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

Abstract

BackgroundMutations 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.MethodsTwo 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.ResultsA 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).ConclusionsWe 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.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0591-z) contains supplementary material, which is available to authorized users.

A High Proportion of Novel ACAN Mutations and Their Prevalence in a Large Cohort of Chinese Short Stature Children

“…In our cohort, 54.5% (6/11) of probands presented with advanced bone age. Thus, so far, among the 19 ACAN carriers found in China (including our data) ( 10 , 16 , 27 ), 47.4% (9/19) showed advanced bone age. Subjective nature of bone age assessment and potential patient ascertainment bias could contribute to the finding regarding bone age differences in ACAN mutation carriers of different ethnicity.…”

“…Interestingly we noticed that the bone age characteristics of ACAN mutation carriers are significantly different across populations. While 87.5% (7/8) of the American population ( 4 , 5 , 9 , 15 , 24 ) and 62.5% (30/48) of the European population showed advanced bone age ( 6 , 7 , 11 , 12 , 14 , 25 ), only 25.0% (4/16) of the Asian population showed advanced bone age by existing data ( 10 , 13 , 16 , 26 , 27 ). In our cohort, 54.5% (6/11) of probands presented with advanced bone age.…”

“…We reviewed the responses of GH treatment of 26 (12 females, 14 male) ACAN mutation carriers, and we plotted the height SDS during the first year of treatment ( 6 , 9 , 11 , 14 , 27 ) (Supplementary Figure 2 ( 19 )). Of these, 10 patients (5 females, 5 male) received additional treatment (1 aromatase inhibitor, 9 gonadotropin-releasing hormone antagonist).…”

Retrospective Diagnosis of a Novel ACAN Pathogenic Variant in a Family With Short Stature: A Case Report and Review of the Literature

“…It's a frequent disorder affecting 3% of the pediatric population and one of the most common causes of pediatric endocrinologist evaluation (Stavber et al, 2020). According to its etiology, short stature can be classified into primary growth disorder, secondary growth disorder and idiopathic short stature (ISS) (Xu et al, 2018). In addition to forms determined by common variants with polygenic inheritance, recent studies have highlighted that monogenic defects could be the cause of the growth disorder observed in non-syndromic children (Grunauer and Jorge, 2018;Vasques et al, 2019).…”

Aggrecan, the Primary Weight-Bearing Cartilage Proteoglycan, Has Context-Dependent, Cell-Directive Properties in Embryonic Development and Neurogenesis: Aggrecan Glycan Side Chain Modifications Convey Interactive Biodiversity

“…Manipulation of the diastrophic dysplasia sulphate-transporter gene ( DDST ) also results in the synthesis of aggrecan with deficient sulphation levels and a variety of skeletal abnormalities such as short stature and joint dysplasia in diastrophic dysplasia [ 151 ], micromelia in atelosteogenesis Type II [ 152 ] and short skeletal proportions due to aberrant trunk and extremity development in achondrogenesis Type II. Heterozygous ACAN mutations result in a phenotypic spectrum of skeletal abnormalities including short stature, accelerated bone maturation, early growth cessation, poor responsiveness to human growth hormone, brachydactyly, early-onset OA and susceptibility to the development of degenerative disc disease due to dysfunctional articular cartilage and IVD tissues [ 147 , 154 , 155 , 156 ]. Osteochondritis dissecans (OCD) is a disabling condition characterised by abnormal deposition of aggrecan in cartilage and the appearance of cracks in the cartilage and subchondral bone.…”