ESPE Abstracts

Introduction: Short stature is a common disorder in children that can become a challenge for clinical and molecular diagnosis. Recent studies in genetics and the implementation of Next-Generation Sequencing (NGS) in growth disorders have demonstrated the great genetic heterogeneity of short stature and the existence of highly varied phenotypes. The absence of homogeneous clinical criteria for conducting studies makes it difficult to evaluate the efficacy of these new technologies.

Objectives: To assess the efficiency of genetic testing in patients with pathological short stature.

Materials and methods: The patient cohort was selected from children (age < 18 years) with pathological short stature and a normal karyotype who attended a tertiary care hospital. Pathological short stature was considered if A) height -3SDS; B): height -2.5SDS with disproportion, associated pathological phenotype (dysmorphia, cardiopathy, intellectual disability etc.) or family history of short stature. Patients with malnutrition, treatment with drugs or chronic diseases that affect growth, as well as patients with GH deficiency due to hypopituitarism, were excluded. Genetic testing based on array and NGS techniques (NGS based panel or clinical exome) was performed sequentially according to standardized clinical criteria. Genetic testing was considered as conclusive when a pathogenic or probably pathogenic variant was responsible for the short stature.

Results: 71 patients (48% male) were recruited, between the years 2018-2021 (mean age 11 years), 26 (36%) for meeting criterion A and 45 (63%) for meeting B. In addition, 44.9% were small for gestational age, 38% had a pathological phenotype, 38% disproportion, and 49% had a family history of short stature. 87% (n=62) of the individuals were studied molecularly. 15% (n=9) were studied by array, 48% (n=30) by NGS techniques and 37% (n=23) by both techniques. Of all the arrays performed (n=32) only in one case was conclusive (0.03%) while of the total NGS studies (n=53, n=41exome and n=12 gene panel) in 50%, the genetic study was conclusive. The yield of the NGS study was 50% in the two clinically established groups (11 in group A and 7 in group B), so no significant differences were found.

Conclusions: Clinical characterization of the individual is essential to improve the efficiency of genetic testing. NGS methods have a higher diagnostic rate (50%) than array, which, in the context of pathological short stature, has low efficiency. Larger series are required to define the performance of genetic testing in short stature.