A number sign (#) is used with this entry because of evidence that multifocal fibromuscular dysplasia (FMDMF) is caused by heterozygous mutation in the COL5A1 gene (120215) on chromosome 9q34.

Multifocal fibromuscular dysplasia (FMDMF) is characterized histologically by medial fibroplasia and angiographically by multiple arterial stenoses with intervening mural dilations. Arterial tortuosity, macroaneurysms, dissections, and rupture may occur (summary by Richer et al., 2020).

Richer et al. (2020) reported 4 unrelated patients, 3 women and 1 man, who exhibited arterial tortuosity, aneurysms, dissections, and multifocal fibromuscular dysplasia (FMD), and had a mutation in the COL5A1 gene. The probands showed variable presentations: proband 1 was a 54-year-old man who experienced a stroke secondary to carotid artery FMD and dissecting aneurysms; proband 2 was a 44-year-old woman with acute leg and hip pain due to ruptured iliac artery dissecting aneurysm; proband 3 was a 52-year-old woman who had a myocardial infarction precipitated by spontaneous coronary artery dissection; and proband 4 was a 64-year-old woman with hypertension requiring 3 drugs, who had a pulmonary artery aneurysm that was incidentally discovered. Angiographic imaging revealed additional vascular lesions in each of the probands: vertebral and internal carotid arteries were tortuous in all probands, and 3 of them also had celiac and iliac artery aneurysm or dissection, whereas the fourth had multifocal stenosis of the celiac artery and irregularity of the iliac artery lumen. Variable features of classic Ehlers-Danlos syndrome (see 130000) were also noted, with skin hyperextensibility of more than 2 cm in family 1 (proband 1, his daughter, and his nephew), and joint hypermobility in family 1 and proband 2. Atrophic scars were present in 3 probands, 2 of whom also experienced postoperative wound dehiscences. Only proband 1 fulfilled the 2017 international classification of classic Ehlers-Danlos syndrome (Malfait et al., 2017). Intraoperatively, vascular tissue friability was noted in proband 1, and histologic analysis of aneurysmal segments from probands 1 and 3 showed extensive fibrosis. In addition, nonaneurysmal areas of the probands' arteries exhibited multifocally and irregularly increased medial collagen, disorganization of smooth muscle cells, and elastin fragmentation. Digital quantitation confirmed that fibrosis was higher in the media of proband arteries compared to those of controls. The medial fibrosis was patchy, and arterial walls exhibited both thinned and thickened areas within a given arterial segment.

The transmission pattern of multifocal fibromuscular dysplasia in family 1 reported by Richer et al. (2020) was consistent with autosomal dominant inheritance.

In 4 unrelated patients with FMDMF, Richer et al. (2020) identified heterozygosity for a missense mutation in the COL5A1 gene (G514S; 120215.0013). Ancestry analysis revealed the probands to be of central European ancestry, and all 4 shared a 160.1-kb haplotype containing G514S. The mutation, which was not found in the gnomAD database, was present in 2 affected members of family 1, with incomplete penetrance: the proband's 24-year-old daughter and 40-year-old nephew both had hyperextensible skin and hypermobile joints, and the daughter showed vascular tortuosity, but neither had experienced arterial dissection. The G514S variant was also reported in the ClinVar database in a female patient with joint pain and normal aortic dimensions on echocardiography; no other vascular imaging was pursued. The authors screened for COL5A1 variants in a cohort of 264 unrelated adult patients with multifocal fibromuscular dysplasia, 134 of whom had dissections or macroaneurysms, and 284 age- and sex-matched controls without vascular disease. Seven nonsynonymous variants that were predicted to be deleterious were identified in 7 of the patients, including the G514S variant in proband 3, who had initially been part of the cohort. Among individuals with multifocal fibromuscular dysplasia, the presence of a predicted deleterious COL5A1 variant was significantly associated with the occurrence of arterial dissections (p = 0.005), involving visceral and lower extremity arteries.