Introduction: Structural alterations of type IV collagen resulting from genetic mutations or immune-mediated injury disrupt epithelial integrity and lead to organ dysfunction. The α1 (IV) and α2 (IV) chains are key components of type IV collagen within the basement membrane of vascular endothelium. To date, few studies have specifically investigated placental lesions associated with COL4A1/A2-related fetal pathology, and only limited cases describing fetal vascular malperfusion have been reported. Materials and Methods: This study includes ten cases of COL4A1/A2-related fetal pathology collected following a collaborative call issued by the French Society of Fetopathology (SOFFOET). All placentas were re-examined histologically using hematoxylin-eosin-saffron (HES)-stained sections, including systematic evaluation of the umbilical cord, membranes, and a minimum of four placental parenchymal samples per case. Immunohistochemistry using anti-collagen IV antibodies and special histochemical stains (PAS, green trichrome, and orcein) were performed in five cases and in two control cases with hemorrhagic brain pathology without COL4A1/A2 abnormalities. Results: Ten fetuses were included in the study. Dysmorphic features were present in five cases, and congenital malformations in three. All cases showed cerebral ischemic and hemorrhagic lesions. One fetus carried a COL4A2 mutation with a normal COL4A1 gene, whereas the remaining fetuses had COL4A1 mutations. Eight placentas were normotrophic and two hypertrophic, with no hypotrophic placentas identified. Fetal vascular malperfusion lesions were observed in five cases. Discussion: All cases in this series were index cases with no known family history, except for a history of intracranial aneurysms in one case, in which the COL4A1 variant occurred de novo. Endothelial detachment of chorionic and stem villous vessels and vacuolization of the tunica media were observed both in the study cases and in the control, placentas lacking COL4A1/A2 variants, suggesting these findings may be non-specific. Immunohistochemical staining for collagen IV did not reveal overt abnormalities of the endothelial basement membrane, possibly due to acute hypoxic injury related to medical termination of pregnancy.
References
[1]
Raija, S., Haka-Risku, T., Prockop, D.J. and Tryggvason, K. (1987) Complete Primary Structure of the α1-Chain of Human Basement Membrane (Type IV) Collagen. FEBS Letters, 225, 188-194. https://doi.org/10.1016/0014-5793(87)81155-9
[2]
Hudson, B.G., Reeders, S.T. and Tryggvason, K. (1993) Type IV Collagen: Structure, Gene Organization, and Role in Human Diseases. Molecular Basis of Goodpasture and Alport Syndromes and Diffuse Leiomyomatosis. Journal of Biological Chemistry, 268, 26033-26036. https://doi.org/10.1016/s0021-9258(19)74270-7
[3]
Hudson, B.G., Tryggvason, K., Sundaramoorthy, M. and Neilson, E.G. (2003) Alport’s Syndrome, Goodpasture’s Syndrome, and Type IV Collagen. New England Journal of Medicine, 348, 2543-2556. https://doi.org/10.1056/nejmra022296
[4]
Plaisier, E. and Ronco, P. (2009) COL4A1-Related Disorders. GeneReviews®. University of Washington, Seattle; 2009-2020. https://www.ncbi.nlm.nih.gov/books/NBK7046/
[5]
Bilguvar, K., DiLuna, M.L., Bizzarro, M.J., Bayri, Y., Schneider, K.C., Lifton, R.P., et al. (2009) COL4A1 Mutation in Preterm Intraventricular Hemorrhage. The Journal of Pediatrics, 155, 743-745. https://doi.org/10.1016/j.jpeds.2009.04.014
[6]
Shannon, P., Hum, C., Parks, T., Schauer, G., Chitayat, D., Chong, K., et al. (2021) Brain and Placental Pathology in Fetal COL4A1 Related Disease. Pediatric and Developmental Pathology, 24, 175-186. https://doi.org/10.1177/1093526620984083
[7]
Redline, R.W. and Pappin, A. (1995) Fetal Thrombotic Vasculopathy: The Clinical Significance of Extensive Avascular Villi. Human Pathology, 26, 80-85. https://doi.org/10.1016/0046-8177(95)90118-3
[8]
Khong, T.Y., Mooney, E.E., Ariel, I., Balmus, N.C.M., Boyd, T.K., Brundler, M., et al. (2016) Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement. Archives of Pathology & Laboratory Medicine, 140, 698-713. https://doi.org/10.5858/arpa.2015-0225-cc
[9]
Gubana, F., Christov, C., Coste, T., Tournier-Lasserve, E., Benachi, A., Fallet-Bianco, C., et al. (2022) Prenatal Diagnosis of COL4A1 Mutations in Eight Cases: Further Delineation of the Neurohistopathological Phenotype. Pediatric and Developmental Pathology, 25, 435-446. https://doi.org/10.1177/10935266221080134
[10]
Meuwissen, M.E.C., Halley, D.J.J., Smit, L.S., Lequin, M.H., Cobben, J.M., de Coo, R., et al. (2015) The Expanding Phenotype of COL4A1 and COL4A2 Mutations: Clinical Data on 13 Newly Identified Families and a Review of the Literature. Genetics in Medicine, 17, 843-853. https://doi.org/10.1038/gim.2014.210
[11]
Gould, D.B., Phalan, F.C., Breedveld, G.J., van Mil, S.E., Smith, R.S., Schimenti, J.C., et al. (2005) Mutations in COL4A1 Cause Perinatal Cerebral Hemorrhage and Porencephaly. Science, 308, 1167-1171. https://doi.org/10.1126/science.1109418
[12]
Allias, F. (2010) Pathologie du placenta. Cas n° 4. Vasculopathie thrombotique fœtale. Annales de Pathologie, 30, 290-295. https://doi.org/10.1016/j.annpat.2010.05.005
