Familial Dysalbuminemic Hyperthyroxinemia Research Articles

Familial dysalbuminemic hyperthyroxinemia (FDH) due to Arg242 His variant in ALB gene in Turkish children.

To investigate ALB gene variations in patients suspected from familial dysalbuminemic hyperthyroxinemia (FDH). Eight Turkish patients were included into the study. Clinical and laboratory characteristics of the subjects and their parents were evaluated and genetic analysis were performed. In genetic analysis, a previously reported heterozygous, c.725G>A variant was detected in exon seven of the ALB gene. FDH is an asymptomatic condition however there is still a risk of misdiagnosis and unnecessary treatment. Therefore, if FDH is considered, initial ALB hotspot sequencing as a rapid and simple method is recommended instead of complex and expensive laboratory and imaging techniques.

Familial Dysalbuminemic Hyperthyroxinemia by Albumin Gene Variant (R242H) in a 19-Year-Old Male: A Case Report

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common inherited cause of high serum total thyroxine (T4) levels in clinically euthyroid individuals. Mutant albumin coding gene (<i>ALB</i>) interferes free T4 assays and leads to discordant thyroid function tests. We describe a 19-year-old male harboring a heterozygous c.725G > A (p.Arg242His) variant using Sanger sequencing for his <i>ALB</i>, which is the second FDH case reported in South Korea. Appropriate genetic testing for subjects suspicious of FDH would prevent unnecessary repeat tests, although the prevalence of FDH is very low in the Asian population.

Familial dysalbuminemic hyperthyroxinemia combined with Graves’ disease: a rare case report

BackgroundFamilial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant disease characterised by an abnormally increased affinity of albumin for serum thyroxine. Assay interference and differential diagnosis remain challenging for FDH. The condition is more complicated when FDH is combined with primary thyroid diseases. Co-occurrence of FDH and Graves’ disease is rare.Case presentationWe report the case of a 28-year-old woman with complex FDH and coexisting Graves’ disease. Initially, the existence of FDH was not recognised. Graves’ disease was relieved after treatment with antithyroid drugs and two administrations of radioactive iodine therapy. She subsequently developed primary hypothyroidism and was prescribed levothyroxine replacement. However, thyroid function failed to normalise despite frequent levothyroxine dose adjustments. Ultimately, syndromes involving the inappropriate secretion of thyroid-stimulating hormone (IST) were considered, and FDH was successfully differentiated from other causes of IST.ConclusionsA greater focus on FDH when investigating the causes of IST is critical to correctly evaluate thyroid function status and avoid inappropriate treatment, especially in complicated cases with concurrent FDH and primary thyroid diseases.

FRI476 Asymptomatic Thyrotropin-secreting Pituitary Microadenoma With Biochemical Secondary Hyperthyroidism: A Diagnostic Conundrum

