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

Abstract

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) Ϯ S.D.: ¹7.35 Ϯ 1.37 vs ¹1.84 Ϯ 1.44 respectively, P < 0.0001), and the wt/wt group (¹1.85 Ϯ 0.81, P ¼ 0.0007). The height of the 13 wt/mt subjects did not differ from the 5 wt/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.

Magnetic resonance imaging study of pituitary morphology in subjects homozygous and heterozygous for a null mutation of the GHRH receptor gene

“…Other reports have suggested a reduction of stature and lower serum IGF-I levels in heterozygous in comparison with homozygous normal individuals (17,28). Our finding of lower IGF-I levels in the heterozygous group may indeed confirm a reduction in GH secretion.…”

“…MRI studies of these patients have been done in a limited number of cases (18, 20, 22 -25, 27), and have never included heterozygous carriers. As heterozygous carriers of GHRHR mutations have been reported to have lower serum insulin-like growth factor-I (IGF-I) than normal subjects (17,28), it is conceivable that they may have a pituitary size that may be intermediate between normal and affected subjects.…”

“…In this study, we have examined brain morphology by MRI in subjects from an extended kindred residing in Itabaianinha, Brazil with high prevalence of familial IGHD IB due to a null mutation in the GHRHR gene that causes severe IGHD in the homozygous state (19,28,29). The goal of this study was to assess pituitary morphology in homozygous adult and pediatric IGHD patients and in heterozygous adult subjects.…”

Heterozygosity for a Mutation in the Growth Hormone-Releasing Hormone Receptor Gene Does Not Influence Adult Stature, But Affects Body Composition

“…GH-naive adults and children from this kindred have very low serum GH and IGF-I, reduced fat free mass, an increase in percentage of fat mass (FM), increased waist/hip ratio, increased total and LDL-cholesterol, and C-reactive protein (CRP) levels, and increased systolic blood pressure, but no insulin resistance and no evidence of pre-mature atherosclerosis (14 -17). In a preliminary study, HTZ subjects have been reported to have lower serum IGF-I than HMZ normal (18), but the small number of subjects and their heterogeneous age compared with controls prevented the drawing of firm conclusions. Here we have studied a significantly larger number of subjects HTZ for the mutation and compared them with age-and sex-matched controls.…”

Genética molecular do eixo GH-IGF1

“…O quadro clínico e laboratorial dos indivíduos homozigotos é o da deficiência isolada de GH, similar ao dos outros indivíduos com mutações no gene do GHRHR, com função tireoideana e níveis de cortisol normais e fertilidade preservada. Já os indivíduos heterozigotos da população de Itabaianinha apresentam estatura similar à dos indiví-duos não portadores da mutação (18).…”