Resistance to thyroid hormone action in the hypothalamic– pituitary– thyroid axis is the hallmark of RTHβ, with inappropriate pituitary TSH secretion driving T4 and T3 production, to establish a new equilibrium with high circulating TH, together with non- sup pressed TSH levels. RTHβ was first described in 1967 in two siblings with high circulating TH levels who were clinically euthyroid and exhibited other features (deaf- mutism, stippled femoral epiphyses, winging of scapulae, pectus carinatum, short stature, and dysmorphic facies) which are unique to this kindred, in which the dis order was recessively inherited.

The prevalence of RTHβ is approximately 1 in 40 000 and several hundred cases (from more than 250 families) have been described. The disorder is usually dominantly inherited and associated with variable clinical features. Many patients are either asymptomatic or have non- specific symptoms and a goitre, prompting testing of thyroid function, which suggests the diagnosis. In such individuals, classified as exhibiting generalized resistance (GRTH), the high thyroid hormone levels are thought to compensate for ubiquitous tissue resistance, resulting in a euthyroid state. In contrast, a subset of individuals with the same TH abnormalities exhibit thyrotoxic clinical features: in adults these can include weight loss, tremor, palpitations, insomnia, and heat intolerance; in children failure to thrive, accelerated growth, and hyperkinetic behaviour have also been noted. When the latter clinical entity was first described, patients were thought to have ‘selective’ or predominant pituitary resistance to thyroid hormone action (PRTH), with preservation of normal responses to TH in peripheral tissues.

However, comparison of characteristics of individuals classified as GRTH or PRTH indicates significant overlap between these entities, with no differences in age, sex ratio, frequency of goitre, or levels of free T4, free T3, or TSH between patients with the two types of RTHβ. Significantly, features such as tachycardia, hyper kinetic behaviour, and anxiety have been documented in individuals with GRTH. Conversely, serum SHBG— a hepatic marker of thyroid hormone action— is normal in patients with PRTH, suggesting that tissue resistance is not solely confined to the pituitary– thyroid axis in this group. Indeed, in some RTHβ cases, hypothyroid features such as growth retardation, delayed dentition, or bone age in childhood or hypercholesterolaemia in adults, may coexist with thyrotoxic symptoms in the same individual. Nevertheless, the absence or presence of overt thyrotoxic symptoms, signifying either GRTH or PRTH phenotypes, respectively, is a clinical distinction which remains useful in guiding management of the disorder.

Clinical Features

Goitre Palpable goitre is present in up to 65% of individuals— especially adult women. Fewer children with RTHβ born to affected mothers exhibit thyroid enlargement (35%) compared to off spring born of unaffected mothers (87%), suggesting that maternal hyperthyroxinaemia may protect against goitre formation. Increased biological activity of circulating TSH may account for goitre and marked hyperthyroxinaemia in some RTHβ patients with normal immunoreactive TSH levels. A multinodular thyroid gland can develop, particularly following previous goitre surgery, but thyroid cancer is rare and most likely represents coincidental micropapillary carcinoma.

Cardiovascular System

In a large cohort of children and adults with RTHβ, resting heart rate was significantly raised with some indices of cardiac systolic and diastolic function (e.g. stroke volume, cardiac output), suggesting a ‘partially hyperthyroid’ cardiac phenotype. Atrial fibrillation is commoner in older RTHβ patients, but they do not exhibit the hypercoagulable state associated with conventional hyperthyroidism.

Skeletal Abnormalities

 Childhood short stature (height <5^th centile) has been noted in 18% and delayed bone age (more than two standard deviations) in 29% in RTHβ, but final adult height is not usually affected. In adults, we have measured bone mineral density in approximately 80 subjects with RTHβ and documented a reduction at both femoral neck (mean Z score – 0.71) and lumbar spine (mean Z score – 0.73), but with normal bone turnover markers (Gurnell, Chatterjee and Beck- Peccoz, unpublished observations).

Metabolic

 Resting energy expenditure (REE) is substantially increased in adults and children with RTHβ, due to mitochondrial uncoupling in skeletal muscle. Increased energy expenditure is accompanied by hunger, reduced satiety, and raised energy intake, with hyperphagia being particularly evident in childhood.

