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Molecular Thyroidology

Address correspondence to William E. Winter, M.D., Department of Pathology, Immunology and Laboratory Medicine, University of Florida Medical School, Box 100275, Gainesville, FL 32610-0275, USA; tel 352 392 4495; fax 352 846 2149; e-mail winter.pathology{at}mail.health.ufl.edu.

	Abstract

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
Novel disorders involving aberrations of the hypothalamic-pituitary-thyroid gland-thyroid hormone axis have been described in the last 5 to 10 years. The following topics are addressed: molecular mutations causing central hypothyroidism (isolated autosomal recessive TRH deficiency; autosomal recessive TRH-receptor inactivating mutations; TSH beta-subunit bio-inactivating mutations; Pit-1 mutations; Prop1 mutations; high molecular weight bio-inactive TSH); defects in response to TSH (mutations in the TSH receptor: TSH receptor gain-of-function mutations; TSH receptor loss-of-function mutations); defects in thyroid gland formation: transcription factor mutations (TTF-2 and Pax8); defects in peripheral thyroid hormone metabolism (defective intrapituitary conversion of T4 to T3; hemangioma consumption of thyroid hormone); and defects in tissue response to thyroid hormone (generalized thyroid hormone resistance, selective pituitary thyroid hormone resistance). While molecular diagnosis of such conditions is rarely indicated for clinical management, knowledge of the molecular mechanisms of these diseases can greatly enhance the clinical laboratory scientist’s ability to advise clinicians about appropriate thyroid testing and to interpret the complex and sometimes confusing results of thyroid function tests.

(received 17 March 2001; accepted 20 March 2001)

Keywords: TRH, TRH receptor, TSH, TSH receptor, thyroid hormone receptor

	Introduction

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
The goal of this review is to introduce the clinical laboratorian to several recent advances in molecular thyroidology. Many novel disorders involving aberrations of the hypothalamic-pituitary-thyroid gland-thyroid hormone axis have been described in the last 5 to 10 years. While molecular diagnosis of such conditions is rarely indicated for clinical management, knowledge of the molecular mechanisms of disease can greatly enhance the laboratorian’s ability to advise clinicians about appropriate thyroid testing, and to interpret the complex and sometimes confusing results of thyroid function tests. This review begins with a brief overview of the normal hypothalamic-pituitary-thyroid gland-thyroid hormone axis.

	Normal Thyroid Function

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
The hypothalamus and anterior pituitary gland thyrotrophs monitor free thyroid hormone levels in the blood stream (Fig. 1). Unbound or free triiodothyronine (FT3) is present in the plasma and enters the parvicellular division of the paraventricular nucleus. Within these paired hypothalamic nuclei that are adjacent to the superior aspect of the third ventricle, intracellular T3 is also derived from monodeiodination of free tetraiodothyronine (free thyroxine, FT4) that has entered the cell cytoplasm from the plasma. If the intracellular level of T3 declines, thyrotropin-releasing hormone (TRH) is released into the hypothalamic-pituitary-portal system to be delivered to the anterior pituitary gland. TRH is the tripeptide pyroGlu-His-Pro-NH₂. The cyclized glutamic acid terminus and an intact amide are required for TRH bioactivity. TRH sensitizes the anterior pituitary thyrotrophs to release more thyroid stimulating hormone (TSH) if intracellular thyrotroph T3 levels are deficient.

View larger version (26K): [in this window] [in a new window]   Fig. 1. The hypothalamus secretes thyrotropin releasing hormone (TRH) into the hypothalamic-pituitary portal system. In turn, TRH regulates the responsiveness of thyrotropin (TSH) to thyroid hormone feedback. TSH circulates systemically and stimulates the thyroid gland to release thyroxine (tetraiodothyronine, T4) and 3,5,3'-triiodothyronine (T3). About 80% of circulating T3 is derived from peripheral monodeiodination of T4 to T3. In target tissues, T4 is also converted to T3 and the T3 interacts with nuclear thyroid hormone receptors.

