Orphanet Journal of Rare Diseases | Developmental Mechanism Study of Criss-cross Heart

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This study, through detailed anatomical and clinical analysis of 16 patients with criss-cross heart (CCH), validated previously proposed developmental mechanisms from mouse models and revealed the association between CCH and outflow tract developmental defects, offering new insights into the molecular mechanisms and surgical strategies for this rare congenital heart disease.

 

Literature Overview
The article Criss cross heart: an outflow tract defect? published in the Orphanet Journal of Rare Diseases reviews and summarizes the clinical and anatomical features of 16 patients with criss-cross heart (CCH), comparing them with mouse models. The study shows that CCH in humans is consistently associated with malposition of the great arteries and ventricular septal defects (VSD), all of which are located in the right ventricular inflow tract, consistent with the outflow tract developmental defect observed in mouse models caused by Greb1l mutation. The research further analyzes surgical repair strategies and long-term prognosis, providing anatomical evidence for clinical decision-making.

Background Knowledge
Criss-cross heart (CCH) is an extremely rare congenital cardiac malformation characterized by vertically crossed atrioventricular inflow vectors, preventing the mitral and tricuspid valves from appearing in the same plane on echocardiographic four-chamber views. CCH is often accompanied by other cardiac anomalies such as outflow tract defects, pulmonary stenosis, and ventricular septal defects (VSD). Due to its complexity, the developmental mechanism of CCH has long been debated, mainly including hypotheses of abnormal ventricular rotation and heart tube connection defects. Recent mouse genetic studies identified that mutations in the Greb1l gene can cause outflow tract developmental arrest, leading to CCH phenotypes, offering novel genetic clues for human CCH research. However, whether human CCH involves Greb1l variants and the optimal surgical strategy remain to be further explored. This study, based on a retrospective analysis of 16 CCH patients combined with imaging and genetic data, verifies whether developmental defects observed in mouse models also exist in humans, and provides anatomical guidance for clinical surgical repair strategies.

 

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Research Methods and Experiments
The study included 16 CCH patients diagnosed between 1999 and 2022 at Necker–Enfants Malades Hospital, all confirmed by echocardiography, CT, or MRI. The Van Praagh segmental analysis method was used to identify cardiac segments, and ventricular septal defects (VSD) were classified according to the IPCCC ICD-11 classification. Whole genome sequencing was performed in six patients to analyze whether pathogenic variants exist in the Greb1l gene or its TAD region.

Key Findings and Perspectives

• CCH in humans is consistently associated with malposition of the great arteries and ventricular septal defects, all located in the right ventricular inflow tract, with some cases showing muscular or outflow tract extension
• 75% of patients exhibited a supero-inferior ventricular arrangement, consistent with mouse models, supporting the hypothesis of early outflow tract developmental arrest
• All patients showed abnormal outflow tract development, manifesting as double outlet right ventricle or transposition of the great arteries, suggesting that abnormal outflow tract rotation is central to CCH pathogenesis
• Whole genome sequencing did not identify pathogenic Greb1l variants, suggesting that human CCH may be oligogenic or non-genetic in origin
• 94% of patients underwent surgical intervention, with 81% receiving single-ventricle repair, likely due to the anatomical limitations imposed by VSD location

Research Implications and Future Directions
This study is the first systematic anatomical description of human CCH and its comparison with mouse models, confirming the central role of outflow tract developmental defects in CCH formation. The findings provide a foundation for future multicenter CCH cohort studies and molecular mechanism investigations. Additionally, precise localization of VSD may be critical for surgical decision-making, highlighting the potential value of imaging and 3D modeling techniques in CCH management.

 

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Conclusion
Criss-cross heart (CCH) is a rare and complex congenital cardiac malformation consistently associated with malposition of the great arteries and ventricular septal defects (VSD), all located in the right ventricular inflow tract in humans. This study found that the anatomical features of human CCH closely resemble the phenotypes observed in mouse models with early outflow tract developmental arrest, supporting the hypothesis that CCH originates from abnormal rotation of the outflow tract. Although no pathogenic Greb1l variants were identified through whole-genome sequencing, the importance of this gene in cardiac development should not be overlooked. Future studies with larger cohorts and multi-omics approaches are needed to further elucidate the genetic basis of human CCH. Furthermore, the location of VSD plays a critical role in surgical decision-making, where inflow tract defects may limit biventricular repair, highlighting the need for more precise preoperative imaging assessment. This study provides crucial insights into the molecular mechanisms and surgical strategy optimization for CCH.

 

Ségolène Bernheim, Adrien Borgel, Véronique Pingault, Sigolène M Meilhac, and Lucile Houyel. Criss cross heart: an outflow tract defect?. Orphanet Journal of Rare Diseases.