ESPE Abstracts

Introduction: Short stature is a common finding that affects per definition about 3% of the population. Isolated, severe short stature may be treated successfully with recombinant human growth hormone (rhGH). Currently, rhGH is offered to short children with specific disorders or biochemically proven growth hormone deficiency (GHD). However, biochemical testing for GHD is artificial and therefore controversial. Adding genetic testing may improve the diagnostic workup. In this pilot study, we performed whole exome sequencing (WES) in children with isolated short stature with biochemically proven GHD or severe idiopathic short stature (ISS) with a normal growth hormone stimulation test to evaluate the added value of a molecular diagnosis.

Methods: Individuals were divided into groups: A) patients with isolated GHD and GH test peak <7ng/dl (13/30, 43.3%); B) isolated GHD and GH test peak 7-10ng/dl (10/30, 33.3%), and C) ISS with GH test peak >10 ng/dl (7/30, 23.3%). WES was performed and analysed with a specific, in-house data filtering algorithm tailored for growth disorders. We used several in silico tools to predict the impact of gene variants and searched for disease-causing variants in literature and in HGMD and ClinVar. Variants were classified according ACMG guidelines.

Results: So far, we studied 30 children with isolated GHD or ISS that are part of a larger study from the University Children’s Hospital Bern. We identified 17 disease causing or candidate gene variants in 13 of 30 patients (43.3%). These were from group A (6/13, 46.1%), followed by group B (5/10, 50.0%) and group C (2/7, 28.6%). Three variants were found in genes that are involved in the GH/IGF axis (GH2, POU1F1, STAT5B), four in components of cartilage extracellular matrix (ACAN, HSPG2, PRG4), five in components of fundamental cellular processes (ARID1B, OCRL, PTCH1, SH3BP2, TP63), four in genes involved in intracellular pathways (PTPN11, RAF1) and one variant in other genes related to syndromic SS (RUNX2).

Conclusions: We identified disease-causing or candidate variants in almost half of the children with isolated, severe short stature in a broad range of genes. These were found in children with isolated GHD and ISS, thus correlation with biochemical testing seems poor. No genotype-phenotype correlation was observed. The high diagnostic yield of WES in the workup of short children demonstrates the added value of a molecular diagnosis. Genetic testing, together with auxiological and biochemical methods may improve the current clinical routine care of patients with short stature and rhGH.