TSH resistance revisited [Review]

Abstract

Abstract. Genetic defects of hormone receptors are the most common form of end-organ hormone resistance. One example of such defects is TSH resistance, which is caused by biallelic inactivating mutations in the TSH receptor gene (TSHR). TSH, a master regulator of thyroid functions, affects virtually all cellular processes involving thyroid hormone production, including thyroidal iodine uptake, thyroglobulin iodination, reuptake of iodinated thyroglobulin and thyroid cell growth. Resistance to TSH results in defective thyroid hormone production from the neonatal period, namely congenital hypothyroidism. Classically, clinical phenotypes of TSH resistance due to inactivating TSHR mutations were thought to vary depending on the residual mutant receptor activity. Nonfunctional mutations in the two alleles produce severe thyroid hypoplasia with overt hypothyroidism (uncompensated TSH resistance), while hypomorphic mutations in at least one allele produce normal-sized thyroid gland with preserved hormone-producing capacity (compensated TSH resistance). More recently, a new subgroup of TSH resistance (nonclassic TSH resistance) that is characterized by paradoxically high thyroidal iodine uptake has been reported. In this article, the pathophysiology and clinical features of TSH resistance due to inactivating TSHR mutations are reviewed, with particular attention to the nonclassic form. Key words: TSH, TSH receptor, TSH resistance, Genetics, MutationThe Thyroid glAnd produces thyroid hormones (T 3 and T 4 ), which upregulate the metabolism of many types of animal cells. The production of thyroid hormones is regulated by the hypothalamus-pituitary axis. Serum thyroid hormone levels are usually kept constant in narrow ranges, but the hormone levels can be lowered in conditions when hypometabolism is beneficial (e.g., undernutrition and acute illness). The TSH receptor (TSHR) is the only receptor that can transduce the signal of TSH. TSHR is expressed in the basal plasma membrane of thyroid follicular cells. Both activating and inactivating mutations in the TSHR gene (TSHR) have been described [1,2], and each of them drastically affects the hormone-producing capacity of the thyroid gland. Activating mutations cause ligand-independent activation of TSHR, and result in overproduction of thyroid hormones (i.e., thyrotoxicosis). This type of mutations can occur in a germline cell or a somatic cell, causing congenital hyperthyroidism [3] or functional thyroid nodule [1], respectively. Conversely, inactivating TSHR mutations cause TSH resistance, which results in congenital hypothyroidism [2]. In this review article, we focus on TSH resistance due to inactivating TSHR mutations, and discuss its pathophysiology and clinical phenotypes. Structure and functions of TShr Structure of TSHRTSHR is a seven-transmembrane G-protein coupled receptor (GPCR). Mammals have more than 1,000 GPCRs, and most of them are odorant receptors [4]. Based on secondary and tertiary structure similarity, TSHR, along with FSH receptor and LHCG receptor, is ...

Mild TSH resistance: Clinical and hormonal features in childhood and adulthood

“…Our study documents a 30% prevalence of inactivating TSHR mutations in a pediatric SCH population (34/111). This percentage is similar to that reported in literature …”

“…Previous studies that analyzed the rate of TSHR mutations in SCH populations reported highly variable frequencies (11%‐29%), with the highest prevalence occurring in consanguineous populations . Our study documents a 30% prevalence of inactivating TSHR mutations in a pediatric SCH population (34/111).…”

“…Patients with monoallelic mutations have a partial RTSH, which results in SCH . To date, more than 60 LOF mutations of the TSHR have been described with a variable prevalence (11%‐29%) depending on the population tested . There are only a few studies in literature that describe the long‐term follow‐up of subjects with TSHR mutations .…”

Mild Hypothyroidism in Childhood: Who, When, and How Should Be Treated?

“…In case of biallelic variants, patients can have complete RTSH, resulting in severe hypothyroidism. Patients with monoallelic mutations have a partial RTSH, which results in nonautoimmune SH [40]. To date, at least 68 loss-of-function mutations of the TSHR have been described [39] with a variable prevalence (11% to 29%) depending on the population tested [38, 41–44].…”

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“…Thyroid-stimulating hormone (TSH) is a peptide hormone synthetized and secreted by pituitary with fundamental importance for thyroid function and balance, affecting iodine uptake, thyroxine and triiodothyronine production and, as a consequence, whole body metabolism [1,2]. It acts through thyroid-stimulating hormone receptor (TSHr), a classical seven transmembrane G-protein coupled receptor [3], being usually coupled to Gαs, increasing cAMP production and activation of PKA or even to Gαq and either activating Ras/Raf/Mek/ Erk or PI3K/Akt signaling pathways [4].…”