TSH circulates systemically. Upon binding of TSH to the TSH receptor located on thyroid follicular cell, many processes are activated to increase the release of thyroid hormone into the circulation. T4 is derived only from the thyroid gland. On the other hand, only about 20% of T3 is directly generated from the thyroid gland, with about 80% of T3 being derived from peripheral monodeiodination of T4 to T3. The majority of thyroid hormone is bound to plasma proteins, including the alpha-1 globulin thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (now called transthyretin), and albumin. Only 0.03% of T4 and 0.3% of T3 are unbound. The unbound or "free" fractions of thyroid hormone are the biologically active forms of thyroid hormone in the circulation. With a rise in plasma FT3 and intracellular T3 in the pituitary (and to a lesser degree in the hypothalamus), TSH and TRH secretion are suppressed, completing the negative feedback loop for control of thyroid hormone synthesis and secretion.

Thyroid hormone is "trophic" for many tissues. Thyroid hormone is important for the growth, differentiation, and maintenance of the central nervous system (very important), skeleton (very important), cardiovascular system, and gastrointestinal system. Basal metabolic rate (BMR) is directly regulated by thyroid hormone. Thyroid hormone also affects and regulates intermediary metabolism, drug metabolism, and the activity of other hormones (eg, growth hormone secretion is impaired in individuals with hypothyroidism).

	Overview of Molecular Thyroidology

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
"New explanations for old diseases" would be an appropriate title for much of this review. The following topics will be addressed:

Molecular mutations causing central hypothyroidism:

• Isolated autosomal recessive TRH deficiency,
  
• Autosomal recessive TRH-receptor inactivating mutations,
  
• Pit-1 mutations,
  
• PROP-1 mutations;
  

TSH beta-subunit bio-inactivating mutations:

• High molecular weight bio-inactive TSH;
  

Defects in response to TSH: mutations in the TSH receptor:

• TSH receptor gain-of-function mutations,
  
• TSH receptor loss-of-function mutations;
  

Defects in thyroid gland formation: transcription factor mutations:

• TTF-2, Pax8 [1];
  

Defects in peripheral thyroid hormone metabolism:

• Defective intrapituitary conversion of T4 to T3 [2],
  
• Hemangioma consumption of thyroid hormone;
  

Defects in response of tissues to thyroid hormone:

• Generalized thyroid hormone resistance [3],
  
• Selective pituitary thyroid hormone resistance.
  

While many defects in thyroid hormone biosynthesis have been described, their etiology is generally understood and they are not reviewed in detail in this paper. However,the clinical laboratory scientist should be familiar with cases of goitrous congenital hypothyroidism and non-autoimmune goitrous hypothyroidism that result from:

• defects in iodine transport into the thyroid gland (autosomal recessive mutations in the sodium/iodide symporter located on chromosome 19p12–13.2) [4],
  
• organification defects (autosomal recessive mutations of thyroperoxidase located on chromosome 2p25 and associated with the Pendred syndrome mutation located at chromosome 7q21–34),
  
• thyroglobulin synthesis defects (autosomal recessive disorder mapping to chromosome 8q24), and
  
• the iodine recycling disorder involving dehalogenase.
  

Recently the gene responsible for Pendred syndrome (hypothyroidism due to defective iodine organification of thyroglobulin associated with congenital or early-onset sensorineural deafness) was cloned and named the PDS (Pendred syndrome) gene [5]. The PDS gene product is a transmembrane protein (pendrin) which transports iodide and chloride [6].

Defects in thyroid hormone transport are also well described in the literature. These defects can cause confusion in the interpretation of elevated total T4 measurements when T-uptake or T3 resin uptake is not also measured. As measurements of free T4 (FT4) replace total T4 measurements, the diagnostic problems posed by thyroxine binding globulin (TBG) excess, familial dysalbuminemic hyperthyroxinemia [7], and familial euthyroid thyroxine excess [8] should wane.

Located on chromosome Xq11–23, TBG is a 395 amino acid 54-kDa acidic glycoprotein with a single iodothyronine binding site. TBG has 4 heterosaccharide side chains with 5–9 sialic acids. As the degree of sialylation increases (an effect of estrogen), the half-life of TBG increases, raising TBG levels. In congenital TBG excess, an X-linked dominant condition, male hemizygotes display 3- to 5-fold elevations in TBG levels, while female heterozygotes display 2- to 3-fold increases in TBG. Besides estrogen effects and congenital excess, other causes of elevated TBG levels include acute liver disease and drugs (eg, phenothiazines).

