Publication Type:

Journal Article


Orphanet Journal of Rare Diseases, Volume 7, Number 1 (2012)



Aortic Aneurysm, artery dilatation, artery disease, article, blood vessel rupture, clinical article, computed tomographic angiography, computer assisted tomography, consanguinity, cutis laxa, diet supplementation, digoxin, diuretic agent, Elastic Tissue, ethnography, exon, Extracellular Matrix Proteins, female, fetus echography, fibulin, fibulin 4, follow up, furosemide, gene mutation, heterozygosity, histopathology, homozygosity, human, Humans, hypertelorism, infant, lethal arteriopathy syndrome, losartan, male, micrognathia, molecular genetics, neonatal respiratory distress syndrome, newborn, nuclear magnetic resonance imaging, phenotype, physiotherapy, propranolol, pulse wave, respiratory care, thorax radiography, unclassified drug, Vascular Diseases


Background: 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. Methods. 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. Results: 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 (≤4 months). Conclusions: 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. © 2012 Kappanayil et al; licensee BioMed Central Ltd.


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Cite this Research Publication

Mai Kappanayil, Nampoothiri, Sb, Kannan, Rc, Renard, Md, Coucke, Pd, Malfait, Fd, Menon, Se, Ravindran, H. Kf, Kurup, Rg, Faiyaz-Ul-Haque, Mh, Kumar, Ka, and De Paepe, Ad, “Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis”, Orphanet Journal of Rare Diseases, vol. 7, 2012.