ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study describes the clinical characteristics of pathogenic variants in the ACAN gene and the response to rhGH treatment over three years in children with a heterozygous ACAN variant. The results indicate that rhGH therapy may be considered to reduce the height deficit in these patients, particularly in prepubertal children with ACAN deficiency.

Aggrecan is the major proteoglycan of the cartilage growth plate. Homozygous pathogenic ACAN variants lead to a severe form of skeletal dysplasia, whereas heterozygous ACAN variants can lead to milder phenotypes such as idiopathic short stature. ACAN variants can cause disproportionate short stature, advanced bone age and early-onset osteoarthritis. This study examined the genotype-phenotype correlations and assess the response to rhGH treatment in children with heterozygous ACAN variants.

36 children (23 boys, 13 girls) from the Dutch National Registry of GH treatment in children, with ACAN deficiency treated with rhGH for at least one year, were included in the analysis. 25 different heterozygous ACAN variants were identified in the 36 subjects. Most children showed features such as disproportionate growth, advanced bone age, early-onset osteoarthritis and dysmorphic features such as midface hypoplasia and brachydactyly. However, about 20% had no specific features. Children with truncating ACAN variants were shorter at the start of rhGH treatment than those with non-truncating variants. Prepubertal children showed a mean height gain of +0.6 SDS after 1 year and +1.0 SDS after 3 years of rhGH treatment. No significant increase in height gain was observed in pubertal children.

In conclusion, the phenotype associated with pathogenic heterozygous ACAN variants is highly variable. Genetic testing for ACAN deficiency is recommended in children with severe short stature, even in the absence of specific dysmorphic features. rhGH treatment may be considered in children with ACAN deficiency, but the variability in response highlights the need for personalized treatment approaches.

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