congenital hypothyroid Flashcards
thyroid gland develops from which embryonic lineages
follicular cells (endodermal pharynx) - produce thyroxine. parafollicular C-cells (neural crest) – produce calcitonin
- 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
- 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.
- List the major transcription factors involved in thyroid gland development and thyroid hormone synthesis.
- 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
- 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
- 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
- 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
