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Highlights • Mutations in the thyroid hormone receptor beta (THRB) lead to relative hyperthyroidism in the brain. • Electrophysiological biomarkers of performance monitoring (ERN and Pe components) show a pattern similar to ADHD in carriers of THRB mutations. • The phenotype of THRB mutation carriers is indistinguishable from ADHD with regard to performance monitoring., Resistance to thyroid hormone beta (RTHβ) is a syndrome of reduced responsiveness of peripheral tissue to thyroid hormone, caused by mutations in the thyroid hormone receptor beta (THRB). Its cognitive phenotype has been reported to be similar to attention deficit hyperactivity disorder (ADHD). This study used electrophysiological biomarkers of performance monitoring in RTHβ to contribute further evidence on its phenotypical similarity to ADHD. Twenty-one participants with RTHβ aged 18–67 years and 21 matched healthy controls performed a modified flanker task during EEG recording. The RTHβ and control groups were compared on behavioural measures and components of event related potentials (ERPs), i.e. the error related negativity (ERN), the error positivity (Pe) and P3 component. There were no significant group differences with regard to behaviour. RTHβ subjects displayed significantly reduced ERN and Pe amplitudes compared to the controls in the response-locked ERPs. In addition, we observed reduced P3 amplitudes in both congruent and incongruent trials, as well as prolonged P3 latencies in RTHβ subjects in the stimulus-locked ERPs. Our findings reveal alterations in error detection and performance monitoring of RTHβ patients, likely indicating reduced error awareness. The electrophysiological phenotype of RTHß subjects with regard to action monitoring is indistinguishable from ADHD.

This manuscript provides guidance on the management of thyroid dysfunction during the COVID-19 pandemic. Autoimmune thyroid diseases are not linked to increased risks of COVID-19. Uncontrolled thyrotoxicosis may result in more severe complications from SARS-CoV-2 infection, including thyroid storm. The management of patients with a new diagnosis of hyperthyroidism is best undertaken with a block-and-replace regimen due to limited biochemical testing availability. Antithyroid drug (ATD)-induced neutropenia may favour the progression of COVID-19 and symptoms of infection may be confused with SARS-CoV-2 infection. The withdrawal of ATDs and urgent measurement of neutrophils should be considered in case of flu-like manifestations occurring in the initial months of treatment. Urgent surgery or 131-I may be undertaken in selected cases of uncontrolled thyrotoxicosis. Patients with COVID-19 infection may present with conjunctivitis, which could cause diagnostic difficulties in patients with new or existing Graves' ophthalmopathy. Patients who are on replacement treatment with thyroid hormones should ensure they have sufficient supply of medication. The usual advice to increase dosage of levothyroxine during pregnancy should be adhered to. Many newly presenting and previously diagnosed patients with thyroid dysfunction can be managed through virtual telephone or video clinics supported by a dedicated nurse-led service, depending on available facilities.

Alemtuzumab-a monoclonal antibody targeting the CD52 glycoprotein expressed by most mature leucocytes-effectively decreases relapse rate and disability progression in early, relapsing-remitting multiple sclerosis (MS). However, secondary autoimmune disorders complicate therapy in nearly 50% of treated patients, with Graves' disease being the most common. Rarely, thyroid eye disease (TED) ensues; only seven such cases have been reported. Our aim was to analyse the largest series of MS patients developing thyroid eye disease after alemtuzumab treatment. We performed a retrospective chart review of MS patients treated with alemtuzumab (1995-2018) and subsequently identified by their treating physicians as having developed TED and referred to our ophthalmology service. As an original trial centre for alemtuzumab, our hospital has treated approximately 162 MS patients with this novel therapy. In total, 71 (44%) developed thyroid dysfunction, most of whom (87%) developed Graves' disease, with ten (16%) referred for ophthalmological evaluation. Two developed active orbitopathy following radioiodine treatment; one occurred after cessation of anti-thyroid drug treatment. Three developed sight-threatening disease requiring systemic immunosuppression, with one refractory to multiple immunosuppressants. The remaining patients were treated conservatively. TSH-receptor antibody (TRAb) levels were significantly raised in all cases, when ascertained. We report sight-threatening as well as mild TED in MS patients after treatment with alemtuzumab. Endocrine instability, radioiodine treatment and positive TRAb are all likely risk factors. The data support at least 6-monthly biochemical and clinical assessment with a low threshold for referral to an ophthalmologist, particularly for those with higher TRAb levels who may be at greater risk of orbitopathy.