Central Nervous System

A history of attention- deficit hyperactivity disorder (ADHD) in childhood was more frequent (75%) in RTHβ patients compared to their unaffected relatives (15%), but screening for RTHβ in ADHD cohorts is negative. Children and adults with RTHβ exhibit problems with language development, manifested by poor reading skills and problems with articulation. Frank intellectual dis ability (IQ less than 60) is quite uncommon but 30% of patients show mild learning disability (IQ less than 85).

Hearing and Vision

 Significant hearing loss has been documented in 21% of RTHβ cases: in most, audiometry indicated a conductive defect, probably related to an increased recurrent ear infections in childhood; ab normal otoacoustic emissions, suggestive of cochlear dysfunction, were also documented in those with hearing deficit. Defective colour vision has been documented in homozygous RTHβ; ab normal photoreceptor electroretinography in heterozygous RTHβ is not associated with overt colour visual dysfunction.

Other Associated Disorders

 RTHβ cases with coexistent autoimmune hypothyroidism or Graves’ disease have been recorded and the increased prevalence of thyroid autoantibodies found in a large RTHβ cohort suggests possible predisposition to thyroid autoimmunity. Inappropriate thyroid ablation in RTHβ results in pituitary thyrotrope hyperplasia, and a small number of RTHβ cases with coexisting pituitary adenomas have also been described. Recurrent otitis media and upper respiratory tract infections are more frequent in RTHβ (30). A higher miscarriage rate and neonatal growth retardation has been documented in unaffected offspring of mothers with RTHβ, suggesting that intrauterine exposure to elevated TH could be detrimental.

Differential Diagnosis

Concordance of elevated free thyroid hormone levels when measured in different immunoassays or by equilibrium dialysis makes artefactual hyperthyroxinaemia due to assay interference from familial dysalbuminaemic hyperthyroxinaemia (FDH) or anti- iodothyronine antibodies less likely. Likewise, linear fall in TSH levels following serial dilution of serum or its adequate recovery following poly ethylene glycol (PEG) precipitation can exclude interference with TSH measurement. Other causes of hyperthyroxinaemia (neonatal period, systemic illness, drugs) are excluded by recognition of the ab normal clinical context or documenting subsequent normalization of thyroid function following recovery or drug withdrawal.

The main differential diagnosis of RTHβ is from a TSH- secreting pituitary tumour (TSHoma), but many factors can make this distinction difficult. There are no differences in age, gender, fT4, fT3, or TSH levels between the two disorders. MRI scan may show an obvious macroadenoma but fail to visualize small microadenomas; the recognized occurrence of pituitary ‘incidentalomas’ in RTHβ can confound diagnosis. Circulating pituitary α- subunit levels can be normal in micro TSHomas; serum SHBG levels are elevated in TSHoma but can be normal with tumours cosecreting growth hormone. Abnormal thyroid function tests (TFTs) in first- degree relatives are highly suggestive of RTHβ but are also a feature of FDH which is dominantly inherited; conversely, normal TFTs in family members does not exclude RTHβ as the disorder does occur sporadically. With most TSHomas, administration of long- acting somatostatin analogue normalizes TH levels whereas fT4 and fT3 levels remain unchanged in RTHβ cases; inhibition of tracer uptake with functional pituitary imaging following somatostatin analogue administration can be invaluable in diagnosis of TSHoma.

Molecular Genetics

 Following cloning of TRs, RTHβ was shown to be tightly linked to the THRB locus. In keeping with the dominant inheritance of RTHβ, affected individuals are heterozygous for THRB mutations, which occur de novo in approximately 10% of sporadic cases. Over 150 different defects (missense, frameshift/ premature stop, in- frame deletions) have been recorded, localizing to three mutation clusters within the hormone- binding domain of the receptor (Figure1).

Fig1. Schematic alignment of TRα1, TRα2 and TRβ1 showing functional regions (N- terminal, DNA- binding domain (DBD), hormone- binding domains); the divergent carboxyterminus of TRα2 is cross- hatched. The location of published (black) and unpublished (orange) RTHα mutations, involving either TRα1 alone or both TRα1 and α2 proteins, is superimposed. Three regions (aminoacids 234 to 282, 309 to 360 and 426 to 460) of TRβ1 within which RTHβ mutations cluster are depicted. The number of different mutations described hitherto within each cluster (orange) is superimposed. No RTHβ mutations have been recorded in regions of the hormone- binding domain that are important for corepressor binding or dimerization with RXR.

THRB mutations have been identified in both GRTH and PRTH, indicating that these clinical entities represent different phenotypic manifestations of a single genetic disorder. Nevertheless, certain TRβ mutations (e.g. R338W/ L, R383C/ H, R429Q) may be particularly associated with a PRTH phenotype.

Nine cases of homozygous or hemizygous RTHβ have been described, associated with a severe clinical phenotype encompassing marked elevation of TH levels, dysmorphic features, audiovisual abnormalities with a propensity to developing life- threatening cardiac failure.

In ~10% of cases, biochemical evidence of RTHβ is not associated with a THRB defect— so- called non- TRβ RTH. Possible explanations include somatic mosaicism with occurrence of TRβ mutations whose expression is restricted so as to be undetectable in peripheral blood leucocyte DNA or non- receptor mechanisms (e.g. cofactor gene defects) whereby thyroid hormone action is disrupted to produce the RTHβ phenotype.

Properties of Mutant Receptors

In keeping with their location in the hormone- binding domain, the ability of TRβ mutants to bind T3 and recruit coactivator is reduced, impairing their ability to regulate target gene transcription.

In the first documented family with RTHβ, both affected siblings were homozygous for complete deletion of THRB. Significantly, their heterozygous parents, with deletion of one THRB allele, were completely normal with no evidence of thyroid dysfunction. Thus, TRβ haploinsufficiency is insufficient to mediate RTH; furthermore, TRβ mutants in heterozygous RTHβ are not simply functionally impaired but also capable of inhibiting the action of their wild- type counterparts in a ‘dominant negative’ manner (Figure2).

Fig2. Possible mechanism for dominant negative inhibition by TRβ or TRα mutants. The upper panel (a) depicts wild- type (WT) TR action on target genes. The unliganded RXR- TR heterodimer recruits a corepressor complex (CoR) to silence basal gene transcription. Receptor occupancy by ligand (T3 ), promotes corepressor dissociation followed by binding of a coactivator complex (CoA) which leads to target gene activation. The lower panel (b) shows mutant receptor action. In comparison to wild- type TR, the primary defect in mutant receptors is impaired hormone- dependent corepressor release or coactivator recruitment. For most receptor mutants, this functional alteration is a consequence of reduced hormone binding. However, a subset exhibits intrinsic enhanced binding to corepressor or impaired recruitment of coactivator, with preserved hormone binding. Constitutive occupancy of thyroid response elements (TREs) by mutant receptor- corepressor complexes results in inhibition of target gene expression.

Pathogenesis of Variable Tissue Resistance

The ability to exert a dominant negative effect within the hypo thalamic– pituitary– thyroid axis is a key property of mutant receptors in RTHβ, generating abnormal TFTs that are the hallmark of the disorder. For some RTHβ mutants, their functional impairment in vitro correlates with the degree of axis resistance in vivo, quantified by the magnitude of elevation in circulating free T4 levels.

Variable tissue resistance is partly mediated by differing tissue distributions of TR subtypes. Thus, TRβ- expressing tissues (hypo thalamus, pituitary, liver) exhibit hormone resistance, exemplified by non- suppressed TSH and normal SHBG levels in patients; conversely, cardiac hyperthyroidism and raised metabolic rate seen in RTHβ represent features of sensitivity of TRα- expressing myocardium and skeletal muscle to elevated TH. Differences in relative expression of wild- type versus mutant TRβ in tissues or variable dominant negative inhibitory potency of TRβ mutants in different target gene contexts are further variables which may influence the degree of hormone resistance.

Management

The management of RTHβ is complex, as variable resistance makes it difficult to maintain euthyroidism in all tissues. In most individuals, the receptor defect is compensated by high circulating thyroid hormone levels, leading to a clinically euthyroid state. Inappropriate thyroid ablation with surgery or radioiodine is commonly unsuccessful, with recrudescence of goitre and disruption of the pituitary– thyroid axis, rendering the RTHβ patient hypothyroid unless levothyroxine (L- T4) is administered in supraphysiologic dosage.

