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 associate...