Type IV collagen belongs to a family of collagen proteins comprising at least 25 distinct members. The COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, and COL4A6 genes encode the six α chains of type IV collagen [1]. These chains (α1 [IV] to α6 [IV]) are selectively expressed in different basement membranes at various stages of embryonic development [2]. This selective expression underlies the tissue-specific distribution of disease and the resulting clinical manifestations. Structural alterations of type IV collagen, whether caused by genetic mutations or immune-mediated injury, disrupt basement membrane integrity and lead to organ dysfunction [3].

The α1 and α2 chains constitute the predominant form of type IV collagen in the basement membrane of the vascular endothelium [4]. Consequently, COL4A1/A2-related disorders encompass a broad spectrum of vascular abnormalities with multi-organ involvement, affecting the brain, kidney, eye, heart, bone marrow, and skeletal muscle [5].

Neurological involvement is a major feature of COL4A1/A2-related pathology and includes ischemic lesions such as porencephaly and schizencephaly, as well as intracranial hemorrhages [6]. In a series of 18 cases of fetal cerebral hemorrhages, 5 cases had a COL4A1 mutation [4], supporting a causal role for COL4A1/A2 variants in fetal brain injury. In contrast, placental findings in COL4A1/A2-related pathology have been only sparsely described, with few studies addressing fetal vascular lesions [6]. Some reported cases have shown features of fetal vascular malperfusion (FVM), suggesting a possible placental contribution to the pathogenesis of cerebral lesions.

Fetal vascular malperfusion was first described in 1995 by Redline and Pappin under the term fetal thrombotic vasculopathy [7] encompassing occlusive lesions of the fetal circulation involving the umbilical, chorionic plate, stem villous, and terminal villous vessels. Five main lesion types were defined: mural or occlusive thrombosis, avascular villi, intramural fibrinoid deposits or endothelial cushions, hemorrhagic endovascular inflammation, and fibromuscular sclerosis. The Amsterdam Placental Workshop Group consensus subsequently refined the classification of FVM, defining two major patterns segmental and global and two grades of severity (low-grade and high-grade) [8] Segmental FVM reflects thrombotic occlusion or obliteration of chorionic plate or stem villous vessels, resulting in complete downstream villous obstruction. Global FVM corresponds to partial or intermittent obstruction of umbilical blood flow and is characterized by venous ectasia, intramural fibrin deposition in large vessels, and/or small foci of avascular or karyorrhectic villi distributed over a wide placental area. High-grade FVM is reserved for severe forms and is defined by the presence of multiple foci of avascular villi or a single focus of another qualifying lesion, including extensive thrombosis of chorionic plate or stem villous vessels [8].

In this context, the present study reports a retrospective series of ten fetal cases with COL4A1/A2-related pathology, with two main objectives: (i) to identify placental lesions potentially associated with ischemic and hemorrhagic cerebral lesions, and (ii) to evaluate the structural integrity of fetal placental vessels.

We report ten cases of fetal pathology associated with COL4A1/A2 mutations, reflecting the rarity of this condition in the antenatal period. Previous reports include eight cases compiled by Gubana et al. [9] and four cases reported in Washington [6]. In families undergoing systematic screening, the number of identified cases increases; for example, Meuwissen et al. [10] described 183 cases in 13 families.

Our series includes only index cases with no known family history, except for one case (Case 1) with a history of intracranial aneurysms; in this fetus, the COL4A1 variant appeared de novo. Molecular genetic analysis identified ten variants (Table 4), nine of which were de novo and one maternally inherited. De novo transmission predominates in several studies [9] and limits recurrence risk, although residual risk may exist due to mosaicism.

Neuropathological findings were detected after 22 weeks of gestation. Six cases exhibited hemorrhagic and ischemic lesions (schizencephaly and porencephaly), whereas four cases presented only ischemic lesions. In previously reported familial cases [10], two patients showed focal cortical malformations: one with a maternally inherited COL4A1 mutation had schizencephaly, porencephaly, and intraventricular hemorrhage, while a second with a paternal COL4A2 mutation displayed left frontal porencephaly and cortical dysplasia.

Mouse models of COL4A1-related pathology demonstrate porencephaly secondary to focal ruptures of the vascular basement membrane [11]. Approximately 50% of mutant mice die from cerebral hemorrhage within the first day of life, and 18% of survivors develop porencephaly, highlighting the pathogenic role of vascular fragility.

Placental and fetal vascular findings have rarely been described in COL4A1/A2 pathology [6] [9]. In our series, five cases exhibited no fetal vascular malperfusion (FVM) lesions or other placental abnormalities, consistent with previous reports: one case in Shannon’s series and four in Gubana’s series also showed no FVM lesions [6] [9].

In all ten cases, as well as in the two control cases without COL4A1/A2 variants, we observed endothelial detachment in chorionic and stem villous vessels, together with tunica media vacuolization. This medial vacuolization has been described previously by Shannon et al. [6]; however, we consider it non-specific, as it is commonly observed post-mortem in placentas from deceased fetuses, irrespective of etiology. In contrast, the fetal vascular malperfusion lesions observed in the five remaining cases were predominantly fibromuscular sclerosis of chorionic and stem villous vessels. The absence of similar lesions in controls argues against procedure-related or post-mortem artefacts and supports their intrinsic association with COL4A1/A2-related pathology.

No old, intramural, or occlusive thromboses were observed, except for one recent thrombosis in Case 5, associated with extensive vascular lesions (intramural fibrin deposits, fibromuscular sclerosis, and chorangioma) and obstructive funicular pathology (hyper-spiral cord). These lesions cannot be definitively attributed to the COL4A1/A2 variant.

Foci of avascular villi, classically evaluated semi-quantitatively according to the Amsterdam criteria [8], were absent. Instead, large fibrohyaline villous trunks without residual vascular structures were observed. Intramural fibrinoid deposits or endothelial cushions were present in Case 2 (without funicular pathology) and Case 5 (with obstructive funicular pathology). These lesions represent focal vascular injury or old thrombosis [12].

The fibromuscular sclerosis affecting chorionic and trunk vessels in five cases was not associated with placental insufficiency: placentas were normotrophic, without infarction or basal decidual hematoma, and maternal vascular malperfusion lesions were absent on microscopy. The sclerosis, which extended across multiple histological sections, often obliterated the vascular lumen and caused severe wall remodeling (Figures 2(a)-(d)). Its grading is not clearly defined in the Amsterdam classification [8].

Histochemical stains and anti-collagen IV immunostaining confirmed the loss of elastic fibers and disorganization of smooth muscle, particularly in the five cases with fibromuscular lesions, rendering it difficult to distinguish veins from trunk arteries (Figure 1(c), Figure 1(d), Figure 6(c), Figure 6(d)). In control cases, arterial and venous walls were well preserved (Figure 5(a), Figure 5(b)). These lesions may reduce vascular tone and lead to hypoperfusion, contributing to the cerebral hemorrhages observed in COL4A1/A2-related pathology.

COL4A1/A2-related fetal pathology is rare. Ischemic and hemorrhagic brain lesions are the main indicators prompting genetic investigation. The relationship between placental lesions, particularly fetal vascular malperfusion, and cerebral pathology remains incompletely understood. In our series of ten cases, fetal vascular malperfusion lesions were observed in half of the placentas. These lesions exhibited vascular sclerosis, occasionally obliterative, with hypertrophic walls lacking smooth muscle and elastic fibers. Such structural vascular alterations may be specifically associated with COL4A1/A2 variants.