Biallelic Frameshift Variant in LAMB1 Associated with Occipital Meningoencephalocele and Pansutural Craniosynostosis: A Case Report and Review of the Literature.

Abstract

The LAMB1 gene encodes the laminin β1 chain, an essential component of the pial basement membrane required for neural morphogenesis. While biallelic LAMB1 mutations typically result in cobblestone lissencephaly and brainstem abnormalities, we report an extreme, lethal syndromic phenotype that significantly expands the gene's known clinical spectrum. Through genomic sequencing of a 36-week stillborn male fetus from consanguineous parents, we identified a novel homozygous frameshift variant in LAMB1 (NM_002291.3:c.3330dup, p.Gly1111Argfs*23). This fetus exhibited severe growth restriction and a massive occipital meningoencephalocele, alongside pansutural craniosynostosis and an underdeveloped cranial base. Multi-system anomalies included gallbladder agenesis and abnormal lung lobation, alongside secondary endocrine failure and placental vascular defects. This report includes a systematic review of 23 confirmed cases, proposing a 4-category phenotypic classification that positions this case as a lethal extreme. Mechanistically, we propose that this loss-of-function variant impairs integrin-β1-mediated mechanotransduction during human neural tube closure, thereby disrupting the extracellular matrix-planar cell polarity axis. Under this mechanism, the primary encephalocele drives downstream pansutural craniosynostosis by reducing intracranial pressure, and endocrine failure by disrupting the hypothalamo-hypophyso-adrenal axis. Ultimately, these findings highlight LAMB1 as an essential, non-redundant scaffold required for both neural architecture and systemic visceral morphogenesis.