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, Pruhová Štepánka, Elblova Lenka, Quintos Jose Bernardo, Segerlund Emma, Sentchordi Lucia, Shinawi Marwan, Stattin Eva-Lena, Swartz Jonathan, Angel Ariadna González Del, Cuéllar Sinhué Diaz, Hosono Hidekazu, Sanchez-Lara Pedro A, Hwa Vivian, Baron Jeffrey, Nilsson Ola, Dauber Andrew
Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm SE-171 76, Sweden.
Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 70941.
J Clin Endocrinol Metab. 2017 Feb 1;102(2):460-469. doi: 10.1210/jc.2016-3313.
Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation.
We sought to characterize the phenotypic spectrum and response to growth-promoting therapies.
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.
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.
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.
聚集蛋白聚糖基因（ACAN）的杂合突变会导致常染色体显性遗传性身材矮小并伴有骨骼成熟加速。
我们试图描述其表型谱以及对促生长疗法的反应。
通过全外显子组测序、靶向二代测序和/或桑格测序，确定并证实了来自20个患有常染色体显性遗传性身材矮小且携带ACAN杂合突变家庭的103名个体（57名女性，46名男性）。从病历中收集临床信息。
所鉴定出的ACAN变异与表型完全共分离。成年个体有轻度不成比例的身材矮小[中位身高，-2.8标准差评分（SDS）；范围，-5.9至-0.9]以及早期生长停滞史。该病症常与早发性骨关节炎（12个家庭）和椎间盘疾病（9个家庭）相关。未发现ACAN突变类型与关节症状之间存在明显的基因型-表型相关性。儿童期身高受影响较小（中位身高，-2.0 SDS；范围，-4.2至-0.6）。大多数携带ACAN突变的儿童骨龄超前（骨龄-实足年龄；中位值，+1.3岁；范围，+0.0至+3.7岁）。19名个体接受了生长激素治疗，有一些生长速度加快的证据。
ACAN杂合突变导致的表型谱范围从轻度且比例正常的身材矮小到伴有不成比例身材矮小和短指畸形的轻度骨骼发育异常。许多受影响个体出现早发性骨关节炎和退行性椎间盘疾病，提示关节软骨和椎间盘软骨功能障碍。需要进一步研究以确定这些患者的最佳治疗策略。
