ESPE2023 Free Communications GH and IGFs (6 abstracts)
Clinical characteristics of heterozygous ACAN gene variants and longer-term response to growth hormone treatment: real-world data
Judith Renes 1,2 , Ardine Reedijk 1 , Monique Losekoot 3 , Sarina Kant 4 , Manouk van der Steen 5 , Danielle van der Kaay 6 , Anita Hokken-Koelega 1,6 , Hermine van Duyvenvoorde 3 & Christiaan de Bruin 7
1Dutch Growth Research Foundation, Rotterdam, Netherlands. 2Department of Pediatrics, Albert Schweitzer Hospital, Dordrecht, Netherlands. 3Department of Clinical Genetics/LDGA, Leiden University Medical Center, Leiden, Netherlands. 4Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands. 5Department of Pediatric Endocrinology, Radboud University Medical Center, Nijmegen, Netherlands. 6Department of Pediatrics, Subdivision of Endocrinology, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, Netherlands. 7Division of Endocrinology, Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
Background: Heterozygous pathogenic variants in the ACAN gene underlie disproportionate short stature with characteristically accelerated bone age (BA) maturation and/or osteochondritis dissecans (OD)/early-onset osteoarthritis (OA).
Objective: To describe the phenotypic spectrum and assess the response and safety of growth hormone (GH) treatment in children with a heterozygous pathogenic ACAN variant.
Patients: Thirty-six (23 boys, 13 girls) short statured children with pathogenic ACAN variants and treated for ≥1 year with GH (1.4 mg/m2/day) were identified in the Dutch National Registry of GH treatment in children.
Results: We identified 25 different pathogenic ACAN variants located throughout the gene in 36 children and adolescents. Twenty-two subjects were prepubertal, 14 subjects were pubertal. Median (IQR) height SDS at start of GH treatment was -2.6 SDS (-3.2 to -2.2). Characteristic features such as disproportion, advanced BA, OD/early-onset OA and dysmorphic features like midface hypoplasia and brachydactyly were present, but in ~20% of children no specific clinical or dysmorphic features were reported. After 3 years of GH treatment, height gain SDS in prepubertal children was 1.0 SDS (0.9 to 1.4, P <0.01). In pubertal children height SDS remained stable, which is in contrast to the significant loss in height SDS that is typically observed in untreated, pubertal ACAN patients. Ten children reached adult height: 4 subjects reached an adult height ≥-2 SDS and in 5 subjects adult height SDS had improved in comparison to the affected parent. GH treatment was well tolerated without the report of severe adverse events or ACAN-related side effects
Conclusion: The phenotype of patients with a heterozygous pathogenic ACAN variant is highly variable. Genetic testing for ACAN deficiency should be considered in any child with disproportionate short stature, also in the absence of specific dysmorphic features or bone-age advancement. We furthermore show that most ACAN patients have a significant response to GH, which is sustained after 3 years of treatment and most likely results in an increased adult height.
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