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

作者：Alexandra Gkourogianni, Melissa Andrew, Leah Tyzinski, Melissa K. Crocker, Jessica Douglas, Nancy Dunbar, Jan Fairchild, Mariana F.A. Funari, Karen E. Heath, Alexander A.L. Jorge, Tracey Kurtzman, Stephen LaFranchi, Seema R. Lalani, Jan Lebl, Yuezhen Lin, Evan Los, Dorothee Newbern, C. Nowak, Micah L. Olson, Jadranka Popovic, Štěpánka Průhová, Lenka Elblová, Jose Bernardo Quintos, Emma Segerlund, Lucia Sentchordi, Marwan Shinawi, Eva-Lena Stattin, Jonathan M. Swartz, Ariadna González del Ángel, Sinhué Diaz Cuéllar, Hidekazu Hosono, Pedro A. Sanchez‐Lara, Vivian Hwa, Jeffrey Baron, Ola Nilsson, Andrew Dauber · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2016 · DOI：10.1210/jc.2016-3313 · 被引用次数：138 · 研究领域：Osteoarthritis Treatment and Mechanisms、Connective tissue disorders research、Proteoglycans and glycosaminoglycans research

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 rangin...