Correspondence

A Family with Complete Resistance to Thyrotropin-Releasing Hormone

N Engl J Med 2009; 360:731-734February 12, 2009

Article

To the Editor:

We report on a family with recessive resistance to the action of thyrotropin-releasing hormone (TRH) due to a nonsense homozygous mutation in the TRH receptor (TRHR) gene (p.R17X). We examined the in vivo effects of complete refractoriness to the TRH signal in this family (Figure 1Figure 1Pedigree of a Family with a TRHR Nonsense Mutation.).

Idiopathic and isolated hypothyroidism was diagnosed in the proband during investigation of growth retardation and short stature accompanied by lethargy and fatigue at 11.0 years of age (bone age, 8.5 years) (Table 1Table 1Characteristics and Serum Chemical Test Results of All Family Members.). A TRHR defect was suggested by the absence of thyrotropin and prolactin responses after TRH stimulation. A single previous report of TRH resistance involved a 9-year-old patient with a similar presentation.1 In contrast, the pregnant 33-year-old sister of the proband in our study received a diagnosis of central hypothyroidism as a result of genetic testing of the proband's family members. The sister had conceived three times, but she had a spontaneous abortion during the first trimester of the second pregnancy. She had never had manifestations of hypothyroidism, but she reported substantial improvement in physical and mental activities after receiving thyroxine-replacement therapy. No obvious cognitive or neurologic deficits were detected in either the proband or his older sister, indicating that, in contrast to the severe hypothyroidism and cretinism seen in patients with thyrotropin-beta mutations,2,3 thyroid stimulation was not overtly impaired in the absence of TRH action at birth and during infancy, when increased thyroid activity should promote the adaptation to extrauterine conditions and development.

Table 1 shows the characteristics of the patients in our study. Written informed consent for genetic, clinical, and biochemical tests was obtained from all of the family members. Basal thyroid-function levels and prolactin levels, as well as thyrotropin and prolactin responses to TRH injection, were unaffected in the heterozygous relatives and in the brother with a wild-type genotype, findings that are consistent with a recessive type of inheritance of TRH resistance. A diminished prolactin response was seen only in the heterozygous father (Subject I-2). Tests for thyroid autoantibodies were negative in all the family members. The proband's sister (Subject II-1) had normal lactation after delivering two babies, and she reported symptoms of hypothyroidism only during the withdrawal of therapy.

The secretion of biologically inactive thyrotropin and a reduced pituitary thyrotropin reserve are considered to be the main mechanisms leading to central hypothyroidism.4,5 In the absence of TRH action during thyroxine withdrawal, the biochemical profile in the proband after 45 days without medication indicated that his pituitary was unable to induce a quantitatively normal increase in the thyrotropin level in response to the low thyroid hormone levels. However, there must have been some circulating thyrotropin bioactivity, since endogenous thyroid hormone levels had increased at 60 days. This increase in thyroid hormone levels was accompanied by a halving of the thyrotropin that was responsive to thyroid hormone feedback but was set to function at a level that was insufficient to ensure euthyroidism in the absence of TRH action. Non-TRH signals influencing pituitary functions may contribute to this particular condition, and in fact, the rhythmic pituitary secretions were conserved in the proband (see the Supplementary Appendix, available with the full text of this letter at NEJM.org).

The proband's older sister delivered two babies at term and breast-fed both of them; this suggests that TRHR is not essential for female fertility and lactation. Therefore, we conclude that TRH action is not required for breast and pituitary development in humans, nor is it required for expression of the thyrotropin-beta gene (TSHβ) or the prolactin gene (PRL).

Marco Bonomi, M.D.
Istituto Auxologico Italiano, 20145 Milan, Italy

Marta Busnelli, B.Sc.
University of Milan, 20100 Milan, Italy

Paolo Beck-Peccoz, M.D.
Fondazione Ospedale Maggiore Policlinico, 20122 Milan, Italy

Daniela Costanzo, M.D.
Associazione Italiana Assistenza Spastici, 20100 Milan, Italy

Francesco Antonica, B.Sc.
Istituto Auxologico Italiano, 20145 Milan, Italy

Claudia Dolci, M.D.
University of Milan, 20100 Milan, Italy

Alba Pilotta, M.D.
Fabio Buzi, M.D.
Children's Hospital, 25100 Brescia, Italy

Luca Persani, M.D., Ph.D.
University of Milan, 20100 Milan, Italy
luca.persani@unimi.it

Supported by a grant (05C801) from Ricerca Corrente of Istituto di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano.

5 References

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   Gilbert Vassart, Sabine Costagliola. (2011) G protein-coupled receptors: mutations and endocrine diseases. Nature Reviews Endocrinology 7:6, 362-372
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   Sarah Catharina Grünert, Miriam Schmidts, Joachim Pohlenz, Matthias Volkmar Kopp, Markus Uhl, Karl Otfried Schwab. (2011) Congenital Central Hypothyroidism due to a Homozygous Mutation in the TSHβ Subunit Gene. Case Reports in Pediatrics 2011, 1-4
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   J. Köhrle, G. Brabant. (2010) Synthese, Stoffwechsel und Diagnostik der Schilddrüsenhormone. Der Internist 51:5, 559-567
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   Leonidas H. Duntas, Charles H. Emerson. (2009) On the Fortieth Anniversary of Thyrotropin-Releasing Hormone: The Hormone that Launched a New Era. Thyroid 19:12, 1299-1301
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