Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human Growth Hormone: 1-Year Response

Abstract

Context: Patients with aggrecan (ACAN) deficiency present with dominantly inherited short stature, often with advanced skeletal maturation and premature growth cessation. There is a paucity of information on the effects of growth-promoting interventions.

Objective: The aim of this study was to evaluate the efficacy and safety of recombinant human growth hormone (rhGH) therapy on linear growth in children with ACAN deficiency.

Methods: Open-label, single-arm, prospective study at Cincinnati Children's Hospital Medical Center. Ten treatment-naïve patients were recruited. Inclusion criteria were a confirmed heterozygous mutation in ACAN, age ≥2 years, prepubertal, bone age (BA) ≥chronological age (CA), and normal insulin-like growth factor I concentration. Treatment was with rhGH (50 µg/kg/day) over 1 year. Main outcomes measured were height velocity (HV) and change in (Δ) height SD score (HtSDS).

Results: Ten patients (6 females) were enrolled with median CA of 5.6 years (range 2.4-9.7). Baseline median HtSDS was -2.5 (range -4.3 to -1.1). Median baseline BA was 6.9 years (range 2.5-10.0), with median BA/CA of 1.2 (range 0.9-1.5). Median pretreatment HV was 5.2 cm/year (range 3.8-7.1), increased to 8.3 cm/year (range 7.3-11.2) after 1 year of therapy (P = .004). Median ΔHtSDS after 1 year was +0.62 (range +0.35 to +1.39) (P = .002). Skeletal maturation did not advance inappropriately (median ΔBA/CA -0.1, P = .09). No adverse events related to rhGH were observed.

Conclusion: Treatment with rhGH improved linear growth in a cohort of patients with short stature due to ACAN deficiency.

Keywords: aggrecan deficiency; growth hormone; short stature.

Figure 1.

(A) Pretreatment height velocity (gray bars) and height velocity (HV) through 1 year of treatment (black bars) with recombinant human growth hormone (rhGH) for 10 study subjects. Median HV increased from 5.2 cm/year (range 3.8-7.1 cm/year) to 8.3 cm/year (range 7.3-11.2 cm/year) after 1 year (P = .004). (B) Height standard deviation score (HtSDS) in 10 subjects, before (gray bars) and after (black bars) 1 year of treatment with rhGH. Median ΔHtSDS after 1 year was +0.62 (range +0.35 to +1.39), P = .002.

Figure 2.

Insulin-like growth factor (IGF)-I values for 10 study patients, with protocol-driven recombinant human growth hormone (rhGH) dose reductions (*) at 6 months for patients 2, 4, 5, and 7, as well as dose reduction at 3 months for patient 9. Patients 6 and 10 had weight adjustment of their rhGH at 6 months. HV, height velocity; HtSDS, height standard deviation score.