{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:02:50Z","timestamp":1787162570115,"version":"build-2736575974"},"reference-count":61,"publisher":"S. Karger AG","issue":"1","license":[{"start":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T00:00:00Z","timestamp":1680652800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Res Paediatr"],"published-print":{"date-parts":[[2024]]},"abstract":"<b><i>Introduction:<\/i><\/b> Among children born small for gestational age, 10\u201315% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. <b><i>Methods:<\/i><\/b> Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and\/or birth weight &lt;\u22122 SD for gestational age and life-minimum height &lt;\u22122.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176\/256). Targeted testing (karyotype\/FISH\/MLPA\/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. <b><i>Results:<\/i><\/b> The genetic aetiology was elucidated in 74\/176 (42%) children. Of these, 12\/74 (16%) had pathogenic or likely pathogenic (P\/LP) gene variants affecting pituitary development (<i>LHX4<\/i>, <i>OTX2<\/i>, <i>PROKR2<\/i>, <i>PTCH1<\/i>, <i>POU1F1<\/i>), the GH-IGF-1 or IGF-2 axis (<i>GHSR<\/i>, <i>IGFALS<\/i>, <i>IGF1R<\/i>, <i>STAT3<\/i>, <i>HMGA2<\/i>), 2\/74 (3%) the thyroid axis (<i>TRHR<\/i>, <i>THRA<\/i>), 17\/74 (23%) the cartilaginous matrix (<i>ACAN<\/i>, various collagens, <i>FLNB<\/i>, <i>MATN3<\/i>), and 7\/74 (9%) the paracrine chondrocyte regulation (<i>FGFR3<\/i>, <i>FGFR2<\/i>, <i>NPR2<\/i>)<i>.<\/i> In 12\/74 (16%), we revealed P\/LP affecting fundamental intracellular\/intranuclear processes (<i>CDC42<\/i>, <i>KMT2D<\/i>, <i>LMNA<\/i>, <i>NSD1<\/i>, <i>PTPN11<\/i>, <i>SRCAP<\/i>, <i>SON<\/i>, <i>SOS1<\/i>, <i>SOX9<\/i>, <i>TLK2<\/i>). SHOX deficiency was found in 7\/74 (9%), Silver-Russell syndrome in 12\/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5\/74 (7%) children. <b><i>Conclusions:<\/i><\/b> The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.<\/jats:p>","DOI":"10.1159\/000530521","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T17:00:39Z","timestamp":1680714039000},"page":"40-52","source":"Crossref","is-referenced-by-count":29,"title":["The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short 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