ESPE Abstracts

Background: Ten percent of children born small for gestational age fail to catch-up and remain short during childhood (SGA-SS). Several genes causing SGA-SS have been described, however, in most cases, the mechanisms of prenatal and postnatal growth impairment remain unknown.

Aim: To decipher genetic etiologies within a large single-center cohort of SGA-SS children in order to better understand the pathophysiological mechanisms leading to prenatal and postnatal growth failure.

Patients and methods: Between the years 2008-2018, a total of 822 patients were treated with growth hormone (GH) in our center, 306 of them were classified as SGA-SS (birth length and/or birth weight <-2 SD for their gestational age and sex, height <-2.5 SD after 4 years of life). In 166/306 GH treated SGA-SS children, the DNA of the child and both of his/her parents was available for genetic testing - these were included to the study. In case of a clinical suspicion on a specific genetic disorder, targeted genetic examination (karyotype/FISH/mlPA/Sanger sequencing) was performed. Children with unknown genetic SGA-SS etiology were subsequently examined using next-generation sequencing methods (whole exome sequencing or targeted panel of 399 growth-related genes). All the genetic variants were classified using American College of Genetics and Genomics (ACMG) guidelines. The parents’ DNA was examined by Sanger sequencing to evaluate the segregation of the genetic variants in the families.

Results: The genetic etiology was elucidated in 84/166 (51%) children so far. We confirmed (likely) pathogenic gene variants affecting components of cartilaginous matrix in 22/84 (26%) (ACAN [in three], COL11A1 [in five], COL1A1, COL1A2, COL2A1 [in five], COL9A2, FLNB [in five], MATN3), impaired paracrine regulation of chondrocytes in 6/84 (7%) (FGFR3 [in two], NPR2 [in three], SOX9), SHOX gene defects in 11/84 (13%), gene variants affecting other components of intracellular regulation and signaling in 11/84 (13%) (CDC42, KMT2A, KMT2D, LMNA, NSD1, SRCAP, PTPN11 [in two], SON, SOS1 [in two]) genes affecting pituitary development and/or the GH-IGF-1 axis in 13/84 (16%) patients (GHR, GHSR, HGMA2 [in two], IGFALS, IGF1R [in three], IGF1, LHX4, OTX2, STAT3, PTCH1) Silver-Russell syndrome (11p15 [in eight], UPD7) in 12/84 (14%), and miscellaneous single-gene or chromosomal aberrations (TRPS1, TRHR, RAI1, chromosomal microdeletions and/or translocations) in 9/84 (11%) children.

Conclusions: The mechanisms leading to SGA-SS can frequently be identified by modern genetic techniques. The etiological spectrum reflects the complexity of growth regulation. Genes affecting the structure and function of the growth plate play a key role.