Abstract Disclosure: G. Al-Naqeeb: None. R. Ghosh: None. P. Veeraraghavan: None. C. Cochran: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Thyrotropin (TSH)-secreting pituitary adenomas (TSHAs) are often macroadenomas (>1 cm), and clinically present with secondary hyperthyroidism (SH), but clinically silent microTSHAs (<1 cm) with only biochemical SH pose a diagnostic challenge. Clinical Case: A 49-year-old, healthy male was referred to our center for evaluation of abnormal thyroid function tests (TFTs). Immunoassay (IA) measurements at an outside hospital had identified elevated free T4 (FT4), and an inappropriately normal TSH, and a pituitary magnetic resonance imaging (MRI) had noted an 8mm x 7mm non-invasive adenoma. The patient denied hyperthyroidism symptoms, medication/herbal supplement intake, radiation exposure, headaches, vision changes, and thyroid/pituitary disorders, or abnormal TFTs in relatives. Physical exam revealed no signs and symptoms of hyperthyroidism. No thyromegaly or cervical lymphadenopathy was felt. IA profile at our institute was consistent with an SH pattern [TSH: 3.32 mIU/L (NL: 0.4 - 4.7); FT4: 3 ng/dL (NL: 0.9 - 1.7); total T4: 14.5 mcg/dL (NL: 4.5 - 11.7); triiodothyronine: 266.6 ng/dL (NL: 80 - 200)], with similar values on repeat measurement. Equilibrium dialysis technique also yielded an elevated FT4 value. TSH-receptor, anti-thyroid peroxidase, and anti-thyroglobulin (Tg) antibody (Ab) titers, serum Tg, and thyroid binding globulin levels were normal. Dilution studies ruled out heterophile Ab interference. Familial dysalbuminemic hyperthyroxinemia was unlikely given the elevated FT4 values. Genetic testing revealed a normal THRB gene, thereby ruling out thyroid hormone resistance. THRA gene was not tested due to absence of behavioral or hearing issues. Markers of hyperthyroidism, including angiotensin converting enzyme, carotene, apolipoproteins, and osteocalcin levels were normal, except for an elevated sex hormone binding globulin of 104 nmol/L (NL: 11 - 78). Biochemical evaluation of other pituitary axes was normal. However, an elevated alpha sub-unit fraction (ASF) was noted on two separate measurements. Sonogram revealed a heterogeneous, hypervascular thyroid. Bone densitometry, echocardiogram, and Holter monitor studies were normal. The combination of biochemical SH, elevated ASF, pituitary adenoma, and exclusion of other etiologies causing SH pattern established the diagnosis of TSHA. An active surveillance approach was implemented. A pituitary MRI done 18 months later showed minimal (2mm in one axis) increase in the adenoma size, and the patient continued to demonstrate biochemical SH but remained asymptomatic. Conclusion: MicroTSHAs can present with asymptomatic SH. In this situation, excluding other biochemical SH etiologies is crucial to prevent unnecessary invasive procedures. But once TSHA diagnosis is established, due to the risk of tumor growth leading to symptomatic SH or mass effects, active surveillance is warranted. Presentation: Friday, June 16, 2023

A Positive Newborn Screen for Congenital Hypothyroidism in a Clinically Euthyroid Neonate—Avoiding Unnecessary Treatment

Newborn screening for congenital hypothyroidism (CH) has dramatically improved the neurocognitive outcomes for newborns with a confirmed positive screening test result. However, screening yields a small number of false positive and false negative results. This report describes the first known case of familial dysalbuminaemic hyperthyroxinaemia presenting with a positive newborn thyroid stimulating hormone screen. This condition is characterized by artefactually elevated free tetraiodothyronine (T4) and triiodothyronine (T3) levels due to increased albumin binding and subsequent dissociation during laboratory assays but normal true free thyroid hormone and thyroid stimulating hormone (TSH) levels in a clinically euthyroid subject. This highlights the need to take care when attributing clinical significance to discordant results.

Clinical characteristics of familial dysalbuminemic hyperthyroxinemia in Chinese patients and comparison of free thyroxine in three immunoassay methods.

Familial dysalbuminemic hyperthyroxinemia (FDH) has not been thoroughly studied in the Chinese population to date. The clinical characteristics of FDH in Chinese patients were summarized, and the susceptibility of common free thyroxine (FT4) immunoassay methods was evaluated. The study included 16 affected patients from eight families with FDH admitted to the First Affiliated Hospital of Zhengzhou University. The published FDH patients of Chinese ethnicity were summarized. Clinical characteristics, genetic information, and thyroid function tests were analyzed. The ratio of FT4 to the upper limit of normal (FT4/ULN) in three test platforms was also compared in patients with R218H ALB mutation from our center. The R218H ALB mutation was identified in seven families and the R218S in one family. The mean age of diagnosis was 38.4 ± 19.5 years. Half of the probands (4/8) were misdiagnosed as hyperthyroidism previously. The ratios of serum iodothyronine concentration to ULN in FDH patients with R218S were 8.05-9.74 for TT4, 0.68-1.28 for TT3, and 1.20-1.39 for rT3, respectively. The ratios in patients with R218H were 1.44 ± 0.15, 0.65 ± 0.14, and 0.77 ± 0.18, respectively. The FT4/ULN ratio detected using the Abbott I4000 SR platform was significantly lower than Roche Cobas e801 and Beckman UniCel Dxl 800 Access platforms (P < 0.05) in patients with R218H. In addition, nine Chinese families with FDH were retrieved from the literature, of which eight carried the R218H ALB mutation and one the R218S. The TT4/ULN of approximately 90% of patients (19/21) with R218H was 1.53 ± 0.31; the TT3/ULN of 52.4% of patients (11/21) was 1.49 ± 0.91. In the family with R218S, 45.5% of patients (5/11) underwent TT4 dilution test and the TT4/ULN was 11.70 ± 1.33 and 90.9% (10/11) received TT3 testing and the TT3/ULN was 0.39 ± 0.11. Two ALB mutations, R218S and R218H, were found in eight Chinese families with FDH in this study, and the latter may be a high-frequency mutation in this population. The serum iodothyronine concentration varies with different mutation forms. The rank order of deviation in measured versus reference FT4 values by different immunoassays (lowest to highest) was Abbott < Roche < Beckman in the FDH patients with R218H.

Familial Dysalbuminemic Hyperthyroxinemia Induced by Mutation R218H of Albumin

Familial Dysalbuminemic Hyperthyroxinemia (FDH) is thought of no clinical significance, but tends to to misdiagnosed and mistreated as Graves’ hyperthyroidism with long time. In a Chinese family to explore clinical characteristics, hereditary features and gene variation of FDH and its effect on pregnancy. Methods: Two propostitus (a father and his son) with hyperthyroidism were re-diagnosed as FDH due to the canonical profile of measured thyroid hormones. After screening thyroid function of the whole family, eight affected of FDH were identified among total thirteen lineal relatives. They were studied in terms of clinical history, biochemical and hormone examination, thyroid imaging and TSH secreting test by dexamethasone and bromocriptine. Three members accepted gene analysis with the next generation sequencing followed by Sanger method. Productive history was investigated in five spouse of the whole family. Results: In the two propostitus, FDH exhibited very high total thyroxine (T4) and mild high total triiodinethyronine (T3), and normal free T4 and T3 besides normal thyroid stimulating hormone (TSH). In addition, ultrasound discovered diffuse goiter and enhanced blood flow, and 99mTc uptake increased, while TSH receptor antibody and pituitary MRI scan remained normal. Other six family members had similar changes of the thyroid hormones and normal TSH which could be suppressed dramatically by dexamethasone and bromocriptine, then were suspected of FDH and thereafter confirmed with gene analysis. Among these eight FDH, four were misdiagnosed with hyperthyroidism and mistakenly received anti-thyroid medication at least one year. Gene analysis of three members revealed R218H variation of albumin gene. Conclusions: R218H associated FDH shows canonical changes of thyroid hormones with increased thyroid function, high penetrance and misdiagnose rate with hyperthyroidism, it exerts no effect on pregnancy.

Variations in the Human Serum Albumin Gene: Molecular and Functional Aspects

The human albumin gene, the most abundant serum protein, is located in the long arm of chromosome 4, near the centromere, position 4q11–3. It is divided by 14 intervening introns into 15 exons, the last of which is untranslated. To date, 74 nucleotide substitutions (mainly missense) have been reported, determining the circulating variants of albumin or pre-albumin. In a heterozygous state, this condition is known as alloalbuminaemia or bisalbuminaemia (OMIM # 103600). The genetic variants are not associated with disease, neither in the heterozygous nor in the homozygous form. Only the variants resulting in familial dysalbuminaemic hyperthyroxinaemia and hypertriiodothyroninaemia are of clinical relevance because affected individuals are at risk of inappropriate treatment or may have adverse drug effects. In 28 other cases, the pathogenic variants (mainly affecting splicing, nonsense, and deletions), mostly in the homozygous form, cause a premature stop in the synthesis of the protein and lead to the condition known as congenital analbuminaemia. In this review, we will summarize the current knowledge of genetic and molecular aspects, functional consequences and potential therapeutic uses of the variants. We will also discuss the molecular defects resulting in congenital analbuminaemia, as well as the biochemical and clinical features of this rare condition