Central diabetes insipidus (CDI) is characterized by hypotonic polyuria due to impairment of AVP secretion from the posterior pituitary. In clinical practice, it needs to be distinguished from renal resistance to the antidiuretic effects of AVP (nephrogenic DI), and abnormalities of thirst appreciation (primary polydipsia). As nephrogenic diabetes insipidus is rare in adults, unless they are treated with lithium salts, the practical challenge is how to differentiate between CDI and clinical disorders of excess thirst. The differential diagnosis is usually straight forward, but the recommended gold standard test, the water deprivation test, is not without interpretative pitfalls. The addition of the measurement of plasma AVP concentrations improves diagnostic accuracy, but the radioimmunoassay for AVP is technically difficult, and is only available in a few specialized centres. More recently, the measurement of plasma copeptin concentrations has been claimed to provide a reliable alternative to measurement of plasma AVP, without the sampling handling challenges. In addition, the measurement of thirst ratings can help the differentiation between CDI and primary polydipsia. Once the diagnosis of CDI is biochemically certain, investigations to determine the cause of AVP deficiency are needed. In this review, we will outline the diagnostic approach to polyuria, revisit the caveats of the water deprivation test and review recent data on value of adding AVP/copeptin measurement. We will also discuss treatment strategies for CDI, with analysis of potential complications of treatment.

Introduction: The short synacthen test (SST) is commonly used to assess adrenal function. Accurate timing and appropriate holding of exogenous steroids are essential to ensure correct interpretation of results. Aims & Methods: We reviewed all SSTs performed on inpatients in our hospital over a 1-year period, in order to determine accuracy of testing. Results: 42 patients (Male 15, Female 27), with mean age 68 years (range 43–90), underwent SST. The majority (39/42; 93%) of tests were requested by internal medicine physicians. The indications for testing were; suspected adrenal insufficiency (18), HPA axis suppression (9), fatigue (7), hyponatremia (5), suspected pituitary disease (2) and vomiting (1). 7 (44%) of the 16 patients taking steroids did not have medication appropriately held. 31 (74%) patients did not have serum ACTH measured prior to the test. 28 (66%) tests were not started at the correct time. Only 10 (24%) of the 30 minute samples were completed within the 25-35min sample window. The mean time between the 0min and 30min samples was 42mins (median 62mins; range 0-209mins). 12 (29%) tests involved an unnecessary 60min sample. 8 (19%) tests had no interpretation of results documented in the medical notes. 4 (10%) patients underwent repeat testing, necessitated by an incorrect first test. Discussion: The vast majority of inpatient SSTs (33/42;79%) were performed suboptimally, with the most common errors pertaining to incorrect timing of the test, inaccurate sampling and inappropriate pre-test steroid administration. Considering these errors, some results may have been interpreted incorrectly. Repeat tests were recognised as required in 10% of patients, with associated inconvenience, cost and discomfort. Improved training and guidelines for performing SSTs should be available to hospital staff to ensure more accurate application of the test.

Background: Thyroid-related causes of mediastinal masses include retrosternal goiters and thymic enlargement associated with Graves’ disease. Here, we present a case of significant unilateral retrosternal growth of the thyroid gland, presenting as an incidental mediastinal mass, without any evidence of contralateral disease. Associated subclinical hyperthyroidism presents a therapeutic challenge. Clinical Case: A 68-year old gentleman presented to the emergency department with a non-infective exacerbation of known Chronic Obstructive Pulmonary Disease. CT Pulmonary Angiogram revealed a right sided 5.6cm paratracheal mass, which seemed to originate from the posterior aspect of the right lobe of the thyroid and extended to the subcarinal region. The mass displaced the oesophagus and was close to, but did not compress, the trachea. The left thyroid lobe was normal. Thyroid ultrasound was reported as normal, but was later acknowledged to be suboptimal at visualization of the posterior aspect of the gland. Thyroid scintigraphy confirmed increased radionuclide uptake within the mass. Thyroid function tests showed subclinical thyrotoxicosis [TSH 0.04 (0.4-4.0mIU/mL), FT4 17.4 (10-22pmol/L) and FT3 3.36 (2.89-4.88 pmol/L)]. TSH receptor antibody was negative [< 1.1 (

