A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia

Context: Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albuminwith 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. 125I-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 T 4 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

Homozygous Resistance to Thyroid Hormone β: Can combined anti-thyroid drug and triiodothyroacetic acid treatment prevent cardiac failure?

Resistance to Thyroid Hormone beta (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five cases reported worldwide; cardiac dysfunction, which can be life-threatening, is recognised in the disorder. Here we describe the clinical, metabolic, ophthalmic and cardiac findings in a nine-year old boy harbouring a biallelic THRB mutation (R243Q), along with biochemical, physiological and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognised features (goitre, non-suppressed TSH 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 yrs. 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 anti-thyroid drug and TRIAC therapy may prevent hyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHβ in which life-threatening hyperthyroid features predominate.Our research is supported by funding from the Wellcome Trust (095564/Z/11/Z to K.C.), National Institute for Health Research Cambridge Biomedical Research Centre (C.M., K.C.), the Great Ormond Street Hospital Children’s Charity (F.V.K., M.D.), and Medical Research Council (MRC Programme no. U105960371 to K.W.). G.E.H. receives research funding from the National Institute for Health Research (United Kingdom) and the Foundation Fighting Blindness (United States)

Neonatal thyrotoxicosis and maternal infertility in thyroid hormone resistance due to a mutation in the TRbeta gene (M313T).

We report two unusual cases of resistance to thyroid hormone (RTH) in one family. The first case, a male infant, had clinical features of thyrotoxicosis in the neonatal period. In the fourth week of life weight gain was poor despite a daily intake of standard infant formula almost double the infant's estimated requirements. At this time serum free T4 (fT4) was 60.7 pmol/l (Normal range [NR] 11-25 pmol/l) and TSH was inappropriately normal at 1.8 mU/l (NR 0.3-4.0 mU/l). The infant responded clinically and biochemically to propylthiouracil (PTU) at a dose of 10 mg/kg/day. Following 27 days of treatment serum fT4 was 22.6 pmol/l and TSH had risen to 24.9 mU/l. As the infant was thriving treatment was discontinued. The infant, now aged 6 months old, remains clinically euthyroid and developmentally normal off treatment. The infant's mother, from whom he had inherited a mutation of the thyroid receptor beta (TRbeta) gene (M313T), presented earlier with secondary infertility and clinical features of thyrotoxicosis. Treatment with PTU restored her fertility and she spontaneously conceived. In the subsequent pregnancy, clinical and biochemical features of RTH improved, and she gave birth to a small but healthy female infant. In the next pregnancy, resulting in the birth of the affected male infant, clinical and biochemical features of RTH worsened, and high doses of PTU were required to maintain a clinically euthyroid state. To our knowledge, these are the first case reports of RTH associated with added features of a hypermetabolic state in infancy and secondary infertility

Familial dysalbuminemic hyperthyroxinemia: a persistent diagnostic challenge

Familial dysalbuminemic hyperthyroxinemia (FDH)1 is a well-characterized condition associated with increased circulating total thyroxine (T4) concentrations and normal physiological thyroid function. It is caused by mutations in the ALB (albumin) gene that increase the affinity of albumin for T4 by approximately 60-fold. When measured by equilibrium or symmetric dialysis, the free T4 (FT4) value is characteristically within the reference interval. Assays that rely on the competition of a T4 analog with unbound T4 in the sample can give spuriously high results in FDH patients, because albumin binding of the T4 analog is enhanced by the FDH mutation. “Two step” methods avoid this problem. Such assay methods are expected to give FT4 results within the reference interval in FDH patients, but this expectation has been questioned. Thyroid-function tests, including 1- and 2-step methodologies, were examined in 4 affected individuals from different families who had their FDH diagnoses proved genetically by DNA sequencing of exon 7 of the ALB gene. A diagnosis of FDH can be excluded by means of biochemical methods and by albumin genotyping. Because all mutations that have been associated with FDH to date involve residue 218 (242 with the signal peptide) in the albumin molecule, molecular genetic testing is comparatively simple and returns an unambiguous result

Familial dysalbuminemic hyperthyroxinemia: a persistent diagnostic challenge.

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Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha 1 and TR alpha 2: clinical, biochemical, and genetic analyses of three related patients

Background The thyroid hormone receptor alpha gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)alpha 1 or a non-hormone-binding variant protein, TR alpha 2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TR alpha 1 and TR alpha 2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TR alpha 1, to delineate the relative roles of TR alpha 1 and TR alpha 2. 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 [T-3], low concentration of total reverse T-3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TR alpha 1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TR alpha 1 and TR alpha 2 proteins. The Ala263Val mutant TR alpha 1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TR alpha 2 matched its normal counterpart. In vitro, high concentrations of T-3 restored transcriptional activity of Ala263Val mutant TR alpha 1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T-3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. Interpretation TR alpha 1 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