ESPE Abstracts

Context: ACAN gene is located at 15q26.1 and encodes aggrecan, which is a critical proteoglycan component of cartilage extracellular matrix. Heterozygous variants in ACAN are associated with short stature, premature growth cessation, and impaired bone maturation. A comprehensive understanding of the genetic and clinical characteristics of patients with ACAN mutations helps to improve the overall management of an individual.

Objective: We sought to analyze eight Chinese short stature children with heterozygous ACAN mutations and perform a literature search to firstly summarize the phenotypic spectrum, secondly elucidate the effects of age, sex and mutation type on the height of ACAN mutations carriers, and finally investigate the treatment outcome of growth-promoting therapy.

Patients and Methods: Eight probands from unrelated families were genetically evaluated by Whole-Exome Sequencing (WES). Subsequently, we reviewed the literature to summarize the clinical characteristics, genetic findings, and the efficacy of growth-promoting therapy in ACAN-positive individuals.

Results: We identified seven novel ACAN mutations and one recurrent variant. Patients in our center showed somewhat hypertelorism (4/8), broad nose (4/8), long philtrum (2/8), flat nasal bridge (2/8), brachydactyly (1/8) and short neck (1/8). Besides, the variants in the ACAN gene might display high penetrance. Combined with the literature review, we found that Hands/feet deformity (50%), spinal deformity (36.26%), and head/neck deformity (30.49%) were more often observed in the patients with ACAN heterozygous mutations. Truncating variants had a more severe effect on height, and height was weakly negatively correlated with age at diagnosis. Individuals had received growth-promoting therapy with variable levels of height SDS score improvement.

Conclusion: This study further expands the variation spectrum of the ACAN gene and suggests that facial dysmorphic features are not prominent in Chinese short stature population. In addition, patients who receive growth-promoting treatment before puberty may reap better therapeutic benefits, while also being aware of the duration of treatment.