ESPE Abstracts

Introduction: The genetic investigation of tall stature (TS) is routinely indicated only in children with clinical suspicion of a specific syndrome associated with TS. After ruling out an endocrine disorder, the remaining tall children mostly receive a clinical diagnosis of “idiopathic” (ITS) or “familial” tall stature (FTS). The aetiology of their TS remains unknown.

Aims: To elucidate genetic cause of excessive growth of children with non-syndromic TS using next-generation sequencing (NGS) methods.

Methods: There was a total of 39 children (25 girls) with TS (height >2 SD) participating in our study, who were examined in our endocrine outpatient clinic in the last year or were already being followed up in our endocrine outpatient clinic for tall stature. In these children we ruled out endocrine cause of TS and there was no clinical suspicion on specific genetic syndrome. The median age was 12 years (IQR 5-20 years) and the median height was 2.86 SD (IQR 2.10- 4.83 SD). Seventeen of the children were clinically classified as FTS (height of taller parent >2 SD), and the remaining 22 as ITS. All the children underwent karyotype and FISH (SHOX region) investigation. Furthermore, the DNA samples were analyzed by NGS using targeted panel of 788 growth-related genes. Detected variants were evaluated by the American College of Medical Genetics (ACMG) standards.

Results: Altogether we identified a monogenic cause of TS in 8/39 (20%) of the children. Two children had sex-chromosome trisomy (karyotype 47, XYY and 47, XXX), 2 had Sotos syndrome (variants c.7939C>T and c.5374_5375insGA in NSD1 gene), 1 had Simpson-Golabi-Behmel syndrome (variant c.81delinsTTC in GPC3 gene), 1 had Loyes-Dietz syndrome (variant c.777T>A in TGFRB2 gene), one had a pathogenic variant c.1959C>A in FGFR3 gene typically associated with CATSHL syndrome and 1 had SHOX gene duplication. Moreover, in additional 6/39 (15%) children we found variants of uncertain significance in genes FBN2, COL6A2, MATN3, COL1A2, COL6A3, TET3 which are currently being investigated in more detail.

Conclusion: Genetic findings typically associated with syndromic tall stature could also be found in tall children with no clinical suspicion of a specific syndrome. Further studies are needed to evaluate if these children are likewise at increased risk of life-threatening oncologic or cardiovascular complications typically associated with several TS syndromes.