different causes of reduced sensitivity to thyroid hormone: diagnosis and clinical management

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This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/cen.12281 This article is protected by copyright. All rights reserved.

Received Date : 16-May-2013 Revised Date: 05-Jun-2013 Revised Date : 30-Jun-2013 Accepted Date : 01-Jul-2013 Article type : Review Corresponding author email id : [email protected]

Different causes of Reduced Sensitivity to Thyroid Hormone: Diagnosis and Clinical

management

Short title:

Syndromes of reduced sensitivity to thyroid hormone

W. Edward Visser, Alies A.A. van Mullem, Theo J. Visser, Robin P. Peeters

Dept of Internal Medicine, Thyroid Division, Erasmus Medical Centre

Corresponding author:

Robin P. Peeters

Dept of Internal Medicine

Erasmus Medical Centre

Dr Molewaterplein 50

Rotterdam

The Netherlands

Phone 0031-10-7044986

Fax 0031-10-7033639

Key words:

Thyroid hormone; transport; metabolism; deiodination; receptor;

No conflicts of interest

Nothing to declare

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This article is protected by copyright. All rights reserved.

Abstract

Normal thyroid hormone (TH) metabolism and action require adequate cellular TH signalling.

This entails proper function of TH transporters in the plasma membrane, intracellular

deiodination of TH and action of the bioactive hormone T3 at its nuclear receptors (TRs). The

present review summarizes the discoveries of different syndromes with reduced sensitivity at

the cellular level. Mutations in the TH transporter MCT8 cause psychomotor retardation and

abnormal thyroid parameters. Mutations in the SBP2 protein, which is required for normal

deiodination, give rise to a multisystem disorder including abnormal thyroid function tests.

Mutations in TRβ1 are a well-known cause of resistance to TH with mostly a mild phenotype,

while only recently patients with mutations in TRα1 were identified. The latter patients have

slightly abnormal TH levels, growth retardation and cognitive defects. This review will

describe the mechanisms of disease, clinical phenotype, diagnostic testing and suggestions

for treatment strategies for each of these syndromes.

General introduction

Thyroid hormone (TH) is essential for normal development and for the physiological function

of virtually all tissues. As a consequence, hypothyroidism affects multiple tissues resulting in

a variety of symptoms such as fatigue, cold intolerance, constipation, congestive heart failure,

and depression. The importance of TH for development is illustrated by the consequences of

untreated congenital hypothyroidism, resulting in severe growth failure and permanent

mental retardation.

The first report of patients with a familial syndrome of reduced sensitivity to TH at the tissue

level was published in 1967 1. These patients had high levels of TH without clinical

symptoms of hormone excess, or even with symptoms of TH deficiency in certain tissues 2.

After cloning of the T3 receptor isoforms TRβ1 3 and TRα1 4, encoded by the THRB and

THRA genes, respectively, it was demonstrated that this clinical syndrome of resistance to TH

(RTH) was due to inactivating mutations in THRB 5. Since then, more than 1000 patients with

RTH have been published (see 6,7 for excellent reviews).

In recent years, other syndromes associated with a reduced sensitivity to TH have been

recognized, involving a defect in transport of TH across the cell membrane 8,9, a defect in the

synthesis of selenoproteins, including TH-deiodinating enzymes resulting in an abnormal TH

metabolism 10, as well as a defect in the T3 receptor TRα1 11,12. Thus, normal TH action

requires both adequate serum TH concentrations and TH signalling at the cellular level of the

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target tissues. The current review focuses on the clinical diagnosis and management of all

known different causes of a reduced sensitivity to TH.

Regulation of TH bioactivity

Serum TH levels are principally regulated by the hypothalamus-pituitary-thyroid (HPT)

axis. The hypothalamus produces thyrotropin releasing hormone (TRH) which stimulates the

pituitary to produce thyroid-stimulating hormone (TSH). TSH acts on the thyroid gland to

synthesize TH. The thyroid secretes predominantly the prohormone T4 and to a lesser extent

the bioactive hormone T3.

TH bioactivity and action are regulated at the cellular level (Figure 1). Most actions of TH

are initiated by binding of T3 to its nuclear T3 receptors (TRs), located on T3 response

elements (TREs) in the promoter region of target genes. Binding of T3 results in a change in

the interaction of TRs with co-activator and co-repressor proteins and consequently in an

altered expression of the target genes. Different TR isoforms are encoded by two genes:

THRA and THRB 13. TRα1 is the predominant TR receptor isoform expressed in brain, bone

and heart, whereas TRβ1 is considered the major isoform in liver, kidney and thyroid.

Through alternative exon usage, TRβ2 differs from TRβ1 at the N-terminus and displays a

more restricted expression pattern (retina, cochlea, pituitary) 14.

Intracellular T3 levels are governed by intracellular deiodinases and TH transporters at the

plasma membrane. Three deiodinating enzymes (D1-3) have been identified which catalyze

the activation of T4 to T3 or the inactivation of T4 to 3,3’,5’-triiodothyronine (reverse T3,

rT3) and of T3 to 3,3’-diiodothyronine (3,3’-T2) 15. D1 is highly expressed in liver, kidney

and thyroid and is considered important for serum T3 production as well as for clearance of

serum rT3. D2 is localized particularly in brain, pituitary, brown adipose tissue, thyroid and

skeletal muscle. It has been firmly established that D2 is crucial for local production of T3 in

different tissues. D3 is an inactivating enzyme catalyzing degradation of T3 and T4. D3 is

mainly expressed in fetal tissues. In adult life, D3 expression is limited to the brain and skin,

but can be reactivated in other tissues under pathological conditions 16,17. Recent studies have

established that intracellular TH signaling can be largely modified by deiodination without

affecting circulating TH levels, thereby modulating processes such as differentiation and

regeneration 16,18,19.

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Since action and deiodination of TH take place intracellularly, transport of the hormone

across the plasma membrane is required. Although many transporters accept TH as a ligand,

only a few have been shown to be specific TH transporters 20. Monocarboxylate transporter 8

(MCT8, SLC16A2) has been shown to specifically transport the iodothyronines T4, T3, rT3

and T2 21,22. The highly homologous MCT10 (SLC16A10) was initially designated as a T-

type aromatic amino acid transporter, but has later been shown to transport TH, with a

preference for T3 over T4 23,24. Both MCT8 and MCT10 are widely expressed. The organic

anion transporting polypeptide 1C1 (OATP1C1) is importantly expressed in brain and

transports T4 25. Possibly, other as-yet-unknown specific TH transporters are important for

human physiology 26.

The last decade has witnessed the discovery of several novel syndromes of reduced

sensitivity to TH, related to dysfunction in TH transport 8,9, deiodination 10 and receptor

function 11,12.

Causes of Reduced Sensitivity to TH

Defect in TH transport

Background

The clinical importance of TH transporters was established by the discovery of mutations

in the MCT8 gene, which is located on the X-chromosome, as a cause of psychomotor

retardation accompanied by TH abnormalities 8,9. Affected males display a severe delay in

motor and neurological development 27. Soon after the description of the first patients, it was

realized that the phenotype had similarities to the Allan-Herndon-Dudley syndrome (AHDS),

the first X-linked mental retardation syndrome described in 1944. Genetic analysis in these

families revealed that MCT8 mutations are the genetic basis of AHDS 27. To date, over 100

families have been reported with pathogenic mutations in MCT8.

Clinical phenotype

Patients have cognitive impairments with intelligence quotient values mostly below 40.

Many patients are unable to speak and are only able to communicate by nonverbal acts. Some

patients have been reported to suffer from seizures. All patients have difficulties with

swallowing. The consequent feeding problems are one of the reasons for the first referral.

Hypotonia of the limbs in childhood progresses into spastic quadriplegia with advancing age.

The severe axial hypotonia, which is manifested by a poor head control, persists into

adulthood. Muscle hypoplasia, in particular of the quadriceps muscle, is observed in all

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patients. Most patients are unable to walk independently. At birth, height and weight are

usually unremarkable. However, during childhood weight declines below the third percentile

in most patients.

Few patients reportedly have somewhat milder features. Some patients are able to walk

without support and can communicate verbally. Patients with a less severe clinical phenotype

typically have less abnormal thyroid parameters. MCT8 mutants of less severely affected

patients also display residual activity in in vitro TH transport assays 28, suggesting a

genotype-phenotype relationship in the AHDS. In general, female carriers do not exhibit

neurological features. However, they have serum FT4 levels in between those in affected

males and unaffected relatives 29.

Laboratory findings and differential diagnosis

Characteristic for all AHDS patients is their remarkable combination of serum TH

abnormalities (Figure 2). Serum (F)T4 concentrations are low or low-normal, while TSH

levels are in the high normal range. In contrast, serum (F)T3 levels are markedly elevated. In

particular during childhood serum T3 levels are far above the upper reference limit. Serum

rT3 levels are largely reduced. Consequently, T3/rT3 ratio's are strongly increased. This

biochemical profile is very similar to the thyroid function tests seen in patients with THRA

mutations (see below), although it appears that serum T3 levels are less elevated than in

AHDS patients.

Mechanisms of disease

The mechanisms behind the clinical and laboratory features of AHDS are only partially

understood. As shown by in vitro transport assays, TH transport is largely or completely

impaired by the MCT8 mutations identified 30. TH transport capacity is also largely reduced

in fibroblasts from MCT8 patients 28. Thus, abnormal handling of TH transport appears the

basis of the disease.

Several mechanisms contribute to the low T4 levels. In Mct8 knockout (KO) mice, kidney

T4 levels are increased despite the low serum T4 levels, suggesting that T4 is trapped in the

kidney 31. At the same time, kidney (and liver) D1 expression is markedly increased, which

should result in a prominent increase in peripheral T4 to T3 conversion. Recently, it was

shown that MCT8 expression in the thyroid gland is required for TH secretion, which is

therefore disturbed in Mct8 KO mice 32,33. The consequent accumulation of T4 within the

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thyroid gland when MCT8 is mutated may thus lead to increased intra-thyroidal conversion

to T3. This will favor an increased T3/T4 ratio in the thyroid, resulting in a net increase in T3

secretion via other efflux pathways. The important contribution of D1 in the thyroid and

peripheral tissues to the high serum T3/T4 ratio in Mct8 deficient mice (and patients) is

supported by findings that Mct8/Dio1 double KO mice have normal serum TH levels 34. Also,

block-and-replace therapy of an AHDS patient with LT4 and the thyrostatic drug

propylthiouracil (PTU), which also inhibits D1, normalized serum T3 concentrations. This

was not the case when methimazole was used, which does not inhibit D1 35. The decreased

serum rT3 levels is caused by reduced availability of its substrate T4 as well as by the

elevated D1 activity, for which rT3 is the preferred substrate.

The high serum T3 levels induce thyrotoxic effects on peripheral tissues which likely

explain the progressive loss of muscle mass as well as the decline in body weight during

childhood. Also SHBG levels, which are T3-dependent and reflect liver thyroid state, are

markedly elevated in AHDS patients. Although FT4 levels are low, TSH levels appear

inappropriately high in the context of the high serum T3 concentrations, suggesting

interference in the feedback of TH at the pituitary and/or hypothalamic level.

The neurological phenotype of AHDS patients is much less understood. The current

hypothesis holds that derangement of TH homeostasis in the brain likely underlies the

mechanism of disease in AHDS, since neuronal differentiation and myelination are TH-

dependent processes 36. This entails a defect of T3 entry in MCT8-expressing neurons and,

thus, deprivation of TH in specific brain regions and perhaps excessive accumulation of T3 in

neurons which use other transporters for their T3 supply. MCT8 is also importantly expressed

in capillaries and, thus, also appears important for transport of both T3 and T4 across the

blood-brain barrier. Mct8 KO mice lack neurological features, despite largely impaired T3

uptake into the brain, while T4 uptake is preserved. Apparently, these mice employ

compensatory mechanisms. Increased cerebral D2 activity in Mct8 KO mice may produce

sufficient T3 for normal brain development. In addition, these animals likely express a

specific T4 transporter, such as Oatp1c1, which mediates T4 transport across the BBB. This

hypothesis is supported by a recent study of Oatp1c1 KO mice which revealed markedly

reduced cerebral T4 levels 37. Expression of Oatp1c1 in the mouse, but perhaps much less so

in the human BBB 38, may well explain the differences in brain phenotype between mice and

humans deficient in MCT8.

