Genetic causes of isolated short stature

Abstract

Short stature is a common feature, and frequently remains without a specific diagnosis after conventional clinical and laboratorial evaluation. Longitudinal growth is mainly determined by genetic factors, and hundreds of common variants have been associated to height variability among healthy individuals. Although isolated short stature may be caused by the combination of variants, with a deleterious impact on the growth of individuals with polygenic inheritance, recent studies have pointed out some monogenic defects as the cause of the growth disorder observed in nonsyndromic children. The majority of these defects are in genes related to the growth plate cartilage and in the growth hormone (GH) -insulin-like growth factor 1 (IGF-1) axis. Affected patients usually present the mildest spectrum of some forms of skeletal dysplasia, or subtle abnormalities of laboratory tests, suggesting hormonal resistance or insensibility. The lack of specific characteristics, however, does not allow formulation of a definitive diagnosis without the use of broad genetic studies. Thus, molecular genetic studies including panels of genes or exome analysis will become essential in investigating and identifying the causes of isolated short stature in children, with a crucial impact on treatment and follow-up.

Genetic syndromes associated with isolated fetal growth restriction

“…This strategy that assesses about 44 relevant genes, minimizes both the risk of identifying incidental findings and the incomplete coverage of those genes. However, the selection of relevant genes has to be accurate and updated, otherwise an incomplete gene selection might result in an important limitation of the panels. A commercial gene panel including 24 genes is available to confirm the clinical suspicion of primordial dwarfism disorders, such as the 3‐M syndrome, MOPD2 and Seckel syndrome.…”

Polymorphism of the growth hormone gene GH1 in Polish children and adolescents with short stature

“…There are numerous genes that control growth, variants of which can contribute or cause short stature [11]. Growth hormone (GH) plays a crucial role among these as a major regulator of growth, and its variants may cause GHD, leading to short stature [12][13][14][15].…”

Differences in Response to Recombinant Growth Hormone Therapy on Height Gain in Patients with Idiopathic Short Stature Vs. Patients with Growth Hormone Deficiency

“…Children presenting with short stature, which has not been linked to any apparent chromosomal abnormalities or genetic factors, are usually diagnosed as having either idiopathic short stature or constitutional growth delay. However, these two terms are often used interchangeably [3]. Growth hormone treatment was mostly used in the treatment of short stature due to GHD until 2003 where it was approved to be used as well in the treatment of ISS [4].…”

“…For example, excessive secretion of GH during childhood or adulthood can lead to gigantism or acromegaly, respectively. On the other hand, reduced production of this hormone can cause growth retardation and short stature [1][2][3]. Exogenous growth hormone treatment had been extracted from human pituitary glands and used to treat mainly those with severe GH deficiency.…”