EXTENSIVE PHENOTYPIC ANALYSIS OF A FAMILY WITH GROWTH-HORMONE (GH) DEFICIENCY CAUSED BY A MUTATION IN THE GH-RELEASING HORMONE-RECEPTOR GENE

GH secretion and release are complex phenomena depending on activation of several genes, including those encoding GH, GHRH, and its receptor (GHRH-R). The GH gene, which is the most extensively analyzed sequenc e in patients with familial GH deficiency (GHD), represents the main k nown target of mutations. To test the involvement of the GHRH-R gene i n this disease phenotype, we investigated one candidate Tamoulean fami ly originating from Sri Lanka. Two brothers, with extremely short stat ure (<-4 SE) and no dysmorphy, were diagnosed as having complete GHD, unresponsive to exogenous GHRH and associated with PRL levels within t he lower normal range. Magnetic resonance imaging examination showed a nterior pituitary hypoplasia with a normal pituitary stalk. Both patie nts increased their growth rate while under GH therapy. Molecular inve stigations revealed a homozygous GHRH-R gene mutation that introduces a stop codon at residue 72. This mutation, which predicts a severely t runcated receptor lacking the seven membrane-spanning domains, is iden tical to that recently reported in one Indian Moslem family, raising t he possibility of a founder effect. There was no clear evidence for he ight reduction in the three heterozygous individuals studied. This obs ervation, which underlines the phenotypic criteria associated with a l oss of GHRH-R function, raises the question of the frequency of GHRH-R abnormalities among GHD patients.