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

Alexandra Gkourogianni, Melissa Andrew, Leah Tyzinski, Melissa Crocker, Jessica Douglas, Nancy Dunbar, Jan Fairchild, Mariana F.A. Funari, Karen E. Heath, Alexander A.L. Jorge, Tracey Kurtzman, Stephen LaFranchi, Seema Lalani, Jan Lebl, Yuezhen Lin, Evan Los, Dorothee Newbern, Catherine Nowak, Micah Olson, Jadranka PopovicStepanka Pruhova, Lenka Elblova, Jose Bernardo Quintos, Emma Segerlund, Lucia Sentchordi, Marwan Shinawi, Eva Lena Stattin, Jonathan Swartz, Ariadna Gonzalez Del Angel, Sinhue Diaz Cuellar, Hidekazu Hosono, Pedro A. Sanchez-Lara, Vivian Hwa, Jeffrey Baron, Ola Nilsson, Andrew Dauber

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 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 the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, 22.8 standard deviation score (SDS); range, 25.9 to 20.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, 22.0 SDS; range, 24.2 to 20.6). Most children with ACAN mutations had advanced bone age (bone age 2 chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy 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. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

Original languageEnglish (US)
Pages (from-to)460-469
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Issue number2
StatePublished - Feb 1 2017

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


Dive into the research topics of 'Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations'. Together they form a unique fingerprint.

Cite this