ESPE Abstracts

Introduction: Familiar short stature (FSS) is a common variant of growth with heterogeneous etiology. Children with FSS are often excluded from further check-up and treatment. However, significant number of children with FSS comply even with the European criteria for growth hormone (GH) therapy – patients with SHOX-deficiency, growth hormone deficiency (GHD) or these born short for gestational age (SGA). The aim of the study was to identify genetic etiology of short stature in children from families with severe FSS treated with GH and classified as SGA and/or GHD.

Materials and methods: Out of 555 children treated with GH for GHD and/or SGA, 32 (5.8%) had severe FSS defined as live-minimum height ≤−2.5 SD in both patient and his/her shorter parent. These were included into further study. Twenty-one were born SGA, 24 had GHD (median of GH level after stimulation 6.7 ug/l). In four, genetic etiology was already known (ACAN variants in two families, NF1 in 1 family, PTPN11 in 1 family). In remaining 28 patients (20 boys, median age 10.2 years, median age at start of GH therapy 7 years) no genetic cause of short stature was elucidated prior the study. Genetic analysis was performed using whole exome sequencing and the obtained results were further evaluated using ACMG standards and guidelines.

Results: A causative gene variant was identified in 17/32 (53%) children of the study cohort. Of these, 9/17 carried gene variants affecting growth plate (COL2A1 in 2 families, COL11A1 in 2 families, ACAN in 2 families, FLNB, FGFR3 and IGF1R in single families). Interestingly, 89% of them (8/9) were born SGA. In 3/17, products of the disrupted genes affected IGF-associated proteins (IGFALS 2 families, HGMA2 1 family). In remaining 5/17 probands, the growth failure was caused by miscellaneous etiologies (genes THRH, MBTPS2, GSHR, NF1, PTPN11). Some variants fully explained the phenotype in proband and his/her family, others definitely contributed to the proband’s short stature but did not explain all features of complex phenotypes within the families.

Conclusion: In children from families with severe FSS who are classified as SGA and/or GHD, genetic etiology of short stature is heterogeneous. Interestingly, genes affecting the structure and function of the growth plate play an important role.

Supported by Ministry of Health, Czech Republic, grant numbers 16-31211A and NV18- 07-00283 and by research project of Grant Agency of Charles University of Prague, GAUK 976718. All rights reserved.