Department of Pediatrics, Hospital Universitario Infanta Leonor, Madrid, Spain.
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autonóma de Madrid, IdiPAZ, Madrid, Spain.
Clin Endocrinol (Oxf). 2018 Jun;88(6):820-829. doi: 10.1111/cen.13581. Epub 2018 Mar 24.
Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis.
This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals.
A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies.
ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias.
在两种常染色体显性骨骼发育不良（Kimberley 型脊椎骨骺发育不良和剥脱性骨软骨炎）、一种严重的常染色体隐性发育不良（聚集蛋白聚糖型脊椎干骺端发育不良）中已发现聚集蛋白聚糖基因（ACAN）的突变，以及在一些身材矮小、骨骼畸形轻微和面部畸形轻微的个体中，下一代测序（NGS）有助于发现杂合 ACAN 突变。这些个体中有些人骨龄（BA）提前、青春期突增不良和生长早期停止以及早发性骨关节炎。
本研究对 16 名杂合 ACAN 变异的先证者进行了临床和遗传特征分析，其中 14 名身材矮小和骨骼畸形轻微（第 1 组），2 名患有 Kimberley 型脊椎骨骺发育不良（第 2 组）。随后，我们查阅文献以确定不同临床特征在 ACAN 阳性个体中的频率。
共发现 16 个位于整个基因中的 ACAN 变异，其中 6 个致病性突变和 10 个意义不明的变异（VUS）。有趣的是，所有先证者均存在短指畸形。第 1 组有致病性突变的先证者往往身材更矮小，60%的人 BA 提前，而 VUS 组中这一比例为 0%。VUS 组中髋关节外翻的发生率较高（37%比 0%）。然而，其他特征的发生率相似。
ACAN 应被视为身材矮小和骨骼畸形轻微患者的候选基因，尤其是那些有短指畸形的患者，以及脊椎骨骺发育不良的患者。还需要注意的是，BA 提前和骨关节炎并发症并非聚集蛋白聚糖病/聚集蛋白聚糖相关发育不良的必备条件。
