Endocrine Abstracts

JOINT791

Background: Small for gestational age (SGA) refers to infants whose size is below the normative range for their gestational age and sex. While up to 90% of these infants experience catch-up growth within the first two years, 10-15% fail to do so and remain short at age 2 (SGA-SS). The causes of this failure remain largely unknown.

Methods: This study investigated the genetic causes of failure to achieve catch-up growth in Korean SGA children. Subjects were recruited from multicenter SGA-SS cohorts across eight hospitals in South Korea. A total of 191 children underwent whole exome sequencing. Copy number variants (CNVs) identified in exome data were validated using chromosomal microarray (CMA). Genetic variants were classified according to ACMG guidelines.

Results: Genetic variants were identified in 36 of 191 children. Half of the genetic abnormalities were CNVs (18/36, 50%). Notably, 22q11. 2 microdeletion syndrome was observed in seven children (7/36, 19. 4%), who presented mild dysmorphic features without significant intellectual disability or congenital anomalies, potentially delaying diagnosis. Sequence variants in growth-related genes were found in 18 children (18/36, 50%). One child had compound heterozygous mutations in the SLC26A2 gene, while the others had heterozygous variants, including five pathogenic, 13 likely pathogenic, and one variant of uncertain significance (VUS). Based on molecular mechanisms of causing reduced height, defects in intracellular pathways (11/18, 61. 1%) were most common, followed by defects in the extracellular matrix (6/18, 33. 3%). Additionally, the first Korean case of familial Silver-Russell syndrome with a CDKN1C mutation was identified.

Conclusion: The genetic basis of SGA-SS is heterogeneous. CNVs play a significant role in this condition. The broad phenotypic spectrum of 22q11. 2 microdeletion syndrome, as seen in cases with mild dysmorphic features, highlights its importance in the differential diagnosis of SGA-SS.