In familial dysalbuminemic hyperthyroxinemia, a mutant dominantly-inherited form of albumin (Arg218His) binds increased amounts of T4 but not T3, producing euthyroid hyperthyroxinemia, with normal T3 levels as well as normal FT4 levels. In contrast, TBG excess raises both T4 and T3. Another cause of euthyroid hyperthyroxinemia is familial euthyroid thyroxine excess that results from a mutant form of transthyretin (TTR, Thr119Met). An older name for TTR is thyroxine-binding prealbumin (TBPA). Encoded by the TTR gene on chromosome 18q11.2, TTR exists as a stable 55 kDa tetramer of 127 amino acid monomers. TTR participates in vitamin A transport by binding to the complex of vitamin A and retinol-binding protein. As a side note, more than 40 TTR mutations have been reported that can cause familial amyloidosis affecting the heart (cardiomyopathy) or nervous system (autonomic neuropathy or polyneuropathy). It is of interest that other causes of familial amyloidoses include mutations in apolipoprotein A-I, gelsolin, fibrinogen, and lysozyme. Gelsolin is a cytoplasmic and plasma calcium-binding protein that binds to and fragments actin filaments. Many reviews of euthyroid hyperthyroxinemia with normal FT4 levels have been published [9] and these disorders are not further discussed in this paper.

	Molecular Mutations with Central Hypothyroidism

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
Central hypothyroidism is diagnosed when clinical hypothyroidism is accompanied by low FT4 (and FT3) and inappropriately normal or low TSH concentration. Most cases of hypothyroidism are primary in etiology and show an elevated TSH concentration in the blood.

Regardless of etiology (eg, either primary or central), the clinical features of hypothyroidism include symptoms of tiredness, constipation, cold intolerance, dry hair or skin, weight gain, menstrual irregularities, breast milk production, and slow mentation. Signs of hypothyroidism can include low heart rate (bradycardia), decreased strength of cardiac contraction causing decline in the usual difference between systolic and diastolic blood pressures (low pulse pressure), myxedema (nonpitting edema), hypercholesterolemia, elevated creatine kinase, growth failure (including congenital hypothyroidism), short stature, retarded bone age, stippled growth plates, decreased reflexes, congestive heart failure, and coma. Newborns with congenital hypothyroidism may display an enlarged posterior fontanelle, large tongue, prolonged jaundice (delayed expression of UDP-glucuronyl transferase), low body temperature, delayed passage of meconium, large body size at birth because of postmaturity (delayed delivery), or excessive body hair.

In cases of central hypothyroidism where low FT4 is accompanied by an inappropriately low TSH level, the clinician’s initial obligation is to exclude by radiology a tumor mass lesion or other anatomic cause of central hypothyroidism that might require surgery or irradiation. Other types of central endocrine deficiencies should also be pursued and treated preoperatively, such as ACTH deficiency causing glucocorticoid deficiency and ADH deficiency causing diabetes insipidus.

Failure to detect and treat glucocorticoid insufficiency preoperatively could lead to fatal intra-operative adrenal crisis. Likewise, failure to recognize diabetes insipidus could cause serious hypovolemia when the patient’s oral intake of food and fluids is restricted preoperatively, or when the patient’s oral intake is restricted postoperatively and sufficient intravenous fluids are not administered to replace excessive urinary fluid loss. If a mass lesion is discovered in the hypothalamus or pituitary that requires surgery or irradiation, all aspects of anterior and posterior pituitary function should also be examined at the conclusion of the tumor therapy.

Isolated autosomal recessive TRH deficiency and TRH receptor mutation.  When anatomic hypothalamic and pituitary pathology have been excluded, the clinician can perform a thyrotropin-releasing hormone (TRH) test to localize the cause of the central hypothyroidism. If TRH is deficient, administration of exogenous TRH will raise the TSH concentrations during the TRH-stimulation test. This substantiates the diagnosis of tertiary (hypothalamic) hypothyroidism. However, if TRH is unable to elicit a TSH response, the pituitary is at fault. This substantiates the diagnosis of secondary (pituitary) hypothyroidism.

Assuming that all other anterior and posterior pituitary axes are intact, which in fact is rare, the clinician and laboratorian should consider in their differential diagnosis: (1) isolated autosomal recessive TRH deficiency (chromosome 3) [10] (Table 1), (2) autosomal recessive TRH-receptor inactivating mutations (chromosome 8q23) (Table 2), and (3) familial TSH deficiency (Table 3, discussed below). Collu et al [11] have reported a child with central hypothyroidism resulting from compound heterozygous mutations in the TRH receptor gene. Etiologies of central hypothyroidism are illustrated in Fig. 2.

View larger version (34K): [in this window] [in a new window]   Fig. 2. The molecular mutations that cause central hypothyroidism are illustrated. See text for details. TRH = thyrotropin releasing hormone; TRHR = thyrotropin releasing hormone receptor; TSH = thyrotropin.

TSH beta mutations: familial autosomal recessive TSH deficiency.  Autosomal recessive TSH deficiency results from homozygosity or compound heterozygosity for TSH beta subunit mutations [13,14] (Table 3). Only TSH is deficient as other anterior pituitary hormones are intact. TSH (molecular weight 28 kD) is similar to LH, FSH, and hCG: all are glycoprotein hormones that share a common alpha subunit (Mr 14,700, two oligosaccharide moieties; chromosome 6q21 [PDB] .1–q23) while each glycoprotein hormone has a unique beta subunit that is responsible for the specific bioactivity of the hormone. The TSH beta chain (Mr = 15,600, one oligosaccharide moiety) gene is located on chromosome 1p. Mutations in both TSH beta chain genes lead to TSH deficiency.

TSH deficiency causes congenital hypothyroidism with low to undetectable TSH values. Central hypothyroidism will be detected in neonatal hypothyroid screening programs that test for depressions in total T4. In programs that depend on elevated TSH levels to diagnose hypothyroidism, TSH deficiency will be missed.

Metabolic findings in cases of TSH deficiency include low basal radioactive iodine uptake (RAIU) that increases after administration of bovine TSH. This proves that the thyroid gland itself is normal. After administration of exogenous TRH, intact TSH and the TSH beta subunit remain undetectable, while the TSH alpha subunit is increased in concentration. With exogenous T3 replacement, the alpha subunit concentration declines, demonstrating that feedback exists centrally. Heterozygotes with one normal and one abnormal TSH beta allele are clinically normal. Recurrence risk in siblings is 25%.

The TSH beta gene has 3 exons. The following mutations have been described:

Base change	Nucleotide position	Mutation
G A	29	Missense
G T	94	Transversion
Base deletion	105	Frameshift

Pit-1 and Prop1 mutations: Familial polyhormone hypopituitarism syndromes (Combined pituitary hormone deficiency, CPHD).  Transcription factors are proteins that regulate gene expression. Pit-1 and Prop1 are transcription factors that regulate the activity of several key genes encoding anterior pituitary hormones.

Encoded by the PIT-1 gene on chromosome 3p11, Pit-1 is a pituitary-specific transcription factor that binds to the DNA regulatory regions of the thyrotroph TSH beta gene, the somatotroph growth hormone gene, and the lactotroph prolactin gene. Pit-1 mutations most commonly produce growth hormone deficiency but also commonly produce central hypothyroidism and prolactin deficiency resulting in a combined pituitary hormone deficiency (CPHD) (Table 4). There is no apparent adverse consequence to being prolactin deficient. However, diagnostically, prolactin deficiency should be sought by measuring prolactin as part of the subject’s TRH stimulation test if the subject is evaluated for central hypothyroidism. Gonatrophs that secrete LH and FSH and corticotrophs that secrete ACTH are uninvolved in cases of Pit-1 deficiency.

Expressed at an early stage in pituitary gland development, the prophet of Pit-1 gene (Prop1) encodes a paired-like homeodomain protein within its 3 exons. Prop1 may regulate Pit-1 [15]. Mutations in Prop1 cause gonadotropin (LH and FSH) deficiency in addition to deficiencies of TSH beta, growth hormone and prolactin [16] (Table 5). At least one Prop1 family has additionally been described with ACTH deficiency [17]. This family had a 301–302delAG Prop1 frameshift mutation. This site is a hot-spot for mutation in the PROP1 gene. Another Prop1 mutation is R120C [18]. Magnetic resonance (MR) imaging in patients with Prop1 mutations can reveal congenital hypoplasia of the anterior pituitary gland [19].