Familial Dysalbuminemic Hyperthyroxinemia as a Cause for Discordant Thyroid Function Tests

IntroductionDiscordant thyroid function tests are routinely encountered in clinical practice. Differential diagnoses include acute thyroxine (T4) ingestion, laboratory interference from heterophilic antibodies, thyroid hormone resistance, thyroid-stimulating hormone (TSH)-secreting pituitary adenomas, and T4 protein binding abnormalities. The impact of abnormal binding proteins may be less recognized since widespread use of free T4 (FT4) assays compared to older total T4 assays.Case reportA 69-year-old female was referred for assessment of discordant thyroid function tests. Biochemistry since July 2015 showed persistently elevated FT4 levels by immunoassay ranging between 25 to 34 pmol/L with normal or slightly decreased TSH ranging between 0.05 to 2.74 mU/L. The patient was clinically euthyroid on 100 mcg daily of levothyroxine for Hashimoto’s thyroiditis. FT4 measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was 19.5 pmol/L. Exome sequencing (confirmed by Sanger sequencing) detected a guanine to adenine substitution at residue 725 of the ALB gene previously associated with dysalbuminemic hyperthyroxinemia. The patient’s daughter had similar thyroid function tests and the same genetic variant. FT4 results from 3 different automated immunoassays showed the Roche Cobas and Siemens Centaur platforms to be most affected by the variant, and Abbott Architect had the best agreement with LC-MS/MS.ConclusionFamilial dysalbuminemic hyperthyroxinemia is a potential cause of discordant thyroid function tests. Clinicians suspecting protein-binding abnormalities may further investigate using reference methods such as LC-MS/MS and equilibrium dialysis if available. The increasing accessibility of exome sequencing offers a cost-effective method of diagnosing genetic variants that cause discordant thyroid function tests.

An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders.

Confirmation of sustained syndrome of inappropriate secretion of thyrotropin (SITSH) is a milestone in diagnosis of β type of resistance to thyroid hormone (RTHβ). The differential diagnoses of RTHβ include TSH-producing pituitary adenoma (TSHoma) and familial dysalbuminemic hyperthyroxinemia (FDH), which also present SITSH. Recently, patients with RTHα caused by a mutation in thyroid hormone receptor α were reported and they did not present SITSH but a decline in the serum T4/T3 ratio. This review was aimed to overview thyroid function tests in RTH and related disorders. First, the characteristics of the thyroid function in RTHβ, TSHoma, and FDH obtained from a Japanese database are summarized. Second, the degrees of SITSH in patients with truncations and frameshifts were compared with those in patients with single amino acid deletions and single amino acid substitutions obtained from the literature. Third, the degrees of SITSH in homozygous patients were compared with those in heterozygous patients with cognate mutations. Finally, the FT3/FT4 ratios in RTHα are summarized. In principle, the TSH values in FDH were within the normal range and apparent FT4 values in FDH were much higher than in RTHβ and TSHoma. The FT3/FT4 values in RTHβ were significantly lower than in TSHoma. The degrees of SITSH in patients with truncations and frameshifts were more severe than those in patients with single amino acid deletions and single amino acid substitutions, and those in homozygous patients were more severe than those in heterozygous patients with cognate mutations. The FT3/FT4 ratios in RTHα were higher than 1.0.

Familial Dysalbuminemic Hyperthyroxinemia: An Underdiagnosed Entity.

Resistance to thyroid hormone (RTH) is a syndrome characterized by impaired sensitivity of tissues to thyroid hormone (TH). The alteration of TH-binding proteins, such as in Familial Dysalbuminemic Hyperthyroxinemia (FDH), can mimic the abnormal serum thyroid tests typical of RTH. We aimed to characterize a population referred to our center with suspected RTH and estimate the proportion of patients with FDH. For 303 different families, we collected clinical and hormonal data and sequenced the thyroid hormone receptor β gene (THRB) and exon 7 of the albumin gene (ALB). We found 56 THRB variants (i.e., 38% of the 303 index cases, called RTHβ group). Among the samples screened for FDH variants, 18% had the variant R218H in ALB (FDH group); in addition, 71% of the cases had neither variant (non-FDH/RTHβ group). Patients with FDH had significantly lower free T3 (fT3) and free T4 (fT4) levels and more often an isolated elevation of fT4 than RTHβ patients. Clinically, patients with FDH had fewer symptoms than patients with RTHβ. Our study suggests that FDH should be systematically considered when examining patients suspected of having RTH. In most cases, they present no clinical symptoms, and their biochemical alterations show an elevation of fT4 levels, while fT3 levels are 1.11 times below the upper limit of the assay.

Familial Dysalbuminemic Hyperthyroxinemia (FDH), Albumin Gene Variant (R218S), and Risk of Miscarriages in Offspring

Familial dysalbuminemic hyperthyroxinemia (FDH) is a rare autosomal dominant disorder whose clinical characteristics remain incompletely understood, we investigated the role of albumin gene mutation in relation to miscarriage rate in a large pedigree of FDH followed up for 4 years. The proband and extended family with unexplained miscarriage and hyperthyroxinemia were identified and genotypes in candidate genes and thyroid function tests (TFTs), including changes in TFTs during pregnancy were comprehensively assessed. We also evaluated the development and growth of children in this large FDH pedigree during four years follow-up. The R218S variant in the albumin gene was identified in the proband and her relatives with hyperthyroxinemia who were diagnosed as FDH. Among the family members who underwent TFTs, 11 of 17 (65%) had similar changes in levels of thyroid hormone, with an estimated FDH heritability of 86%. Moreover, 32% (95% CI 16-54%) of FDH women experienced miscarriages at a rate that was substantially higher than the spontaneous abortion rate reported in the general population in China (7-14%). During the follow-up, results revealed that free triiodothyronine (fT3) and thyroid stimulating hormone (TSH) levels were normal during the entire gestational period; comparing to their age-adjusted peers, both FDH affected and FDH unaffected children in this pedigree appeared to have lower body weight and height. Albumin gene variant (R218S) not only causes FDH but also may be associated with a higher risk of miscarriages, although the growth of their children appears not to be affected by the age of 2 years.

MON-483 Familial Dysalbuminemic Hyperthyroxinemia with False Hypercortisolemia

Background: Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant disease characterized by hyperthyroxinemia without symptoms of thyrotoxicosis, due to a high affinity of mutant albumin for thyroxine. No report has described cortisol-albumin binding in FDH patient, and here we present a case of FDH presenting with false hypercortisolemia.Clinical Case: A 46-year man, previously diagnosed with FDH by genetic test (1), was pointed out hypercortisolemia with normal ACTH level (ACTH 64.7 pg/mL, Cortisol 34.7 μg/dL) during the investigation for Parkinson’s syndrome and referred to our department for further examination. Cortisol was 7.1 μg/dL at midnight, 14.9 μg/dL after low dose dexamethasone overnight test, and DDAVP test was positive. ACTH and cortisol responded to CRH load, although basal and peak cortisol levels were high (35.4 and 53.9 μg/dL, respectively). High dose dexamethasone overnight test showed suppressed ACTH and cortisol, and MRI showed no obvious pituitary adenoma.In spite of significant high cortisol level, no Cushing sign’s or metabolic abnormalities were observed and urinary free cortisol was within the normal range (30.7 μg/day), suggesting the presence of factors affecting the laboratory testing. We removed albumin from serum with immunoprecipitation using anti-albumin antibody and measured cortisol with LC-MS/MS. The decrease of cortisol was 4% in control serum but 38% in the patient serum after removing albumin, suggesting the binding rate of cortisol to mutant albumin in the patient was increased, leading to false hypercortisolemia.Conclusion: This is the first case demonstrating the false hypercortisolemia in a FDH patient. Clinicians should consider the possibility of the abnormal cortisol binding to albumin in differential diagnosis of hypercortisolemia with normal ACTH level.Reference: (1) Norio Wada, et al: A Novel Missense Mutation in Codon 218 of the Albumin Gene in a Distinct Phenotype of Familial Dysalbuminemic Hyperthyroxinemia in a Japanese Kindred. Journal of Clinical Endocrinology and Metabolism 1997;82;3246–3250

