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

Abstract

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). Fiftyone 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 4097 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, 2 6.1 standard deviation score (SDS); 5.7 kg, 2 3.4 SDS). Assessment, however, revealed GHIS with absent GH-binding protein. Thereafter, the patient received intermittent recombinant human IGF-I (rhIGF-I; 80 mg/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 4097 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.European Journal of Endocrinology 150 635-642

Insulin-Like Growth Factor-I Treatment in Primary Growth Hormone Insensitivity: Effect of Recombinant Human IGF-I (rhIGF-I) and rhIGF-I/rhIGF-Binding Protein-3 Complex

“…The family history as well as the effect of the first intermittent rhIGF-I therapy (Igef®; Pharmacia & Upjohn, Dübendorf, Switzerland) has been previously described in detail [5]. …”

“…In this report we describe the long-term effect of various IGF-I forms (rhIGF, rhIGF-I and rhIGFBP-3) in a previously reported Tamil family [5]. …”

DIAGNOSIS OF ENDOCRINE DISEASE: Limitations of the IGF1 generation test in children with short stature

“…Most data are from individual cases or small studies. In reports where the standard protocol was used, the mean IGF1 increment was !15 ng/ml (7,33,34,35,36). Similarly, in reports where the 7-day, high-dose protocol was used, the mean increment in IGF1 was also !…”

Laron syndrome: A case report

“…The best response is seen in very young patients and treatment should therefore be started as early as possible 3,9 . Intermittent therapy is shown to be equally cost effective as daily treatment 3 . There is an inverse relationship between age at start of rhIGF-I treatment and total height gain in patients treated for more than 4 years 9 .…”

“…It was first reported by Laron and colleagues in 1966 in 3 Israeli Jewish siblings with hypoglycaemia and clinical phenotype of GHD. It has been reported from the Mediterranean, mideastern region and Indian subcontinent 1,2 and has been described in a Sri Lankan child who lived in Switzerland 3 . We report a three year old girl with Laron syndrome diagnosed in Sri Lanka.…”