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

Abstract

Context Aggrecan, encoded by ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated. Objective We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone (GH) therapies. Patients and Methods Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by Next-generation sequencing (NGS)-based test. Result We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort, it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, five out of eleven ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SDS improvement. Conclusion Our data suggested that ACAN mutation is one of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.

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

“…Up to now 18 different mutations in exon 12 have been described (Figure 1; Table 3) (Gleghorn et al, 2005;Quintos et al, 2015;Gkourogianni et al, 2017;Hattori et al, 2017;Hauer et al, 2017;Tatsi et al, 2017;Van der Steen et al, 2017;Sentchordi-Montané et al, 2018;Zeng et al, 2018;Fukuhara et al, 2019;Uchida et al, 2020;Lin et al, 2021). This represents the exon with the highest number of mutations, accounting for the 19% of ACAN alterations (Liang et al, 2020;Lin et al, 2021). Exon 12 encodes for the chondroitin sulfate attachment domains (CS1 and CS2) and along with exon 11, for the keratan sulfate attachment domain (KS).…”

Evaluation of Growth Hormone Therapy in Seven Chinese Children With Familial Short Stature Caused by Novel ACAN Variants

“…In terms of treatment of this disease, the height of patients has been shown to benefit from the early use of rhGH and the timely use of gonadotropin-releasing hormone analogs (GnRHa), as well as from their appropriately combined application with aromatase inhibitors in some male patients to inhibit the progression of bone age (9,11,12,(18)(19)(20). A previous study (11) revealed that appropriate growth-promoting treatment improved the height of patients with heterozygous ACAN variants; the therapeutic efficacy was not associated with the treatment plan and variant type.…”

“…Nevertheless, the average treatment time for all patients was relatively short, and long-term follow-up was still needed to observe the height change to prove the effect of rhGH treatment. Currently, most of the research on the treatment of patients with ACAN variants has been largely represented by case reports, whereas the long-term treatment data has been rather limited (9,11,12,(18)(19)(20). Individual responses to rhGH may be difficult to judge due to different growth patterns in childhood, preadolescence, and adolescence.…”

“…Subsequent investigations in subjects of different ethnic backgrounds have also revealed that ACAN variants were associated with short stature with advanced bone age(12,(14)(15)(16). However, recent studies(3,7,9,11) found that the bone age of some patients was normal or even delayed. Liang et al(11) established that the proportion of the advanced bone age group was 32.65% (16/49) based on the difference between the bone age and the chronological age being >1 year.…”

Should Skeletal Maturation Be Manipulated for Extra Height Gain?

“…Approximately 50% of children with ACAN haploinsufficiency present with an accelerated BA ( 85 ) and mean height SDS decreases by age ( 79 ), so clinicians have been tempted to investigate the potential role of rhGH plus GnRHa to increase AH. In a large international patient series, five children received rhGH plus GnRHa, which indeed appeared to halt skeletal maturation ( 79 ) (LoE 4).…”