Familial dysalbuminaemic hyperthyroxinemia (FDH), most commonly due to an Arginine to Histidine mutation at residue 218 (R218H) in the albumin gene, causes artefactual elevation of free thyroid hormones in euthyroid individuals. We have evaluated the susceptibility of most current free thyroid hormone immunoassay methods used in the UK, Europe and Far East to interference by R218H FDH. Methods: Different, one- and two-step immunoassay methods were tested, measuring Free T4 (FT4) and Free T3 (FT3) in 37 individuals with genetically-proven R218H FDH. Results: With the exception of Ortho VITROS, FT4 measurements were raised in all assays, with greatest to lowest susceptibility to interference being Beckman ACCESS > Roche ELECSYS > FUJIREBIO Lumipulse > Siemens CENTAUR > Abbott ARCHITECT > Perkin-Elmer DELFIA. Five different assays recorded high FT3 levels, with the Siemens CENTAUR method measuring high FT3 values in up to 30% of cases. However, depending on the assay method, FT4 measurements were unexpectedly normal in some, genetically-confirmed, affected relatives of index FDH cases. Conclusions: All FT4 immunoassays evaluated are prone to interference by R218H FDH, with their varying susceptibility not being related to assay architecture but likely due to differing assay conditions or buffer composition. Added susceptibility of many FT3 assays to measurement interference, resulting in high FT4 and FT3 with non-suppressed TSH levels, raises the possibility of R218H FDH being misdiagnosed as Resistance to Thyroid Hormone beta or TSH-secreting pituitary tumour, potentially leading to unnecessary investigation and inappropriate treatment., Research is supported by funding from the Wellcome Trust (210755/Z/18/Z to KC) and NIHR Cambridge Biomedical Research Centre (CM, MG, KC).

Background Energy expenditure prediction equations are used to estimate energy intake based on general population measures. However, when using equations to compare with a disease cohort with known metabolic abnormalities, it is important to derive one's own equations based on measurement conditions matching the disease cohort. Objective We aimed to use newly developed prediction equations based on a healthy pediatric population to describe and predict resting energy expenditure (REE) in a cohort of pediatric patients with thyroid disorders. Methods Body composition was measured by DXA and REE was assessed by indirect calorimetry in 201 healthy participants. A prediction equation for REE was derived in 100 healthy participants using multiple linear regression and z scores were calculated. The equation was validated in 101 healthy participants. This method was applied to participants with resistance to thyroid hormone (RTH) disorders, due to mutations in either thyroid hormone receptor β or α (β: female n = 17, male n = 9; α: female n = 1, male n = 1), with deviation of REE in patients compared with the healthy population presented by the difference in z scores. Results The prediction equation for REE = 0.061 * Lean soft tissue (kg) − 0.138 * Sex (0 male, 1 female) + 2.41 (R2 = 0.816). The mean ± SD of the residuals is −0.02 ± 0.44 kJ/min. Mean ± SD REE z scores for RTHβ patients are −0.02 ± 1.26. z Scores of −1.69 and −2.05 were recorded in male (n = 1) and female ( n = 1) RTHα patients. Conclusions We have described methodology whereby differences in REE between patients with a metabolic disorder and healthy participants can be expressed as a z score. This approach also enables change in REE after a clinical intervention (e.g., thyroxine treatment of RTHα) to be monitored.

Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves' disease (GD), followed by hypothyroidism and thyroiditis; Graves' orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1-3); (2) monitoring during/after IRT (recommendations 4-7); (3) management of TD post-IRT (recommendations 8-17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy. ispartof: EUROPEAN THYROID JOURNAL vol:8 issue:4 pages:173-185 ispartof: location:England status: published

Background Resistance to thyroid hormone beta (RTHbeta) is a rare genetic disorder caused by a defective beta form of the thyroid hormone receptor and is characterized by elevated T3 and T4, non-suppressed TSH and variable tissue resistance to thyroid hormone (TH). In most cases a heterozygous mutation in THRB gene is identified. Clinical case A 32 year old adopted Caucasian woman presented with chest pain in the primary care setting in December 2016. Associated symptoms included palpitations, insomnia, poor concentration, restlessness, tremor, mood swings, headaches, irritability, increased appetite, dry scalp, cold extremities, weight gain and diarrhoea. She had no goitre. Based on thyroid function test (TFT) results, she was suspected to have hyperthyroidism and was commenced on antithyroid drugs for 13 months, but treatment was later stopped due to mouth ulcers. At this stage, further tests in our hospital showed elevated fT3 (8.4 pmol/L, RR 3.5-6.5 pmol/L) and fT4 (33.5 pmol/L, RR 10.0-19.8 pmol/L) and non-suppressed TSH (1.35 mU/L, RR 0.35-5.50 mU/L), without evidence of assay interference. SHBG and MRI pituitary were normal. THRB sequencing identified a heterozygous pathogenic mutation (R438H). She further reported that she struggled in school which prevented her from completing university education and remembered that her biological mother had learning disability. She was further assessed in our clinical research facility. Surprisingly, TFT results were very different: fT3 23.6 pmol/L, fT4 97.3 pmol/L and fully suppressed TSH (

