**3. Etiology**

Abnormal development of thyroid gland (thyroid dysgenesis) is the most common cause of CH. Thyroid dysgenesis accounts for 85% of cases of CH and is usually sporadic. It has three major forms thyroid ectopy, athyreosis and thyroid hypoplasia. Thyroid ectopy: it is the most common form and accounts for two thirds of cases of thyroid dysgenesis and is twice more common in females [15]. The exact etiology of thyroid dysgenesis is not known but largely its considered a sporadic disease and although the etiology remains elusive in most of cases some mutations in transcription factor genes i.e. TSHR, PAX8, NKX21, FOXE1, that regulate thyroid gland development have been reported, but only 2–5% of cases with thyroid dysgenesis are found to have such genetic mutations [16]. Recently, several other genes have found to be associated with thyroid gland dysgenesis, including NKX25, JAG1 and GLIS3 although each of them contributes to only a small fraction of cases [17–21]. Each of these transcription factors has a role in the development of organ systems too, and mutations of these genes are generally associated with additional congenital defects. In remaining onethird of cases, CH results from absence of thyroid (athyrosis) and thyroid hypoplasia. Dyshormonogenesis, or defects in peripheral thyroid hormone transport, metabolism, or action are accounted in approximately 15% of cases [22]. Defects in thyroid hormone biosynthesis are familial and usually autosomal recessive in inheritance [23]. These include mutations in the genes coding for the sodiumiodide symporter (NIS; SLC5A5), thyroid peroxidase (TPO), thyroglobulin (Tg), apical iodide transporter pendrin (PDS; SLC26A4), iodotyrosine deiodinase (IYD), dual oxidase (DUOX2) and its necessary protein(DUOXA2) [23]. Defective thyroid hormone transport (mutations in monocarboxylase transporter 8), metabolism (selenocysteine insertion sequencebinding protein 2), or resistance to action (mutations of thyroid hormone receptor) are some rare causes. Among the aforementioned defects, mutations of the thyroid peroxidase (TPO) gene form the most prevalent cause of inherited defects in CH [24]. The incidence of thyroid dyshormonogenesis has been increasing and now accounts for 30–40% case of CH but thyroid dysgenesis remains the most common cause of CH [12].

Maternal thyrotropin receptor–blocking antibodies, exposure to maternal antithyroid medications, iodine deficiency or iodine excess are the major causes of transient CH in children.

Central congenital hypothyroidism is rare and is usually associated with and is usually associated with developmental anomaly of the pituitary gland and is usually associated with other pituitary hormone deficiencies like adrenocorticotropin and gonadotropins [25]. If isolated, it usually results from a mutation in the thyroid stimulating hormone β TSHβ subunit gene or TRH receptor gene. Less often it is due to mutation in transcription factor gene regulating pituitary development i.e. HESX1, LHX3, LHX4, OTX2, SOX3, PIT1 and PROP1 [1].
