Silver-Russell syndrome (SRS) is a syndrome of severe pre- and postnatal growth retardation and typical dysmorphic features. Rare chromosomal aberrations have been reported in SRS; among these are two balanced translocations involving 17q24-q25. Recently, we described a patient with a paternally inherited heterozygous deletion of the chorionic somatomammotropin hormone 1 (CSH1) gene. The CSH1 gene is member of the growth hormone (GH) gene cluster on 17q, which consists of two growth hormone genes and three CSH genes. Genomic alterations in the GH cluster are well known, causing different phenotypes depending on the size of the deletion and the genes involved. By screening 63 SRS cases with marker D17S254, we have detected 2 further patients with a heterozygous deletion in the GH cluster. Quantitative analysis using restriction assays confirmed these findings. Additionally, in a cohort of 17 patients with isolated intrauterine and postnatal growth retardation, we detected a further patient to be carrier of a CSH1 deletion. Screening of 141 unrelated controls revealed hemizygosity in one person for which data on growth were not available. We additionally analyzed our cohort of SRS patients for mutations in CSH1 and its 3' neighbour GH2. However, analyses failed to reveal any pathogenic mutation. While the central role of GH1 in human growth is well established, the physiological roles of CSH1 and other components of the cluster are unclear. The increased prevalence of hemizygosity of CSH1 in our population in comparison to controls indicates a role for CSH1 haploinsufficiency in the etiology of growth retardation. Investigation of CSH1 deletions in further SRS and growth retarded patients will enable us to establish under which circumstances haploinsufficiency of CSH1 is likely to result in clinical changes.
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.
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