Conversely, reduction in thyroid hormone levels may be of benefit in the management of patients with thyrotoxic symptoms. However, conventional antithyroid drug administration results in marked elevation of TSH levels with consequent further thy roid enlargement and pituitary thyrotrope hyperplasia, with a risk of autonomous tumour formation. 3,5,3’- triiodothyroacetic acid (TRIAC), a TH analogue which acts centrally to inhibit TSH secretion thereby reducing thyroid hormone levels, yet is devoid of peripheral thyromimetic activity, has been shown to be beneficial in both childhood and adult cases. A daily dose of 1.4– 4.5 mg is used, with one study suggesting that twice- daily administration inhibits TSH secretion more effectively. Given spontaneous variation in thyrotoxic symptoms in RTHβ, periodic cessation of TRIAC therapy and re- evaluation of the clinical status of the patient is advisable. The use of TRIAC in one pregnancy controlled maternal thyrotoxic symptoms but may have induced fetal goitre. Use of antithyroid drugs in combination with TRIAC may be of value in homozygous RTHβ associated with cardiac hyperthyroidism. Thyroid ablation followed by thyroxine replacement in subphysiological dosage could also be used in RTHβ associated with life- threatening, thyrotoxic cardiac failure.

TRIAC treatment is not always successful and dextro- thyroxine (D- T4) is another agent which has been shown to be effective in some cases. Bromocriptine or octreotide have been used in RTHβ but, unlike TSHomas, pituitary TSH secretion escapes from their inhibitory effects.

The treatment of RTHβ with thyrotoxic manifestations (for ex ample, failure to thrive) in childhood also requires careful monitoring to ensure that any reduction in thyroid hormone levels is not associated with growth retardation or adverse neurological sequelae. Indeed, control of cardiac and peripheral sympathetic overactivity with β- blockade may be the safest course in this context. One study showed that L- T3 therapy improved hyperactivity in nine children with ADHD, including three individuals who were unresponsive to methylphenidate.

Dyslipidaemia should be managed with statin therapy if associated cardiac risk factors suggest benefit; in future, TRβ- selective thyromimetics may prove a more targeted therapeutic option. If reduced bone mineral density is identified, usual lifestyle measures (weight bearing exercise, calcium and vitamin D supplementation) can be advised. Whether bisphosphonate therapy is beneficial in RTHβ remains unknown.

During pregnancy, normal fetal growth and heart rate in the third trimester may provide reassurance that significant fetal thyrotoxicosis is not present. In women with RTHβ and a history of recurrent miscarriage, antithyroid drug treatment in early pregnancy could be considered.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم رعاية الصحن الشريف ينشر لافتات الحزن بذكرى شهادة الإمام الجواد (عليه السلام)

قسم العلاقات العامة يقيم مجلس عزائه الأسبوعي لاستذكار فضائل أهل البيت (عليهم السلام)

متحف الكفيل يستعرض درعًا هنديًّا يعود إلى القرن التاسع عشر

ضمن محفلها الأسبوعيّ.. دار علوم نهج البلاغة تقدّم محاضرةً عن تحرير الإنسان من قيود المنصب

المزيد

الآخبار الصحية

طريقة مبتكرة للكشف المبكر عن أمراض القلب والشرايين

منظمة الصحة تحذر من خطر إدمان الشباب لأكياس النيكوتين

خبراء يحذرون من عادة شائعة تهدد صحة الملايين

خبير يكشف 5 حقائق طبية صادمة وغير معروفة

المزيد

الآخبار التكنلوجية

الأولى في العالم.. الصين تجري تجربة رائدة في الفضاء باستخدام "جنين اصطناعي"

دراسة حديثة تفند ربط التستوستيرون بالمخاطرة لدى الرجال

ميتا تضيف وضع "المحادثة المخفية" إلى تطبيق "واتساب"

فوبيا المرتفعات ليست من الدماغ.. دراسة تكشف السبب

المزيد

مواضيع ذات صلة

Selenoprotein Deficiency— A Disorder of Thyroid Hormone Metabolism

Allan- Herndon- Dudley Syndrome— A Disorder of Thyroid Hormone Transport

Glucose Phosphate Isomerase Deficiency

Pyruvate Kinase Deficiency

Complications of Thalassemia and Their Management: Endocrinopathies

Complications of Thalassemia and Their Management: Skeletal Changes

Complications of Thalassemia and Their Management : Complications Related to Ineffective Erythropoiesis

Glucose-6-Phosphate Dehydrogenase Deficiency

Pathobiology of Sickle Cell Disease : Disease pathogenesis

Alpha-Thalassemia Syndromes

Acute Intermittent Porphyria

Porphyrias: Genetic Aspects