Genetics of congenital hypothyroidism: Modern concepts

Abstract

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.

Keywords: Congenital hypothyroidism; Development; Dyshormonogenesis; Genetic; High‐throughput sequencing; Oligogenism; Thyroid dysgenesis.

FIGURE 1

Hormonal regulation of the thyroid gland. TRH, thyrotropin‐releasing hormone; TSH, thyroid‐stimulating hormone; T3, triiodothyronine; T4, thyroxine.

FIGURE 2

Diagrammatic representation of thyroid development and function, as well as associated congenital hypothyroidism.

FIGURE 3

Production of thyroid hormones in the thyrocytes. NIS, sodium/iodide symporter; KCNQ1 and KCNE2, voltage‐gated K⁺ channels; TSH, thyroid‐stimulating hormone; MCT8, monocarboxylate transporter 8; DUOX2, dual oxidase 2; DUOXA2, maturation factor of dual oxidase 2; TPO, thyroperoxidase; DEHAL, iodotyrosine dehalogenase. (Reprinted with permission Carvalho 2007)

FIGURE 4

Family trees of families carrying BOREALIN and TUBB1 mutations., CH/E, congenital hypothyroidism with ectopia; CH/A, congenital hypothyroidism with athyreosis; Asym, asymmetry of the lobes; LU, single lobe; m: disease allele; N or +, normal allele; NA, not available, thyroid ultrasonography.

FIGURE 5

(A) Diagram of a microtubule with tubulin dimers (α/β). (B) Location of TUBB1 mutations in cDNA (exons from 1 to 4) and corresponding protein changes in the GTP (guanosine triphosphate), MAP (protein binding activity domains associated with microtubules). In bold: mutations associated with congenital hypothyroidism; in italics: mutations associated with macrothrombocytopaenia. (C) Phenotype analysis of Tubb1‐/‐ mice. Top: Morphology of the thyroid analyzed by immunohistochemistry with Nkx2‐1 in red at E9.5 and E11.5 (sagittal sections) and at E13.5, E15.5, and E17.5 (transverse sections) of Tubb1‐/‐ and wild‐type (wt) mice. Delays in migration of the thyroid were observed at E11.5 and E13.5 (arrow) in Tubb1‐/‐ mice. tr: trachea; ub: ultimobranchial body. Scale bar: 50 μm. Bottom, from left to right: percentage of growth: proportion of Nkx2‐1‐positive cells marked with Ki67 at E9.5 in proportion to the total number of Nkx2‐1‐positive cells. The total area of the thyroid (μm²). Percentage of the T4 or calcitonin (CT) surface area in proportion to the total surface area of the thyroid at the E17.5 stage. (D) Top: Serum assays of TSH and T4 in 3‐month‐old Tubb1‐/‐ and wild‐type mice. Tubb1‐/‐ mice have hypothyroidism with a high level of TSH and reduced T4. Bottom: Ultrastructural alterations highlighted by electron microscopy in the thyroids of Tubb1‐/‐ and wild‐type mice: disorganization of secretion vesicles (white asterisks) and rods with identical density to the secretion vesicles (white arrow). TSH, thyroid‐stimulating hormone; Co, colloid. The results are given in the form of mean ± SEM. Student t‐test, *P < 0.05, **P < 0.01 and ***P < 0.001.