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OBJECTIVES: Thyroid hormone analog 3,5,3'-triiodothyroacetic acid (TRIAC) is effective in reducing the hypermetabolism in monocarboxylate transporter 8 (MCT8)-deficient individuals. Because of the structural similarity between TRIAC and 3,3',5'-triiodothyronine (T3), we sought to investigate the degree of cross-reactivity of TRIAC with various commercially available total and free T3 assays. METHODS: Varying concentrations (50-1,000 ng/dL) of TRIAC (Sigma Aldrich) were added to pooled serum and assayed for total T3 (TT3) and free T3 (FT3) on the following platforms: e602 (Roche Diagnostics), Architect (Abbott Diagnostics), Centaur (Siemens Healthcare Diagnostics), IMMULITE (Siemens Healthcare Diagnostics), DxI (Beckman Coulter), and Vitros (Ortho Clinical Diagnostics)...

Background: Congenital hypothyroidism is often caused by genetic mutations that impair thyroid hormone (TH) production, resulting in growth and development defects. XB130 (actin filament associated protein 1 like 2) is an adaptor/scaffold protein that plays important roles in cell proliferation, migration, intracellular signal transduction, and tumorigenesis. It is highly expressed in thyrocytes, however, its function in the thyroid remains largely unexplored. Methods: Xb130-/- mice and their littermates were studied...

A family with congenital hypothyroidism was identified with two novel deleterious compound heterozygous thyroid peroxidase ( TPO ) mutations ( c.962C>A , and c.1577C>T ). Serum thyroid tests showed higher-than-expected serum-free thyroxine (T4) relative to TT3, while reverse triiodothyronine (rT3) was also elevated. Two siblings manifested a more severe phenotype of developmental delay compared with another sibling and were found to harbor an additional novel heterozygous deleterious iodothyronine deiodinase 1 ( DIO1 ) mutation ( c...

Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transport across the cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as the inability of standard biomarkers of neonatal screening to provide early detection. In this study, we report, for the first time, the ability to detect MCT8 deficiency at birth using dried blood spot (DBS) samples...

Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH) and its more common form is caused by mutations in the thyroid hormone receptor beta (THRB) gene, termed RTHβ. The characteristic biochemical profile is that of elevated serum TH levels in absence of thyrotropin suppression. Although most individuals are considered clinically euthyroid, there is variability in phenotypic manifestation among individuals harboring different THRB mutations and among tissue types in the same individual due in part to differential expression of the mutant TRβ protein...

BACKGROUND: Thyroid hormone (TH) has important functions in controlling hepatic lipid metabolism. Individuals with resistance to thyroid hormone beta (RTHβ) who harbor mutations in the THRB gene experience loss-of-function of thyroid hormone receptor beta (TRβ), which is the predominant TR isoform expressed in the liver. We hypothesized that these RTHβ individuals may have increased hepatic steatosis. METHODS: Controlled attenuation parameter (CAP) was assessed in individuals harboring the R243Q mutation of the THRB gene (n = 21) and in their wild type (WT) first-degree relatives (n = 22) using the ultrasound-based transient elastography (TE) device (FibroScan, Echosense, France)...

Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of Arid1a, Arid2 , or Smarcb1 in mouse BRAFV600E -mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAFV600E -mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition...

Resistance to thyroid hormone alpha (RTHα) is caused by mutations in thyroid hormone receptor α ( THRA ). Little is known about the natural history and treatment of RTHα, and diagnosis before the age of 1 year has not been previously reported. A de novo heterozygous THRA mutation (pC380SfsX9) was identified in a 10-month-old female investigated for developmental delay, hypotonia, macrocephaly, and severe constipation. Treatment with levothyroxine was accompanied by an appropriate rise in thyroxine (T4), triiodothyronine (T3), as well as decrease in thyrotropin levels and in the T3/T4 ratio with a trend toward normalization of peripheral markers of thyroid hormone action...

Background: Mutations of the thyroid hormone (TH)-specific cell membrane transporter, monocarboxylate transporter 8 ( MCT8 ), produce an X-chromosome-linked syndrome of TH deficiency in the brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia, and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia, and increased metabolism, associated with high serum levels of the active TH, T3)...

Background: Iodothyronine deiodinase-1 (D1) selenoenzyme regulates the systemic supply of active thyroid hormone (TH). Transient decrease in D1 enzymatic activity is clinically relevant and adaptive in nonthyroidal illness such as fasting or acute illness. However, DIO1 gene defects have not been reported in humans. Methods: Genetic analysis was performed using whole-exome sequencing in members of two unrelated families presenting with abnormal serum thyroid function tests. Plasmid constructs containing the two pathogenic DIO1 variants were used for in vitro studies assessing the kinetics of their enzymatic activity...

