Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
Mol Genet Genomic Med. 2020 Apr;8(4):e1178. doi: 10.1002/mgg3.1178. Epub 2020 Feb 26.
Agnathia-otocephaly is a rare and lethal anomaly affecting craniofacial structures derived from the first pharyngeal arch. It is characterized by agnathia, microstomia, aglossia, and abnormally positioned auricles with or without associated anomalies. Variants affecting function of OTX2 and PRRX1, which together regulate the neural crest cells and the patterning of the first pharyngeal arch as well as skeletal and limb development, were identified to be causal for the anomaly in a few patients.
Family-based exome sequencing (ES) on a fetus with severe agnathia-otocephaly, cheilognathopalatoschisis, laryngeal hypoplasia, fused lung lobes and other organ abnormalities and mRNA expression analysis were performed.
Exome sequencing detected a de novo SMAD3 missense variant in exon 6 (c.860G>A) associated with decreased mRNA expression. Variants in SMAD3 cause Loeys-Dietz syndrome 3 presenting with craniofacial anomalies such as mandibular hypoplasia, micro- or retro-gnathia, bifid uvula and cleft palate as well as skeletal anomalies and arterial tortuosity. The SMAD3 protein acts as a transcriptional regulator in the transforming growth factor β (TGFB) and bone morphogenetic (BMP) signaling pathways, which play a key role in the development of craniofacial structures originating from the pharyngeal arches.
Agnathia-otocephaly with or without associated anomalies may represent the severe end of a phenotypic spectrum related to variants in genes in the interacting SMAD/TGFB/BMP/SHH/FGF developmental pathways.
无颌-耳-头畸形是一种罕见且致命的异常，影响源自第一咽弓的颅面结构。其特征为无颌、小口畸形、无舌、耳位置异常，伴有或不伴有相关畸形。少数患者的异常与 OTX2 和 PRRX1 变异有关，这些变异共同调节神经嵴细胞和第一咽弓的模式以及骨骼和肢体发育。
对一名严重无颌-耳-头畸形、唇腭裂、喉发育不良、肺叶融合和其他器官异常胎儿进行基于家系的外显子组测序（ES）和 mRNA 表达分析。
外显子组测序检测到一个位于外显子 6（c.860G>A）的 SMAD3 错义变异，与 mRNA 表达降低相关。SMAD3 变异导致 Loeys-Dietz 综合征 3，表现为颅面畸形，如下颌发育不良、小下颌或后缩下颌、分叉悬雍垂和腭裂，以及骨骼畸形和动脉扭曲。SMAD3 蛋白作为转化生长因子 β（TGFB）和骨形态发生蛋白（BMP）信号通路中的转录调节剂，在源自咽弓的颅面结构发育中起关键作用。
伴有或不伴有相关畸形的无颌-耳-头畸形可能代表与相互作用的 SMAD/TGFB/BMP/SHH/FGF 发育途径中基因变异相关的表型谱的严重端。
