ESPE Abstracts

Background: Approximately 10% of children born small for gestational age (SGA) fail to catch-up nd remain short (SGA-SS). Although several mechanisms causing SGA-SS have been elucidated, the primary cause remains speculative in most cases.

Aim: To decipher genetic causes of SGA-SS defined as birth length and/or birth weight <-2 SD for gestational age, and body height <-2.5 SD after the 3rd year of life within a large single-center cohort.

Methods and Patients: In 208/304 children with SGA-SS treated with GH at our center within years 2008 – 2018 triplet DNA samples (child and both parents) were available for genetic testing. Targeted genetic examination (karyotype/FISH/MLPA/Sanger sequencing) was performed in case of clinical suspicion of a specific genetic condition (42/208). The remaining patients were examined using next-generation sequencing methods (whole exome sequencing or targeted panel of 399 growth-related genes). Identified genetic variants were classified using American College of Genetics and Genomics (ACMG) guidelines.

Results: Genetic etiology of SGA-SS was elucidated in 79/208 children (38%). Of these, 18/79 (23%) carried (likely) pathogenic gene variants affecting components of cartilaginous matrix (ACAN [4], COL11A1 [2], COL1A1, COL1A2, COL2A1 [5], COL9A2, COL9A1, FLNB [2], MATN3), 8/79 (10%) had impaired paracrine chondrocyte regulation (FGFR3 [2], FGFR2, NPR2 [4], SOX9), 10/79 (13%) carried SHOX gene defects, in 13/79 (16%) gene variants affecting other components of intracellular regulation and signaling were revealed (CDC42, KMT2D, LMNA, NSD1, PTPN11 [2], PROKR2, SRCAP, SON, SOS1 [2], TLK2, THRA), 11/79 (14%) had variants affecting abnormal regulation of pituitary development and/or of GH-IGF-1 axis (GHSR, HGMA2, IGFALS, IGF1R [in three], LHX4, OTX2, STAT3, POU1F1, PTCH1), 13/79 (16%) had Silver-Russell syndrome (11p15 [in eight], UPD7) and 6/79 (7%) additional miscellaneous single-gene or chromosomal aberrations (THRA, TRHR, TRPS1, RAI1, chromosomal microdeletions and/or translocations).

Conclusions: High percentage of pathogenic variants found in our cohort sheds a new light on the etiology of short stature in children born SGA-SS. The spectrum of genes in which we have detected pathogenic variants reflects the complex regulation of growth, with the central role of the growth plate, and with substantial contributions from the GH-IGF-1 axis and from the fundamental processes of intracellular regulation and signaling.