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

• DOI: 10.1210/jc.2016-3313
• Publication Date: 2016-11-21T19:07:00Z
• Authors: Alexandra Gkourog...; Melissa Andrew; Leah Tyzinski; Melissa Crocker; Jessica Douglas; Nancy Dunbar; Jan Fairchild; Mariana F. A. Funari; Karen E. Heath; Alexander A. L. J...; Tracey Kurtzman; Stephen LaFranchi; Seema Lalani; Jan Lebl; Yuezhen Lin; Evan Los; Dorothee Newbern; Catherine Nowak; Micah Olson; Jadranka Popovic; Štěpánka Průhová; Lenka Elblova; Jose Bernardo Qui...; Emma Segerlund; Lucia Sentchordi; Marwan Shinawi; Eva-Lena Stattin; Jonathan Swartz; Ariadna González ...; Sinhué Diaz Cuéllar; Hidekazu Hosono; Pedro A. Sanchez-...; Vivian Hwa; Jeffrey Baron; Ola Nilsson; Andrew Dauber
• Keywords: Aggrecan; Idiopathic short stature

Abstract Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize phenotypic spectrum and response growth-promoting therapies. Patients Methods: One hundred three individuals (57 females, 46 males) from 20 families heterozygous ACAN were identified confirmed using whole-exome sequencing, targeted next-generation and/or Sanger sequencing. Clinical information was collected medical records. Results: Identified variants showed perfect cosegregation phenotype. Adult had mildly disproportionate [median height, −2.8 standard deviation score (SDS); range, −5.9 −0.9] a history of early growth cessation. The condition frequently associated early-onset osteoarthritis (12 families) intervertebral disc disease (9 families). No apparent genotype–phenotype correlation found between type mutation presence joint complaints. Childhood height less affected (median −2.0 SDS; −4.2 −0.6). Most children advanced bone age (bone − chronologic age; median, +1.3 years; +0.0 +3.7 years). Nineteen received hormone therapy some evidence increased velocity. Conclusions: result ranging mild proportionate dysplasia brachydactyly. Many developed degenerative disease, suggesting dysfunction articular cartilage cartilage. Additional studies are needed determine optimal treatment strategy for these patients.