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.
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.
authors.affiliation: Departments of Pediatric Cardiology, Amrita Institute of Medical Sciences and Research Centre, Kochi, India. maheshpeds@yahoo.co.in
authors.forename: Mahesh
authors.initials: M
authors.lastname: Kappanayil
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kannan
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Renard
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.forename: Swapna
authors.initials: S
authors.lastname: Menon
authors.forename: Hiran K
authors.initials: HK
authors.lastname: Ravindran
authors.forename: Renu
authors.initials: R
authors.lastname: Kurup
authors.forename: Muhammad
authors.initials: M
authors.lastname: Faiyaz-Ul-Haque
authors.forename: Krishna
authors.initials: K
authors.lastname: Kumar
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
mesh_terms: D001014:Aortic Aneurysm / Q000175:diagnosis / Q000235:genetics; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D014652:Vascular Diseases / Q000235:genetics* / Q000473:pathology
chemical_list: C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins