ESPE Abstracts

Background: Short stature is defined as a height more than two standard deviations below the mean for age and sex. Pathologic causes of short stature include growth hormone deficiency, hypothyroidism, celiac disease, inflammatory bowel disease or other chronic diseases, hormonal abnormalities, and genetic disorders, such as Turner syndrome. Moreover, among other variants of short stature, scholarship also described familial short stature, constitutional delay of growth and puberty, and idiopathic short stature (ISS). 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 the genes involved in the function of the growth hormone/insulin-like growth factor-I axis as well as in growth plate physiology. However, many cases of ISS remain idiopathic.

Aim: focusing on genetic investigations, our study aims to better understand the etiology of short stature in a cohort of children initially identified as affected by ISS.

Patients and Methods: 120 children with ISS aged between 3 and 18 years were enrolled. All children were submitted to auxological, hormonal and imaging investigations, aimed to exclude the most frequent causes of hyposomia. Successively, genetic screening was performed with the help of the Next Generation Sequencing (NGS) panel. All the coding regions and exon-intron boundaries of 105 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed.

Results: Pathogenic variants were found in 26 patients (21.7%) of our cohort. In 10 children, a syndromic condition was diagnosed. Moreover, in 91 children we found 253 variants of uncertain clinical significance that in some cases might be responsible for their clinical phenotype.

Conclusion: The NGS panel resulted effective for the rapid screening of genetic etiologies associated with short stature and allowed a definitive diagnosis in 21.7% of cases previously identified as ISS. Genetic diagnosis for short stature is important for affected individuals and their families since it may modify the management of their clinical condition and their treatment decisions.