Abstract
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.
Highlights
Congenital hydrocephalus affects 4.65 per 10,000 births and its prevalence has been estimated at 1.1 per 1000 infants when including cases diagnosed before 1 year of age in the absence of other extrinsic causes and afterMarguet et al acta neuropathol commun (2021) 9:104 exclusion of neural tube defects [16, 20]
AP1S2 is a subunit of the AP1 adaptin protein complex, one of the major regulators of lysosomal protein sorting involved in clathrin-coated vesicle assembly and transport of proteins between the trans-Golgi network and lysosomes [14]
In a recent study including 138 patients with neural tube defect (NTD), rare heterozygous variants in the PARD3 gene were identified and were shown to be significantly enriched in the aPKC-binding region resulting in defective tight junction formation via disrupted aPKC binding, suggesting that these deleterious variants contribute to human NTDs possibly by preventing apical tight junction formation and subsequent polarization process of the neuroepithelium [3]
Summary
Congenital hydrocephalus affects 4.65 per 10,000 births and its prevalence has been estimated at 1.1 per 1000 infants when including cases diagnosed before 1 year of age in the absence of other extrinsic causes and after. Whereas syndromic hydrocephalus has been associated with more than 100 disease-causing genes, only four genes are currently known to be linked to congenital hydrocephalus as isolated or as the major clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Case presentation A 31-year-old woman, gravida I, para 0, underwent routine ultrasonography (US) at 22 weeks of gestation (WG), which revealed macrocephaly (head circumference >> 97th percentile) with severe bilateral ventriculomegaly, but with no other associated brain, visceral or growth parameter abnormalities. Based on these findings, a medical termination of the pregnancy (TOP) was achieved at 23 WG in accordance with the French law.
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