Scientific Programme & Abstracts from the International Meeting in Pediatric Endocrinology (IMPE)
IMPE Abstracts (2023) 96 P94

1Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina. 2Servicio de Genética, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina


Introduction: Short Stature (SS), defined as height below -2 SD, is a common reason for referral to pediatric endocrinologists. Genetic factors determine ~80% of adult height. Lately, next-generation sequencing (NGS) has led to the discovery of an increasing number of novel monogenic causes for SS.

Objective: The aim of this work was to identify the genetic etiology of SS of unknown origin (SSUO) in children.

Methods: Patients with SSUO were included. They had undergone extensive prior clinical and endocrinological workup to exclude systemic diseases, growth hormone deficiency, known skeletal dysplasias and syndromic diseases. Whole-exome sequencing or gene panels were performed in those patients. Identified variants were prioritized according to their potential pathogenic impact based on type of variant, population frequency, relevance of the affected gene related to growth, presumed inheritance pattern, segregation analysis, and in vitro functional studies; and were classified according to ACMG criteria. CGH+SNP array was performed in patients with dysmorphic features and/or neurodevelopmental delay; or when no diagnosis was achieved after NGS studies. The study was approved by the institutional Ethics Review Board.

Results: Thirty children from a SS cohort study (n=216) met the inclusion criteria as SSUO. We prioritized 21 variants in 20 out of 30 patients (66%): 10 pathogenic, 10 likely pathogenic and 1 VUS. Seven of them had been previously reported in literature and 14 were novel. Two variants were found in components of GH-IGF-1 axis (IGF1, STAT5B), 4 in components of cartilage extracellular matrix (FBN1, COL2A1, ACAN), 4 in paracrine factors of the growth plate (NPR2, LRP5, FGFR3), 2 in components of intracellular pathways (MAP2K1, KMT2D), 6 in components of fundamental cellular processes (PIK3R1, SRCAP, ARID1B, POC1A, HDAC8, EP300) and 3 in other genes related to syndromic SS (ARCN1, CSNK2A1, SIN3A). Also, a heterozygous deletion encompassing 3 exons of HMGA2 gene was identified by WES (and confirmed by MLPA) in one patient with Silver-Russell syndrome-like phenotype. Microarray was performed in 20 patients, with a diagnostic yield of 10%. A heterozygous pathogenic 3.5 Mb-deletion in 2p11.2 was detected in one patient and a 0.76 Mb-duplication in Xq25q26.1 in another, explaining their clinical features.

Conclusions: We identified pathogenic and likely pathogenic variants in 66% of the patients, a high diagnostic yield when the cohort is carefully selected, and the patients present features suggestive of a genetic cause for SS. This study supports the utility of high-throughput molecular techniques for the etiological diagnosis of SSUO.

Volume 96

IMPE 2023

Buenos Aires, Argentina
04 Mar 2023 - 07 Mar 2023

International Meeting in Pediatric Endocrinology 

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