ESPE Abstracts

Aggrecan, encoded by ACAN, is a major proteoglycan component in the extracellular matrix of the growth plate. At least 25 pathological ACAN mutations have been identified in patients with highly variable phenotypes of syndromic or non-syndromic short stature. A 6-year-old boy was referred to our Centre for short stature (height 103.60 cm, −3.14 SDS) in familial short stature. Mid-Parental target height was 161.15 cm (−2.38 SDS); His father (height 167.3 cm) is from Ecuador; his mother of Italian origin displays a lightly disproportionate short stature (height 143 cm). The boy was born at 41 weeks of gestation with a birth length of 49 cm (−1.17 SDS) and a birth weight of 2840 g (−1.73 SDS). He had normal psychomotor development. The physical examination did not show dysmorphic features. Bone age corresponded to the chronological age. Growth hormone (GH) stimulation tests showed discordant results (GH peak of 20.9 ng/ml with dexamethasone, 5.6 ng/ml and 11.1 ng/ml with arginine). Other blood tests (liver and renal function, screening for coeliac disease, thyroid and adrenal function tests) resulted within limits. Brain MRI was normal. At the age of 6 years 8 months he was started on rhGH therapy for a reduction on height velocity (−1.51 SDS) starting at a dosage of 0.03 mg/kg per die (7 days a week); this treatment was gradually reduced in dosage and then definitively suspended 21 months later due to poor response (increase in height: +0.36 SDS) and high IGF1 levels. Genetic screening for short stature with Next Generation Sequencing revealed a heterozygous variant of uncertain significance of the ACAN gene p.(Gly676Ser), never described previously. Currently he is 12.5 years old, 134 cm tall (−2.64 SDS) with a height velocity of 7.8 cm/yr (+2.9 SDS). Arm span is greater than his height (140 cm). His Tanner stage is P3G3. Pubertal development started at the age of 11 years 7 months. Bone age is equal to his calendar age, but advanced compared to his height. He does not report any pain or dysfunction of joints. IGF1 is within limits (281 ng/ml-normal range 100–460). This case report implies to consider ACAN mutations in the genetic evaluation of patients with idiopathic short stature, even in the absence of characteristic features of a skeletal dysplasia. GH treatment efficacy is still controversial.