ESPE Abstracts

Introduction: Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated thus far. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children.

Patients and Methods: Of 747 patients treated with growth hormone (GH) in our centre, 95 met the inclusion criteria of FSS (Pre-treatment height ≤-2 SD in both child and his/her shorter parent, excluded secondary short stature, excluded Turner/Prader-Willi syndrome). Their median age was 12 years (IQR 9-15 years), their life-minimum height was -3.0 SD (-3.5 to -2.7 SD), and the height of their shorter parent was -2.7 SD (-2.9 to -2.2 SD). Of them, 64 were classified as having growth hormone deficiency (GHD), 51 children were born small for gestational age (SGA), 20 children therefore had combined GHD and SGA. Genetic etiology was known in 11/95 children before the study, the remaining 84 were examined by targeted next-generation sequencing panel containing 398 genes known to influence growth. All the variants with a potential clinical significance were evaluated by the American College of Medical Genetics (ACMG) standards. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cut-offs for the predictors.

Results: Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 children (81%) carried causative genetic variants affecting the growth plate (SHOX [6], COL2A1 [5], NPR2 [4], COL11A1 [2], ACAN [2], FGFR3 [2], PTPN11 [2], COL11A2, COL1A2, COMP, MATN3, EXT2, and NF1 genes), and 4 children (11%) carried variants affecting the GH-IGF1 axis (GHSR, HMGA2, IGFALS, and OTX2 genes), the remaining 3 children carried variants in miscellaneous genes (TRHR, SALL4, and MBTPS2 genes). Lower shorter parent’s height (P=0.015) and less delayed bone age (BA) before GH treatment (P=0.026) predicted monogenic FSS. In children with BA delayed less than by 0.4 years and with shorter parent heights <-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases.

Conclusion: In FSS children treated with GH, a monogenic etiology is frequent, gene variants affecting the growth plate are the most common. Shorter parent’s height and a less delayed bone age predict monogenic form of FSS.

The study is funded by AZV grant NU22J-07-00014.