ESPE Abstracts

Introduction: Aggrecan, a chondroitin sulfate proteoglycan encoded by the ACAN gene, is an important structural component of the cartilage matrix. Variants in the ACAN gene are associated with a group of skeletal dysplasias called aggrecanopathy, which shows a broad phenotypic spectrum. It has been reported that some heterozygous variants in this gene are responsible for the etiology of familial or idiopathic short stature located at the lightest end of the spectrum. In some of these cases, advanced bone age(BA) and early-onset osteoarthritis can be detected. Here, a case of familial short stature with a newly identified variant of ACAN is presented.

Case: He was born 3000g at the time, there was a 4th degree consanguinity between his parents, and there were short individuals in his mother’s family. His height was 103.2 cm (-1.69SDS), weight was 15.7kg(-1.37SDS), and his BMI was 14.74kg/m²;(-0.55SDS). Malar hypoplasia, X-leg deformity, shortened distal phalanx and pes planus were detected. His mother/father height was 138 cm (-4.27SDS)/160.3 cm (-2.58SDS), target height was 155.6 cm (-3.5SDS). His BA was 5-6years old, chronic disease screening was normal, and nonossifying fibroma was detected in the distal metaphysis of the right femur in bone survey. When evaluated for low growth velocity at 9years 8months of age height 124.4 cm (-2.03SDS), weight 32.25kg(0.16SDS), BMI 20.84kg/m²;(1.34 SDS), BA 10years 6months, his IGF-1 was 170ng/mL(-1/meanSD), IGFBP-3 was 4360ng/mL(-1/meanSD) and had insufficient response to two growth hormone stimulation tests. Anterior pituitary height was 3.6mm on pituitary MRI. In clinical exome sequencing analysis, heterozygous variant of c.6991T>C(p.Cys2331Arg) in the ACANgene(NM_013227.3) was reported. It was predicted that the variant could lead to significant changes in protein structure and function by in silico models. The variant was determined to be of maternal origin by Sanger sequencing analysis. At 12years and 3months of age, his BA was 11-11.5years, had Tanner StageII puberty and GH treatment at a dose of 0.2mg/kg/week was started. With the growth hormone treatment, his growth velocity was measured by 1.9 cm in the first three months of treatment.

Conclusion: The prevalence of heterozygous ACAN variants in different short stature cohorts is 1.4-6%. ACAN defect should be considered in cases of familial or idiopathic short stature, in the presence of advanced BA and a gradual decrease in annual growth rate. Evaluating anamnesis, physical examination and laboratory findings together and supporting them with genetic analysis can provide important experiences in terms of diagnosis and treatment in the early period.

Keywords: ACAN gene, aggrecan protein, familial short stature.