Clinical and molecular features of patients with COL1-related disorders: Implications for the wider spectrum and the risk of vascular complications

Abstract

Abnormalities in type I procollagen genes (COL1A1 and COL1A2) are responsible for hereditary connective tissue disorders including osteogenesis imperfecta (OI), specific types of Ehlers-Danlos syndrome (EDS), and COL1-related overlapping disorder (C1ROD). C1ROD is a recently proposed disorder characterized by predominant EDS symptoms of joint and skin laxity and mild OI symptoms of bone fragility and blue sclera. Patients with C1ROD do not carry specific variants for COL1-related EDS, including classical, vascular, cardiac-valvular, and arthrochalasia types. We describe clinical and molecular findings of 23 Japanese patients with pathogenic or likely pathogenic variants of COL1A1 or COL1A2, who had either OI-like or EDS-like phenotypes. The final diagnoses were OI in 17 patients, classical EDS in one, and C1ROD in five. The OI group predominantly experienced recurrent bone fractures, and the EDS group primarily showed joint hypermobility and skin hyperextensibility, though various clinical and molecular overlaps between OI, COL1-related EDS, and C1ROD as well as intrafamilial phenotypic variabilities were present. Notably, life-threatening vascular complications (vascular dissections, arterial aneurysms, subarachnoidal hemorrhages) occurred in seven patients (41% of those aged >20 years) with OI or C1ROD. Careful lifelong surveillance and intervention regarding bone and vascular fragility could be required.

Keywords: COL1-related overlap disorder; COL1A1; COL1A2; Ehlers-Danlos syndrome; osteogenesis imperfecta.

FIGURE 1

Schematic structure, location of domain organizations, and distribution of the mutations in COL1A1 (a) and COL1A2 (b). The numbers in the upper center rectangles indicate the exon numbers, and the rectangles in the lower center indicate the domain organizations of the proteins. Variants found in the current study are shown above the exon rectangles; unpublished variants are displayed in red, and previously published variants are displayed in blue. Variants in previous publications are shown below the domain rectangles. Variants both identified in the current study and previous publications are displayed in blue. aEDS, Ehlers‐Danlos syndrome arthrochalasia type; C1ROD, COL1‐related overlap disorder; OI, osteogenesis imperfecta; cEDS Ehlers‐Danlos syndrome classical type; vEDS, Ehlers‐Danlos syndrome vascular type

FIGURE 2

Radiographic findings of three patients with vascular complications. (a−e, patient #1) A brain enhanced computed tomography (CT)‐based angiography (a) shows a left inner carotid artery aneurysm (arrowhead). A brain CT reveals an occipital subarachnoid hemorrhage (b). Chest CT images (c, d) and chest to abdominal CT‐based angiography (e) show an extensive aortic dissection from the ascending aorta, aortic arch, and descending thoracic to abdominal aorta (arrowheads). (f, patient #7) A magnetic resonance imaging (MR)‐based angiography shows a right inner carotid artery aneurysm of 2 mm in diameter (f). (g−j, patient #23) A diffusion‐weighed brain MR imaging (g, h) shows a high intensity area in the left middle cerebral artery region. A digital subtraction angiography shows stenotic lesions (arrowheads) of the right (i) and left (j) inner carotid arteries

FIGURE 3

Transmission electron microscopic findings of skin specimens from patient #22 (a) and #23 (b). Occasional abnormal cauliflower‐like collagen fibrils with irregular margins (arrowheads) are noted in both images