	Defects in Thyroid Follicular Cell Response to TSH

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
Mutations in the TSH receptor.  TSH action on the thyroid follicular cell is mediated through a TSH receptor (TSHR)-G protein-adenyl cyclase-coupled production of intracellular cyclic adenosine monophosphate (cAMP). The TSHR is a member of the superfamily of G-protein-coupled receptors. Other members of this receptor superfamily include the ACTH receptor, alpha-adrenergic and beta-adrenergic catecholamine receptors, LH receptor, FSH receptor, hCG receptor, glucagon receptor, PTH receptor, and somatostatin receptor. A rise in intracellular cAMP in the follicular thyrocyte leads to increased iodide uptake, increased thyroperoxidase and thyroglobulin synthesis, hormone secretion, expression of type 1 deiodinase, and growth of the thyroid follicular cell. At high TSH concentrations, TSH activates the Ca²⁺-phosphatidylinositol-phosphate protein kinase C cascade, which stimulates H₂O₂ generation and I^- efflux.

The 10-exon TSH receptor gene, located on chromosome 14q31, covers 60 kb. The predominant mRNA is 4.3 kb,with smaller transcripts also observed. After glycosylation, the TSHR weighs ~100 kDa. Prior to glycosylation, the apoprotein core weighs 84.5 kDa. The N-terminal extracellular domain of 398 amino acids is encoded by the first 9 exons. There are 6 N-glycosylation sites in the extracellular domain. TSH binds to this region of the TSHR. The 346 amino acid carboxyl half of the receptor, which is encoded by a single large exon 10, contains the 7 hydrophobic transmembrane segments that are connected by 3 extra-and 3 intracellular loops and the cytoplasmic portion of the TSHR. This portion of the TSHR demonstrates homology with other G protein-coupled receptors and activates the G_s complex upon TSH binding to the extracellular domain of the TSHR.

Upon TSH binding to the extracellular domain of the TSHR, a conformational change is believed to take place in the TSH receptor. This would allow interactions between the TSHR and the G_s (G stimulatory) complex. Alternatively, the TSHR may exist in 2 forms: an "on" form which interacts with the G_s complex and an "off " form that does not interact with the G_s complex. In the absence of TSH, the TSHR predominantly exists in the "off " form and no signal transduction occurs. However with TSH binding, the equilibrium shifts to the "on" form and signaling continues. In the basal state, the 3 subunits of the G_s complex, alpha, beta, and gamma, are associated and alpha subunit non-covalently binds guanosine diphosphate (GDP). The G protein family has more than 50 members. These proteins bind either GDP or guanosine triphosphate (GTP). The larger G proteins of 80 to 90 kDa function in hormone pathways. The G_s alpha subunit is located on chromosome 20q13.2.

When the TSHR interacts with the basal G_s complex, the alpha subunit dissociates from the beta and gamma subunits. The alpha subunit sheds GDP, which is replaced by guanosine triphosphate (GTP). This "activated" G_s alpha subunit with GTP attached activates adenyl cyclase. Adenyl cyclase converts ATP to cAMP. As a mechanism of internal negative feedback regulation, the "activated" G_s alpha subunit does acquire GTPase activity. This converts the attached GTP to GDP (plus phosphate). The G_s alpha subunit with GDP then recombines with beta and gamma and G_s returns to its basal inactive state (Fig. 3).

View larger version (26K): [in this window] [in a new window]   Fig. 3. Thyrotropin (TSH) binds to a specific TSH receptor on thyroid follicular cells. The Gs protein dissociates into the beta/gamma subunits and an alpha subunit. The alpha subunit loses GDP and gains GTP and becomes active. Through the interaction of the active Gs with adenyl cyclase, adenyl cyclase acquires enzymatic activity and converts ATP to cAMP. Active Gs also expresses an intrinsic GTPase activity. GTPase cleaves GTP to GDP plus Pi. The Gs subunit with GDP is inactive and binds to the beta/gamma subunits to return to its basal state

View larger version (27K): [in this window] [in a new window]   Fig. 4. This schematic diagram illustrates the locations of thyrotropin receptor (TSHR) mutations that produce gain-of-function or loss-of-function effects.

