Primary GH insensitivity '(Laron syndrome) caused by a novel 4 kb deletion encompassing exon 5 of the GH receptor gene:: effect of intermittent long-term treatment with recombinant human IGF-I

Objective: GH insensitivity syndrome (GHIS: Laron syndrome) is clinically characterized by severe postnatal growth failure and very low serum levels of IGF-I despite increased secretion of GH. This mainly autosomal recessive syndrome is clinically indistinguishable from isolated GH deficiency (IGHD). Fifty-one different mutations in the GH receptor (GHR) gene have been discovered, whereas only three deletions causing the disorder have been reported so far. In this report, we describe a consanguineous family from Sri Lanka with a novel deletion of 409 7 bp in length encompassing exon 5. Subjects and methods: Parents of normal phenotype presented their second child (boy) to our clinic at the age of 7 months with severe growth retardation and the clinical features of IGHD (58 cm. -6.1 standard deviation score (SDS): 5.7 kg. - 3.4 SDS). Assessment, however, revealed GHIS with absent GH-binding protein. Thereafter. the patient received intermittent recombinant human IGF-I (rhIGF-1: 80 mug/kg twice daily) treatment prepubertally for 5.5 years. Genomic DNA was extracted for genetic analysis and each exon was PCR amplified individually. Further, in order to amplify the GHR gene from exon 4 to 6. Expand Long Template PCR (Roche) was carried out. In addition, RNA isolation and RT-PCR were performed. Results: Separate PCRs of each of the exons of the GHR gene revealed that exon 5 in the patient was missing. Thereafter, 'Long PCR' from exons 4 to 6 revealed a 409 7 bp deletion encompassing exon 5. in a homozygous state in the patient and in a heterozygous state in both parents. RT-PCR analysis revealed an exact absence of exon 5 resulting in a frameshift, leading to a stop codon in exon 6, which predicts a truncated, non-functional GHR protein. Conclusion: Fifty-one different mutations within the GHR gene causing GHIS have been reported so far. In contrast. only three deletions within the GHR gene are known. We describe a patient suffering from GHIS caused by a novel 4 kb deletion of the GHR gene encompassing exon 5 and, additionally. we focus on the effect of intermittent rhIGF-I treatment during prepuberty.