Clinical Characteristics of Pathogenic <i>ACAN</i> Variants and 3-Year Response to Growth Hormone Treatment: Real-World Data

<b><i>Introduction:</i></b> Heterozygous variants in the <i>ACAN</i> gene may underlie disproportionate short stature with characteristically accelerated bone age (BA) maturation and/or early-onset osteoarthritis (OA). <b><i>Methods:</i></b> The objective of this study was to describe phenotype, analyze genotype-phenotype correlations, and assess the response of growth hormone (GH) treatment in children with a heterozygous <i>ACAN</i> variant. Thirty-six subjects (23 boys, 13 girls) with <i>ACAN</i> deficiency and treated for ≥1 year with GH were identified in the Dutch National Registry of GH treatment in children. <b><i>Results:</i></b> We identified 25 different heterozygous <i>ACAN</i> variants in 36 subjects. Median (interquartile range) height SDS at start of GH was −2.6 SDS (−3.2 to −2.2). Characteristic features such as disproportion, advanced BA, early-onset OA, and dysmorphic features like midface hypoplasia and brachydactyly were present in the majority of children, but in ∼20%, no specific features were reported. Subjects with a truncating <i>ACAN</i> variant had a shorter height SDS compared to subjects with a non-truncating variant (−2.8 SDS and −2.1 SDS, respectively, <i>p</i> = 0.002). After 3 years of GH, height gain SDS in prepubertal children was 1.0 SDS (0.9–1.4). In pubertal children, height SDS remained relatively stable. <b><i>Conclusion:</i></b> The phenotype of subjects with pathogenic heterozygous <i>ACAN</i> variants is highly variable, and genetic testing for <i>ACAN</i> deficiency should be considered in any child with significant short stature, even in the absence of disproportion, specific dysmorphic features, or BA advancement. Furthermore, children with <i>ACAN</i> deficiency may benefit from GH with a modest but significant response, which is sustained during 3 years of treatment.