ESPE Abstracts

Background: Aggrecan (ACAN) is a proteoglycan found in the extracellular matrix of articular and growth plate cartilage. Animal studies have shown that mutations in the ACAN gene lead to premature hypertrophic chondrocyte maturation, causing accelerated cartilage ossification. Patients with ACAN deficiency present with dominantly inherited short stature, often with advanced skeletal maturation and premature growth cessation, as well as early-onset joint disease. The objective of this study was to evaluate therapy with recombinant human growth hormone (rhGH) on linear growth in children with ACAN deficiency.

Methods: This was an open-label, single-arm, prospective study examining the effects of rhGH (50 mcg/kg/day SQ) in treatment-naïve pediatric patients with ACAN deficiency. Main inclusion criteria: confirmed heterozygous mutation in ACAN, age ≥ 2 years (yr), pre-pubertal, bone age (BA) ≥ chronological age (CA), and normal IGF-I concentration. Main outcomes measured: height velocity (HV) and change in (Δ) height standard deviation score (SDS).

Results: Ten patients (six females), ages 2.4-9.7 yrs were treated with rhGH. At baseline, mean height SDS was -2.55 (range, -4.27 to -1.07), mean HV was 5.2 cm/yr (range, 3.8 to 7.1) and median BA advancement was 1.2 yrs (range, -0.9 to 1.9 yrs). Mean HV during the first year increased to 8.9 cm/yr (range, 7.3 to 11.2 cm/yr), 7.4 cm/yr (range, 5.9 to 8.8 cm/yr) during the second year, and 6.7 cm/yr (range, 4.9 to 8.6 cm/yr) during the third year. The Δ height SDS was +0.74 (range, +0.35 to +1.39) during the first year, +0.40 (range, +0.21 to +0.55) in the second year, and +0.16 (range, -0.11 to +0.53) during the third year. Four female subjects entered puberty (but weren’t treated with pubertal blockade), with two starting menses towards the end of the trial. Nevertheless, the overall rate of skeletal maturation was similar to change in CA, with Δ BA / CA of -0.1. Joint complaints were infrequent, with one patient experiencing a possible anterior cruciate ligament tear with a sports injury. There otherwise were no unexpected adverse events.

Conclusion: Treatment with rhGH was tolerated well and showed improved linear growth in a cohort of patients with ACAN deficiency. On average, catch-up growth was largest in the first year of treatment, less in the second year, and afterwards still at least maintaining normal HV for age. Longitudinal follow-up is needed to assess the long-term efficacy of rhGH and impact on adult height.