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Purpose: In resistance to thyroid hormone due to mutations in thyroid hormone receptor β, peripheral tissues are variably refractory to the action of circulating thyroid hormones. We evaluated parameters contributing to atherosclerotic risk in this disorder., Methods: We measured low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), nonesterified fatty acids (NEFA), intrahepatic lipid (IHL) and intramyocellular lipid (IMCL), Homeostasis-model assessment of insulin resistance (HOMA-IR), augmentation index (AIx) and pulse wave velocity (PWV), flow-mediated dilatation, and carotid intima-media thickness (cIMT) in an unselected, genetically confirmed cohort of adult RTHβ patients (n = 27-77) and compared these with measurements in healthy subjects (up to n = 100) and thyrotoxic patients (n = 40)., Results: Resistance to thyroid hormone beta (RTHβ) patients exhibited higher LDL-C (P = 0.008) and TG (P = 0.002) and lower HDL-C concentrations (P = 0.015 × 10-2) than control subjects, with LDL-C being higher than in thyrotoxic patients with comparable hyperthyroxinemia. Proprotein convertase subtilisin/kexin 9 (P = 0.002) and apolipoprotein B (P = 0.0009) levels were reduced in thyrotoxic patients but not lower in RTHβ patients or control subjects. Intrahepatic lipid (P = 0.02 × 10-4), IMCL (P = 0.002), HOMA-IR (P = 0.01 × 10-2), and NEFA (P = 0.04 × 10-6) were significantly higher in RTHβ patients than control subjects. Flow-mediated dilatation was increased (P = 0.04) but cIMT (P = 0.71), PWV P = 0.81), and AIx (P = 0.95) were unaltered in RTHβ patients., Conclusions: We have documented mixed dyslipidemia with hepatic and IMCL accumulation in RTHβ, suggesting that surveillance for these metabolic abnormalities is warranted. How they combine with enhanced endothelial function and unaltered vessel wall thickness and compliance to determine overall cardiometabolic risk in this disorder remains to be defined., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Neonatal screening in Macedonia detects congenital hypothyroidism (CH) with an incidence of 1 in 1,585, and more than 50% of cases exhibit a normally located gland- in-situ (GIS). Monogenic mutations causing dyshormonogenesis may underlie GIS CH; additionally, a small proportion of thyroid hypoplasia has a monogenic cause, such as TSHR and PAX8 defects. The genetic architecture of Macedonian CH cases has not previously been studied. We recruited screening-detected, non-syndromic GIS CH or thyroid hypoplasia cases ( n = 40) exhibiting a spectrum of biochemical thyroid dysfunction ranging from severe permanent to mild transient CH and including 11 familial cases. Cases were born at term, with birth weight >3,000 g , and thyroid morphologies included goiter ( n = 11), thyroid hypoplasia ( n = 6), and apparently normal-sized thyroid. A comprehensive, phenotype-driven, Sanger sequencing approach was used to identify genetic mutations underlying CH, by sequentially screening known dyshormonogenesis-associated genes and TSHR in GIS cases and TSHR and PAX8 in cases with thyroid hypoplasia. Potentially pathogenic variants were identified in 14 cases, of which four were definitively causative; we also detected digenic variants in three cases. Seventeen variants (nine novel) were identified in TPO ( n = 4), TG ( n = 3), TSHR ( n = 4), DUOX2 ( n = 4), and PAX8 ( n = 2). No mutations were detected in DUOXA2, NIS, IYD , and SLC26A7 . The relatively low mutation frequency suggests that factors other than recognized monogenic causes (oligogenic variants, environmental factors, or novel genes) may contribute to GIS CH in this region. Future non-hypothesis-driven, next-generation sequencing studies are required to confirm these findings., (Copyright © 2020 Zdraveska, Kocova, Nicholas, Anastasovska and Schoenmakers.)

Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition., Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function., Patients, Design, and Setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting., Main Outcome Measures: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates., Results: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels., Conclusions: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure., (© Endocrine Society 2019.)

