Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations

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

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 102, n. 2, p. 460-469, FEB 1 2017.
• Web of Science Citations: 26

Abstract

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, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] 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, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - 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. (AU)

• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants