Alternative titles; symbols
ORPHA: 597939; DO: 0080219;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 18q12.1 | [Dystransthyretinemic hyperthyroxinemia] | 145680 | Autosomal dominant | 3 | TTR | 176300 |
A number sign (#) is used with this entry because dystransthyretinemic hyperthyroxinemia (DTTRH) is caused by heterozygous mutation in the TTR gene (176300) on chromosome 18q12.
Dystransthyretinemic hyperthyroxinemia (DTTRH) is characterized by an increased affinity for thyroxine (T4) by transthyretin in clinically euthyroid individuals (summary by Moses et al., 1990).
Maxon et al. (1982) described familial elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities. They interpreted this as representing an elevated threshold for the amount of free thyroxine substrate required to maintain adequate T3 production from the peripheral monodeiodination of T4. Family studies supported autosomal dominant inheritance; male-to-male transmission was noted. Other forms of peripheral resistance to thyroid hormone with euthyroidism and hyperthyroxinemia appear to have a defect in the nuclear receptor for thyroid hormone (see 274300).
Moses et al. (1982) reported a family in which 2 euthyroid persons had an elevated total T4, an elevated or normal T3 resin uptake, and an increased free T4 index. Free T4 and total and free T3 concentrations were normal. This abnormality was secondary to increased binding of T4 to immunoreactive thyroxine-binding prealbumin (transthyretin).
Lalloz et al. (1987) reported an extraordinary family in which 2 separately inherited abnormal T4 transport proteins were found. The proband, a girl aged 15 years at the time of investigation (the authors referred to her as the propositus), had both variant prealbumin and variant albumin (103600), as did her 2 sisters. The mother had only the abnormal albumin and the father had only the variant prealbumin. By methods combining immunodetection with isoelectric focusing, Whitehouse et al. (1985) found few variants in thyroxine-binding prealbumin.
The transmission pattern of DTTRH in the families reported by Moses et al. (1990) and Refetoff et al. (1996) was consistent with autosomal dominant inheritance.
In a family studied by Moses et al. (1982) with euthyroid hyperthyroxinemia, Moses et al. (1990) detected heterozygosity for a missense mutation in exon 4 of the TTR gene (176300.0015). Refetoff et al. (1996) (see 176300.0038) and others reported similar findings.
Lalloz, M. R. A., Byfield, P. G. H., Goel, K. M., Loudon, M. M., Thomson, J. A., Himsworth, R. L. Hyperthyroxinemia due to the coexistence of two raised affinity thyroxine-binding proteins (albumin and prealbumin) in one family. J. Clin. Endocr. Metab. 64: 346-352, 1987. [PubMed: 3098776] [Full Text: https://doi.org/10.1210/jcem-64-2-346]
Maxon, H. R., Burman, K. D., Premachandra, B. N., Chen, I.-W., Burger, A., Levy, P., Georges, L. P. Familial elevations of total and free thyroxine in healthy, euthyroid subjects without detectable binding protein abnormalities. Acta Endocr. 100: 224-230, 1982. [PubMed: 6287778] [Full Text: https://doi.org/10.1530/acta.0.1000224]
Moses, A. C., Lawlor, J., Haddow, J., Jackson, I. M. D. Familial euthyroid hyperthyroxinemia resulting from increased thyroxine binding to thyroxine-binding prealbumin. New Eng. J. Med. 306: 966-969, 1982. [PubMed: 6801514] [Full Text: https://doi.org/10.1056/NEJM198204223061605]
Moses, A. C., Rosen, H. N., Moller, D. E., Tsuzaki, S., Haddow, J. E., Lawlor, J., Liepnieks, J. J., Nichols, W. C., Benson, M. D. A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J. Clin. Invest. 86: 2025-2033, 1990. [PubMed: 1979335] [Full Text: https://doi.org/10.1172/JCI114938]
Refetoff, S., Marinov, V. S. Z., Tunca, H., Byrne, M. M., Sunthornthepvarak ul, T., Weiss, R. E. A new family with hyperthyroxinemia caused by transthyretin val-109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study. J. Clin. Endocr. Metab. 81: 3335-3340, 1996. [PubMed: 8784093] [Full Text: https://doi.org/10.1210/jcem.81.9.8784093]
Whitehouse, D. B., Hopkinson, D. A., Hill, A. V. S., Bowden, D. K. Analysis of genetic variation in two human thyroxine-binding plasma proteins by immunodetection after isoelectric focusing. Ann. Hum. Genet. 49: 259-262, 1985. [PubMed: 3935040] [Full Text: https://doi.org/10.1111/j.1469-1809.1985.tb01701.x]