Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
Dentaland Clinic, Chiang Mai, Thailand.
Eur J Orthod. 2021 Jan 29;43(1):45-50. doi: 10.1093/ejo/cjaa023.
Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction.
To report for the first time the molecular aetiology of JHS.
Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed.
Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect.
Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.
Juberg-Hayward 综合征（JHS；MIM 216100）是一种罕见的常染色体隐性畸形综合征，其特征为唇裂/腭裂、小头畸形、上睑下垂、身材矮小、拇指发育不良或缺失、桡骨头脱位和肱骨与桡骨融合导致肘部活动受限。
首次报道 JHS 的分子病因。
进行临床和影像学检查、全外显子组测序、Sanger 测序、突变蛋白模型构建以及 Esco2 在小鼠胚胎中的原位杂交。
患者的临床发现包括唇裂/腭裂修复、小头畸形、上睑下垂、身材矮小、骨龄延迟、手指和拇指发育不良、第五指内弯、肱骨桡骨融合导致肘部活动受限。智力正常。对整个家族进行全外显子组测序显示，先证者的 ESCO2 中存在一个新的纯合碱基替换 c.1654C>T。其姐妹为野生型纯合子。父母为该突变的杂合子。该突变预计会导致提前终止密码子 p.Arg552Ter。已知参与黏合复合物形成的基因 ESCO2 的突变会导致 Roberts/SC 短肢畸形综合征。Roberts/SC 短肢畸形综合征和 JHS 具有相似的临床特征，包括常染色体隐性遗传、身材矮小、唇裂/腭裂、严重的上肢异常和指（趾）发育不良。在唇、腭、眼睑、手指、上肢和下肢的早期发育过程中 Esco2 的表达以及截短蛋白模型与缺陷一致。
我们的研究表明，Roberts/SC 短肢畸形综合征和 JHS 是等位基因且不同的实体。这是首例报道 ESCO2 突变导致 JHS，即一种黏合蛋白病。