MON-472 A Case of Resistance to Thyroid Hormone with Concurrent Hashimoto’s Thyroiditis and Post-Surgical Hypothyroidism

Introduction: Resistance to thyroid hormone (RTH) is a rare defect that results in impaired sensitivity to thyroid hormone. While most commonly caused by mutations in the thyroid hormone receptor beta (THRβ) gene, in 15% of patients with the RTH phenotype, no mutation is identified.1 This entity is known as non-thyroid hormone receptor RTH (nonTR-RTH). Patients with RTH have an increased risk of autoimmune thyroid disease with a reported odds ratio of 2.36.2 Hashimoto’s thyroiditis or other etiologies of hypothyroidism add a layer of complexity to RTH as such individuals may require high doses of levothyroxine to overcome hormone resistance.Clinical Case: A 36-year-old male was referred for abnormal thyroid function tests. He denied symptoms of thyroid dysfunction. Physical examination was notable for a goiter. Weight was 83 kg. Initial labs revealed TSH 6.8 mcIU/mL (0.3-4.7 mcIU/mL), free T4 2.0 ng/dL (0.8-1.7 ng/dL), free T3 491 pg/dL (222-383 pg/dL), and thyroid peroxidase antibody >600 IU/mL (≤20 IU/mL). Additional work-up demonstrated elevated free T4 by equilibrium dialysis 2.5ng/dL (0.9-2.2 ng/dL) and elevated TSH with HAMA treatment 5.96 mIU/L (0.40-4.50 mIU/L), thereby ruling out familial dysalbuminemic hyperthyroxinemia and HAMA interference. Alpha-subunit of 0.30 ng/mL (<0.55 ng/mL) and normal pituitary MRI did not support a TSH-secreting adenoma. Quest Diagnostics RTH Gene Sequencing was negative for a mutation in the THRβ gene. The patient was subsequently diagnosed with nonTR-RTH. Thyroid ultrasound showed multiple thyroid nodules, including a 1.8 cm hypoechoic, complex nodule in the left inferior gland and a 1.7 cm isoechoic nodule in the right inferior gland. Fine needle aspiration of the left nodule was suspicious for papillary thyroid carcinoma and the right nodule showed lymphocytic thyroiditis. The patient underwent total thyroidectomy and pathology demonstrated a benign left nodule and an incidental 0.3 cm right papillary thyroid carcinoma. The patient started levothyroxine 150 mcg daily (1.8 mcg/kg) post-operatively with subsequent TSH of 18.1 mcIU/mL. His dose was increased to 200 mcg daily (2.4 mcg/kg) and TSH was still elevated at 11.7 mcIU/mL. His levothyroxine dose was subsequently increased to 250 mcg daily (3 mcg/kg) and TSH is outstanding.Conclusions: This case highlights the diagnostic challenge in nonTR-RTH. It also demonstrates the complex management of patients with RTH and concurrent hypothyroidism. Such patients need close monitoring and aggressive titration of levothyroxine to achieve desired hormone levels.1. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid hormone. Biochim Biophys Acta 2013;1830:3987-4003.2. Barkoff MS, Kocherginsky M, Anselmo J, Weiss RE, Refetoff S. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 2010;95:3189-93.

Familial dysalbuminemic hyperthyroxinemia confounding management of coexistent autoimmune thyroid disease.

