Background: Although isolated GH deficiency (IGHD) is one of the most frequent causes of postnatal proportional undergrowth, up to 8590% of IGHD cases are still classified as idiopathic. On the other hand, previous reports identified up to 40 different GH1 proximal promoter haplotypes, some of which show hypomorphic effects, significantly reducing GH1 expression levels.
Objective and hypotheses: To investigate the frequency of GH1 proximal promoter hypomorphic allelic haplotypes in a cohort of patients with IGHD.
Method: Subjects: 53 children with proportional undergrowth and IGHD (height <−2.5 SDS and peak GH <10 ng/ml). Molecular studies: Mutation screening/genotyping of the coding sequences, intron/exon boundaries and regulatory regions of GH1; GH1 proximal promoter haplotype classification was performed according to Horan et al. (2003) and Wolf et al. (2009).
Results: We identified a total of 19/53 (35.8%) patients presenting with hypomorphic allelic haplotypes of the GH1 proximal promoter. Three out of 53 patients (5.7%) presented also with three known GH1 mutations c.291+1G>A, p.Arg42Cys and p.Arg209His, in heterozygosis, located in GH1 intron 3, and exons 2 and 5 respectively.
Conclusion: Up to 36% of the examined patients with proportional undergrowth and IGHD present with hypomorphic allelic haplotypes of the GH1 proximal promoter. These novel data suggest that the hypomorphic allelic haplotypes of the GH1 proximal promoter represent an important causative/contributing factor of IGHD, which has been underestimated or overseen so far. Furthermore, according to the clinical information submitted by the referring endocrinologists, most of the patients presenting with GH1 promoter hypomorphic allelic haplotypes who were treated with rhGH showed a positive response. Previous reports have shown that the GH1 proximal promoter haplotype diversity is the consequence of a very high rate of interlocus gene conversion, which is caused by the high degree of sequence homology (>92%) between the 5 genes present in chromosome 17 GH cluster.
Funding: This work was supported by grants: PI09/01266 and PI12/00643 from the Spanish Ministry of Health (ISCIII) to A.C-B; S22010/BMD ENDOSCREEN-CM to A.C-B and I.G-C., and by an Investigator Initiated Research Grant from Pfizer (IIR WI181614) to A.C-B and I. G-C.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology