The Challenge of Defining and Investigating the Causes of Idiopathic Short Stature and Finding an Effective Therapy

Abstract

Idiopathic short stature (ISS) comprises a wide range of conditions associated with short stature that elude the conventional diagnostic work-up and are often caused by still largely unknown genetic variants. In the last decade, the improvement of diagnostic techniques has led to the discovery of causal mutations in genes involved in the function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis as well as in growth plate physiology. However, many cases of ISS remain idiopathic. In the future, the more frequent identification of the underlying causes will allow a better stratification of subjects and offer a tailored management. GH therapy has been proposed and approved in some countries for the treatment of children with ISS. To improve the efficacy of GH therapy, trials with GH combined with GnRH agonists, aromatase inhibitors, and even IGF-I have been conducted. This review aims to revise the current definition of ISS and discuss the management of children with ISS on the basis of the most recent evidence.

Relationship between hemoglobin and insulin-like growth factor-1 in children and adolescents with idiopathic short stature

“…China. 3 School of Health Management and Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.…”

“…Idiopathic short stature (ISS) is defined by a height more than two standard deviation scores (SDS) below the median height for the relevant age and sex of the subject for whom, with the currently available diagnostic tools, no etiology has been established [ 1 ]. Although there are no clear causes, several studies have attempted to identify potential mechanisms for impaired linear growth in children with ISS [ 2 , 3 ]. The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis is central to the regulation of child growth and development during critical periods.…”

Important Tools for Use by Pediatric Endocrinologists in the Assessment of Short Stature

“…If a child is noted to be particularly short, the cause should be determined and referral to a pediatric endocrinologist is likely, where a diagnosis can often be assigned from factors such as body proportions and clinical and family history ( 1 , 4 ). Although genetic abnormalities associated with short stature are continually being identified ( 5 ), a high percentage of cases remain idiopathic with no specified cause ( 6 ). While identified causes are often associated with defects in the growth hormone (GH)–insulin-like growth factor-1 (IGF-1) axis, a large proportion of cases do not involve GH or IGF-1 abnormalities, but may involve factors such as growth plate abnormalities ( 3 , 5 , 7 ).…”

Prevalence of celiac disease in patients with short stature: A systematic review and meta‐analysis

“…A delay in the diagnosis of the cause of growth failure may preclude effective and timely management, which can lead to long‐term adverse consequences 6,7 . In most of the cases, short stature is attributable to constitutional and familial growth delays; however, a significant proportion of the cases are secondary to readily treatable conditions 8 . Short stature is among the most common extraintestinal manifestations of CeD 9 .…”

“…6,7 In most of the cases, short stature is attributable to constitutional and familial growth delays; however, a significant proportion of the cases are secondary to readily treatable conditions. 8 Short stature is among the most common extraintestinal manifestations of CeD. 9 A diagnosis of CeD and institution of gluten-free diet (GFD) in patients is associated with early catch-up growth for the initial 2-3 years.…”