Abstract: Background X-linked recessive chondrodysplasia punctata（CDPX1） is a rare congenital disorder of bone and cartilage development caused by ARSE gene mutations.In China，there are only a few related reports，with neonates as the subjects，and there is no report about the phenotypes of childhood.Objective　To analyze the clinical phenotypes and genotypes of CDPX1 caused by mutation of ARSE gene.Methods　Clinical features and whole exon sequencing results of a case of CDPX1 caused by ARSE gene mutations who was diagnosed and treated in the Third Affiliated Hospital of Zhengzhou University in June 2018 were collected and analyzed. And a literature review was performed to assess studies of CDPX1 caused by ARSE gene mutations searched in databases of CNKI，WANFANG DATA，PubMed and Human Gene Mutation Database（HGMD） from inception to February 2010 using “点状软骨发育不良”“芳香基硫酸酯酶E”“chondrodysplasia punctate” and“ARSE” as search terms. Then the clinical phenotypes and genotypes of this disease were summarized.Results　The patient selected from the Third Affiliated Hospital of Zhengzhou University is male，had a low and flat nose suggested by fetal ultrasound，and presented postnatal dyspnea，mixed deafness，nasal dysplasia，short stature，limbs and fingers，cognitive and motor retardation，and atrial septal defect.X-ray indicated spotty calcifications of feet and spine. The whole exon sequencing revealed the semi-zygotic variation of ARSE gene c.1219G>A（p.E407k），which has not been reported in the literature at home and abroad. His mother was heterozygous mutation，his father and sister were wide-type.23 cases with detailed descriptions of phenotypes were identified in related studies，including 22 males and 1 female，4 were diagnosed in the prenatal period（including 2 live births，1 abortion at 26 weeks of gestation and 1 unknown case），and 1 died due to DIC in neonatal period. Clinical manifestations of these cases in general: midfacial hypoplasia，brachytelephalangy，stippled epiphyses in spine and limbs，respiratory dysfunction，hearing loss，rachiocamposis or abnormal centrum，stenomycteria or atretorrhinia，short stature，congenital heart disease，cognitive impairment，short neck，calcification of trachea and/or bronchus，airway stenosis，calcifications of larynx，hypotonia，symphysodactylia，slow increase of weight，feeding difficulties，intrauterine growth restriction，small for gestational age，cataract，small thorax，spinal stenosis，contracture of joint. Among them，fetal stage performance: flat facial profile，various degrees of nasal hypoplasia，collapse of the nasal bridge，rachiocamposis，abnormal centrum，spinal stenosis，short upper limbs，diffuse stippled calcification in osteoepiphysis and spine，long bone dysplasia，intrauterine growth restriction.47 variations in ARSE gene were retrieved by searching HGMD，including point mutation，single or multiple exon deletion，complete deletion including ARSE gene，and chromosome translocation.Conclusion　We gave the first report about CDPX1 caused by mutation of ARSE gene c.1219G>A，expanding the mutation spectrum of ARSE gene.And the summary of the phenotypes of patients from fetal period to 2 years old contributes to the understanding of CDPX1 phenotypes and genotypes.

Key words: X-linked recessive chondrodysplasia punctate；Genetic diseases, X-Linked；Genes, recessive；Arylsulfatases；ARSE gene；Chondrodysplasia punctata；Whole exome sequencing

摘要： 背景　X-连锁隐性遗传点状软骨发育不良（CDPX1）是一种罕见的先天性骨骼和软骨发育障碍性疾病，致病基因为ARSE基因。目前国内报道较少，且均为新生儿，尚无儿童患者表型报道。目的　分析ARSE基因突变致CDPX1的临床表型和基因型。方法　收集郑州大学第三附属医院2018年6月确诊的1例ARSE基因突变致CDPX1患者的临床资料，对其临床特征及全外显子测序结果进行分析，并以“点状软骨发育不良”“芳香基硫酸酯酶E”和“chondrodysplasia punctate”“ARSE”为检索词，分别在中国知网、万方数据知识服务平台、PubMed以及人类基因组突变数据库（HGMD）检索建库至2020年2月的相关文献，总结ARSE基因突变致CDPX1患者的临床表型和基因型。结果　本例患儿，男性，胎儿超声发现鼻梁低平，出生后呼吸困难，混合性耳聋，鼻发育不良，四肢短，手指短，认知及运动发育落后，房间隔缺损，X线检查示有典型的点状钙化。全外显子测序结果发现ARSE基因c.1219G>A（p.E407k）半合子变异，患儿父亲与姐姐该位点为野生型，患儿母亲为杂合突变，该变异国内外未见文献报道。经数据库检索到ARSE基因突变致CDPX1且有详细临床表型的病例23例，其中男22例，女1例，胎儿期确诊4例，其中2例活产，1例26周流产，1例不详；1例因出现新生儿期合并弥散性血管内凝血（DIC）死亡。临床表现：面中部发育不良，远端指骨短，脊柱及四肢长骨等点状骨骺，呼吸功能不全，听力异常，脊柱弯曲或椎体形态异常，鼻孔狭窄或闭锁，矮小，先天性心脏病，认知障碍，颈部短，气管及支气管钙化，气道狭窄，喉软骨钙化，肌张力低下，并趾畸形，体质量增长缓慢，喂养困难，宫内生长受限，小于胎龄儿，白内障，胸廓小，椎管狭窄，关节挛缩。其中胎儿期表现：面部扁平，不同程度的鼻发育不良，鼻梁凹陷，脊柱弯曲异常，椎体异常，椎管狭窄，上肢短，骨骺及脊柱弥漫性点状钙化，长骨发育不良，胎儿生长受限。通过HGMD检索到47个ARSE基因突变，包括点突变、单个或多个外显子缺失、完全缺失、染色体易位。结论　首次报道ARSE基因c.1219G>A变异所致CDPX1，扩大了ARSE基因的突变谱，且报道了患者从胎儿期到2岁的临床表型，有助于对CDPX1临床表型及基因型的认识。

关键词: X-连锁隐性遗传点状软骨发育不良；遗传性疾病, X连锁；芳基硫酸酯酶类；ARSE基因, 隐性；ARSE基因；点状软骨发育异常；全外显子测序