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Altogether, AHDS patients exhibit clinical features caused by a combination of

hyperthyroid and hypothyroid tissues. Thus, depending on expression of MCT8 or other TH

transporters, tissues of AHDS patients are either deprived of TH (brain) or exposed to excess

TH ( liver and muscle).

Therapy

Unfortunately, no effective treatment is available for AHDS patients at present. General

supportive care should be provided, including adequate feeding support to avoid aspiration

and anti-epileptic drugs to prevent seizures if necessary.

Given the low FT4 levels, LT4 suppletion was initiated in some patients with no beneficial

effects on peripheral thyrotoxicity 39,40. Normalization of serum T4 and T3 levels was readily

achieved in a few AHDS patients by block-and-replace therapy using PTU and LT4 35,41. This

had some beneficial effects such as an increased body weight and reduction in SHBG levels.

Hypothetically, cerebral regions which do not rely on MCT8 for their TH supply might also

benefit from this treatment. However, treatment with PTU and LT4 did not result in an

improvement of cognitive functions in these older patients of 16 and 37 years of age.

Effective therapy should not only normalize toxic TH effects in peripheral tissues but also

normalize the disturbed TH signaling in brain. Some studies have been performed with the

T3 analogs diiodothyropropionic acid (DITPA) and triiodothyroacetic acid (Triac, TA3) and

the T4 analog tetraiodothyroacetic acid (Tetrac, TA4)42-44. TA4 is efficiently activated by D2

to TA3, and TA4 and TA3 are inactivated by D3, thus following the normal deiodination

routes. It was shown in Mct8 KO mice made hypothyroid that TA4 was able to restore brain

development 42. Studies in Mct8 KO mice with DITPA demonstrated the normalization of TH

parameters and attenuation of the thyrotoxic state of peripheral tissues 43. Importantly, an

improvement of several indices of TH action in brain was observed. These observations

prompted a study of the possible beneficial effects of DITPA therapy in four AHDS patients,

the results of which were published recently 44. The main consistent findings were a

significant decrease in serum T3, with little change in serum T4 and TSH levels. The

normalization of T3 levels appeared beneficial for the liver and heart as suggested by the

decrease in SHBG levels and heart rate, respectively. Weight gain was noted in some patients

but also a progressive weight loss in another patient. None of the patients showed

improvement in psychomotor development.

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Future strategies to define optimal treatment for AHDS patients may explore the use of

alternative TH analogs. The abovementioned studies in AHDS patients all have in common

that these therapies were carried out in patients in whom impaired brain development is likely

irreversible. Therefore, it is important to diagnose MCT8 mutations as early as possible.

Defect in TH metabolism

Background

Metabolism of TH is importantly controlled by the iodothyronine deiodinases (see above).

Deiodinases are selenoproteins, a small group of proteins within the human proteome

containing the rare amino acid selenocysteine (Sec). Sec is crucially required for normal

enzyme function, since it is located in the catalytic domain of the deiodinases. An intricate

system ensures the incorporation of Sec in selenoproteins and, thus, also in the deiodinases.

Sec is encoded by a UGA codon that normally functions as translation termination codon.

Recoding of UGA for incorporation of Sec requires the presence of a Sec insertion sequence

(SECIS) located in the 3'-UTR of the deiodinase mRNA. The stem-loop structure of the

SECIS element is recognized by SECIS-binding protein 2 (SBP2). Subsequently, various

factors are recruited including the specific Sec tRNA which ultimately results in the

incorporation of Sec.

In 2005 a novel syndrome of delayed growth and abnormal thyroid parameters was

ascribed to mutations in SBP2 10. Until now, a total of 8 families have been identified 6. See 6

for a recent excellent overview.

Clinical phenotype

The most prominent feature in all identified families is the growth retardation 6. In

addition to delayed growth, (mild) mental and motor retardation, muscle weakness,

hypoglycemia and impaired hearing infertility are variably reported 45. One adult patient has

been reported with primary infertility and skin photosensitivity as well 45. As almost all

identified patients are children, the natural course of disease is presently unknown. All

patients identified until now have residual SBP2 activity. Complete lack of SBP2 is thought

to be lethal 6.


The typical biochemical findings in patients with SBP2 mutations are elevated serum

(F)T4 and rT3 levels, low to low-normal serum T3 levels and normal to slightly elevated

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serum TSH levels. Serum total selenium levels are reduced 10. Similar to patients with

mutations in TRα1, growth retardation is the most prominent clinical feature. However, all

patients identified so far with TRα1 mutations have low FT4 and rT3 levels. The biochemical

profile of elevated (F)T4 levels and slightly elevated TSH levels is also seen in patients with

RTH or a TSH-producing pituitary adenoma (see below), but these patients have elevated T3

levels as well whereas patients with SBP2 mutations have low or low-normal T3 levels.

Mechanisms

The human genome encodes about 30 selenoproteins, whose syntheses are all impaired by

SBP2 mutations. It is not surprising therefore that SBP2 mutations result in a multisystem

disorder where the function of many tissues is affected 45. The deranged TH parameters result

from affected synthesis of the deiodinases. At present, it is unknown to which extent each

deiodinase contributes to the phenotype. The TH abnormalities seen in patients with SBP2

mutations are reminiscent of most TH serum parameters of mice deficient in both D1 and D2 6. In line with this, baseline and stimulated D2 activities are much lower in fibroblasts from

patients than in cells from unaffected relatives 10. In vivo studies demonstrated that patients

required much higher LT4 doses to suppress TSH levels than unaffected subjects, whereas

TSH levels showed a similar response to LT3 treatment in patients and controls 10. These data

suggest a decreased conversion of T4 to T3 at the pituitary level in these patients. The

delayed growth may partially result from low T3 levels. Thus, the most prominent features of

this disease, i.e. growth retardation and abnormal serum thyroid parameters, are explained by

impaired function of TH deiodination.

The low serum selenium concentrations in patients with SBP2 mutations result from

impaired synthesis of selenoprotein P (SePP) and glutathione peroxidase 3 (Gpx3), which are

the major carriers of Se in serum. Detailed investigations suggest that some symptoms (e.g.

myopathy) result from tissue-specific selenoprotein deficiency, while other features (e.g.

hearing loss, impaired T cell function) are mediated by impaired cellular antioxidant defence

and, thus, increased ROS levels 45.

Therapy

Several reports have described the effects of LT3 suppletion to children with SBP2

mutations 45,46. A strong initial catch-up growth was noticed on LT3 treatment, although

complete normalization was not reached.

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Administration of selenium to different patients raised serum SePP and consequently

selenium levels 46,47. However, selenium supplementation for a few months failed to

normalize GPx activity or serum TH abnormalities. Selenium supplementation appears not to

have benefits for these patients.

As increased ROS levels underlie parts of the syndrome, antioxidant therapy may be

useful to prevent and possibly revert some features. In vitro studies suggest beneficial effects

of antioxidants in patient’s cells 45. Studies are awaited to demonstrate the usefulness of

antioxidant therapy in patients.

Defect in nuclear T3 receptors

Mutations in THRB (RTH)

Background

It is known for more than twenty years that heterozygous mutations in the ligand-binding

domain (LBD) of TRβ1/2, impairing their hormone binding and/or transcriptional activity,

result in RTH 5. The mutant TRβ interferes with the function of wild-type (WT) TRβ,

resulting in a dominant-negative effect and dominant inheritance 48. In contrast, RTH caused

by THRB gene deletions has a recessive inheritance, due to a lack of dominant-negative

interference with the WT receptor 49. Homozygous mutations in TRβ are rare and result in a

severe phenotype 7.

To date, more than 1000 patients with mutations in THRB have been described, belonging to

more than 350 families 6,7,50,51. The mutations cover about 50 different amino acids and are

located in three separate clusters.

Clinical phenotype

Patients with RTH have a variable phenotype including goiter, tachycardia, raised energy

expenditure, hyperactive behaviour, delayed bone age, and learning disabilities 50,52 (Table 1).

In general, RTH is characterized by a relative lack of symptoms despite high serum levels of

T4 and T3. Symptoms are due to a combination of low TH action in predominantly TRβ-

expressing tissues, and TH overexposure in TRα-expressing tissues 53. Patients who receive

treatment to normalize their TH values often develop typical symptoms of hypothyroidism.


