Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective

Abstract

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.

Laboratory investigations in the diagnosis and follow-up of GH-related disorders

“…The evolution of both, specificity and sensitivity of the analytical methods to measure GH is the main reason why there is a continuous decline in the GH cut-offs proposed by guidelines. In GHD, earlier recommendations referred to concentrations above 10 µg/L, while many of the newer recommendations propose cut-offs at 7 μg/L or lower (23). Similarly, GH concentrations after glucose suppression stated in guidelines on diagnosis and management of acromegaly droppeded from < 5 µg/L and < 2.5 µg/L to < 0.4 µg/L (8,24,25).…”

“…This observation might be explained by the fact that for many IGF-I assays, the lower end of the reference interval in younger children overlaps with the limit of quantification of the assay. Accordingly, a recent consensus on diagnosis of GHD in children emphasized assay sensitivity as a critical quality criterion (23). Beyond the age of 50, IGF-I concentrations can be low in healthy subjects and overlap with concentrations seen in GHD patients.…”

Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty

“…However, few clinical studies have explored whether the final adult height (FAH) can reach the normal range after GH therapy. FAH is considered the golden indicator for evaluating the efficacy of GH therapy [4,5]. However, the predicted FAH following a short period of treatment is dynamic and cannot reflect the actual FAH.…”

A Bayesian Approach to Diagnose Growth Hormone Deficiency in Children: Insulin-Like Growth Factor Type 1 Is Valuable for Screening and IGF-Binding Protein Type 3 for Confirmation

“…The assessment of the growth hormone (GH)/insulin-like growth factor type 1 (IGF-1) axis is mandatory in the evaluation of most children with short stature, mainly to diagnose GH deficiency (GHD) [1]. This condition is relatively rare (an estimated prevalence of <2% among short children) [2], though frequently remembered in the differential diagnosis of short stature.…”

“…Due to the low prevalence of GHD, every test available has a considerable false-positive rate, bringing a clear degree of uncertainty to interpret these tests. Therefore, the diagnosis of GHD is based on clinical appraisal, GH/IGF-1 axis assessment, and neuroimaging evaluation [1, 3].…”