Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czechia.
Horm Res Paediatr. 2024;97(1):40-52. doi: 10.1159/000530521. Epub 2023 Apr 5.
Among children born small for gestational age, 10-15% 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.
Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age and life-minimum height <-2.5 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.
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 (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). 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.
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.
在胎龄小的生长受限儿童中，有 10-15%的儿童无法赶上生长速度而仍然身材矮小（SGA-SS）。其潜在机制尚不清楚。我们旨在通过一个大型单中心队列来解码 SGA-SS 的遗传病因。
在接受生长激素（GH）治疗的 820 名患者中，有 256 名被归类为 SGA-SS（出生长度和/或出生体重 <-2 个胎龄标准差，最终身高 <-2.5 个标准差）。如果有特定的遗传疾病具有临床提示意义，则对具有可用 DNA 三联体（儿童及其父母双方）的患者进行靶向检测（核型/FISH/MLPA/特定 Sanger 测序）。所有其余患者均接受 MS-MLPA 以鉴定 Silver-Russell 综合征，对于未知遗传病因的患者，随后使用全外显子组测序或 398 个生长相关基因的靶向面板进行检查。使用 ACMG 指南对遗传变异进行分类。
在 176 名患者中有 74 名（42%）明确了遗传病因。其中，12 名（16%）患者存在影响垂体发育的致病性或可能致病性（P/LP）基因变异（LHX4、OTX2、PROKR2、PTCH1、POU1F1）、GH-IGF-1 或 IGF-2 轴（GHSR、IGFALS、IGF1R、STAT3、HMGA2）、2 名（3%）患者存在甲状腺轴（TRHR、THRA）的变异、17 名（23%）患者存在软骨基质（ACAN、各种胶原、FLNB、MATN3）的变异，以及 7 名（9%）患者存在旁分泌软骨细胞调节（FGFR3、FGFR2、NPR2）的变异。在 12 名（16%）患者中，我们发现 P/LP 影响基本的细胞内/核内过程（CDC42、KMT2D、LMNA、NSD1、PTPN11、SRCAP、SON、SOS1、SOX9、TLK2）。在 74 名患者中有 7 名（9%）患者存在 SHOX 缺乏症，12 名（16%）患者存在 Silver-Russell 综合征（11p15、UPD7），5 名（7%）患者存在其他染色体异常。
高诊断率为 SGA-SS 的遗传图谱提供了新的认识，其中生长板起着核心作用，同时 GH-IGF-1 和甲状腺轴以及细胞内调节和信号转导也有重要贡献。