SummaryFamilial dysalbuminemic hyperthyroxinemia (FDH) is a cause of discordant thyroid function tests (TFTs), due to interference in free T4 assays, caused by the mutant albumin. The coexistence of thyroid disease and FDH can further complicate diagnosis and potentially result in inappropriate management. We describe a case of both Hashimoto’s thyroiditis and Graves’ disease occurring on a background of FDH. A 42-year-old lady with longstanding autoimmune hypothyroidism was treated with thyroxine but in varying dosage, because TFTs, showing high Free T4 (FT4) and normal TSH levels, were discordant. Discontinuation of thyroxine led to marked TSH rise but with normal FT4 levels. She then developed Graves’ disease and thyroid ophthalmopathy, with markedly elevated FT4 (62.7 pmol/L), suppressed TSH (<0.03 mU/L) and positive anti-TSH receptor antibody levels. However, propylthiouracil treatment even in low dosage (100 mg daily) resulted in profound hypothyroidism (TSH: 138 mU/L; FT4: 4.8 pmol/L), prompting its discontinuation and recommencement of thyroxine. The presence of discordant thyroid hormone measurements from two different methods suggested analytical interference. Elevated circulating total T4 (TT4), (227 nmol/L; NR: 69–141) but normal thyroxine binding globulin (TBG) (19.2 µg/mL; NR: 14.0–31.0) levels, together with increased binding of patient’s serum to radiolabelled T4, suggested FDH, and ALB sequencing confirmed a causal albumin variant (R218H). This case highlights difficulty ascertaining true thyroid status in patients with autoimmune thyroid disease and coexisting FDH. Early recognition of FDH as a cause for discordant TFTs may improve patient management.Learning points:The typical biochemical features of familial dysalbuminemic hyperthyroxinemia (FDH) are (genuinely) raised total and (spuriously) raised free T4 concentrations due to enhanced binding of the mutant albumin to thyroid hormones, with normal TBG and TSH concentrations.Given the high prevalence of autoimmune thyroid disease, it is not surprising that assay interference from coexisting FDH may lead to discordant thyroid function tests confounding diagnosis and resulting in inappropriate therapy.Discrepant thyroid hormone measurements using two different immunoassay methods should alert to the possibility of laboratory analytical interference. The diagnosis of FDH is suspected if there is a similar abnormal familial pattern of TFTs and increased binding of radiolabelled 125I-T4 to the patient’s serum, and can be confirmed by ALB gene sequencing.When autoimmune thyroid disease coexists with FDH, TSH levels are the most reliable biochemical marker of thyroid status. Measurement of FT4 using equilibrium dialysis or ultrafiltration are more reliable but less readily available.

A Chinese Family with Familial Dysalbuminemic Hyperthyroxinemia (FDH) due to R242H Mutation on Human Albumin Gene: Reevaluating the Role of FDH in Patients with Asymptomatic Hyperthyroxinemia.

Objective Familial dysalbuminemic hyperthyroxinemia (FDH) has now become an established cause for spurious asymptomatic hyperthyroxinemia. Several different codon mutations on albumin gene had been identified. We here provided an established but rarely reported heterozygous mutation based on gene sequencing results from a Chinese family. Methods The proband is a 14-year-old girl with light goiter and asymptomatic clinical presentations, whose thyroid function test by a one-step immunoassay showed increased free thyroxine (FT4) and free triiodothyronine (FT3) but nonsuppressed thyrotropin (TSH). All thyroid auto-antibodies were in the normal range. Blood samples were collected from her and most of her immediate family members for target gene sequencing and verification. Results Hyperthyroxinemia was also confirmed in the proband's mother and one of her uncles and his son. In the proband and these three pedigrees, the high-throughput gene screening sequencing and the following Sanger sequencing disclosed a heterozygous mutation in the albumin gene, which located in its exon 7 (c.725G > A), and correspondingly leads to an arginine replacement with a histidine (R242H) in its protein. This is an established mutation named as R218H if present without signal peptide sequence. Conclusions For patients with asymptomatic hyperthyroxinemia, FDH should be clinically excluded before embarking on further investigations for other specific causes.

