Journal of Endocrinological Investigation

, Volume 25, Issue 2, pp RC4–RC6 | Cite as

Genetic analyses and evaluation of peripheral parameters of thyroid hormone action for the differential diagnosis of RTH. A novel heterozygous missense mutation (M334T) discovered

  • D. Mannavola
  • G. Vannucchi
  • L. Fugazzola
  • N. Cerutti
  • L. Persani
  • Paolo Beck-PeccozEmail author
Rapid Communication


Resistance to thyroid hormone (RTH) is a rare disease characterized by goiter and elevated free thyroid hormone (TH) levels in the presence of detectable concentrations of TSH. Most RTH patients harbor mutations in the ligand binding domain (LBD) of thyroid hormone receptor ß (TRß) gene, without a clear correlation between genotype and phenotype. Clinical, biochemical and genetic analyses were performed in several members of one family, because the index case presented with elevated free TH, measurable TSH and no hyperthyroid manifestations, but with a pituitary lesion at MRI. High free TH levels and TSH concentrations in the normal range were found also in 4 relatives. The presence of euthyroidism in all patients together with peripheral parameters of TH action in the normal range led to the diagnosis of generalized RTH (GRTH). In the five affected members, the genetic analysis revealed a novel heterozygous missense mutation at codon 334 (M334T). A different mutation at codon 334 was previously described in association with selective pituitary resistance to thyroid hormone (PRTH). Therefore, we confirm that substitutions at Methionine 334 are critical for the structural integrity of TRß LBD. The association of different phenotypes with substitutions affecting the same codon is another contribution confirming that RTH phenotype does not generally depend upon the site of the mutation in the LBD of TRß1.


Thyroid hormone resistance syndrome RTH mutation TRβ gene SHBG ACE ICTP peripheral parameters glycoprotein α-subunit (α-GSU) pituitary incidentaloma 


  1. 1.
    Beck-Peccoz P., Chatterjee V.K.K. The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 1994, 4: 225–232.PubMedCrossRefGoogle Scholar
  2. 2.
    Beck-Peccoz P., Brucker-Davis F., Persani L., Smallridge R.C., Weintraub B.D. Thyrotropin-secreting pituitary tumors. Endocr. Rev. 1996, 17: 610–638.PubMedGoogle Scholar
  3. 3.
    Weiss R.E., Refetoff S. Resistance to thyroid hormone. Reviews in Endocrine &Metabolic Disorders. Kluwer Academic Publishers, Boston, 2000, pp. 97–108.Google Scholar
  4. 4.
    Usala S.J., Bale A.E., Gesundheit N., et al. Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbAß gene. Mol. Endocrinol. 1988, 2: 1217–1220.PubMedCrossRefGoogle Scholar
  5. 5.
    Adams M., Matthews C., Collingwood T.N., Tone Y., Beck- Peccoz P., Chatterjee V.K.K. Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. J. Clin. Invest. 1994, 94: 506–515.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Brucker-Davis F., Scarulis M.C., Grace M.B., Benichou J., Hauser P., Weintraub B.D. Genetic and clinical features in 42 kindreds with resistance to thyroid hormone. Ann. Intern. Med. 1995, 123: 572–583.PubMedCrossRefGoogle Scholar
  7. 7.
    Yen P.M., Chin W.W. Molecular mechanism of dominant negative activity by nuclear hormone receptors. Mol. Endocrinol. 1994, 8: 1450–1454.PubMedGoogle Scholar
  8. 8.
    Collingwood T.N., Adams M., Tone Y., Chatterjee V.K.K. Spectrum of transcriptional, dimerization, and dominant negative properties of twenty different mutant thyroid hormone beta- receptors in thyroid hormone resistance syndrome. Mol. Endocrinol. 1994, 8: 1262–1277.PubMedGoogle Scholar
  9. 9.
    Lin K.H., Zhu X.G., Shieh H.Y., et al. Identification of naturally occurring dominant negative mutants of thyroid hormone a1 and ß1 receptors in a human hepatocellular carcinoma cell line. Endocrinolology 1996, 137: 4073–4081Google Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2002

Authors and Affiliations

  • D. Mannavola
    • 1
  • G. Vannucchi
    • 1
  • L. Fugazzola
    • 1
  • N. Cerutti
    • 1
  • L. Persani
    • 2
  • Paolo Beck-Peccoz
    • 1
    Email author
  1. 1.Institute of Endocrine SciencesUniversity of Milan, Ospedale Maggiore-IRCCSMilanItaly
  2. 2.Istituto di Scienze Endocrine (Pad. Granelli)Ospedale Maggiore IRCCSMilanoItaly

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