Human-robot interactions are not foreign to popular culture, and many contemporary works of science-fiction romanticise these interactions by questioning whether or not artificially-intelligent robots have emotions, personalities, and, essentially, autonomy. Similar questions appear in more scholastic works of robot ethics, even in the absence of romanticised fictional narratives. I think these writings ask the wrong questions. I claim that there has not been enough work to examine the potentially violent effects that contemporary models of sexualised, embodied AI may have for the subjects these sex robots represent. Even in academic, socio-scientific analyses of contemporary sex robots that do highlight aspects of rape-culture violence, studies continue to make the mistake of conflating the objecthood of the sex robot with the subjecthood of individuals. Recognising the need for further applied, interdisciplinary, feminist research in this area, I draw primarily from postcolonial theory and deconstructionist gender theory, taking a queered lens to qualitatively analyse the relevant forms of embodied AI (i.e. sex robots) created by 3 central companies. I take a necessarily-intersectional feminist approach to this analysis, influenced by the works of Kimberle Crenshaw and the Combahee River Collective, in order to recognise the convergences of multiple presentations of societal violence which inform the rape-culture narratives to which, I argue, these robots appeal (1986). I interpret exemplary models of embodied AI in order to analyse the narratives which inform the models’ respective constructions, rather than ascribing my findings to the phenomenon of sexualised robots as a whole, because digital media can always be used in oppositional manners. My examination consists in 3 sections in which I argue that the use and design of these contemporary models of sex robots reify and reproduce the oppressive dynamics which inform their respective constructions.

This paper presents the development of the digital acquisition chain for the upgrade of the Beam Position Monitor (BPM) system for the Super Proton Synchrotron (SPS) at CERN. The front-end electronics will be based on logarithmic amplifiers and, including the digitization, it will be located inside the accelerator tunnel, with optical latency deterministic transmission to surface back-end electronics, where the data stream is processed in a Field Programmable Gate Array. The paper focuses on the processing techniques for the position estimation out of beam data conditioned by logarithmic amplifiers. The elements of the acquisition chain have been tested in laboratory and with beam signals.

ObjectiveHyperthyroidism is associated with a hypercoagulable state, but the underlying mechanism is unknown. Patients with resistance to thyroid hormone (RTH) due to defective thyroid hormone receptor β (THRB orTHRB) exhibit elevated circulating thyroid hormones (TH) with refractoriness to TH action inTHRB-expressing tissues. We tested the hypothesis that the hypercoagulable state in hyperthyroidism is mediated via theTHRB.DesignWe conducted a cross-sectional study from November 2013 to January 2015 in 3 hospitals in the Netherlands and the United Kingdom.MethodsPatients with RTH due to defectiveTHRB(n=18), patients with hyperthyroidism (n=16) and euthyroid subjects (n=18) were included. TH concentrations and markers of coagulation and fibrinolysis were measured. Data are expressed as median (interquartile range).ResultsFree thyroxine (FT4) levels were slightly higher in hyperthyroid patients than in RTH patients (53.9 (30.5–70.0) and 34.9 (28.4–42.2)pmol/L, respectively,P=0.042). Both groups had raised FT4levels compared with euthyroid subjects (14.0 (13.0–15.8)pmol/L,P≤0.001). Levels of von Willebrand factor (VWF), factor (F) VIII, fibrinogen andd-dimer were significantly higher in hyperthyroid patients than in RTH patients (VWF 231 (195–296) vs 111 (82–140)%, FVIII 215 (192–228) vs 145 (97–158)%, fibrinogen 3.6 (3.0–4.4) vs 2.8 (2.5–3.2)g/L,d-dimer 0.41 (0.31–0.88) vs 0.20 (0.17–0.26)mg/L, respectively,P≤0.001), while there were no differences between RTH patients and euthyroid controls.ConclusionsParameters of coagulation and fibrinolysis were elevated in hyperthyroid patients compared with patients with RTH due to defectiveTHRB, whereas these parameters were not different between euthyroid controls and RTH patients, despite elevated FT4concentrations in RTH patients. This indicates that the procoagulant effects observed in hyperthyroidism are mediated via theTHRB.

