Vascular elasticity is crucial for maintaining hemodynamics. Molecular
mechanisms involved in human elastogenesis are incompletely understood. We
describe a syndrome of lethal arteriopathy associated with a novel,
identical mutation in the fibulin 4 gene (FBLN4) in a unique cohort
of infants from South India.
Clinical characteristics, cardiovascular findings, outcomes and molecular
genetics of twenty-two infants from a distinct population subgroup,
presenting with characteristic arterial dilatation and tortuosity during the
period August 2004 to June 2011 were studied.
Patients (11 males, 11 females) presented at median age of 1.5 months,
belonging to unrelated families from identical ethno-geographical
background; eight had a history of consanguinity. Cardiovascular features
included aneurysmal dilatation, elongation, tortuosity and narrowing of the
aorta, pulmonary artery and their branches. The phenotype included a
variable combination of cutis laxa (52%), long philtrum-thin vermillion
(90%), micrognathia (43%), hypertelorism (57%), prominent eyes (43%),
sagging cheeks (43%), long slender digits (48%), and visible arterial
pulsations (38%). Genetic studies revealed an identical
c.608A > C (p. Asp203Ala) mutation in exon 7 of the FBLN4
gene in all 22 patients, homozygous in 21, and compound heterozygous in one
patient with a p. Arg227Cys mutation in the same conserved cbEGF sequence.
Homozygosity was lethal (17/21 died, median age 4 months). Isthmic
hypoplasia (n = 9) correlated with early death
A lethal, genetic disorder characterized by severe deformation of elastic
arteries, was linked to novel mutations in the FBLN4 gene. While describing
a hitherto unreported syndrome in this population subgroup, this study
emphasizes the critical role of fibulin-4 in human elastogenesis.