Analysis of children with familial short stature: who should be indicated for genetic testing?

Abstract

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. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤-2 SD in child and his/her shorter parent, excluded secondary short stature, excluded Turner/Prader-Willi syndrome). Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by ACMG guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, four (11%) a variant affecting GH-IGF1 axis, and three (8%) a variant in miscellaneous 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 0.4 years and with shorter parent heights <-2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, 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 bone age are clinical predictors of monogenic FSS.