Congenital Hypothyroidism

Question 1

PAX8

Answer 1

Autosomal dominant mutation; gene is important in thyroid cell differentiation and proliferation

Phenotypes vary amongst family members from mild to severe hypoplasia associated with subclinical or overt hypothyroidism, ectopy, or normal thyroid at birth

Question 2

TITF2

Answer 2

Mutation in gene important for migration of thyroid precursor cells and transcriptional control of TG and TPO expression

Homozygous mutations result in Bamforth-Lazarus Syndrome

Question 3

Bamforth-Lazarus Syndrome

Answer 3

Congenital Hypothyroidism
Cleft Palate
Spiky Hair
Bifid epiglottis 
Choanal atresia 

Associated with TITF2 mutation

Question 4

TITF1

Answer 4

Homeobox TF important in transcriptional control of TG, TPO, and TSH receptor genes; also expressed in lung, forebrain, and pituitary

Heterozygous mutation associated with:

Congenital hypothyroidism
Respiratory distress
Neurological disorders

Question 5

TSHR mutation

Answer 5

Heterozygous loss of function mutations in TSHR cause partial resistance to TH with a normal sized gland and TSH elevation

Homozygous TSHR mutations cause congenital hypothyroidism with hypoplastic gland and decreased T4 synthesis

Question 6

NIS

Answer 6

Sodium/iodide transporter responsible for rate-limiting step in TH synthesis

Mutations cause hypothyroidism of variable severity depending on dietary intake of iodine

Question 7

SCL26A4

Answer 7

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

Mutations cause Pendred’s Syndrome (Autosomal recessive)

Congenital sensorineural deafness (10% of hereditary deafness)
Goiter (usually euthyroid)
Rarely present with congenital hypothyroidism

Question 8

TPO Mutations

Answer 8

Thyroid peroxidase (TPO) is responsible for organification of iodide and iodotyrosine coupling

Defects in TPO cause congenital hypothyroidism via iodide organification defect

*Most common genetic cause of congenital hypothyroidism

Question 9

TG Mutations

Answer 9

Quantiative or qualitative

Causes congenital hypothyroidism of variable severity

Question 10

THOX1 and THOX2

Answer 10

Encode NADPH oxidases which are involved in H2O2 generation in the thyroid; H2O2 is an essential co-factor for iodination and coupling

Mutations cause congenital hypothyroidism