congenital hypothyroid

Question 1

thyroid gland develops from which embryonic lineages

Answer 1

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

Question 2

1. Describe how the thyroid gland develops.

Answer 2

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

Question 3

List locations of arrested thyroid migration

Answer 3

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

Question 4

When does thyroid hormone synthesis begin

Answer 4

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

Question 5

Where does iodination of thyroglobulin occur

Answer 5

in the colloid

Question 6

compare the types of deiodinase

Answer 6

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

Question 7

When is the hypothalamic-pituitary-thyroid axis functional

Answer 7

midgestation- HPT feedback control is evident by 25 weeks

Question 8

Maternal/fetal thyroid hormone

Answer 8

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 )

Question 9

Fetal TSH and T4/T3 levels

Answer 9

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

Question 10

Compare T4 in term vs premature infant

Answer 10

T4 is higher in term infants

Question 11

Causes of congenital hypothyroidism

Answer 11

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

Question 12

Etiology of thyroid dysgenesis

Answer 12

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

Question 13

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

Answer 13

1. PAX8 2.TITF2. 3. TITF1.

Question 14

Function of PAX8

Answer 14

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

Question 15

PAX8 mutations- sx

Answer 15

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

Question 16

TITF2 functions

Answer 16

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

Question 17

TITF2 mutations

Answer 17

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

Question 18

TITF1 functions

Answer 18

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

Question 19

Where is TITF1 located

Answer 19

thyroid, plus lung, forebrain, pituitary gland

Question 20

TITF1 mutations

Answer 20

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

Question 21

Function of TSH receptor

Answer 21

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

Question 22

TSH receptor mutations

Answer 22

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

Question 23

Function of NIS

Answer 23

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

Question 24

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

Answer 24

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

Question 25

Function of SCL26A4

Answer 25

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

Question 26

Mutations of SCL26A4- Sx

Answer 26

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

Question 27

Function of thyroid peroxidase

Answer 27

Enzyme responsible for iodide oxidation, organification, and iodotyrosine coupling

Question 28

Mutations of thyroid peroxidase- sx

Answer 28

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

Question 29

THOX1 and THOX2 function

Answer 29

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

Question 30

Define central hypothyroidism

Answer 30

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

Question 31

Signs/Sx of congenital hypothyroidism

Answer 31

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

Question 32

When are newborns screened for congenital hypothyroidism

Answer 32

3-5 days of age

Question 33

Methods for newborn screening for congenital hypothyroidism

Answer 33

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.

Question 34

What should you do if positive screening test for congenital hypothyroidism

Answer 34

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

Question 35

How to interpret free and total T4 values

Answer 35

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

Question 36

How to interpret T3 uptake

Answer 36

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

Question 37

treatment of congenital hypothyroidism

Answer 37

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

Question 38

Outcome of congenital hypothyroidism

Answer 38

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