SUN-LB008 Clinical Phenotype and Genotype Analysis of Short Stature Patients with Skeletal Dysplasia

Abstract

Background: Skeletal dysplasia is a frequent cause of congenital disproportionate short stature, and genetic defects of cartilage extracellular matrix (ECM) affect growth plate structure and functions. However, precise diagnosis remains difficult due to high heterogeneity of phenotypes. Objective: We sought to identify phenotype spectrum and genetic causes for Chinese patients with skeletal related short stature. Patients and Methods: 86 short stature patients clinically diagnosed or suspected of skeletal dysplasia from 2013 to 2018 were included, and clinical information were systematically collected. Next generation sequencing (NGS) was informed and conducted in all these patients, and pathogenicity of candidate genes were analyzed based on clinical data. Results: 45 of the 86 patients had confirmed mutations, and 46.7% of them (21 to 45) were identified with heterozygous mutations relevant of cartilage extracellular matrix. 19 variants of 5 genes were identified including 9 of COL2A1, 1 of COL9A1, 4 of COL10A1, 4 of COMP and 3 of FBN1. The age at diagnosis was 9.47±5.46 years, and the height SDS was -4.78±1.65. The phenotypic spectrum ranged from proportionate short stature with mild upper limb deformity to typical, severe disproportionate manifestations. Deformities of limbs and vertebral anomalies were more frequently encountered presentations. Patients with COL2A1 mutations were more likely to show facial features, pectus carinatum, scoliosis and epiphyseal dysplasia while those with COL10A1 variants mainly presented genu varum and scoliosis. 5 probands (2 COL10A1, 3 COL2A1) were maternal inherited and 12 of 14 affected family members were female. Individuals with COMP variants had the severest height loss (medium height, -6.24 SDS; range, -7.56 to -5.97) and showed typical short-limb dwarfism, irregular epiphyses and dysfunction of joints in early ages. None of the patients with FBN1 mutations had significant facial features or spinal deformity, but bowing of limbs, brachydactyly and decreased joint mobility were visible. 4 of 20 individuals underwent rhGH therapy but had limited effects. Facial dysmorphism was a significant feature to exclude patients with FGFR3 mutations, while limb and spine deformities were frequently encountered in both ECM and FGFR3 patients. Conclusion: NGS is an efficient tool to identify genetic cause of skeletal dysplasia due to its clinical and molecular heterogeneity, and variants of genes encoding cartilage extracellular matrix are the most common cause. Sources of Research Support: The National Key Research and Development Program of China” (No. 2016YFC0901501) and CAMS Innovation Fund for Medical Science (CAMS-2016-I2M-1-002). Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.