Advanced search
1 file | 5.82 MB Add to list

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

Author
Organization
Abstract
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.
Keywords
Cardiovascular imaging, Founder effect, Mappila muslims, Vascular elasticity, Genetic vasculopathy, Aortic aneurysm, Arterial tortuosity, Fibulin-4 mutation, Lethal mutation, Connective tissue disorder, Abnormal elastogenesis, Malabar, ARTERIAL-TORTUOSITY-SYNDROME, CUTIS-LAXA, ELASTIC FIBER, CARDIOVASCULAR MANIFESTATIONS, PHENOTYPIC FEATURES, AORTIC-VALVE, FAMILY, PULMONARY, ANEURYSM, HOMOZYGOSITY

Downloads

  • Kappanayil et al 2012.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 5.82 MB

Citation

Please use this url to cite or link to this publication:

MLA
Kappanayil, Mahesh, Sheela Nampoothiri, Rajesh Kannan, et al. “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 7 (2012): n. pag. Print.
APA
Kappanayil, M., Nampoothiri, S., Kannan, R., Renard, M., Coucke, P., Malfait, F., Menon, S., et al. (2012). 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, 7.
Chicago author-date
Kappanayil, Mahesh, Sheela Nampoothiri, Rajesh Kannan, Marjolijn Renard, Paul Coucke, Fransiska Malfait, Swapna Menon, et al. 2012. “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 7.
Chicago author-date (all authors)
Kappanayil, Mahesh, Sheela Nampoothiri, Rajesh Kannan, Marjolijn Renard, Paul Coucke, Fransiska Malfait, Swapna Menon, Hiran K Ravindran, Renu Kurup, Muhammad Faiyaz-Ul-Haque, Krishna Kumar, and Anne De Paepe. 2012. “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 7.
Vancouver
1.
Kappanayil M, Nampoothiri S, Kannan R, Renard M, Coucke P, Malfait F, et al. 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. 2012;7.
IEEE
[1]
M. Kappanayil et al., “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.
@article{3101580,
  abstract     = {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.},
  articleno    = {61},
  author       = {Kappanayil, Mahesh and Nampoothiri, Sheela and Kannan, Rajesh and Renard, Marjolijn and Coucke, Paul and Malfait, Fransiska and Menon, Swapna and Ravindran, Hiran K and Kurup, Renu and Faiyaz-Ul-Haque, Muhammad and Kumar, Krishna and De Paepe, Anne},
  issn         = {1750-1172},
  journal      = {ORPHANET JOURNAL OF RARE DISEASES},
  keywords     = {Cardiovascular imaging,Founder effect,Mappila muslims,Vascular elasticity,Genetic vasculopathy,Aortic aneurysm,Arterial tortuosity,Fibulin-4 mutation,Lethal mutation,Connective tissue disorder,Abnormal elastogenesis,Malabar,ARTERIAL-TORTUOSITY-SYNDROME,CUTIS-LAXA,ELASTIC FIBER,CARDIOVASCULAR MANIFESTATIONS,PHENOTYPIC FEATURES,AORTIC-VALVE,FAMILY,PULMONARY,ANEURYSM,HOMOZYGOSITY},
  language     = {eng},
  pages        = {14},
  title        = {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},
  url          = {http://dx.doi.org/10.1186/1750-1172-7-61},
  volume       = {7},
  year         = {2012},
}

Altmetric
View in Altmetric
Web of Science
Times cited: