Novel aggrecan variant, p. Gln2364Pro, causes severe familial nonsyndromic adult short stature and poor growth hormone response in Chinese children

Abstract Background Mutations in the aggrecan (ACAN) gene can cause short stature (with heterogeneous clinical phenotypes), impaired bone maturation, and large variations in response to growth hormone (GH) treatment. For such cases, long-term longitudinal therapy data from China are still scarce. We report that a previously unknown ACAN gene variant reduces adult height and we analyze the GH response in children from an affected large Chinese family. Methods Two children initially diagnosed with idiopathic short stature (ISS) and a third mildly short child from a large Chinese family presented with poor GH response. Genetic etiology was identified by whole exome sequencing and confirmed via Sanger sequencing. Adult heights were analyzed, and the responses to GH treatment of the proband and two affected relatives are summarized and compared to other cases reported in the literature. Results A novel ACAN gene variant c.7465 T > C (p. Gln2364Pro), predicted to be disease causing, was discovered in the children, without evident syndromic short stature; mild bone abnormity was present in these children, including cervical-vertebral clefts and apophyses in the upper and lower thoracic vertebrae. Among the variant carriers, the average adult male and female heights were reduced by − 5.2 and − 3.9 standard deviation scores (SDS), respectively. After GH treatment of the three children, first-year heights increased from 0.23 to 0.33 SDS (cases in the literature: − 0.5 to 0.8 SDS), and the average yearly height improvement was 0.0 to 0.26 SDS (cases in the literature: − 0.5 to 0.9 SDS). Conclusions We report a novel pathogenic ACAN variant in a large Chinese family which can cause severe adult nonsyndromic short stature without evident family history of bone disease. The evaluated cases and the reports from the literature reveal a general trend of gradually diminishing yearly height growth (measured in SDS) over the course of GH treatment in variant-carrying children, highlighting the need to develop novel management regimens