ESPE Abstracts

Introduction: Aggrecanopathies are rare disorders associated with idiopathic short stature. They are caused by pathogenic variants in the ACAN gene.

Case: Female, was referred to our clinic for short stature. Born at 34+3 weeks from a Thai mother and Caucasian father, birth weight was 2190g (0.14 SDS), length 45cm (0.21 SDS) and head circumference 31cm (-0.13 SDS). Pregnancy was obtained by in vitro fertilization. Mother was in therapy with steroids and hydroxychloroquine for systemic lupus erythematosus. At birth she showed transient hypoglycaemia, hypocalcaemia, jaundice treated with phototherapy, trigonal hyperechogenicity at transfontanellar ultrasound. Normal neurodevelopment. Short stature in mother (145 cm). Target height was 157 cm (-0.96 SDS). At first evaluation at 4.5 years: height 94.2cm (-2.61 SDS), weight 13.10 kg (-2.45 SDS), head circumference 48.5 cm (-0.82 SDS), prepubertal. She showed brachydactyly in absence of asymmetries and bone disproportions. Bone age was 7.8 years according to Greulich&Pyle atlas. The haematological tests including IGF-1 and IGFBP3 were normal according to reference ranges for age. Due to a low growth velocity/year (5.12 cm/yr, -1.30 SDS) a growth hormone (GH) stimulation test was performed with normal GH peak (GH 11 ng/ml). MRI of hypothalamus-hypophyseal area and X-rays of limbs and spine did not show substantial abnormalities. In consideration of persistent short stature and advanced bone age and growth failure, in the suspicion of genetic aetiology of short stature, after authorization of Regional Commission, at the age of 6.2 years, GH therapy was started at dose of 0.025 mg/kg/die with optimal response (growth velocity 8.07 cm/y, +2.47 SDS). Next Generation Sequencing showed the heterozygous truncating variant c.4780G>Tp.(Glu1594Ter) in the exon 12 of the ACAN gene, probably pathogenic, yet undescribed.

Discussion: Aggrecan, encoded by ACAN, plays a key role in the morphogenesis of cartilage and bone. Heterozygous variants in ACAN gene have been associated with short stature, variable bone age and a clinical phenotype, ranging from moderate skeletal abnormalities to early-onset osteoarthritis/osteochondritis dissecans or spondyloepiphyseal dysplasia. Since ACAN and GH pathway are strongly associated, many patients are treated with GH therapy with variable response. Our case had a very mild phenotype, genetic aetiology was suspected for short stature with persistent growth failure associated with advanced bone age (>2 years). Molecular analyses, in particular of the ACAN gene, are necessary in case of short stature, as showed in in our case, in order to begin therapy and improve final height of patients.