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, highthroughput 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.

Evaluation of patients diagnosed with congenital hypothyroidism by newborn screening between 2011–2019 in Diyarbakir, Turkey

“…It is usually inherited autosomal recessively. [22–25] In a study by Taheri-Soodejani et al, [15] which was conducted in Iran, the risk of CH was higher in newborns with a family history of hypothyroidism. In a study conducted by Asena et al, the parental consanguinity rate in patients diagnosed with permanent CH was 55%.…”

“…Thyroid dysgenesis and dyshormonogenesis account for respectively 65% to 85% and 10% to 15% of permanent CH cases, respectively. [22][23][24] Genetic mutations can also cause permanent or transient CH. It is usually inherited autosomal recessively.…”

Normal intellectual ability and hyperprolactinemia as unique clinical manifestations of congenital hypothyroidism: A case report and review of hypotheses

“…The thyroid hormone plays a vital role in optimal growth and neurological development, especially throughout childhood. Hypothyroidism during this period is a significant cause of preventable intellectual disability worldwide [ 5 , 11 ]. In this particular case, the patient did not exhibit intellectual disability typically associated with congenital hypothyroidism.…”

Diagnosis and Management of Congenital Hypothyroidism: An Updated Overview

“…An important point to note is that Pendrin syndrome, which results from mutations in the Pendrin gene, results in impaired iodine organification, goiter, and sensorineural deafness (9). Conversely, individuals with congenital hypothyroidism with mutations in thyroglobulin genes responsible for producing the iodinated precursor glycoprotein of active thyroid hormone in thyroid follicles exhibit goiter and low serum thyroglobulin levels (20,21).…”