(b) Familial hyperthyroidism.  If the gain-of-function TSHR mutation occurs in the germline, theoretically all thyroid cells would display a degree of autonomy in the production of thyroid hormone resulting in a nonautoimmune form of hyperthyroidism. Nonautoimmune familial hyperthyroidism has been known for at least 20 years [25] (Table 8). Because such gain-of-function mutations are inherited as autosomal dominant characteristics, familial nonautoimmune hyperthyroidism would be recognized in succeeding generations. Nevertheless, we must recall that most cases of familial hyperthyroidism do result from Graves disease where thyroperoxidase, thyroid microsomal, thyroglobulin, or TSH receptor autoantibodies are detected, as well as exophthalmus and pretibial myxedema in adults (pretibial myxedema is rare in children with Graves disease). The TSH receptor autoantibodies (TRAbs) can be assayed by determining thyroid stimulating immunoglobulins (TSIs) or thyrotropin-binding inhibitory immunoglobulins (TBIIs). Autoimmune thyroid disease is often inherited in an autosomal dominant mode, with women more often affected than men. Among autoimmune thyroid disease cases, Hashimoto thyroiditis is more common than Graves disease, but both Graves disease and Hashimoto thyroiditis can be seen in the same family [26]. Familial gain-of-function mutations have been described at TSHR amino acid positions 505, 509, 650, 670, and 672.

(d) TSHR sensitivity to human chorionic gonadotropin (hCG).  A unique form of TSHR gain-of-function mutation was described by Rodien et al [28]. A woman and her mother are described who both developed transient hyperthyroidism that developed only during pregnancy. Analysis of the TSHR DNA sequence revealed a K183R mutation (lysine replaced by arginine at amino acid position 183). When the K183R TSHR was expressed in COS-7 cells in vitro, the COS-7 cells responded normally to the addition of bovine TSH. However, when COS-7 cells were exposed to human chorionic gonadotropin (hCG) in a concentration comparable to the second trimester of pregnancy, the cells with the mutant TSHR showed a 350% increase in cAMP generation (versus TSH stimulation) versus no increase in cAMP in cells with the wild-type TSHR. Thus, while the mutant TSHR responded normally to TSH, the mutant TSHR was able to respond to hCG, which would produce hyperthyroidism only during pregnancy when hCG levels are high.

TSHR loss-of-function mutations;  (a) Euthyroid hyperthyrotropinemia.  Loss-of-function mutations result in decreased respond to TSH. Mild "TSH-resistance" can be overcome by a sufficient elevation in TSH. Such cases with compensated primary hypothyroidism (elevated TSH and normal T4) carry the eponym "euthyroid hyperthyrotropinemia" (Table 9). The first report was of 3 euthyroid sisters similarly affected with elevated TSH levels. They were shown to be compound heterozygotes [P162A (partially functional) and I167N (nonfunctional)] [29]. Cases of euthyroid hyperthyrotropinemia have been summarized by Gagne et al [30].

Several reviews concerning TSHR mutations have recently been published [36–38]. Table 11 summarizes these disorders.

Somatic gain-of-function G_s alpha subunit mutations have been recognized in ~4% of thyroid toxic adenomas and thyroid adenomas in McCune-Albright syndrome (Table 12). The entire thyroid gland is not hyperactive in McCune-Albright syndrome because of mosaicism. In fact, embryonic somatic mosaicism in the gain-of-function G_s alpha subunit mutation explains the "patchy" pattern of skin and tissue involvement in McCune-Albright syndrome.

Gain-of-function G_s alpha subunit mutations also can cause testotoxicosis in association with pseudo-hypoparathyroidism type Ia, 30–40% of non-McCune-Albright growth hormone-secreting pituitary adenomas (somatotrophinomas), and a small percentage of non-secreting and ACTH-secreting pituitary adenomas [39]. Testotoxicosis results from a G_s alpha subunit gain-of-function mutation associated with the LH receptor or from a gain-of-function mutation in the LH receptor itself [40]. This disorder is characterized by the development of precocious puberty in boys where the testes are determined to be the spontaneous source of androgen (eg, testosterone) in the absence of elevated gonadotropin levels. In testotoxicosis there is no evidence for testicular tumor. Expression of the gain-of-function G_s alpha subunit mutation appears temperature-dependent: the gain-of-function mutation may be expressed only in the testes, where the temperature is less than the core body temperature [41].

A loss-of-function mutation in the G_s alpha subunit or absence of the G_s alpha subunit have been described and induce hormone resistance syndromes when the receptor ligand fails to produce the expected result. For example, in Albright hereditary osteodystrophy (pseudohypoparathyroidism type Ia) there is a partial congenital defect in the expression of the G_s alpha subunit. Therefore there is defective response to PTH with ensuing hypocalcemia and hyperphosphatemia. To date, no loss-of-function G_s mutations have been described as causes of thyroid disease.

	Defects in Thyroid Gland Formation

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
Mutations of thyroid transcription factor-2 (TTF-2) and PAX8.  Defects in the intrinsic formation or biochemistry of the thyroid gland can produce congenital hypothyroidism [42,43]. Mutations in two transcription factors have been reported as causes of congenital hypothyroidism: thyroid transcription factor-2 (TTF-2) and Pax8. The homozygous TTF-2 missense mutation (Ala65Val) produced congenital hypothyroidism in siblings and was associated with cleft palate and choanal atresia [44] (Table 13). The forkhead/winged-helix domain transcription factors are often key regulators of embryogenesis. TTF-2 is a member of this family. FKHL15 is the human homologue of mouse TTF-2 .

	Defects in Extrathyroidal Thyroid Hormone Metabolism

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
Disordered conversion of T4 to T3 and decreased metabolism of rT3 (reverse T3, 3,3',5'-triiodothyronine), leading to depressed serum T3 and elevated rT3 concentrations in patients with nonthyroidal illness, are well described in the literature. The following disorders of peripheral thyroid hormone metabolism are not so well known: (1) depressed intracellular-pituitary thyrotroph conversion of T4 to T3, producing either TSH-dependent hyperthyroidism or hyperthyrotropinemia after T4 replacement in primary hypothyroidism and (2) the expression of type 3 iodothyronine deiodinase in infantile hemangiomas.

Defective intrapituitary conversion of T4 to T3.  In the pituitary, conversion of T4 to T3 normally provides the thyrotroph with sufficient levels of intracellular T3 to suppress TSH synthesis and secretion, thereby maintaining the euthyroid state. A family has been reported with TSH-dependent hyperthyroidism where T3, but not T4, administration was able to induce a euthyroid state [50] (Table 15). Either this family displayed isolated pituitary T3 resistance or suffered from a defect in the conversion of T4 to T3 within the pituitary thyrotroph. The hypothesized cause of the hyperthyroidism was that, whereas supra-normal FT3 levels were required to suppress TSH secretion, the normal extra-pituitary peripheral sensitivity of the body to elevated FT3 levels produced clinical hyperthyroidism.

	Defects in Tissue Response to Thyroid Hormone

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

There are two TR genes: TR and TRß, respectively, encoded on chromosomes 17 and 3 (Fig. 5). Alternative splicing of the TR mRNA produces two forms of TR proteins: TR1 and TR2. Similarly, alternative splicing of the TRß mRNA produces two forms of TRß proteins: TRß1 and TRß2. Paradoxically, TR2 does not bind T3. TR1, TR2, TRß1, and TRß2 are expressed to different degrees in various tissues. The sizes of the TRs are given in Table 19 [56].

View larger version (25K): [in this window] [in a new window]   Fig. 5. The genes for the thyroid hormone receptor alpha (TR-alpha) and beta (TR-beta) are in boxes. Below each gene are the various mRNAs that can be transcribed: TR-alpha 1 and TR-alpha 2; and TR-beta 1 and TR-beta 2.

View larger version (19K): [in this window] [in a new window]   Fig. 6. The intranuclear thyroid hormone receptor functions as a transcription factor with characteristic transactivation, DNA-binding/dimerization (DBD), hinge, and ligand-binding domains. Homo or heterodimers of the thyroid hormone receptors may form that can bind co-repressors or co-activators.

View larger version (31K): [in this window] [in a new window]   Fig. 7. Upper left: Thyroid hormone receptors (TRs) that form heterodimers do so with TRs called thyroid receptor accessory (auxiliary) proteins (TRAPs). An example of a TRAP is the retinoid X receptor (RXR). In the normal state when the heterodimer TR-TRAP is bound to the thyroid hormone response element (TRE) in the absence of T3, gene transcription is inactivated as a co-repressor is bound to the TR-TRAP complex and the basal transcriptional machinery (BTM). The BTM is bound to the TATA box. Lower left and upper right: Upon T3 binding, the co-repressor leaves the TR-TRAP complex and a co-activator associates with the TR-TRAP complex. Lower right: The co-activator can subsequently interact with the basal transcriptional machinery to activate gene transcription.