Background: Familial nontoxic multinodular goiter (MNG) is a rare disease. One of the associated genes is Kelch-like ECH-associated protein 1 ( KEAP1 ), which encodes the main inhibitor of nuclear factor erythroid 2-related transcription factor 2 (Nrf2), a central mediator of antioxidant responses. The association of KEAP1 with familial MNG is based on only two loss-of-function mutations identified in two families, only one of which included proper phenotyping and adequate demonstration of co-segregation of the phenotype and the mutation...

Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients...

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Background: Resistance to thyroid hormone beta (RTHβ) is characterized by elevated thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), caused by thyroid hormone receptor beta gene ( THRB ) defects. Most mutations producing RTHβ phenotype are located in CG-rich regions of THRB , encoding the T3-binding and hinge domains of the receptor. However, a region encompassing codons 384-425 is virtually devoid of RTHβ-causing mutations, termed "cold region." Case: A 49-year-old woman was diagnosed with Hashimoto thyroiditis in her twenties, and levothyroxine (LT4) was initiated...

BACKGROUND: Isolated central congenital hypothyroidism (ICCH) is a rare form (1:50,000 newborns) of congenital hypothyroidism, which can present with growth and neuropsychological retardation. Unlike the more common primary CH (1:1,500-1:4,000), which presents on newborn screening with elevated serum thyroid-stimulating hormone (TSH) and low thyroxine (T4) and triiodothyronine (T3), ICCH presents with low TSH and low thyroid hormone levels. ICCH, therefore, may be missed in most newborn screens that are based only on elevated TSH...

Non-autoimmune hyperthyroidism caused by activating mutations in the GNAS gene is a rare condition. Here we report a 5-year-old girl diagnosed with non-autoimmune hyperthyroidism and tall stature harboring a somatic mosaic gain-of-function mutation in the GNAS gene (NM_080425.3: c.2530C>T;p.Arg844Cys previously reported as NM_000516.5:c.601C>T;p.Arg201Cys) and referred thereafter as R201C, in three of four quadrants of the thyroid gland. Provision of a molecular diagnosis may avoid unnecessary complete ablation of the thyroid gland...

The thyroglobulin (TG) gene encodes a protein required for thyroid hormone synthesis and iodine storage. Deleterious TG mutations produce congenital hypothyroidism (CH) often presenting undetectable serum TG. Alu elements, common throughout the human genome, have a poly(dA) tract along the 3' end of the strand. Herein two of four siblings of a consanguineous Sudanese family with CH, goiter, high initial serum TSH and undetectable TG had a novel frameshift insertion of an Alu element within a coding exon of the TG gene: c...

CONTEXT: Congenital hypothyroidism (CH) is due to dyshormonogenesis in 10-15% of subjects worldwide, but accounts for 60% of CH cases in the Sudan. OBJECTIVE: To investigate molecular basis of CH in Sudanese families. DESIGN: Clinical phenotype reporting and serum thyroid hormone measurements. DNA extraction for whole exome sequencing and Sanger sequencing. SETTING: University research center. PATIENTS: 26 Sudanese families with CH...

Mutations in the cell-membrane thyroid hormone (TH) transporter MCT8 produce severe neuropsychomotor defects and characteristic thyroid function tests (TFT) abnormalities. Two children with mild neurological phenotypes and normal TFT were found to harbor MCT8 gene variants of unknown significance (VUS), MCT8-R388Q that occurred de novo, and MCT8-Q212E. Normal TH transport and action in fibroblasts of MCT8-R388Q was demonstrated in a novel nonradioactive functional assay measuring the intracellular TH availability after L-T3 treatment...

Euthyroid individuals with Familial Dysalbuminemic Hyperthyroxinemia (FDH) have often falsely elevated serum free T4 (FT4) concentrations determined by different automated immunoassays. We measured serum FT4 using direct dialysis coupled with tandem mass spectrometry (FT4 DDMS) in individuals with the common albumin gene mutation (ALB R218H) from 14 FDH families and compared to results obtained by direct immunometric assay (FT4 DIMM) and free T4 index (FT4I). While all 14 individuals with FDH had elevated total serum T4, the FT4 measured by DIMM was elevated in 12, by FT4I in 5, and by DDMS in 1...