Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations

Importance of molecular genetic analysis in the diagnosis and classification of congenital hypothyroidism

“…Genetic abnormalities in any of the key thyroid proteins can produce CH [3,4]. Based on genetic alterations, the CH can be classified into two main groups: (i) those caused by disorders of thyroid gland development (dysembriogenesis or dysgenesis), which accounts for 80-85 % of cases; and (ii) by defects in any step of thyroid hormone synthesis (dyshormonogenesis), which accounts for remaining 15-20 % of cases [3,4].…”

“…Genetic abnormalities in any of the key thyroid proteins can produce CH [3,4]. Based on genetic alterations, the CH can be classified into two main groups: (i) those caused by disorders of thyroid gland development (dysembriogenesis or dysgenesis), which accounts for 80-85 % of cases; and (ii) by defects in any step of thyroid hormone synthesis (dyshormonogenesis), which accounts for remaining 15-20 % of cases [3,4]. Thyroid dysembryogenesis results from a thyroid gland that is completely absent in orthotopic or ectopic location (agenesis or athyreosis), severely reduced in size but in the proper position in the neck (orthotopic hypoplasia) or located in an unusual position (thyroid ectopy) at the base of the tongue or along the thyroglossal tract [4].…”

“…Thyroid dysembryogenesis results from a thyroid gland that is completely absent in orthotopic or ectopic location (agenesis or athyreosis), severely reduced in size but in the proper position in the neck (orthotopic hypoplasia) or located in an unusual position (thyroid ectopy) at the base of the tongue or along the thyroglossal tract [4]. In a very minority of these patients (5 %), the CH is associated with mutations in genes responsible for the development or growth of thyroid follicular cells: NKX2.1 FOXE1, PAX-8, NKX2.5, and TSHR genes [3,4]. Consequently, the molecular mechanisms underlying the defect in thyroid organogenesis in the great majority of cases remain to be elucidated.…”

“…Consequently, the molecular mechanisms underlying the defect in thyroid organogenesis in the great majority of cases remain to be elucidated. In contrast, thyroid dyshormonogenesis has been linked in more than 90 % of cases to mutations in the sodium iodide symporter (NIS), SLC26A4 (which encodes pendrin), thyroperoxidase (TPO), dual oxidase 2 (DUOX2), DUOX maturation factor 2 (DUOX-A2), dehalogenase 1 (DEHAL1), and thyroglobulin (TG) genes [3,4]. These mutations produce a heterogeneous spectrum of congenital goitrous hypothyroidism, usually transmitted in an autosomal recessive mode.…”

“…Dyshormonogenesis due to TG gene mutations is a rare cause of CH with an estimated incidence of approximately 1 in 100,000 newborns [3]. The clinical spectrum ranges from euthyroid to mild or severe hypothyroidism.…”