Hermanns Pia, Unger Sheila, Rossi Antonio, Perez-Aytes Antonio, Cortina Hector, Bonafé Luisa, Boccone Loredana, Setzu Valeria, Dutoit Michel, Sangiorgi Luca, Pecora Fabio, Reicherter Kerstin, Nishimura Gen, Spranger Jürgen, Zabel Bernhard, Superti-Furga Andrea
Center for Pediatrics and Adolescent Medicine, University of Freiburg, 79106 Freiburg, Germany.
Am J Hum Genet. 2008 Jun;82(6):1368-74. doi: 10.1016/j.ajhg.2008.05.006.
Deficiency of carbohydrate sulfotransferase 3 (CHST3; also known as chondroitin-6-sulfotransferase) has been reported in a single kindred so far and in association with a phenotype of severe chondrodysplasia with progressive spinal involvement. We report eight CHST3 mutations in six unrelated individuals who presented at birth with congenital joint dislocations. These patients had been given a diagnosis of either Larsen syndrome (three individuals) or humero-spinal dysostosis (three individuals), and their clinical features included congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfoot, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation but enhanced 4-O-sulfation, confirming functional impairment of CHST3 and distinguishing them from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells. These observations provide a molecular basis for recessive Larsen syndrome and indicate that recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia Omani type form a phenotypic spectrum.
迄今为止，仅在一个家族中报道过碳水化合物硫酸转移酶3（CHST3，也称为软骨素-6-硫酸转移酶）缺乏症，且与伴有进行性脊柱受累的严重软骨发育不良表型相关。我们报告了6名无亲缘关系个体中的8个CHST3突变，这些个体出生时即患有先天性关节脱位。这些患者被诊断为Larsen综合征（3例）或肱骨-脊柱发育不全（3例），其临床特征包括先天性膝关节脱位、肘关节发育不良伴半脱位和伸展受限、髋关节发育不良或脱位、马蹄内翻足、身材矮小以及儿童晚期出现的脊柱侧凸。对皮肤成纤维细胞中硫酸软骨素蛋白聚糖的分析显示，6-O-硫酸化明显减少，但4-O-硫酸化增强，证实了CHST3的功能受损，并将它们与缺乏硫酸化发育不良硫酸盐转运蛋白（DTDST）的细胞区分开来。这些观察结果为隐性Larsen综合征提供了分子基础，并表明隐性Larsen综合征、肱骨-脊柱发育不全和阿曼型脊椎骨骺发育不良构成了一个表型谱。