RTH is characterized by elevated serum TH levels and a non-suppressed TSH. RTH patients

secrete a form of TSH rich in sialic acid with a higher bioactivity 54. This explains the high

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prevalence of goiter, although TSH levels may be within the normal range or only slightly

elevated. RTH patients treated by thyroidectomy and/or radioiodine therapy and substituted

with different doses of LT4 show a negative log-linear TSH-FT4 relationship with a slope

lower than non-RTH patients in concordance with the decreased affinity of the mutated TRβ

receptor for T3 55. Serum thyroglobulin levels tend to be high, reflecting hyperactivity of the

thyroid. Serum rT3 levels are high resulting from a decreased activity of D1, which gene is

T3-dependent and under control of TRβ 15.

Diffuse goiter and sinus tachycardia are the most common clinical findings. The combination

with high levels of TH may easily lead to the incorrect diagnosis of hyperthyroidism. The

differential diagnosis of RTH includes all other causes of elevated TH levels in combination

with a non-suppressed TSH. First, abnormalities in serum binding of TH, such as familial

dysalbuminemic hyperthyroxinemia, thyroid binding globulin (TBG) excess, or transthyretin

excess should be excluded by measuring FT4 and T3 using a different method or equilibrium

dialysis 56,57. The subsequent distinction between RTH and a TSH producing pituitary

adenoma (TSHoma) may be the most challenging, since in both conditions the FT4 and T3

will be elevated independent of the method used. However, where RTH is usually

characterized by a relative lack of symptoms, most patients with a TSHoma are hyperthyroid 58. About 85 percent of patients with TSHomas have high concentrations of the glycoprotein

hormone alpha-subunit, with a relative greater increase than serum TSH. As a result, a high

molar serum alpha-subunit to TSH ratio is almost pathognomonic for a TSHoma 50,58.

A mutation in the THRB gene confirms the diagnosis of RTH. However, in about 10-15% of

patients with classical RTH no mutation in THRB can be detected (see below) 59,60. Elevated

TH levels and a non-suppressed TSH in other family members may help to distinguish

between RTH and a TSHoma. If not, additional stimulation and repression tests using TRH

and/or T3 can be required to confirm the diagnosis 6,50,58.


Mutations in THRB identified in RTH patients are located in the C-terminus of TRß1/2,

mostly contained within three CpG rich “hot spots” in the LBD (aa 242-460 in TRβ1) and

adjacent hinge domain (aa 234-243) of the receptor protein 50. The mutant TRß proteins have

a reduced affinity for T3, and/or abnormal interaction with cofactors (decreased interaction

with coactivators 61 or increased interaction with corepressors 62). Interestingly, mutations

resulting in a complete lack of T3 binding in combination with a reduced affinity for

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corepressors, may result in a minimal phenotype 48,50. The severity of TH resistance varies

not only among different tissues in an affected individual, but also among different subjects

carrying the same gene mutation, even within the same family 63,64. The reasons for this

variability are not yet understood, but it probably results from genetic variability of cofactors

involved in TH action. Despite this variability, careful analyses of patients with various

THRB mutations have demonstrated a partial genotype-phenotype correlation of receptor

dysfunction vs. clinical symptoms 48.

Mouse models replicating mutations observed in patients have been generated (such as TRβ-

PV and T337 Δ). Heterozygous mice show very similar characteristics as heterozygous

human patients with RTH. In addition, homozygous mice develop metastatic thyroid cancer 65.

In about 15% of patients and families with RTH, no mutation in THRB has been identified 59,60. The phenotype of this so-called “non-TR RTH” is not different from RTH due to TRβ

gene mutations. Although screening of different coactivators and repressors for mutations has

not identified a cause for non-TR RTH yet, it is likely that new mutations will be identified in

the near future now that techniques such as exome and whole genome sequencing become

more widely available.

Therapy

In most patients, treatment is not necessary because the resistance seems to be adequately

compensated by the elevated levels of T4 and T3. Tachycardia and tremor as symptoms of

hyperthyroidism can be adequately treated using beta adrenergic blockers such as atenolol. In

rare cases, treatment with TA3, which has a higher affinity for TRβ than for TRα, can be used

to lower serum TSH and TH levels and thereby reduce clinical symptoms of hyperthyroidism 66.

