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

Autor: Paul Coucke, Marjolijn Renard, Sheela Nampoothiri, Mahesh Kappanayil, Renu P. Kurup, Krishna Kumar, Hiran K Ravindran, Muhammad Faiyaz-Ul-Haque, Fransiska Malfait, Swapna Menon, Anne De Paepe, Rajesh Kannan
Jazyk: angličtina
Předmět:
Male
Pathology
Fibulin-4 mutation
ELASTIC FIBER
Compound heterozygosity
PULMONARY
Malabar
Medicine and Health Sciences
Genetics(clinical)
Pharmacology (medical)
HOMOZYGOSITY
Mappila muslims
Hypertelorism
Genetics (clinical)
PHENOTYPIC FEATURES
Medicine(all)
Extracellular Matrix Proteins
Aortic aneurysm
ARTERIAL-TORTUOSITY-SYNDROME
Genetic disorder
General Medicine
Anatomy
Founder effect
Hypoplasia
FAMILY
CARDIOVASCULAR MANIFESTATIONS
Genetic vasculopathy
Female
medicine.symptom
Arterial tortuosity
Lethal mutation
Arterial tortuosity syndrome
medicine.medical_specialty
Consanguinity
Biology
ANEURYSM
medicine
Humans
Vascular Diseases
AORTIC-VALVE
Research
Vascular elasticity
Abnormal elastogenesis
Infant
Newborn
Infant
medicine.disease
Elastic Tissue
Connective tissue disorder
Fibulin
Cardiovascular imaging
CUTIS-LAXA
Cutis laxa
Zdroj: Orphanet Journal of Rare Diseases
ORPHANET JOURNAL OF RARE DISEASES
ISSN: 1750-1172
DOI: 10.1186/1750-1172-7-61
Popis: 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 (
Databáze: OpenAIRE
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