic neonates, cord blood T4 level is about 20% normal )
The placenta allows passage of small quantities of maternal T4 (in athyrotic neonates, cord blood T4 level is about 20% normal )
The placenta allows passage of small quantities of maternal T4 (in athyrotic neonates, cord blood T4 level is about 20% normal )


Fetal TSH and T4/T3 levels

Within 30 minutes after birth, TSH rises to levels of 60-80 uU/ml. This results in in increases in T4 and T3 to 15-19 ug/dl by 24 hours. TSH and T4 will then drop to normal levels by day 5


Compare T4 in term vs premature infant

T4 is higher in term infants


Causes of congenital hypothyroidism

Dysgenesis (abnormal development of thyroid- 85%), thyroid dyshormonogenesis, thyroid aplasia, thyroid hypoplasia, thyroid ectopy


Etiology of thyroid dysgenesis

Genetic factors play role: more prominent in girls, different ethnic groups, higher in blood related marriages, higher family incidence.


2. List the major transcription factors involved in thyroid gland development and thyroid hormone synthesis.

1. PAX8 2.TITF2. 3. TITF1.


Function of PAX8

PAX8- Initiation of thyroid cell differentiation, maintenance of the differentiated state, and thyroid cell proliferation.


PAX8 mutations- sx

Autosomal dominant. Phenotypes vary from mild to severe hypoplasia associated with compensated or overt hypothyroidism, ectopy, normal glands at birth. Few cases associated with renal agensis


TITF2 functions

Migration of thyroid precursor cells and transcriptional control of the TG (thyroglobulin) and the TPO (thyroid peroxidase) gene promoters in thyroid development


TITF2 mutations

Homozygous mutations result in Bamforth-Lazarus syndrome: CH, cleft palate, spiky hair, and variably bifid epiglottis and choanal atresia


TITF1 functions

Homeobox domain trxn factor. Development of the gland and in transcriptional control of the TG, TPO, and TSH receptor genes.


Where is TITF1 located

thyroid, plus lung, forebrain, pituitary gland


TITF1 mutations

Humans with heterozygous mutations associated with various combinations of CH, respiratory distress and neurological disorders


Function of TSH receptor

mediates the effects of TSH and is critical for the development and function of the thyroid gland


TSH receptor mutations

Heterozygous loss-of-function mutations – partial resistance with normal size gland and TSH elevation. Homozygous TSHR mutations usually cause CH with hypoplastic gland and decreased T4 synthesis


Function of NIS

NIS (sodium/iodide symporter) -iodide transport from the blood into thyroid cell (basal membrane). This is the rate limiting step in thyroid hormone synthesis.


Mutations of NIS- Sx and who is more likely to be affected

Mutations cause hypothyroidism of variable severity and goiter is not always present -individuals with a higher dietary iodine intake are less likely to have severe hypothyroidism than those with iodine deficient diets


Function of SCL26A4

Encodes pendrin which is important for efflux of iodide at the apical membrane of thyroid follicular cells


Mutations of SCL26A4- Sx

Mutations cause Pendred’s syndrome, an autosomal recessive disorder associated with sensorineural congenital deafness and goiter. Rarely present with CH; the majority of individuals are euthyroid, at least under conditions of normal iodine intake


Function of thyroid peroxidase

Enzyme responsible for iodide oxidation, organification, and iodotyrosine coupling


Mutations of thyroid peroxidase- sx

Defects in the TPO gene cause congenital hypothyroidism by a total iodide organification defect


THOX1 and THOX2 function

Encode NADPH oxidases which are involved in H2O2 generation in the thyroid. H202 is essential cofactor for iodination and coupling reactions


Define central hypothyroidism

Hypothalamic or pituitary deficiency. Usually occurs in setting of multiple pituitary hormone deficiency. Ie. septo-optic dysplasia


Signs/Sx of congenital hypothyroidism

Baby usually appears normal. Large posterior fontanel, prolonged jaundice, macroglossia, hoarse cry, umbilical hernia, hypotonia


When are newborns screened for congenital hypothyroidism

3-5 days of age


Methods for newborn screening for congenital hypothyroidism

1. primary T4: If T4 is in the lowest 10% of results on a given day, TSH will be measured. TSH is abnormal if >20uU/ml- call PCP. 2. Primary TSG: will miss central hypothyroidism though.


What should you do if positive screening test for congenital hypothyroidism

1. Measure free T4 hormone and total T4 2. T3 uptake


How to interpret free and total T4 values

If total T4 is low, but free T4 is nl, then there is a thyroid binding globulin deficiency


How to interpret T3 uptake

1. If T3-Uptake and T4 are in same direction – thyroid disease. Ie. low uptake and low T4 means hypothyroid. 2. If T3-Uptake and T4 are in opposites directions – TBG abnormality. Ie. high uptake and low T4 means TBG deficient


treatment of congenital hypothyroidism

Start levothyroxine aASAP. Use brand name and crush tablet. Levels are monitored every 3 months in first 3 years of life plus 4 weeks after dose change


Outcome of congenital hypothyroidism

Before screening programs, IQ of CH children was 76 with 40% requiring special education. Now with early (<3 weeks) and high-dose treatment, developmental outcomes are excellent