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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: <jats:italic>L1CAM, AP1S2, MPDZ<\/jats:italic> and <jats:italic>CCDC88C<\/jats:italic>. In the past 10\u00a0years, pathogenic variants in <jats:italic>CCDC88C<\/jats:italic> 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 <jats:italic>CCDC88C<\/jats:italic> 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\u00a0weeks 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. <jats:italic>CCDC88C<\/jats:italic> 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 <jats:italic>PARD3<\/jats:italic> 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 <jats:italic>CCDC88C<\/jats:italic> should be carefully considered whether brain lesions are isolated or associated with malformations suspected to result from disorders of planar cell polarity.<\/jats:p>","DOI":"10.1186\/s40478-021-01207-5","type":"journal-article","created":{"date-parts":[[2021,6,6]],"date-time":"2021-06-06T21:03:23Z","timestamp":1623013403000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants"],"prefix":"10.1186","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7306-0520","authenticated-orcid":false,"given":"Florent","family":"Marguet","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Vezain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Marcorelles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9verine","family":"Audebert-Bellanger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00e9vin","family":"Cassinari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Drouot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Chambon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno J.","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie","family":"Horowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Laquerriere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Saugier-Veber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,6]]},"reference":[{"key":"1207_CR1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1146-1","author":"H Adle-Biassette","year":"2013","unstructured":"Adle-Biassette H, Saugier-Veber P, Fallet-Bianco C, Delezoide AL, Razavi F, Drouot N et al (2013) Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases. 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Autopsies were performed in the two foetuses with the informed written consent of the parents in accordance with the French law. The parents provided written informed consent for targeted sequencing and Whole Exome Sequencing.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"104"}}