Background: The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 ( DUOX2 ) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both DUOX2 and its accessory protein DUOXA2 may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort. Methods: A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. DUOX2 was sequenced in 52 patients with a bsTSH of 6-19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland in situ . DUOXA2 was sequenced in DUOX2 mutation-negative cases, and novel DUOXA2 mutations were functionally characterized. Results: A total of 26 (50%) patients harbored likely pathogenic mutations in DUOX2 ( n  = 20; 38%) or DUOXA2 ( n  = 6; 12%), including novel gene variants ( DUOX2 , n  = 3; DUOXA2 , n  = 7). Two recurrent DUOX2 mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range ( M  = 9.3 pmol/L, range <3.9-15.8 pmol/L), Conclusions: Targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring DUOX2 / DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.

Introduction: Heterozygous mutations or haploinsufficiency of NKX2-1 are associated with the brain-lung-thyroid syndrome incorporating primary hypothyroidism, respiratory distress, and neurological disturbances., Case Presentation: We report a patient presenting in the neonatal period with multiple pituitary hormone deficiency including central hypothyroidism and hypoadrenalism, growth hormone deficiency, undetectable gonadotrophins, and a small anterior pituitary on MRI. CGH microarray revealed haploinsufficiency for NKX2.1 and during subsequent follow-up, she has exhibited the classic triad of brain-lung-thyroid syndrome with undetectable tissue on thyroid ultrasonography. Whilst the role of NKX2-1 is well described in murine pituitary development, this report constitutes the first description of multiple pituitary dysfunction in humans associated with the syndrome and haploinsufficiency NKX2-1., Conclusion: The report highlights a potential need for pituitary screening in patients with established brain-lung-thyroid syndrome and implicates NKX2.1 in human pituitary disease., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Objective: Loss-of-function mutations in IGSF1 result in X-linked central congenital hypothyroidism (CeCH), occurring in isolation or associated with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred., Design, Patients and Measurements: A novel hemizygous IGSF1 mutation was identified by direct sequencing in two brothers with CeCH, and its functional consequences were characterized in vitro. Genotype-phenotype correlations were investigated in the wider kindred., Results: The mutant IGSF1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a TSH-based CH screening programme, which does not detect CeCH; therefore, genetic ascertainment preceded biochemical diagnosis of moderate CH in five of seven boys as well as their 75-year-old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (FT3) and low/low normal reverse T3 (rT3) concentrations suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed., Conclusions: As observed with other IGSF1 mutations, p.L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasize the need for multi-generation genetic ascertainment in affected families, especially where TSH-based CH screening programmes may fail to detect CeCH at birth., (© 2018 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.)

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

Objectives: Central hypothyroidism (CeH) is a rare form of hypothyroidism characterized by insufficient thyroid stimulation due to disturbed pituitary and/or hypothalamic functioning. Due to its origin and the whole clinical context, CeH represents a challenging condition in clinical practice as it is characterized by suboptimal accuracy of clinical and biochemical parameters for diagnosis and management. Since no expert consensus or guidance for this condition is currently available, a task force of experts received the commitment from the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence., Study Design: The task force started to work in February 2017 and after a careful selection of appropriate references (cohort studies, case reports, expert opinions), a preliminary presentation and live discussion during the 2017 ETA meeting, and several revision rounds, has prepared a list of recommendations to support the diagnosis and management of patients with CeH., Results: Due to the particular challenges of this rare condition in the different ages, the target users of this guidance are pediatric and adult endocrinologists. Experts agreed on the need to recognize and treat overt CeH at all ages, whereas treatment of milder forms may be dispensable in the elderly (> 75 years)., Conclusions: Despite the lack of randomized controlled clinical trials, the experts provide 34 recommendations supported by variable levels of strength that should improve the quality of life of the affected patients and reduce the metabolic and hormonal consequences of inadequate management.