The treatment of RTH during pregnancy is beyond the scope of this review, and for this

reason the reader is referred to an excellent overview article by Weiss and colleagues 67,68.

Mutations in THRA

Background

Ever since its characterization in 1987, investigators have searched for patients with

mutations in THRA 4. As TRα1 is not involved in the negative feedback action of TH, no

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major changes in serum TH levels were expected. To unravel the physiological role of TRα,

different mouse models were generated. Interestingly, mice devoid of all TRs have less

symptoms of hypothyroidism than wild-type hypothyroid mice, consistent with a repressive

effect of unliganded TRs 69. Unliganded TRα1 seems to play a major role in the cerebellar

damage in hypothyroid mice 70 71-75. Only very recently, the first human patients with

heterozygous inactivating mutations in TRα1 were identified 11,12.

Clinical features

The phenotype of these first patients with inactivating mutations in TRα1 includes growth

retardation (Figure 3A), delayed bone development (Figure 3B), mildly delayed motor and

mental development, abnormal thyroid function tests, low GH and IGF1 levels, and

constipation 11,12 76. These findings support an important role of TRα1 in bone, brain,

intestine, and possible involvement in GH regulation.

In addition to the growth retardation, delayed bone development is an important part of the

phenotype. Both young patients had a delayed tooth eruption, delayed closure of the skull

sutures, and a clearly delayed bone age 11,12,76. Also motor and mental development were

delayed in both patients. One of the two patients was even admitted to the hospital at 9

months of age because of a delayed motor development. At that age, she was not able to sit

by herself and she did not have full control of head movement (personal communication from

D. Chrysis).

Mice with a TRα1 mutation have a very diverse phenotype, depending on the location and the

severity of the mutation. These diverse phenotypes are probably due to different interactions

of unliganded TRα1 mutants with co-repressors, whose expression is tissue-dependent and

developmentally regulated 62,77. Although the phenotypes of the first patients with mutations

in THRA are similar 11,12,76, there are differences as well. For example, constipation is more

severe in the patient described by Bochukova and colleagues, whereas the serum T3 is much

more elevated in the other two patients. Similar to the different mouse models, it can be

expected that mutations with a different location or a less detrimental effect on the function

of TRα1, will have a different or more subtle effect on the clinical phenotype.

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The abnormal thyroid function tests in patients with mutations in TRα1 include low (F)T4,

high T3, low rT3, but normal TSH levels. The high T3/T4 ratio as well as the low rT3 levels

in all three patients with a TRα1 mutation suggest an altered expression of deiodinases, which

are the most important mediators of peripheral metabolism of TH (see above). TRα1-PV

mutant mice, with a similar frame-shift mutation in TRα1 as two of the three patients, have

increased levels of hepatic D1 71. Increased D1 activity results in increased T4 to T3

conversion and degradation of rT3. In addition, TRα1-/- mice have an impaired regulation of

D3, which leads to a reduced production of rT3 and degradation of T3 78,79. Both changes in

D1 and D3 expression may contribute to the particular TH changes in patients with TRα1

mutations.

Although patients with TRα1 mutations may have several clinical symptoms of

hypothyroidism 11,12 76, the diagnosis will be easily missed when only TSH and/or FT4 are

measured, since both can be normal. From the patients who have been identified so far, it

seems that an elevated T3/T4 ratio and a low serum rT3 are the hallmarks of the biochemical

diagnosis. These changes in thyroid function tests are very similar to those seen in patients

with MCT8 mutations, suffering from severe X-linked mental retardation (see above).

It remains to be determined if patients with more subtle mutations in TRα1 have a similar

biochemical profile. The identification and detailed characterization of additional patients

with mutations in THRA is of critical importance. Since one affected allele is sufficient to

develop the disease and patients seem to be fertile 12, THRA mutations may be a relatively

frequent cause of growth abnormalities and/or cognitive defects which may respond to LT4

treatment depending on the severity of the mutation (see below).


The mutations identified in the first human patients (F397fs406X, E403X) are located in the

C-terminal domain of TRα1. Figure 4 shows the lack of T3 stimulation of the TRα1-

F397fs406X mutation, which has been identified in two (father and daughter) of the three

patients described so far 11,12. The mutant TRα1 has a dominant negative effect over WT

TRα1 when transfected in a 1:1 ratio, explaining the autosomal dominant effect.

