Genetics of primary congenital hypothyroidism: three decades of discoveries and persisting etiological challenges

Abstract

Primary congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, and may be etiologically subdivided into thyroid dysgenesis, referring to abnormal thyroid development, and dyshormonogenesis, where a defective thyroid hormone biosynthesis pathway results in inadequate hormone production despite a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in irreversible neurodevelopmental impairment; therefore, where available, CH screening programs facilitate prompt diagnosis. However, the molecular basis for CH remains unclear in most of the cases. This review summarizes current understanding of the genetic etiologies underlying primary CH and associated phenotypes. Classical genetic causes are discussed in the context of their role in normal thyroid physiology. Genes recently reported to play a role in the pathogenesis of CH are discussed, and novel genomic mechanisms in CH are described.

Keywords: congenital hypothyroidism; dyshormonogenesis; genetics; thyroid dysgenesis.

Figure 1

Schematic illustration of normal and pathologic human thyroid development. The key steps of organogenesis and structural and functional differentiation are shown. Numbers refer to specific steps of organogenesis in the figure. Phenotypes of thyroid dysgenesis resulting from specific disrupted developmental steps are shown below. In the human embryo, at approximately 22 days post-conception/embryonic days (dpc), the median anlage starts to form a thickened endodermal epithelium (thyroid bud) on the floor of the tongue (pink in the figure) at the foramen cecum. The bud proliferates ventrally and then expands laterally, giving the bilobed form to the thyroid. It detaches progressively from the endodermal plate by 24 dpc and migrates along the neck close to the aortic arch. It is initially connected to the pharyngeal epithelium and the foramen cecum by an epithelial stalk (called the thyroglossal duct), which atrophies between 28 and 40 dpc. The lateral anlages also migrate caudally and finally fuse with the median anlage at 44 dpc. The thyroid reaches its final pretracheal position at 45–50 dpc, followed by the onset of folliculogenesis at 60 dpc. Once the thyroid is in its final position, the lobes expand and the gland reaches its definitive form, with a narrow isthmus connecting the two lateral lobes. The final steps in thyroid development comprise folliculogenesis, terminal differentiation and the onset of hormonogenesis at the end of the first trimester. During this phase, changes in the structure and the function of thyroid gland take place. The median anlage provides most of the follicular cells, which will form follicles, and the lateral anlages are the main source of parafollicular or C-cells secreting calcitonin. The structural differentiation of primitive thyroid comprises three steps occurring from the 7th GW, classified as the precolloid phase, the beginning of colloidal formation and the follicular growth stage. During the initial precolloid phase (from the 7th–10th GW), the cells are organized in a compact manner without polarization. At the beginning of the colloidal phase (lasting from the 10th–11th GW), small follicles containing polarized thyrocytes appear. Terminal differentiation begins following completion of migration and thyroid follicles are formed, with thyrocytes commencing expression of essential proteins for TH synthesis. Expression of thyroid-specific genes follows a strict temporal pattern, which is crucial for TH production. From the 12th GW, the follicles increase in size, permitting iodine accumulation and synthesis of TH(8). This figure was created in Biorender.com.

Figure 2

Schematic illustrating TH biosynthesis in polarized thyroid follicular cells surrounding a central colloid matrix at the apical lumen, predominantly comprising thyroglobulin (TG). The sodium–iodide symporter (NIS, SLC5A5) mediates electrogenic symport of two sodium ions for one circulating iodide ion across the thyrocyte basolateral membrane down an electrochemical gradient generated by the Na⁺/K⁺ ATPase. Apical membrane transporter molecules (e.g. pendrin, SLC26A4) facilitate iodide efflux into the follicular lumen, e.g., probably by exchanging I⁻ for Cl⁻. The thyroid peroxidase enzyme (TPO) catalyzes the H₂O₂-dependent oxidation of I⁻ into I⁺, the iodination of tyrosyl residues on the surface of TG to form mono- and diiodotyrosyl (MIT and DIT) and their subsequent coupling to produce THs (thyroxine (T4) and triiodothyronine (T3)). H₂O₂ is produced by DUOX2 and its accessory protein, DUOXA2. TG-bound T3 and T4 are endocytosed back into the cell, then proteolytically cleaved and secreted into the circulation by transporters including monocarboxylate transporter 8 (MCT8). Iodotyrosine deiodinase (IYD) recycles unused iodide moieties. I⁻ (purple), I⁻ following oxidation for which the intermediates are not clear (pink). This figure was created in Biorender.com.

Figure 3

Proposed classification of genes involved in thyroid development and disease, as causal, susceptibility factor for congenital hypothyroidism (CH) or associated with CH. This figure was created in Biorender.com.

Figure 4

Schematic summarizing current knowledge regarding the classification and etiology of CH, including known and recently reported genetic causes and their anticipated relative contributions, phenotypic insights, putative mechanisms (oligogenicity, epigenetic factors, germline predisposition, somatic mutations and two-hit hypothesis) and environmental factors (iodine status and endocrine disruptors), for which the relative contribution to CH alone or in concert, remains unclear. Dashed lines – recent or putative data. This figure was created in Biorender.com.