Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes.

中文翻译：

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26例致死性多发性先天性挛缩胎儿的临床和分子特征

胎儿运动不能引起的多发性先天性挛缩 (MCC) 表现为多种疾病，从轻度远端关节弯曲到致命的胎儿运动不能变形序列。我们在此介绍来自 18 个家庭的 26 个表现出严重 MCC 表型的胎儿，并描述了详细的产前超声检查结果、尸检临床评估和遗传研究。最常见的产前检查结果是面部轮廓异常（65%）、中枢神经系统异常（62%）、羊水过多（50%）、颈项透明度增加（50%）和胎儿水肿（35%）。尸检发现了其他异常现象，包括面部畸形、发育不良的骨骼变化、鱼鳞病、多发性翼状胬肉和肌病，从而可以对多名患者的特定孟德尔疾病进行初步诊断。对父母的评估显示，有一个家庭的母亲患有握力肌强直。通过外显子组测序和靶向测试，我们在 15 个家庭中确定了ACTC1、CHST14、COG6、DMPK、DOK7、HSPG2、KLHL7、KLHL40、KIAA1109、NEB、PSAT1、RAPSN、USP14和WASHC5的致病变异，以及一名患者与双等位基因NEB变异相关的诊断。三名患者获得双重诊断。在 44% 的队列中观察到新发现的基因或最近与新 MCC 表型相关的先前已知基因的致病性改变。我们的结果为致命 MCC 表型的临床和分子景观提供了新的见解。