Hyperthyroxinemia, Familial Dysalbuminemic

A number sign (#) is used with this entry because familial dysalbuminemic hyperthyroxinemia (FDAH) is caused by heterozygous mutation in the ALB gene (103600) on chromosome 4q13.

Description

Familial dysalbuminemic hyperthyroxinemia is an autosomal dominant condition characterized by the presence of a variant serum albumin with preferential affinity for thyroxine (T4) in clinically euthyroid individuals. Individuals have consistently elevated total T4 and elevated or normal free T4 values with normal TSH levels. The condition may be confused with hyperthyroidism or thyroid hormone resistance syndromes, prompting repeated unnecessary laboratory testing and possibly even inappropriate treatment (summary by Heufelder et al., 1995).

Clinical Features

Ruiz et al. (1982) studied 15 euthyroid patients from 8 families who showed elevated serum thyroxine and free-thyroxine index, both due to an abnormal serum albumin that preferentially binds thyroxine. Results of thyrotropin-releasing hormone and thyroid suppressions tests, as well as direct measurements of the free-thyroxine concentration by equilibrium dialysis were normal. Ruiz et al. (1982) noted that some of their patients had mistakenly been thought to be hyperthyroid and that some had received unnecessary treatment. Ruiz et al. (1982) called the disorder 'familial dysalbuminemic hyperthyroxinemia.'

Lalloz et al. (1985) subdivided FDH into 3 types, depending on the coexistence of T3 and rT3 excess with hyperthyroxinemia. Seemingly, the binding of drugs by albumin and the release of thyroid hormone to the tissues are not altered in ways that have clinical significance.

DeCosimo et al. (1987) presented evidence indicating that familial dysalbuminemic hyperthyroxinemia is unusually frequent in Hispanics of Puerto Rican origin.

Yeo et al. (1987) reported the largest kindred with familial dysalbuminemic hyperthyroxinemia thus far reported. Two of the patients had mistakenly been treated for hyperthyroidism. Two women with the disorder were receiving oral contraceptives, which produced an increase in serum thyroxine-binding globulin (314200). Yeo et al. (1987) pointed out that the coexistence of acquired high TBG or significant thyroid malfunction may confound the diagnosis of dysalbuminemic hyperthyroxinemia.

Yabu et al. (1987) described a variant form of albumin with a markedly enhanced binding activity for L-3,5,3-prime-triiodothyronine (T3), a somewhat increased activity for thyroxine (T4), and a normal activity for 3,3-prime,5-prime-triiodothyronine (rT3). The presence of the variant albumin was recognized in a patient with Graves disease after successful subtotal thyroidectomy. The findings could be misdiagnosed as T3 toxicosis or peripheral resistance to thyroid hormones.

Premachandra et al. (1988) commented that in patients with familial dysalbuminemic hyperthyroxinemia, treatment of hypothyroidism with thyroxine has special considerations because of binding of the drug to the atypical albumin, and raised the possibility that other forms of drug therapy may require custom tailoring.

Mapping

In a large Amish family of Swiss descent in which 22 members had dysalbuminemic hyperthyroxinemia, Weiss et al. (1995) showed linkage between the disorder and the ALB gene, using as markers a SacI polymorphism in the coding sequence of the ALB gene and the GC gene, located less than 1 cM from the ALB gene (multipoint lod of 5.53 at theta = 0.0).

Molecular Genetics

In 2 unrelated patients with dysalbuminemic hyperthyroxinemia, Petersen et al. (1994) identified a heterozygous mutation in the ALB gene (R218H; 103600.0041). During the preparation of the manuscript, a third patient with the same mutation was found, suggesting that R218H may be a frequent cause of this disorder.

Sunthornthepvarakul et al. (1994) identified the R218H mutation in affected members of 8 unrelated families with dysalbuminemic hyperthyroxinemia.

Wada et al. (1997) documented 6 members of a Japanese family with the FDH phenotype. All were heterozygous for a missense mutation in the ALB gene (R218P; 103600.0055). Wada et al. (1997) proposed the existence of a distinct ethnic phenotype of FDH characterized by extremely elevated serum total T4 levels and relatively elevated serum total T3 and rT3 levels in the Japanese.

Petitpas et al. (2003) characterized the structure of the interaction between thyroxine and albumin. Using crystallographic analyses, they identified 4 binding sites for thyroxine on albumin distributed in subdomains IIA, IIIA, and IIIB. Mutations of arg218 within subdomain IIA--i.e., arg218 to his (R218H; 103600.0041) and arg218 to pro (R218P; 103600.0055)--greatly enhanced the affinity for thyroxine and caused the elevated serum thyroxine levels associated with FDH. Structural analyses of these 2 mutants showed that this effect arises because substitution of arg218, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions on thyroxine binding at this site. Petitpas et al. (2003) also found that, although fatty acid binding competes with thyroxine at all 4 sites, it induces conformational changes that create a fifth hormone-binding site in the cleft between domains I and III, at least 9 angstroms from arg218. These structural observations were consistent with binding data showing that albumin retains a high-affinity site for thyroxine in the presence of excess fatty acid that is insensitive to FDH mutations.