Context: Bi-allelic mutations in the GHRH receptor (GHRHR) gene (GHRHR) are a frequent cause of isolated GH deficiency (IGHD). Although heterozygous carriers of these mutations appear normal, we hypothesized that heterozygosity for a GHRHR mutation might be associated with a sub-clinical 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 yrs) heterozygous for the mutation (WT/MT) with 77 sex-matched controls from the same population who are homozygous for the wild-type GHRHR allele (WT/WT).

Results: We found no difference in adult height and standard deviation score for serum IGF-I between the two groups. Body weight, body mass index, skin folds, waist (W) and hip (H) circumferences, and lean mass were all reduced in WT/MT subjects. Percent fat mass and W/H ratio were similar in the two groups. Fasting insulin and Homeostasis Model Assessment of Insulin Resistance were lower in WT/MT. The other biochemical parameters (total and fractionated cholesterol, triglycerides, Lp(a), 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.