MON-612 Familial Dysalbuminemic Hyperthyroxinemia Cases in Five Unrelated Japanese Families and the Influences on Free T4 Measurement

Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by abnormal human serum albumin (HSA) with an increased thyroxine (T4) affinity leading to euthyroid hyperthyroxinemia. In Japanese FDH patients with the HSAR218P mutation, not only one-step but also two-step immunoassays for free T4 (FT4) can yield false-positive results. Therefore, it is difficult to distinguish FDH from syndrome of inappropriate secretion of TSH, even when multiple assays are used. Patient 1 was a 29-year-old pregnant woman. A radiographic examination and hormone stimulation test were not performed. We suspected that the patient had FDH because of her family history such as abnormal thyroid function and hyperthyroxinemia (Total T4 level was greater than the measurement sensitivity). Genetic analysis using direct sequencing for HSA revealed that she was consistent with FDH. She experienced a normal delivery. Other patients were performed the thyroid test with Chief complaints of infertility or depression and their thyroid function abnormalities were pointed out. Thyroid function tests revealed elevated FT4 and FT3 levels; their TSH level was within the reference range in all patients. To investigate T4 to HSA binding, gel filtration high-performance liquid chromatography was used for the biochemical analyses. Furthermore, FT4 was measured in FDH patients using one-step method LUMIPULSE (Fujirebio) using T3 as an antigen and an anti-T4 antibody as a label. The genomic analysis revealed a heterozygous missense mutation in HSA(R218P). In FDH patient sera, the albumin effluent corresponded to the peaks for total T4 (TT4); approximately 60% of the T4 in the effluent was detected as FT4. Mean FT4 level measured with LUMIPULSE was 1.28 ng/dL within the reference value range. In the FDH patients, a relatively larger quantity of T4 was bound to abnormal HSA. This bound T4 was measured as FT4 during the analysis. When thyroid function abnormality without clinical findings is observed, it is considered preferable to understand the antigen and antibody to be used and to select measurement method.

Thyroid hormone pattern in Familial Dysalbuminemic Hyperthyroxinemia (R218H mutation) on different assay platforms

Thyroid hormone pattern in Familial Dysalbuminemic Hyperthyroxinemia (R218H mutation) on different assay platforms

Familial dysalbuminemic hyperthyroxinemia associated with thyroid papillary cancer: one case report and review of literature

Familial dysalbuminemic hyperthyroxinemia associated with thyroid papillary cancer: one case report and review of literature

Assessing the clinical and molecular diagnosis of inherited forms of impaired sensitivity to thyroid hormone from a single tertiary center

Resistance to thyroid hormone (RTH), characterized by persistent hyperthyroxinemia with non-suppressed thyrotropin (TSH), is mostly caused by mutations in thyroid hormone receptor beta gene (THRB). Two differential diagnoses should be considered due to similar clinical and laboratory findings: TSH-producing pituitary adenoma (TPA) and Familial Dysalbuminemic Hyperthyroxinemia (FDH). The aim of this study is to describe our single tertiary center experience in the molecular diagnosis of RTH in Brazilian patients, analyzing their clinical and laboratory characteristics and the most common differential diagnosis. We enrolled 30 subjects with clinical and laboratory features of RTH. Patient´s evaluations included clinical examination, thyroid hormone profile and imaging tests. Sequencing analysis for THRB hot spot region was conducted on all patients, and those without mutations in beta isoform of the thyroid hormone receptor (TRβ) (non-TR-RTH) were investigated for albumin gene (ALB) mutation. Seventeen patients presented mutations in TRβ (RTHβ); six were non-TR-RTH, three had a diagnosis of FDH with a mutation in ALB, and four were diagnosed with TPA. Two characteristics were different to what is commonly described in the literature: higher serum TSH levels in RTHβ patients when compared to the non-TR-RTH group, but this difference did not extend to free T4 (FT4) level; also the percentage of non-TR-RTH was higher than what was reported in other series. In the present series, most cases were RTHβ with higher levels of TSH. We described three novel mutations in THRB (p.M313V, p.R320G and p.R438P) and the first patients with FDH molecular diagnosis (p.R242H) documented in Brazil.