ESPE Yearbook of Paediatric Endocrinology

J Endocr Soc. 2024 Oct 10;8(12):bvae177. PMID: 39502477. doi: 10.1210/jendso/bvae177

Brief Summary: Despite the growing recognition of aggrecan (ACAN) deficiency as a cause of short stature, current evidence on the effectiveness of growth-promoting therapies remains heterogeneous, largely due to variable growth hormone (GH) treatment regimens across published reports.

This prospective, open-label, 3-year study evaluated the efficacy and safety of recombinant human growth hormone (rhGH) in 10 prepubertal children (median age 5.6 years, range 2.4–9.7 years) with heterozygous ACAN variants and short stature. Participants received rhGH at an initial dose of 50 µg/kg/day, with adjustments guided by monitored IGF-I levels. Median height standard deviation score (HtSDS) increased by +1.21 (range +0.82 to +1.94; P = 0.002) from a baseline of −2.52 to −1.09 after 3 years. Height velocity increased from a median of 5.2 cm/year at baseline to 8.3 cm/year in the first year, 7.7 cm/year in the second year, and 6.8 cm/year in the third year, consistently above pretreatment rates. Median Predicted adult height (PAH)increased by +6.8 cm over the study period (P = 0.002).

No adverse events attributable to rhGH were reported. Some patients developed or had pre-existing osteochondritis dissecans (OD), a known phenotypic feature of ACAN deficiency, but rhGH treatment did not worsen these joint manifestations. Bone age advancement remained stable overall. An increased rate of skeletal maturation was observed in 4girls who entered puberty during follow-up. No changes were noted in body proportionality or bone mineral density.

rhGH therapy appears to be both effective and safe in promoting linear growth in children with ACAN deficiency. The findings suggest that earlier initiation of treatment may lead to more favorable outcomes due to a stronger early growth response and a longer prepubertal growth window. Continued longitudinal follow-up is essential to assess final adult height and long-term safety.

References: 1. van der Steen M, Pfundt R, Maas S, Bakker-van Waarde WM, Odink RJ, Hokken-Koelega ACS. ACAN gene mutations in short children born SGA and response to growth hormone treatment. J Clin Endocrinol Metab. 2017;102(5):1458-1467.2. Deng S, Hou L, Xia D, et al. Description of the molecular and phenotypic spectrum in Chinese patients with aggrecan deficiency: novel ACAN heterozygous variants in eight Chinese children and a review of the literature. Front Endocrinol (Lausanne). 2022;13: 1015954.3. Liang H, Miao H, Pan H, et al. Growth-promoting therapies may be useful in short stature patients with nonspecific skeletal abnormalities caused by acan heterozygous mutations. Six Chinese cases and literature review. Endocr Pract. 2020;26(11):1255-1268.