The prevalence of congenital hydrocephalus has been estimated at 1.1 per 1000 infants when including cases diagnosed before 1 year of age after exclusion of neural tube defects. Classification criteria are based either on CSF dynamics, pathophysiological mechanisms or associated lesions. Whereas inherited syndromic hydrocephalus has been associated with more than 100 disease-causing genes, only four genes are currently known to be linked to congenital hydrocephalus either isolated or as a major clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. In the past 10 years, pathogenic variants in CCDC88C have been documented but the neuropathology remains virtually unknown. We report the neuropathology of two foetuses from one family harbouring two novel compound heterozygous pathogenic variants in the CCDC88C gene: a maternally inherited indel in exon 22, c.3807_3809delinsACCT;p.(Gly1270Profs*53) and a paternally inherited deletion of exon 23, c.3967-?_c.4112-?;p.(Leu1323Argfs*10). Medical termination of pregnancy was performed at 18 and 23 weeks of gestation for severe bilateral ventriculomegaly. In both fetuses, brain lesions consisted of multifocal atresia-forking along the aqueduct of Sylvius and the central canal of the medulla, periventricular neuronal heterotopias and choroid plexus hydrops. The second fetus also presented lumbar myelomeningocele, left diaphragmatic hernia and bilateral renal agenesis. CCDC88C encodes the protein DAPLE which contributes to ependymal cell planar polarity by inhibiting the non-canonical Wnt signaling pathway and interacts with MPDZ and PARD3. Interestingly, heterozygous variants in PARD3 result in neural tube defects by defective tight junction formation and polarization process of the neuroepithelium. Besides, during organ formation Wnt signalling is a prerequisite for planar cell polarity pathway activation, and mutations in planar cell polarity genes lead to heart, lung and kidney malformations. Hence, candidate variants in CCDC88C should be carefully considered whether brain lesions are isolated or associated with malformations suspected to result from disorders of planar cell polarity.

中文翻译：

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与 CCDC88C 致病变异相关的胎儿脑积水的神经病理学特征

先天性脑积水的患病率估计为每 1000 名婴儿 1.1 人，其中包括排除神经管缺陷后 1 岁前诊断的病例。分类标准基于脑脊液动力学、病理生理机制或相关病变。尽管遗传性综合征性脑积水与 100 多种致病基因有关，但目前已知只有四种基因与先天性脑积水有关，无论是孤立的还是作为主要临床特征：L1CAM、AP1S2、MPDZ 和 CCDC88C。在过去的 10 年中，CCDC88C 的致病变异已被记录在案，但神经病理学实际上仍然未知。我们报告了来自一个家族的两个胎儿的神经病理学，这些胎儿在 CCDC88C 基因中有两个新的复合杂合致病变异：外显子 22 中的母系遗传插入缺失，c.3807_3809delinsACCT;p.(Gly1270Profs*53) 和外显子 23 的父系遗传缺失，c.3967-?_c.4112-?;p.(Leu1323Argfs*10)。由于严重的双侧脑室扩大，在妊娠 18 周和 23 周时进行了药物终止妊娠。在这两个胎儿中，脑损伤包括沿 Sylvius 导水管和髓质中央管的多灶性闭锁分叉、脑室周围神经元异位和脉络丛积水。第二胎也出现腰椎脊髓脊膜膨出、左侧膈疝和双侧肾发育不全。CCDC88C 编码蛋白质 DAPLE，它通过抑制非经典 Wnt 信号通路促进室管膜细胞平面极性，并与 MPDZ 和 PARD3 相互作用。有趣的是，PARD3 中的杂合变异通过有缺陷的神经上皮紧密连接形成和极化过程导致神经管缺陷。此外，在器官形成过程中，Wnt 信号是平面细胞极性通路激活的先决条件，平面细胞极性基因的突变导致心脏、肺和肾脏畸形。因此，应仔细考虑 CCDC88C 中的候选变体是孤立的还是与怀疑由平面细胞极性障碍引起的畸形有关。