Familial growth hormone deficiency with mutated GHRH receptor gene: clinical and hormonal findings in homozygous and heterozygous individuals from Itabaianinha

Endocrine-Genetics Unit/LIM 25, Endocrine Division, Department of Medicine, Sao Paulo University School of Medicine, 01246-903, Sao Paulo, Brazil.

OBJECTIVE: To characterize clinically and hormonally the syndrome of autosomal recessive familial growth hormone deficiency (FGHD) recently identified in Itabaianinha, Sergipe, Brazil, caused by a novel mutation (mt) that inactivates the growth hormone-releasing hormone receptor (GHRH-R) gene. DESIGN: Clinical and hormonal evaluations were performed in 21 FGHD individuals (mt/mt group) aged 8 to 63 years, 13 heterozygotes for the GHRH-R mutation (wt/mt group) and 5 homozygotes for the wild type (wt) allele (wt/wt group), identified by genotyping of peripheral blood leukocyte DNA. METHODS: Clinical and hormonal characterization included physical examination and measurement of GH, IGF-I, IGF binding protein-3 (IGFBP-3), cortisol, prolactin, LH, FSH, and free thyroxine (FT4). RESULTS: Clinical features were consistent with isolated growth hormone deficiency. Height was significantly reduced in the mt/mt group compared with the wt/mt group (mean height standard deviation score (SDS) +/- s.d.: -7.35+/-1.37 vs -1.84+/-1.44 respectively, P<0. 0001), and the wt/wt group (-1.85 +/- 0.81, P=0.0007). The height of the 13 wt/mt subjects did not differ from the 5wt/wt individuals. Serum GH, IGF-I, IGF-I SDS, IGFBP-3 and IGFBP-3 SDS were all significantly lower in the mt/mt group than in the wt/mt and wt/wt groups. Two affected children treated with GH for 1 year showed a normal growth response. Serum IGF-I and IGF-I SDS were lower in wt/mt compared with wt/wt group, but did not reach statistical significance. IGF-I and IGF-I SDS correlated inversely with age in wt/mt group. CONCLUSIONS: FGHD due to an autosomal recessive GHRH-R gene mutation leads to marked dwarfism, phenotypically and hormonally indistinguishable from other forms of isolated GH deficiency. Heterozygotes for the GHRH-R mutation appear to have a partial defect in the GH/IGF axis, with no apparent height impairment.

This article has been cited by other articles:

				A. T. McElvaine, A. I. Korytko, S. M. Kilen, L. Cuttler, and K. E. Mayo Pituitary-Specific Expression and Pit-1 Regulation of the Rat Growth Hormone-Releasing Hormone Receptor Gene Mol. Endocrinol., August 1, 2007; 21(8): 1969 - 1983. [Abstract] [Full Text] [PDF]

				R. M. C. Pereira, M. H. Aguiar-Oliveira, A. Sagazio, C. R. P. Oliveira, F. T. Oliveira, V. C. Campos, C. T. Farias, T. A. R. Vicente, M. B. Gois Jr, J. L. M. Oliveira, et al. Heterozygosity for a Mutation in the Growth Hormone-Releasing Hormone Receptor Gene Does Not Influence Adult Stature, But Affects Body Composition J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2353 - 2357. [Abstract] [Full Text] [PDF]

				R. G. Gondo, M. H. Aguiar-Oliveira, C. Y. Hayashida, S. P. A. Toledo, N. Abelin, M. A. Levine, C. Y. Bowers, A. H. O. Souza, R. M. C. Pereira, N. L. Santos, et al. Growth Hormone-Releasing Peptide-2 Stimulates GH Secretion in GH-Deficient Patients with Mutated GH-Releasing Hormone Receptor J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3279 - 3283. [Abstract] [Full Text] [PDF]

				H. G. Maheshwari, S. S. Pezzoli, A. Rahim, S. M. Shalet, M. O. Thorner, and G. Baumann Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E943 - E951. [Abstract] [Full Text] [PDF]