Integrative Review of Molecular, Metabolic, and Environmental Factors in Spina Bifida and Congenital Diaphragmatic Hernia: Insights into Mechanisms and Emerging Therapeutics

Abstract

Spina Bifida (SB) and Congenital Diaphragmatic Hernia (CDH) are complex congenital anomalies that pose significant challenges in pediatric healthcare. This review synthesizes recent advancements in understanding the genetic, metabolic, and environmental factors contributing to these conditions, with the aim of integrating mechanistic insights into therapeutic innovations. In SB, key findings highlight the roles of KCND3, a critical regulator of spinal cord development, and VANGL2, essential for planar cell polarity and neural tube closure. MicroRNAs such as miR-765 and miR-142-3p are identified as key regulators of these genes, influencing neural development. Additionally, telomere shortening-a marker of cellular senescence-alongside disruptions in folate metabolism and maternal nutritional deficiencies, significantly increases the risk of SB. These findings underscore the crucial role of telomere integrity in maintaining neural tissue homeostasis during embryonic development. For CDH, genetic deletions, including those on chromosome 15q26, and chromosomal abnormalities have been shown to disrupt lung and vascular development, profoundly impacting neonatal outcomes. MicroRNAs miR-379-5p and miR-889-3p are implicated in targeting essential genes such as IGF1 and FGFR2, which play pivotal roles in pulmonary function. Promising emerging therapies, including degradable tracheal plugs and fibroblast growth factor-based treatments, offer potential strategies for mitigating pulmonary hypoplasia and improving clinical outcomes. This review underscores the intricate interplay of genetic, metabolic, and environmental pathways in SB and CDH, identifying critical molecular targets for diagnostics and therapeutic intervention. By integrating findings from genetic profiling, in vitro models, and clinical studies, it aims to inform future research directions and optimize patient outcomes through collaborative, multidisciplinary approaches.

Keywords: Diaphragmatic Hernia; Spinal Bifida; genetic pattern; metabolic markers.

Figure 1

PRISMA flowchart diagram.

Figure 2

Genetic Pathways in Spina Bifida. This schematic highlights key genetic and epigenetic contributors to neural tube closure, including the planar cell polarity pathway (VANGL2), ion channel regulation (KCND3), and their regulation by microRNAs (miR-765, miR-142-3p). Environmental factors such as folate deficiency, oxidative stress, and telomere shortening are also included as upstream modulators. The integrative layout is designed to guide future research toward the most relevant mechanistic targets and regulatory interactions.

Figure 3

Simplified Pathogenetic Model of CDH. This diagram presents genetic and environmental factors contributing to abnormal diaphragm and lung development in CDH. Key genes include GATA4, COUP-TFII, and FGFR2, influenced by retinoic acid signaling, chromosomal deletions (e.g., 15q26), and teratogenic exposures. The figure underscores the interplay between developmental signaling and structural outcomes, serving as a framework for identifying candidate genes and pathways for future translational studies.