Complete resistance to TRH in a family

TOPIC: A biologically inactive TRH due to a mutant TRH-receptor

Title: A family with complete resistance to thyrotropin-releasing hormone

Authors: Bonomi M, Busnelli M, Beck-Peccoz P, Constanzo D, Antonica F, & Dolci C.

Reference: New England Journal of Medicine 360: 731-734, 2009

Summary

Background

Recessive resistance to the action of TRH is a rare disorder resulting in central hypothyroidism.

Purpose

To detect a nonsense homozygous mutation in the TRH receptor gene and examine the in vivo effects of complete refractoriness to the TRH signal in the family.

Methods & Main Outcome measures

The coding region of the TRH-receptor gene (TRH-R) was amplified and the purified PCR products directly sequenced in a family with two affected siblings, the heterozygous parents and two grand children.

Results

The proband, with growth retardation and short stature, accompanied by lethargy and fatigue at 11 years of age (bone age of 8.5 years) had absent TSH & PRL responses after TRH stimulation. In contrast, his 33 year-old sister was diagnosed with central hypothyroidism. She conceived 3 times (with 1 spontaneous abortion) and never had manifestations of hypothyroidism, but reported a substantial improvement after the introduction of l-T4 therapy. In both siblings, no cognitive/neurological deficits were detected, suggesting that their thyroidal stimulation was not impaired – in the absence of TRH action – at birth and in infancy. The proband had a low serum TSH level, with no response to TRH stimulation. Serum free T4 was 0.36 ng/dL (normal: 0.9 – 1.7 ng/dL). By contrast, his sister had normal serum TSH with low serum free T4. Both were homozygous for a “C-to-T” transition at position 49 in the TRH-R gene, leading to the formation of a premature stop codon at position 17 (p.R17X) and synthesis of a TRH-R that lacked entirely its trans-membrane domain. The heterozygous patients were non consanguineous (possibility of a common ancestor).

Conclusions

The proband’s sister delivered two heterozygous babies at term and breastfed both of them. The authors concluded that TRH action was not required for breast and pituitary development in humans nor was it required for expression of the TSH-b gene or the prolactin gene.

Commentary

The secretion of biologically inactive TSH and a reduced pituitary thyrotrophic reserve are considered to represent the main mechanisms leading to central hypothyroidism. In this family, a rare mutation in the TRH receptor markedly affected the homozygous proband, but his sister, who was also homozygous for the nonsense mutation had normal lactation after delivering two babies and only reported symptoms of hypothyroidism during withdrawal of thyroxine therapy. Moreover, both homozygous siblings had no signs and symptoms of hypothyroidism during the early neonatal period and infancy. Later on in the proband, the pituitary was unable to induce a quantitatively normal increase in TSH levels in response to low serum thyroid hormone levels. The rhythmic pituitary hormones secretions were conserved in the proband.

By contrast, a homozygous frame shift GNRH1 mutation (c.18-19in A) induced isolated familial hypogonadotropic severe hypogonadism in two of four children of non consanguineous parents. The GNRH1 mutation reported recently (see Bouligand et al.: Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. NEJM 360:2742, 2009) appears to be a unique example of a genetic aberration causing complete inactivation of a human hypothalamic hypophysiotropic neuro-hormone gene in constrast with the TRH-R mutation reported by Bonomi et al. in the present report.

The comparison of these two studies is opportune in the sense that they indicate a dramatic difference between the adaptive capacity of the hypothalamic-pituitary-thyroid axis in the family with a defective TRH Receptor mutation, while the hypothalamic defective GNRH1 ultimately resulted in severe hypogonadism.

Summary & Commentary prepared by Geraldo Medeiros-Neto (Related to Chapters 4 and 16b of TDM)