Congenital Hypothyroidism

Question 1

embryonic lineages of thyroid and development

Answer 1

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

Gland originates as proliferation of endodermal epithelial cells on median surface of pharyngeal floor between 1st and 2nd arches

Initially hollow, then solidifies and becomes bilobed
Thyroid connected to tongue via thyroglossal duct as it begins initial descent
Completes its descent in 7th gestational week

Following migration (10-12 weeks), thyroid follicular cells undergo further differentiation characterized by the expression of genes that are essential for thyroid hormone synthesis

Thyroid gland begins to trap iodide and secrete thyroid hormones at 10-12 weeks

Question 2

Location of T4 and T3 synthesis

Answer 2

occurs in colloid of thyroid follicle and requires several steps

Question 3

Enzymes for hormone synth

Answer 3

Type I Deiodinase and Type II deiodinase turn T4 into active T3

Type III deiodinase turns T4 into rT3

Question 4

When is HPT axis functional?

Answer 4

midgestation
TSH is detectable in serum at 12 weeks and increases from 18th week until term

HPT feedback control evident by 25 weeks

Question 5

Can maternal T4 pass to child?

Answer 5

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

Fetal brain rich in type II deiodinase which converts T4 into active hormone T3

Within 30 minutes after birth, TSH rises to levels of 60-80 uU/ml

TSH rise results in increases in T4 and T3 to 15-19 ug/dl by 24 hours

Question 6

Congenital hypothyroidism epidemiology

Answer 6

1:4000 live births
F:M 2:1
higher in hispanic, less common in black
newbrn screening routine
assoc heart disease 5%

Question 7

85% of congenital hypothyroidism caused by

Answer 7

abnormal thyroid gland devel (dysgenesis)

• aplasia
• hypoplasia
• ectopy

Question 8

PAX8

Answer 8

Initiation of thyroid cell differentiation, maintenance of the differentiated state, and essential for thyroid cell proliferation
Autosomal dominant pattern of inheritance
Phenotypes vary from mild to severe hypoplasia associated with compensated or overt hypothyroidism, ectopy, normal glands at birth
Few cases assoc w/ renal agenesis

Question 9

TITF2

Answer 9

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

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

Question 10

TITF1

Answer 10

A homeobox domain transcription factor
Development of the gland and in transcriptional control of the TG, TPO, and TSH receptor genes.
Also expressed in the lung (resp distress can occur at birth), the forebrain, and the pituitary gland
Humans with heterozygous mutations associated with various combinations of CH, respiratory distress and neurological disorders

Also choreoathetosis

Question 11

TSH receptor mutations

Answer 11

encodes a transmembrane receptor present on follicular cells which mediates the effects of TSH and is critical for the development and function of the thyroid gland
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 12

Other 15% of Congenital hypothyroidism

Answer 12

due to inborn error of thyroid hormonogenesis (thyroid dyshomonogenesis)

• AR
• Goiter may be present
• mutations in several genes coding for proteins imp in thyroid hormone synthesis have been found

Question 13

NIS

Answer 13

NIS (sodium/iodide symporter) -iodide transport from the blood into thyroid cell (basal membrane)

Rate-limiting step in thyroid hormone synthesis

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

Question 14

SCL26A4

Answer 14

Encodes pendrin which is important for efflux of iodide at the apical membrane of thyroid follicular cells
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 15

TG and TPO

Answer 15

TPO -thyroid peroxidase
Enzyme responsible for iodide oxidation, organification, and iodotyrosine coupling
Defects in the TPO gene cause congenital hypothyroidism by a total iodide organification defect

TG –thyroglobulin
Glycoprotein which is a key element in thyroid hormone synthesis and storage

Question 16

THOX1 and THOX2

Answer 16

Encode NADPH oxidases which are involved in H2O2 generation in the thyroid

H202 is essential cofactor for iodination and coupling reactions

Question 17

Central hypothyroidism

Answer 17

Hypothalamic or pituitary deficiency (usually TRH or TSH deficiency)

Usually in setting of multiple pituitary hormone deficiency - i.e., septo-optic dysplasia

Must evaluate other pituitary hormones and get cranial MRI

Question 18

Signs/sx of congenital hypothyroidism

Answer 18

Almost always overlooked
Baby usually appears entirely normal!
Large posterior fontanel
Prolonged jaundice
Macroglossia
Hoarse cry
Umbilical hernia
Hypotonia

Newborn screen done at birth AND 2 weeks of age

Question 19

Newborn screening

Answer 19

-best at 3-5 d
Two Methods
1. PrimaryT4: If T4 is in the lowest 10% of results on a given day, TSH will be measured
- Health department will consider screen abnormal if TSH greater than 20 uU/ml and call PCP
- If TSH less than 20, will not call but could still be abnormal (ie central hypothyroidism)

2.Primary TSH – this will miss central hypothyroidism

Question 20

Dx

Answer 20

If abnormal screen, draw confirmatory labs

In infants with proven CH, 90% have TSH greater than 50 and 75% have T4 less than 6.5

Measurement complicated by protein binding of T4 and T3:
TBG - thyroid-binding globulin binds 75% of serum T4
TBPA - thyroxine-binding prealbumin binds 20% of T4
Albumin – binds 5% of T4

Ex: If TBG excess: will look like high total
-Free T4 is imp biologically (but difficult to test for free T4 with accuracy)

Question 21

T3 uptake

Answer 21

Take sample, add radiolabeled T3 tracer, which will bind to regular binding sites in pt.
Exchange resin added to serum
Whatever T3 didn’t bind get take up by Resin
Normal is 25-35% taken up by resin. (if hypothyroid, low uptake)

TBG deficiency and euthyroid have a high uptake

**
If T3-Uptake and T4 are in same direction – thyroid disease
Low uptake and Low T4 – Hypothyroid

If T3-Uptake and T4 are in opposites directions – TBG abnormality
High uptake and Low T4 – TBG deficient

Question 22

T4 should be greater than

Answer 22

8 or 9

Question 23

Tx

Answer 23

levothyroxine ASAP

• Use brand name and crush tablet
• levels monitored every 3 months in first 3 years of life in addition to 4 weeks after dose change.

Before screening: low IQ, special education; good outcomes now if less than 3 weeks and high dose tx