The mutations in the first three human patients are very similar to mutations in the different

TRα1 mouse mutants that have been generated 71-75. TRα1-T394fs406X and TRα1-L400R

have been reported to lack affinity for T3 as well 71,73. Interestingly, the phenotypes of TRα1-

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T394fs406X (TRα1-PV) and TRα1-L400R mice are very similar to the phenotype of the first

human patients, with severe growth retardation as the most prominent phenotype 71,73. In

contrast, TRα1-R384C mutant mice exhibit a more severe cerebral phenotype, although these

mice have mild growth retardation as well 80,81. The TRα1 mutation in these mice is more

subtle, resulting in some residual T3 binding capacity of TRα1.

Therapy

An initial catch-up in growth rate and bone age was observed in the index patient identified

by our group when TH therapy was started at 6 years of age (Figure 3A), although no clear

effect of LT4 on growth was observed in the other patient identified 11,12,76. Additional GH

treatment had little effect in our patient 12. In addition to the initial catch-up in growth rate,

we observed a normalization of the dyslipidemia, as well as a response in serum IGF1, SHBG

and creatine kinase in the index patient 76. Besides this biochemical response, LT4 also

resulted in an improvement of the constipation 11,12,76, whereas cognitive and fine motor skill

defects remained. Thyroxine treatment in the other patient (50 mcg daily for 9 months)

resulted in a normalization of her basal metabolic rate and circulating IGF-1 levels, whereas

heart rate and blood pressure remained low 11. At this dosage, her growth rate and intestinal

transit time did not change significantly.

Interestingly, growth retardation can be overcome in TRα1-R384C mice, whose receptor has

a 10 times decreased affinity for T3, by raising serum TH levels 74,80,81. Furthermore, these

mice display neurological damage which improves after T3 treatment. A delayed cerebellar

development and locomotor dysfunction is prevented by postnatal T3 treatment, whereas

anxiety-like behaviour and reduced recognition memory is relieved by T3 treatment in

adulthood 80. All patients who have been identified so far have mutations resulting in a

complete lack of T3 binding. Based on these studies in TRα1-R384C mice, it is tempting to

speculate about the beneficial effects of LT4 treatment in human patients with milder

mutations in TRα1 resulting in a decreased instead of a lack of T3 affinity.

General conclusion

Normal TH metabolism and action require adequate cellular TH signalling. The last decade

has witnessed the identification of several novel syndromes resulting from defects in TH

transport, deiodination and receptor function. Since the clinical consequences can be severe,

it is of utmost important to develop adequate treatment strategies for these different clinical

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syndromes. These important recent discoveries may hold the promise that the route of TH

signalling will turn out to be even more exciting in the near future.

References:

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Model of TH regulation at the cellular level. Transporters are required for uptake and release

of T4 and T3. MCT8 is prototypic for cellular T3 and T4 transport. Three deiodinases are

involved in activation or inactivation of TH. D1 is mainly involved in TH regulation in serum

and, therefore, is not shown in the figure. D2 and D3 are important for local TH regulation.

D2 converts T4 to bioactive T3, whereas D3 degrades T3 to 3,3’-T2. Insertion of the

selenocystein into the deiodinases requires SBP2. Ultimately, T3 binds to its nuclear

receptors (TRs) and modulates gene expression of T3-target genes.

Figure 2.

Thyroid parameters in serum from 25 patients from 21 families with MCT8 mutations. Serum

levels of TSH, fT4, T3, and rT3 in affected males are depicted as box plots. Reference

ranges are indicated in grey.

Figure 3.

A. Height chart of the 6-year-old girl with a heterozygous frame-shift mutation in TRα1

(F397fs406X). B. Bone age determined by X-ray images of the left hand versus calendar age.

Initiation of LT4 treatment is indicated by arrows. Adapted from 12.

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Figure 4.

Functional analysis of wild-type (WT) and mutant (F397fs406X) TRα1 with a luciferase

reporter construct. Mutant TRα1 does not respond to activation by T3. Furthermore, mutant

TRα1 has a dominant negative effect over the WT receptor. Adapted from 12.

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different causes of reduced sensitivity to thyroid hormone: diagnosis and clinical management

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