Familial dysalbuminemic hyperthyroxinemia in a 4-year-old girl with hyperactivity, palpitations and advanced dental age: how gold standard assays may be misleading

Choudhary, Abha; Sriphrapradang, Chutintorn; Refetoff, Samuel; Antal, Zoltan

doi:10.1515/jpem-2014-0019

Cited by 8 publications

(8 citation statements)

References 5 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, it should be noted that FDH-T4, which does not call for treatment, could mask the simultaneous presence of true thyroid disease such as hypothyroidism, autoimmune thyroiditis, or thyrotoxicosis ( 1 , 2 , 26 , 27 ).…”

Section: Diagnosis Of and Differential Diagnosis To Fdh-t4mentioning

confidence: 99%

“…To these numbers can be added some of the cases with more than one diagnosis referred to in Section “ Diagnosis of and Differential Diagnosis to FDH-T4 .” Thus, three members of a family have both FDH-T4 and congenital hypothyroidism ( 26 ). In another family, a young girl has autoimmune thyroid disease as well as FDH-T4, whereas her father has only FDH-T4 ( 27 ); he is included in Table 1 . Geographically, this type of FDH-T4 has been detected in North America, Western Europe, Eastern Asia, and in New Zealand.…”

Section: Fdh-t4 Causing Mutationsmentioning

confidence: 99%

See 1 more Smart Citation

Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia

2017

View full text Add to dashboard Cite

Familial dysalbuminemic hyperthyroxinemia (FDH-T4) and hypertriiodothyroninemia (FDH-T3) are dominantly inherited syndromes characterized by a high concentration of thyroid hormone in the blood stream. The syndromes do not cause disease, because the concentration of free hormone is normal, but affected individuals are at risk of erroneous treatment. FDH-T4 is the most common cause of euthyroid hyperthyroxinemia in Caucasian populations in which its prevalence is about 1 in 10,000 individuals, but the prevalence can be much higher in some ethnic groups. The condition is caused by a genetic variant of human serum albumin (HSA); Arg218 is mutated to histidine, proline, or serine or Arg222 is changed to isoleucine. The disorder is characterized by greater elevation in serum l-thyroxine (T4) than in serum triiodothyronine (T3); T4 can be increased by a factor 8–15. The high serum concentration of T4 is due to modification of a binding site located in the N-terminal half of HSA (in subdomain IIA). Thus, mutating Arg218 or Arg222 for a smaller amino acid reduces the steric restrictions in the site and creates a high-affinity binding site. The mutations can also affect binding of other ligands and can perhaps cause modified pharmacokinetics of albumin-binding drugs. In normal HSA, the high-affinity site has another location (in subdomain IIIB). Different locations of these sites imply that persons with and without FDH-T4 can have different types of interactions, and thereby complications, when given albumin-binding drugs. FDH-T3 is caused by a leucine to proline mutation in position 66 of HSA, which results in a large increment of the binding affinity for T3 but not for T4. For avoiding unwanted treatment of euthyroid persons with hyperthyroxinemia or hypertriiodothyroninemia, protein sequencing and/or sequencing of the albumin gene should be performed.

show abstract

Section: Diagnosis Of and Differential Diagnosis To Fdh-t4mentioning

confidence: 99%

Section: Fdh-t4 Causing Mutationsmentioning

confidence: 99%

Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia

2017

View full text Add to dashboard Cite

show abstract

“…The mutation involves codon 218, which is normally arginine, and it gets replaced with histidine, proline, or serine (or codon 222), which is also arginine that gets replaced with isoleucine. These mutations in the codon 218 and codon 222 for a smaller amino acid reduces the steric hindrances and creates a high-affinity binding site for T4 [ 2 , 9 ]. Individuals with FDH are heterozygous for the mutation.…”

Section: Discussionmentioning

confidence: 99%

“…To confirm or better delineate an abnormal result, direct equilibrium dialysis is the next test of choice, as it was in our patient. While this method has a better ability to accurately report true free T4 values in the face of confounding variables, false-positives may still occur [ 9 ]. Hoshikawa et al have reported false-positive results of elevated free T4 assays using equilibrium dialysis/radioimmunoassay (RIA), and they suggest that this assay is not an ultimate standard for diagnosing FDH, especially in patients with the R218P mutation of the ALB gene [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Albumin Polymorphism on Thyroid Hormones: A Case Report and Literature Review

Mahendhar¹,

Shahbaz²,

Riaz³

et al. 2018

Cureus

View full text Add to dashboard Cite

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of the inherited increase of serum thyroxine in Caucasians. This disorder occurs due to a missense mutation in the human serum albumin, resulting in an increased affinity of thyroxine to the binding sites on the human serum albumin (HSA) molecule. HSA is a carrier protein of thyroid hormones and only 10% of thyroxine (T4) is bound to human serum albumin, 75% is bound to thyroxine-binding globulin, 15% to transthyretin, and 0.03% is free. The disorder is characterized by a greater elevation of serum thyroxine than triiodothyronine (T3). The high serum concentration of T4 is due to the modification of a binding site located in the N-terminal half of HSA (in subdomain IIA). Arg218 or Arg222 gets replaced with smaller amino acids, such as histidine, proline, or serine, due to missense mutation; this reduces the steric hindrances in the binding site and creates a high-affinity binding site for thyroxine. We herein report a case of FDH with a characteristically elevated total T4 and normal free T4 (measured by equilibrium dialysis).

show abstract

“…This relatively low T 4 and T 3 differentiates individuals with both conditions from those with classic Graves’ disease. Once hyperthyroidism is treated and the TSH stabilizes, the free T 4 concentration may remain falsely elevated due to accuracy of free T 4 methods when binding proteins are extremely low (19, 20). Measuring free T 4 by direct equilibrium dialysis bypasses these issues.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation Causing Complete Thyroid Binding Globulin Deficiency (Tbg-Cd Mia) In A Male With Coexisting Graves Disease

Berger

Creech

Hannoush

et al. 2017

AACE Clinical Case Reports

View full text Add to dashboard Cite

Objective An asymptomatic male was found on screening to have a low serum TSH and total T4. The diagnosis of Graves’ disease was made with positive thyroid stimulating immunoglobulin (TSI) and elevated free T4 in the presence of complete TBG deficiency (TBG-CD). Genetic testing of the patient and family members revealed a novel frameshift mutation in the TBG (SERPINA7) gene resulting in a complete deficiency of the protein. Methods The laboratory testing included total T4, free T4 by analog method and direct dialysis and TBG measurements. Sequencing of genomic DNA was performed from peripheral blood. Results A 35-year-old East Indian male was referred to endocrinology because of abnormal thyroid function tests (TFTs): TSH 0.01 mIU/L (0.4–3.6), total T4 3.0 µg/dl (5.5–10.5) done as part of a “routine office visit”. Upon further testing, the serum free T4 2.0 ng/dl (0.8–1.8) and TSI 355% (<140% baseline) were elevated and the diagnosis of Graves’ disease was made. TBG deficiency was suspected because the total T4 concentration was inconsistent with hyperthyroidism and further testing confirmed TBG was undetectable. Sequencing of the TBG gene revealed a novel hemizygous frameshift mutation: p.Ala64ProfsTer106, TBG-CD Mia (numbering excludes 20 a.a. signal peptide) associated with the complete deficiency of TBG in a patient with Graves’ disease. Conclusion Patients with Graves’ disease harboring a TBG mutation have conflicting TFTs. If a clinically hyperthyroid patient presents with normal or low total T4, serum TBG should be measured to identify an abnormality and prevent unnecessary testing.

show abstract

Familial dysalbuminemic hyperthyroxinemia in a 4-year-old girl with hyperactivity, palpitations and advanced dental age: how gold standard assays may be misleading

Cited by 8 publications

References 5 publications

Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia

Clinical, Genetic, and Protein Structural Aspects of Familial Dysalbuminemic Hyperthyroxinemia and Hypertriiodothyroninemia

Effect of Albumin Polymorphism on Thyroid Hormones: A Case Report and Literature Review

A Novel Mutation Causing Complete Thyroid Binding Globulin Deficiency (Tbg-Cd Mia) In A Male With Coexisting Graves Disease

Contact Info

Product

Resources

About