ESPE Abstracts

Objective: To analyze the clinical features and causative genes in children with undiagnosed short stature and study the causative genes in our hospital. Methods Clinical manifestations, laboratory test and whole exome sequencing (WES) results of children with undiagnosed short stature who visited pediatric endocrinology department of our hospital from January 2018 to August 2019 were analyzed retrospectively. Causative genes were classified and analyzed according to different pathogenic mechanisms. Results A total of 48 children met the inclusion criteria, including 30 males and 18 females, aged 7.73 ± 3.97 years, and height standard deviation score was -3.63 ± 1.67 SD. Clinical manifestations included 33 cases (68.8%) with facial anomalies, 31 cases (64.6%) with skeletal abnormalities, 26 cases (54.2%) with perinatal abnormalities including 61.5% small for gestational age (SGA), 24 cases (50.0%) with endocrine disorders including 87.5% growth hormone (GH) peak concentration below normal, 21 cases (43.8%) with family history of short stature. Laboratory tests showed that GH peak concentration following stimulation test was 9.72 ± 7.25 ng / ml, IGF-1 SDS was -0.82 ± 1.42 SD, and the difference between bone age and chronological age was -0.93 ± 1.39 years. Potential causative genes were found in 25 cases through WES. 17 cases (68.0%) were pathogenic, 4 cases (16.0%) were likely pathogenic, and 4 cases (16.0%) were uncertain significance. A total of 15 genes were identified with pathogenic/likely pathogenic variants, which were classified as (1) affecting intracellular signaling pathways: PTPN11, RAF1, RIT1, ARID1B, ANKRD11, CSNK2A1, SRCAP, CUL7, SMAD4, TRPV4 and FAM111A; (2) affecting extracellular matrix (ECM) components or functions: ACAN, FBN1, COL10A1 and COMP. Conclusion Rare monogenic disease should be considered as probably etiology for children with severe short stature accompanied by facial anomalies, disproportionate body, skeletal abnormalities, SGA, GH peak concentration below normal and family history of short stature. WES played an important role in identifying the causes for children of short stature with monogenic disorders. This study indicated that affecting growth plate cartilage formation through intracellular signaling pathways and ECM components or functions were the main machenisms of causative genes leading to severe short stature in children. Further research will help to discover and study new pathogenic variants and gene functions.