Effects of heterozygosity for the E180 splice mutation causing growth hormone receptor deficiency in Ecuador on IGF-I, IGFBP-3, and stature

Context & objective: The Ecuadorian GH receptor deficiency (GHRD)/Laron syndrome population is the only large cohort with a single GHR mutation (E180 splice), permitting identification of numerous carrier and noncarrier first-degree relatives, to ascertain effects of heterozygosity on GH-dependent IGF-I and IGFBP-3 concentrations and on growth. Design: First-degree relatives (n = 212) of GHRD patients had specimens taken for IGF-I, IGFBP-3, and GHR genotyping. Normal statured (n = 40) and short statured (n = 40) unrelated controls had measurement of IGF-I, IGFBP-3, and stature. Results: There were no significant differences between heterozygous and homozygous normal relatives in IGF-I or IGFBP-3 standard deviation scores (SDS). Heterozygous relatives had lower mean height SDS than did homozygous normals, but with extensive overlap between genotype groups in both child and adult relatives. Height SDS in general did not relate to IGF-I or IGFBP-3 concentrations. Conclusions: GH-dependent IGF-I and IGFBP-3 secretion is not affected by heterozygosity for the E180 splice mutation that causes GHRD/Laron syndrome in the Ecuadorian population. Heterozygosity is associated with reduction in mean statural SDS, but this is not sufficient to be clinically important and not mediated through measurable differences in circulating IGF-I or IGFBP-3 related to genotype.