We present a case of cerebellar dysfunction due to severe hypothyroidism induced by pembrolizumab, a member of the 'immune checkpoint inhibitor' class of cancer immunotherapies. Thyroxine replacement completely resolved his symptoms and signs. We also discuss the neurological immune-related complications of checkpoint inhibitors.

Resistance to thyroid hormone β (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five kindreds reported worldwide. Cardiac dysfunction, which can be life-threatening, is recognized in the disorder. Here we describe the clinical, metabolic, ophthalmic, and cardiac findings in a 9-year-old boy harboring a biallelic THRB mutation (R243Q), along with biochemical, physiologic, and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognized features (goiter, nonsuppressed thyroid-stimulating hormone levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHβ, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHβ had died of cardiac failure at age 13 years. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass, and improved growth and cardiac function. A combination of antithyroid drug and TRIAC therapy may prevent thyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHβ in which life-threatening hyperthyroid features predominate., A child with severe resistance to thyroid hormone, homozygosity for mutation in thyroid hormone receptor β and cardiomyopathy was treated successfully with a combination of TRIAC and carbimazole.

Thyroid hormone (TH) acts via nuclear thyroid hormone receptors (TRs). TR isoforms (TRα1, TRα2, TRβ1, TRβ2) are encoded by distinct genes (THRA and THRB) and show differing tissue distributions. Patients with mutations in THRB, exhibiting resistance within the hypothalamic-pituitary-thyroid axis with elevated TH and nonsuppressed thyroid-stimulating hormone (TSH) levels, were first described decades ago. In 2012, the first patients with mutations in THRA were identified. Scope of this review: This review describes the clinical and biochemical characteristics of patients with resistance to thyroid hormone alpha (RTHα) due to heterozygous mutations in THRA. The genetic basis and molecular pathogenesis of the disorder together with effects of levothyroxine treatment are discussed.The severity of the clinical phenotype of RTHα patients seems to be associated with the location and type of mutation in THRA. The most frequent abnormalities observed include anemia, constipation, and growth and developmental delay. In addition, serum (F)T3 levels can be high-normal to high, (F)T4 and rT3 levels normal to low, while TSH is normal or mildly raised. Despite heterogeneous consequences of mutations in THRA, RTHα should be suspected in subjects with even mild clinical features of hypothyroidism together with high/high-normal (F)T3, low/low-normal (F)T4, and normal TSH.

Background: Thyroid hormone (TH) acts via nuclear thyroid hormone receptors (TRs). TR isoforms (TRα1, TRα2, TRβ1, TRβ2) are encoded by distinct genes (THRA and THRB) and show differing tissue distributions. Patients with mutations in THRB, exhibiting resistance within the hypothalamic–pituitary–thyroid axis with elevated TH and nonsuppressed thyroid-stimulating hormone (TSH) levels, were first described decades ago. In 2012, the first patients with mutations in THRA were identified. Scope of this review: This review describes the clinical and biochemical characteristics of patients with resistance to thyroid hormone alpha (RTHα) due to heterozygous mutations in THRA. The genetic basis and molecular pathogenesis of the disorder together with effects of levothyroxine treatment are discussed. Conclusions: The severity of the clinical phenotype of RTHα patients seems to be associated with the location and type of mutation in THRA. The most frequent abnormalities observed include anemia, constipation, and growth and developmental delay. In addition, serum (F)T3 levels can be high-normal to high, (F)T4 and rT3 levels normal to low, while TSH is normal or mildly raised. Despite heterogeneous consequences of mutations in THRA, RTHα should be suspected in subjects with even mild clinical features of hypothyroidism together with high/high-normal (F)T3, low/low-normal (F)T4, and normal TSH.

