Fibromuscular Dysplasia
Description
Fibromuscular dysplasia (FMDA) is a nonatherosclerotic, noninflammatory arterial disease that most commonly involves the renal and carotid arteries. The prevalence of symptomatic renal artery FMDA is about 4 in 1,000 and the prevalence of cervicocranial FMDA is about half of that. Histologic classification includes 3 main subtypes, intimal, medial, and perimedial, which may be associated in a single patient. Angiographic classification includes the multifocal type, with multiple stenoses and the 'string of beads' appearance that is related to medial FMDA, and tubular and focal types, which are not clearly related to specific histologic lesions (summary by Plouin et al., 2007)
Clinical FeaturesMettinger and Ericson (1982) reported observations on a genetic basis in relation to fibromuscular dysplasia leading to stroke.
Among cases of fibromuscular dysplasia of arteries, particularly familial cases, von Recklinghausen neurofibromatosis (162200) should be suspected as an occasional 'cause' (Kousseff and Gilbert-Barness, 1989).
Gatalica et al. (1992) described the case of a previously healthy 18-year-old black man with generalized fibromuscular dysplasia who developed dissection of the aorta beginning in the ascending aorta and extending into the abdominal aorta where complete occlusion below the origin of the renal arteries was found. The aneurysm had ruptured into the retroperitoneal space in the region of the right kidney. Tromp et al. (1993) demonstrated a point mutation in the gene for type III collagen (120180.0018) in this patient, who was later found to have Ehlers-Danlos syndrome type IV (130050). Fibromuscular dysplasia of arteries has also been observed in cutis laxa (219100).
Safioleas et al. (2001) described the association of hypertrophic cardiomyopathy (see CMH1, 192600) and fibromuscular dysplasia of the superior mesenteric artery causing ischemic colitis. The patient was a 33-year-old man in whom cardiomyopathy had been diagnosed by echocardiography 3 years previously, after his father, who died suddenly, was found at autopsy to have had that disorder. He was asymptomatic but did have left ventricular hypertrophy on electrocardiography. Hospital admission was for diffuse abdominal pain with signs of peritoneal irritation. On exploratory laparotomy, gangrene of the small bowel, about 50 cm proximal to the ileocecal valve, was found. The pathologic specimen showed dysplasia of the superior mesenteric artery. Digital subtraction angiography of the celiac and mesenteric arteries showed a 'chain of beads' appearance typical of fibromuscular dysplasia. Safioleas et al. (2001) suggested that there may be a connection between hypertrophic cardiomyopathy and fibromuscular dysplasia of arteries since both have severe disorganization of the muscle fibers. Furthermore, they found a report of another case of the association (Moncure and Rashid, 1995).
InheritanceEarly reports documented fibromuscular dysplasia in sibs but often did not examine earlier generations (Wood and Borges, 1963; Hansen et al., 1965; Halpern et al., 1965; Major et al., 1977).
The first formal analysis of the genetics of the disorder was that of Rushton (1980), who studied the families of 20 probands. In 8 families only the proband was affected. In the other 12 families, between 1 and 11 other relatives were thought to have been affected. Vertical transmission was demonstrated repeatedly, suggesting autosomal dominant inheritance in contrast to the individual reports in sibs. Unfortunately, histologic proof of fibromuscular dysplasia was apparently lacking in all the familial cases; the diagnosis was based on hypertension, stroke, claudication and myocardial infarction occurring at an early age. Eight of the 12 probands in the familial cases were female; of affected relatives, 24 were female and 20 male. In 1 family, 2 sisters had documented fibromuscular dysplasia. Fibromuscular hyperplasia of the renal arteries leading to hypertension occurs almost only in females, manifesting itself in early adulthood as a rule.
Gladstien et al. (1980) concluded that the family data are consistent with autosomal dominant inheritance with variable and often no clinical effect.
Molecular GeneticsAssociations Pending Confirmation
Guo et al. (2017) demonstrated that biallelic mutations in the YY1AP1 gene (607860) cause Grange syndrome (602531), a disorder that encompasses features of fibromuscular dysplasia. Analysis of exome sequencing data from 282 individuals with FMDA and renal, carotid, and mesenteric artery disease as well as 286 age-, gender-, and race/ethnicity-matched controls showed no increased burden of YY1AP1 variants in the FMDA-affected case subjects, although 1 sporadic patient with FMDA involving the renal and extracranial carotid arteries was found to be heterozygous for a frameshift mutation in the YY1AP1 gene. Noting that the mother of 3 sibs with Grange syndrome who was heterozygous for a nonsense mutation in YY1AP1 (607860.0001) had refractory hypertension due to left renal artery stenosis, Guo et al. (2017) suggested that heterozygous loss-of-function YY1AP1 mutations might be associated with susceptibility to FMDA in the general population.