Severe short stature and endogenous growth hormone resistance in twin brothers without growth hormone gene mutations

Abstract

Growth failure in children with high growth hormone (GH) levels, low insulin-like growth factor 1 (IGF-1) levels, and accelerated linear growth in response to exogenous GH is presumed to result from biologically inactive GH. A molecular diagnosis has only been made in two such patients. We analyzed the presentations and the GH-1 genes of twin Egyptian brothers with this phenotype. At 8 yr of age, the boys’ heights were −4 SD. Their IGF-1 levels were 64 and 60 ng/mL, baseline GH levels were 2.1 and 11.7 mU/L, and growth hormone binding protein levels were normal. Twin B attained a peak GH level of 30.6 mU/L after l-dopa stimulation (Twin A was not tested). After 1 yr of exogenous GH, their growth velocities were >11 cm/year (>97%). Analysis of their GH-1 exons and introns revealed no mutations, but five polymorphisms were identified that have not been previously reported. The GH-1 DNA sequence was transfected into human cells and the resulting GH-1 transcripts were analyzed. Wildtype GH-1 mRNAs were observed, demonstrating that the polymorphisms do not affect transcript processing. Therefore, although no evidence of GH-1 gene mutations or abnormal GH-1 mRNA processing was found, the subjects’ excellent response to exogenous GH supports a trial of GH in children with severe short stature, low IGF-1 levels and normal GH responses to stimulation testing.