The first human cases (female, age 6 y; father and daughter, ages 47 and 11 y, respectively) with growth retardation/short stature, skeletal dysplasia, constipation, and defective thyroid receptor α (TRα) have been recently described.A 45-year-old, short, overweight female with cognitive impairment, epilepsy, and constipation was investigated.Clinical, biochemical, and radiological assessment and THRA sequencing were undertaken. The patient's thyroid status and her biochemical and physiological parameters were evaluated at baseline and after T4 therapy.The patient exhibits disproportionate short stature, macrocephaly, low free T4/free T3 ratio and rT3 levels, together with subnormal heart and basal metabolic rate. She is heterozygous for a novel frameshift/premature stop (Ala382ProfsX7) THRA mutation, generating a mutant TRα with constitutive corepressor binding and negligible coactivator recruitment, which inhibits its wild-type counterpart in a dominant-negative manner-both in vitro and in mutation-containing patient blood mononuclear cells studied ex vivo. Her alertness and constipation responded to T4 therapy, which readily suppressed TSH levels, raised basal metabolic rate, and normalized elevated muscle creatine kinase, but cardiac parameters (heart rate, contractility) remained relatively refractory. The patient and a previous childhood case showed reduced red cell mass with macrocytosis unresponsive to T4 therapy.Clinical (short stature, macrocephaly, constipation) and biochemical (low free T4/free T3 ratio, subnormal rT3) findings that are congruent with previous cases and newly recognized features (epilepsy) in this adult female with defective TRα define a shared phenotype in TRα-mediated resistance to thyroid hormone, with differential tissue responses to T4 treatment.

International audience; Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome–encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2′-O-methylribosylation at uridine 34 in mutant tRNA[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA[Ser]Sec. This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis.

Summary Objective Central diabetes insipidus is a rare clinical condition with a heterogenous aetiology. Up to 40% of cases are classified as idiopathic, although many of these are thought to have an autoimmune basis. Published data have suggested that anterior hypopituitarism is common in childhood-onset idiopathic diabetes insipidus. We aimed to assess the incidence of anterior hypopituitarism in a cohort of adult patients with idiopathic diabetes insipidus. Design and patients We performed a retrospective review of the databases of two pituitary investigation units. This identified 39 patients with idiopathic diabetes insipidus. All had undergone magnetic resonance imaging scanning and dynamic pituitary testing (either insulin tolerance testing or GHRH/arginine and short synacthen testing) to assess anterior pituitary function. Results One patient had partial growth hormone deficiency; no other anterior pituitary hormonal deficits were found. Thirty-three percent had at least one autoimmune disease in addition to central diabetes insipidus. Conclusions Our data suggest that anterior hypopituitarism is rare in adult idiopathic diabetes insipidus. Routine screening of these patients for anterior hypopituitarism may not, therefore, be indicated. The significant prevalence of autoimmune disease in this cohort supports the hypothesis that idiopathic diabetes insipidus may have an autoimmune aetiology.

Primary resistance to dopamine agonists occurs in 10-15% of prolactinomas but secondary resistance following initial biochemical and anti-proliferative response is very rare and has only been hitherto described in four previous cases, two with bromocriptine and two with cabergoline. We describe a case of a 57-year-old woman who presented with a large macroprolactinoma with suprasellar extension. She was initially treated with bromocriptine therapy with a resolution of symptoms, marked reduction in prolactin concentration and complete tumour shrinkage; a response which was subsequently maintained on cabergoline. After 8 years of dopamine agonist therapy, her prolactin concentration began to rise and there was symptomatic recurrence of her tumour despite escalating doses of cabergoline up to 6 mg weekly. Non-compliance was outruled by observed inpatient drug administration. The patient underwent surgical debulking followed by radiotherapy with good response. This case adds to the previous two cases of secondary resistance to cabergoline therapy in prolactinomas a marked initial response. While the mechanism of secondary resistance remains unknown and not possible to predict, close observation of prolactinoma patients on treatment is necessary.

A 13-½-year-old boy was referred to the Department of Endocrinology as a case of thyrotoxicosis for initiation of antithyroid medication. His chief complaint was a swelling in front of the neck, which was incidentally noted by his mother 2 weeks prior to presentation. He denied any history of symptoms suggestive of hyperthyroidism or ophthalmological involvement. His physical examination was unremarkable except for a grade 2 goitre. Thyroid function test revealed elevated free triiodothyronine and tetraiodothyronine in the face of an unsuppressed thyroid-stimulating hormone level. Technetium-99 uptake scan showed increased uptake indicating enhanced thyroid activity. However, he was clinically euthyroid. This raised the possibility of resistance to thyroid hormones, which was confirmed by documenting similar thyroid function test abnormalities in other members of his family and genetic testing. The family was reassured of the benign nature of the condition.

