Inherited growth hormone insensitivity (GHI) is usually caused by mutations in the GH receptor (GHR). Patients present with short stature associated with a mid-facial hypoplasia (Laron facial features) or with normal facial appearance. We previously described an intronic mutation in the GHR gene (A−1 to G−1 substitution in intron 6) resulting in the activation of a pseudoexon (6Ψ) in four related GHI patients with normal facial features. The mutant GHR has 36 additional amino acids resulting in impaired cell surface trafficking. We have now found seven more GHI patients with the pseudoexon mutation and in the present study we analyze the clinical and genetic characteristics of this cohort and assess the genotype-phenotype relationship.
Auxological, biochemical, genetic and haplotype data were collected.
One patient belongs to the same extended family previously reported. Her height is −5 SDS and she has normal facial features. Her IGF-I levels are in the low-normal range for age like the other family members. The six unrelated patients, four of whom have typical LS facial features, have heights ranging from −3.4 to −6.0 SDS and IGF-I levels that vary from normal to undetectable. All seven patients have normal GHBP levels and low ALS levels. We hypothesize that the marked difference in biochemical and clinical phenotypes might be due to variations in the splicing efficiency of the pseudoexon.
In conclusion, activation of the pseudoexon in the GHR gene can lead to a variety of GHI phenotypes. Therefore, screening for the presence of this mutation should be carried out in all patients without mutations in the GHR coding exons.