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

Context: Biallelic mutations in the GHRH receptor (GHRHR) gene (GHRHR) are a frequent cause of isolated GH deficiency (IGHD). Althoughheterozygouscarriersofthesemutationsappearnormal,we hypothesized that heterozygosity for a GHRHR mutation might be associated with a subclinical phenotype. Methods: We studied members of a large Brazilian kindred with IGHD (Itabaianinha cohort) caused by a homozygous null GHRHR mutation. We compared 76 adult subjects (age, 25–75 yr) heterozygousforthemutation(WT/MT)with77sex-matchedcontrolsfromthe samepopulationwhoarehomozygousforthewild-typeGHRHRallele (WT/WT). Results: We found no difference in adult height and SD score for serum IGF-I between the two groups. Body weight, body mass index, skin folds, waist and hip circumferences, and lean mass were all reduced in WT/MT subjects. Percentage fat mass and waist/hip ratio were similar in the two groups. Fasting insulin and homeostasis model assessment of insulin resistance were lower in WT/MT. The otherbiochemicalparameters[totalandfractionatedcholesterol,triglycerides, lipoprotein (a), and C-reactive protein] were not different between the two groups. Conclusions: Heterozygosity for a null GHRHR mutation is not associated with reduction in adult stature or in serum IGF-I but is associated with changes in body composition and possibly an increase in insulin sensitivity. These effects do not seem to be modulated by changes in circulating IGF-I. (J Clin Endocrinol Metab 92: 2353–2357, 2007)