Background\ud The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2.\ud \ud Methods\ud We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence.\ud \ud Findings\ud The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine:free tri-iodothyronine [T3], low concentration of total reverse T3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TRα1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TRα1 and TRα2 proteins. The Ala263Val mutant TRα1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TRα2 matched its normal counterpart. In vitro, high concentrations of T3 restored transcriptional activity of Ala263Val mutant TRα1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells.\ud \ud Interpretation\ud TRα1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA.\ud \ud Funding\ud Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe.

Thyroid function tests (TFTs) are amongst the most commonly requested laboratory investigations in both primary and secondary care. Fortunately, most TFTs are straightforward to interpret and confirm the clinical impression of euthyroidism, hypothyroidism or hyperthyroidism. However, in an important subgroup of patients the results of TFTs can seem confusing, either by virtue of being discordant with the clinical picture or because they appear incongruent with each other [e.g. raised thyroid hormones (TH), but with non-suppressed thyrotropin (TSH); raised TSH, but with normal TH]. In such cases, it is important first to revisit the clinical context, and to consider potential confounding factors, including alterations in normal physiology (e.g. pregnancy), intercurrent (non-thyroidal) illness, and medication usage (e.g. thyroxine, amiodarone, heparin). Once these have been excluded, laboratory artefacts in commonly used TSH or TH immunoassays should be screened for, thus avoiding unnecessary further investigation and/or treatment in cases where there is assay interference. In the remainder, consideration should be given to screening for rare genetic and acquired disorders of the hypothalamic-pituitary-thyroid (HPT) axis [e.g. resistance to thyroid hormone (RTH), thyrotropinoma (TSHoma)]. Here, we discuss the main pitfalls in the measurement and interpretation of TFTs, and propose a structured algorithm for the investigation and management of patients with anomalous/discordant TFTs.

Background/objectives: The objective of this study was to develop approaches to expressing resting energy expenditure (REE) and lean body mass (LM) phenotypes of metabolic disorders in terms of Z-scores relative to their predicted healthy values. Subjects/methods: Body composition and REE were measured in 135 healthy participants. Prediction equations for LM and REE were obtained from linear regression and the range of normality by the standard deviation of residuals. Application is demonstrated in patients from three metabolic disorder groups (lipodystrophy, n=7; thyrotoxicosis, n=16; and resistance to thyroid hormone (RTH), n=46) in which altered REE and/or LM were characterised by departure from the predicted healthy values, expressed as a Z-score. Results: REE (kJ/min)=−0.010 × age (years)+0.016 × FM (kg)+0.054 × fat-free mass (kg)+1.736 (R2=0.732, RSD=0.36 kJ/min). LM (kg)=5.30 × bone mineral content (kg)+10.66 × height2 (m)+6.40 (male). LM (kg)=0.20 × fat (kg)+14.08 × height2 (m)−2.93 (female). (male R2=0.55, RSD=3.90 kg; female R2=0.59, RSD=3.85 kg). We found average Z-scores for REE and LM of 1.77 kJ/min and −0.17 kg in the RTH group, 5.82 kJ/min and −1.23 kg in the thyrotoxic group and 2.97 kJ/min and 4.20 kg in the LD group. Conclusion: This approach enables comparison of data from individuals with metabolic disorders with those of healthy individuals, describing their departure from the healthy mean by a Z-score.

Background: Thyroid hormone acts via receptor subtypes (TR alpha 1, TR beta 1, TR beta 2) with differing tissue distributions, encoded by distinct genes (THRA, THRB). THRB mutations cause a disorder with central (hypothalamic-pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels. Scope of review: This review describes the clinical features, genetic and molecular pathogenesis of a homologous human disorder mediated by defective THRA. Clinical features include growth retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels and a low T4/T3 ratio, together with subnormal reverse T3 levels. Heterozygous TRa1 mutations in affected individuals generate defective mutant receptors which inhibit wild-type receptor action in a dominan Major conclusions: Mutations in human TR alpha 1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis. General significance: Human THRA mutations could be more common but may have eluded discovery due to the absence of overt thyroid dysfunction. Nevertheless, in the appropriate clinical context, a thyroid biochemical signature (low T4/T3 ratio, subnormal reverse T3 levels), may enable future identification of cases. This article is part of a Special Issue entitled Thyroid hormone signalling. (C) 2013 Elsevier B.V. All rights reserved.