Table 2.

Genetic etiologies in Isolated Central Hypothyroidism.

GENETIC CONGENITAL HYPOTHYROIDISM
Gene	Characteristics	Biochemical assessment
TRHR	- Autosomal recessive inheritance - Described in a few families both in males and females - Mild to moderate hypothyroidism usually asymptomatic until puberty (growth retardation)	↔ or rarely ↑ TSH levels in affected individuals ↑ TSH levels in carriers
TSHB	- Autosomal recessive inheritance - Most frequent cause of inheritable ICH that affects both males and females - Severe hypothyroidism with precocious onset	↔ or ↓ TSH levels in affected individuals ↑↑ α-subunit
IGSF1	- X-linked inheritance - Mild to moderate hypothyroidism associated to macroorchidism, GH deficiency in childhood and increased GH secretion in male adults with acromegaloid features - Delayed menarche and increased BMI in female carriers	↔ TSH levels in affected individuals ↔ or ↓ fT4 levels in female carriers
TBL1X	- X-linked inheritance with incomplete penetrance - Mild to moderate hypothyroidism in males associated to hearing loss - Mild hypothyroidism to euthyroidism in female carriers	↔ TSH levels in affected individuals ↔ or ↓ fT4 levels in female carriers
IRS4	- X-linked inheritance - Mild hypothyroidism	↔ or rarely ↑ TSH levels in affected individuals ↔ or ↓ fT4 levels in female carriers

↔ normal; ↑ increased; ↓ reduced; ICH, Isolated central hypothyroidism; TSH, Thyroid stimulating hormone; fT4, free thyroxine; GH, Growth hormone; BMI, Body Mass Index.