Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations

Context:Heterozygous mutations in the Aggrecan gene (ACAN) cause autosomal dominant short stature with bone age (BA) acceleration, premature growth cessation and minor skeletal abnormalities.Objective:Characterize the phenotypic spectrum, associated conditions and response to growth-promoting therapies.Design:Retrospective international cohort study.Patients:Information from 103 individuals (57 female, 46 male) from 20 families with confirmed heterozygous ACAN mutations were included.Methods:Families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next generation sequencing, and/or Sanger sequencing. Clinical information was collected from medical records.Results:Identified ACAN variants showed perfect co-segregation with phenotype. Adult individuals had mildly disproportionate short stature (median height: -2.8 SDS, range: -5.9 to -0.9) and histories of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). There was no apparent genotype-phenotype correlation between type of ACAN mutation and presence of joint complaints. During childhood, height was less affected (median height: -2.0 SDS, range: -4.2 to -0.6). In contrast to most children with short stature, the majority of children had advanced BA (BA – CA, median: +1.3y; range +0.0 to +3.7y) reflecting a reduction in remaining growth potential. Nineteen individuals had received GH with some evidence of increased growth velocity.Conclusions:Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. In several of the families, affected individuals developed early-onset osteoarthritis and degenerative disc disease requiring intervention, suggesting dysfunction of articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.