A review of genetic factors underlying craniorachischisis and omphalocele: Inspired by a unique trisomy 18 case

Abstract

Very few cases of craniorachischisis (CRN) with concomitant omphalocele (OMP) in the setting of trisomy 18 are reported in literature. Solitary midline closure defects are estimated to be more prevalent in trisomy 18 compared to the general population. Neurulation defect comparisons include anencephaly 0-2% versus 0.0206%, spina bifida 1-3% versus 0.0350%, and encephalocele 0-2% versus 0.0082% [Parker et al. (2010); Birth Defects Research. Part A: Clinical and Molecular Teratology, 88:1008-1016; Springett et al. (2015); American Journal of Medical Genetics. Part A, 167A:3062-3069]. The solitary anterior malformation OMP has been reported as high as 6% with trisomy 18 [Springett et al. (2015); American Journal of Medical Genetics. Part A, 167A:3062-3069]. We report the third published case of CRN with concomitant OMP observed in a likely trisomy 18 fetus that screened positive by noninvasive prenatal screening. Furthermore, we review and analyze the current literature to augment understanding of the genetic basis for anterior and posterior closure defects such as CRN and OMP. Although the current genetic lexicon lacks any definitive association with the simultaneous defects presented, previous research elucidated various genes related to anterior or posterior closure interruption individually. By consolidating current research, the authors advance knowledge of interconnected genetic pathology and direct future genetic mapping efforts.

Prenatal Lethal Diagnosis of 8p23.1 Duplication Syndrome Associated with Omphalocele and Encephalocele

“…The concomitant presence of omphalocele and neural tube defects has been described in cases of Trisomy 18. Attempts to identify specific genes implicated in both of these anomalies have been investigated, though few have been definitively associated; though of note, when the SCRIB gene on the long arm of chromosome 8 is duplicated in mouse models, craniorachischisis is observed [ 7 ]. Further research may elucidate a role for this gene in the phenotype present in this patient associated with 8p23.1 duplication syndrome.…”

The role of Lrp6-mediated Wnt/β-catenin signaling in the development and intervention of spinal neural tube defects in mice

“…The noncanonical Wnt/planar cell polarity (PCP) signaling pathway regulates cytoskeleton dynamics and collective tissue movements, such as convergent extension, which may drive neural tube closure ( Copp et al, 2003 ; Wallingford, 2006 ; Wang et al, 2019 ; Ybot-Gonzalez et al, 2007 ). The rare but severest type of NTDs, craniorachischisis, is characterized by an entirely open brain and spinal cord ( Tobin et al, 2019 ), and results from failure of the initial neural tube closure at the boundary between the future hindbrain and spinal cord. Craniorachischisis is associated with defective convergent extension and has been mainly found in mice with mutant PCP signaling genes, such as Ptk7 and the Vangl, Celsr, Dvl and Fzd families ( De Marco et al, 2011 ; Juriloff and Harris, 2012 ).…”

Single-Cell Transcriptomics of Cultured Amniotic Fluid Cells Reveals Complex Gene Expression Alterations in Human Fetuses With Trisomy 18

“…The other two critical regions, one within 18q12.1-18q21.2 and one within 18q22.3-18qter, have been proposed ( Boghosian-Sell et al, 1994 ; Koide et al, 2011 ; Roberts et al, 2016 ). Due to limited samples, pathogenesis of trisomy 18 is poorly studied ( Tobin et al, 2019 ). Because amniocytes are derived from embryonic and extra-embryonic tissues and originate from all three germ layers, amniotic fluid cells are becoming an efficient source of samples for the study of genetic diseases ( Underwood et al, 2005 ; Montemurro et al, 2008 ).…”