Towards identification of molecular mechanisms of short stature

International Journal of Pediatric Endocrinology

Dennis J Chia¹  Lindsey A Waldman¹ 

[1] Institutional addresses: Division of Pediatric Endocrinology & Diabetes, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA

关键词: Chromatin;    Sequencing;    Chromosomal microarray;    GWAS;    IGF-1;    Growth hormone;    Short stature;   

Others  :  811459
DOI  :  10.1186/1687-9856-2013-19

 received in 2013-10-03, accepted in 2013-11-08,  发布年份 2013

【 摘 要 】

Growth evaluations are among the most common referrals to pediatric endocrinologists. Although a number of pathologies, both primary endocrine and non-endocrine, can present with short stature, an estimated 80% of evaluations fail to identify a clear etiology, leaving a default designation of idiopathic short stature (ISS). As a group, several features among children with ISS are suggestive of pathophysiology of the GH–IGF-1 axis, including low serum levels of IGF-1 despite normal GH secretion. Candidate gene analysis of rare cases has demonstrated that severe mutations of genes of the GH–IGF-1 axis can present with a profound height phenotype, leading to speculation that a collection of mild mutations or polymorphisms of these genes can explain poor growth in a larger proportion of patients. Recent genome-wide association studies have identified ~180 genomic loci associated with height that together account for approximately 10% of height variation. With only modest representation of the GH–IGF-1 axis, there is little support for the long-held hypothesis that common genetic variants of the hormone pathway provide the molecular mechanism for poor growth in a substantial proportion of individuals. The height-associated common variants are not observed in the anticipated frequency in the shortest individuals, suggesting rare genetic factors with large effect are more plausible in this group. As we advance towards establishing a molecular mechanism for poor growth in a greater percentage of those currently labeled ISS, we highlight two strategies that will likely be offered with increasing frequency: (1) unbiased genetic technologies including array analysis for copy number variation and whole exome/genome sequencing and (2) epigenetic alterations of key genomic loci. Ultimately data from subsets with similar molecular etiologies may emerge that will allow tailored interventions to achieve the best clinical outcome.

【 授权许可】

   
2013 Waldman and Chia; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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