Analysis of Components of the Growth Hormone (GH) Axis in (GH Deficient) Patients with Silver-Russell Syndrome

Abstract

Silver-Russell syndrome (SRS) is a heterogeneous clinical syndrome with evidence for a substantial role of genetic factors in its aetiology. Disturbances of chromosome 7, i.e. duplications in 7p and uniparental disomies, have been described in more than 10% of patients; a putative SRS gene in 7p can therefore be assumed. Furthermore, in approximately 5-10% of patients with SRS a growth hormone (GH) deficiency can be observed. Since the growth hormone-releasing hormone receptor (GHRH-R) is localised in 7p and mutations in this gene are associated with GH deficiency, we screened five GH deficient SRS patients for mutations in the GHRH-R gene by direct sequencing of the whole coding region. To exclude mutations in genes of the other major members of the GH axis, growth hormone releasing hormone (GHRH) and GH itself (GH1), these genes were also investigated for genomic variations. While we did not observe variants in GH1 and GHRH, we detected three base-pair substitutions in the coding region of GHRH-R. These variants were detected in a cohort of 45 non-GH deficient SRS patients and 15 patients with isolated growth retardation as well as in 50 healthy controls. In conclusion, we exclude a major role of GHRH, GHRH-R and GH1 as central members of the GH axis in the pathogenesis of SRS.

Genomic characterisation of C7orf10 in Silver-Russell syndrome patients

“…1 It is possible that SRS is a contiguous gene syndrome or the result of mutations in several components of one metabolic pathway resulting in the same phenotype, as suggested for the GH/IGF axis. 11 With respect to the SRS candidate region in 7p, more than 90 SRS patients have been screened for duplications and genomic rearrangements, 5 12 13 but no evidence for a central role of duplications in 7p was obtained. The patients in these studies were screened by microsatellites, fluorescence in situ hybridisation (FISH), or quantitative approaches aimed at certain genes or regions, that is, the genes for GRB10, IGFBP1, and IGFBP3.…”