Context: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the thyroid peroxidase-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic congenital hypothyroidism (CH) that may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (e.g., dietary iodine) and oligogenic modifiers (e.g., variants in the homologous reduced form of NAD phosphate-oxidase DUOX1). However, loss-of-function mutations in DUOX1 have not hitherto been described, and its role in thyroid biology remains undefined., Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (p.R434*); P1, P2: thyrotropin >100 µU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (c.1823-1G>C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred., Conclusion: This is a report of digenic mutations in DUOX1 and DUOX2 in association with CH, and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically ascertained CH., (Copyright © 2017 Endocrine Society)

In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother's second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin ( TG ) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases., Learning Points: CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.

Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

Background: Coexistence of congenital adrenal hyperplasia (CAH) and congenital hypothyroidism (CH) due to TG mutation in the same non-consanguineous family is rare., Case Series: We report 4 siblings born to unrelated parents, the father being an asymptomatic carrier of homozygous p.V281L and heterozygous p.I172N CYP21A2 mutations. Sibling 1 had salt-wasting CAH (CYP21A2 genotype Intron 2 splice/p.I172N and p.V281L). She also had CH (TG genotype p.R296/ p.T1416Rfs*30) and learning difficulties. Poor compliance and morbid obesity resulted in short stature, precocious puberty, hirsutism, amenorrhoea, insulin insensitivity and a possible adrenal adenoma. Sibling 3 (CYP21A2 and TG genotype similar to sibling 1) is a boy presenting with salt-wasting CAH, CH, and developmental delay. He was overweight and underwent precocious puberty. Although siblings 2 and 4 (both females) share the same CYP21A2 genotype (Intron 2 splice/p.V281L), the former only had biochemical evidence of CAH, while the latter presented at 9.8 years of age with a history of pubarche at 7 years and advanced bone age., Conclusions: We report the unusual occurrence of 2 rare autosomal recessive diseases, CAH and CH. Our cases highlight the phenotypic variability of CAH and CH due to TG mutations, even within a single family, and illustrate the importance of optimal disease control.
., (© 2017 S. Karger AG, Basel.)

Context: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken., Objective: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico., Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico., Results: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases., Conclusions: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

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.

Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic-pituitary-thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed., (© 2015 The authors.)

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Context: Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albumin with increased T4 affinity, causes artefactual elevation of free T4 concentrations in euthyroid individuals., Objective: Four unrelated index cases with discordant thyroid function tests in different assay platforms were investigated., Design and Results: Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. (125)I-T4 binding to both serum and albumin in affected individuals was markedly increased, comparable with known familial dysalbuminemic hyperthyroxinemia cases. Sequencing showed heterozygosity for a novel ALB mutation (arginine to isoleucine at codon 222, R222I) in all four cases and segregation of the genetic defect with abnormal biochemical phenotype in one family. Molecular modeling indicates that arginine 222 is located within a high-affinity T4 binding site in albumin, with substitution by isoleucine, which has a smaller side chain predicted to reduce steric hindrance, thereby facilitating T4 and rT3 binding. When tested in current immunoassays, serum free T4 values from R222I heterozygotes were more measurably abnormal in one-step vs two-step assay architectures. Total rT3 measurements were also abnormally elevated., Conclusions: A novel mutation (R222I) in the ALB gene mediates dominantly inherited dysalbuminemic hyperthyroxinemia. Susceptibility of current free T4 immunoassays to interference by this mutant albumin suggests likely future identification of individuals with this variant binding protein.

Context: 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., Objective: A 45-year-old, short, overweight female with cognitive impairment, epilepsy, and constipation was investigated., Design and Intervention: 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., Results: 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., Conclusions: 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.

Background: Thyroid hormone acts via receptor subtypes (TRα1, TRβ1, TRβ2) 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 dominant negative manner., Major Conclusions: Mutations in human TRα1 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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Primary colorectal signet ring cell carcinoma (SRCC) is rare and often affects younger patients. It demonstrates a different biological behaviour and has a less favourable prognosis than the more conventional colorectal adenocarcinoma., Case Description: Patient A, a 65-year-old man, presented with a change in bowel habit. Colonoscopy showed a stenosis with signs of a nonspecific inflammation. However, laparoscopy revealed a primary colorectal SRCC with diffuse peritoneal metastases. Standard chemotherapy was unsuccessful. Patient A died 13 months after diagnosis., Conclusion: Based on clinical and molecular differences, SRCC can be recognized as a separate subtype of colorectal cancer. The case description illustrates that this group of patients may benefit from a different management strategy than the usual therapy. A greater understanding of the characteristics of this specific malignancy is needed.

Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.

Potato cyst nematodes (PCNs) are quarantine organisms, and they belong to the economically most relevant pathogens of potato worldwide. Methodologies to assess the viability of their cysts, which can contain 200 to 500 eggs protected by the hardened cuticle of a dead female, are either time and labor intensive or lack robustness. We present a robust and cost-efficient viability assay based on loss of membrane integrity upon death. This assay uses trehalose, a disaccharide present at a high concentration in the perivitelline fluid of PCN eggs, as a viability marker. Although this assay can detect a single viable egg, the limit of detection for regular field samples was higher, ≈10 viable eggs, due to background signals produced by other soil components. On the basis of 30 nonviable PCN samples from The Netherlands, a threshold level was defined (ΔA(trehalose) = 0.0094) below which the presence of >10 viable eggs is highly unlikely (true for ≈99.7% of the observations). This assay can easily be combined with a subsequent DNA-based species determination. The presence of trehalose is a general phenomenon among cyst nematodes; therefore, this method can probably be used for (for example) soybean, sugar beet, and cereal cyst nematodes as well.

Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.

Selenium, a trace element that is fundamental to human health, is incorporated into some proteins as selenocysteine (Sec), generating a family of selenoproteins. Sec incorporation is mediated by a multiprotein complex that includes Sec insertion sequence-binding protein 2 (SECISBP2; also known as SBP2). Here, we describe subjects with compound heterozygous defects in the SECISBP2 gene. These individuals have reduced synthesis of most of the 25 known human selenoproteins, resulting in a complex phenotype. Azoospermia, with failure of the latter stages of spermatogenesis, was associated with a lack of testis-enriched selenoproteins. An axial muscular dystrophy was also present, with features similar to myopathies caused by mutations in selenoprotein N (SEPN1). Cutaneous deficiencies of antioxidant selenoenzymes, increased cellular ROS, and susceptibility to ultraviolet radiation-induced oxidative damage may mediate the observed photosensitivity. Reduced levels of selenoproteins in peripheral blood cells were associated with impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion, and telomere shortening. Paradoxically, raised ROS in affected subjects was associated with enhanced systemic and cellular insulin sensitivity, similar to findings in mice lacking the antioxidant selenoenzyme glutathione peroxidase 1 (GPx1). Thus, mutation of SECISBP2 is associated with a multisystem disorder with defective biosynthesis of many selenoproteins, highlighting their role in diverse biological processes.

Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor beta (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13C/31P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor alpha sensitivity to elevated thyroid hormone levels.

The purpose of this study was to investigate the effectiveness of a single session of cognitive restructuring in a sample of phobic dental patients. Fifty-two patients were randomly assigned to one of three conditions: cognitive restructuring (modification of negative cognitions), provision of information (about oral health and dental treatment), and a waiting list control condition. Both interventions maximally lasted one hour. In comparison with the waiting list control condition and the information intervention condition, the cognitive intervention condition not only showed a large decrease in frequency and believability of negative cognitions, but also exhibited a clear decline in dental trait anxiety. Analysis at a follow-up of one year demonstrated a further, drastic reduction in dental anxiety in both intervention conditions, wherein the difference among these conditions was not maintained. It is concluded that it is possible to obtain substantial reductions of dental trait anxiety through a single session of cognitive restructuring. Nevertheless, repeated exposure to the dental situation seems necessary for a further reduction of anxiety.