View larger version (27K): [in this window] [in a new window]   Fig. 8. Upper and lower left: If a thyroid hormone receptor (TR) homodimer (TR-TR) is bound to the thyroid hormone response element (TRE), T3 binding to TR-TR liberates TR-TR from the TRE. Upper right : Liberation of the TR homodimer allows TR and a thyroid receptor accessory (auxiliary) protein (TRAP) to bind to the TRE. Lower right: With TR-TRAP binding to the TRE, gene transcription can begin once T3 and a co-activator bind.

View larger version (18K): [in this window] [in a new window]   Fig. 9. Mutations in the thyroid hormone receptor beta protein are located predominantly in 2 domains: mutant domain 1 and mutant domain 2, although some mutations are located outside of these domains. One mutation in the dimerization domain outside of the mutant domains has been strongly associated with isolated pituitary resistance.

View larger version (23K): [in this window] [in a new window]   Fig. 10. If the thyroid hormone receptor (TR) is mutated and doesn’t bind T3 effectively, there will be decreased transcription of genes normally activated by thyroid hormone.

View larger version (23K): [in this window] [in a new window]   Fig. 11. If the thyroid hormone receptor (TR) is mutated and doesn’t bind T3 effectively, there will be decreased release of TR-TR homodimers and decreased transcription of genes normally activated by thyroid hormone.

If thyroid hormone resistance occurs only, or predominantly, in the pituitary gland, TSH hypersecretion produces peripheral hyperthyroidism (Table 22). In this latter rare case, a TSH-secreting pituitary adenoma must be excluded as a cause of TSH-dependent hyperthyroidism. In contrast, in generalized resistance to thyroid hormone, both the pituitary and periphery are resistant to the effects of thyroid hormone. The clinical features of TSH-dependent hyperthyroidism include typical clinical hyperthyroidism, diffuse thyromegaly, lack of exophthalmus, elevated T4, FT4, T3, FT3, high normal to mildly elevated TSH, and absence of thyroid and TSHR autoantibodies. To exclude a pituitary adenoma as the source of excess TSH, the glycoprotein alpha subunit must be measured and a computed tomograph (CT) or magnetic resonance image (MRI) of the pituitary must be obtained. In cases of TSH-secreting tumors, the alpha subunit can be elevated and a mass is radiologically observed. If the alpha subunit is not elevated and no mass is observed on CT/MRI, selective pituitary resistance is likely. Furthermore, TSH-secreting tumors are unresponsive to exogenous administration of TRH. The features of TSH-secreting tumors are summarized in Table 23. There has been debate whether or not isolated pituitary resistance actually exists. The argument for this disorder was strengthened by Safer et al [61], when they described a case clinically compatible with isolated pituitary resistance and a novel TRß mutation not observed in generalized thyroid hormone resistance. This R383H mutation was also located outside domain I and domain II of TRß where previously almost all TRßmutations had been identified.

	Therapy

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

	Summary

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 
While none of the molecular mutations described above are common, such mutations explain a variety of clinical disorders that otherwise defy interpretation. For example, there is now an extensive list of molecular causes of congenital hypothyroidism (Table 24). The astute clinical laboratory scientist needs to be aware of the "new pathobiology" of the hypothalamic-pituitary-thyroid axis in order to consult effectively with clinicians about many types of thyroid laboratory abnormalities that do not fit traditional explanations. The "modern" model of the hypothalamic-pituitary-thyroid axis is becoming more complex (Fig. 12). Yet this model helps to explain otherwise incongruous laboratory results.

View larger version (24K): [in this window] [in a new window]   Fig. 12. The hypothalamic-pituitary-thyroid axis now needs to be understood in terms of cell surface and intranuclear receptors in addition to the traditional thyroid hormones T4 and T3.

	References

Top Abstract Introduction Normal Thyroid Function Overview of Molecular... Molecular Mutations with Central... Defects in Thyroid Follicular... Defects in Thyroid Gland... Defects in Extrathyroidal... Defects in Tissue Response... Therapy Summary References

 

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