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. 2012 Sep 3:7:61.
doi: 10.1186/1750-1172-7-61.

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

Mahesh Kappanayil  1 , Sheela Nampoothiri, Rajesh Kannan, Marjolijn Renard, Paul Coucke, Fransiska Malfait, Swapna Menon, Hiran K Ravindran, Renu Kurup, Muhammad Faiyaz-Ul-Haque, Krishna Kumar, Anne De Paepe
Affiliations

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

Mahesh Kappanayil et al. Orphanet J Rare Dis. .

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.

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Figures

Figure 1
Figure 1
Clinical features and histopathology.A : Typical facial features – long philtrum thin upper lip, prominent eyes, broad forehead, sagging cheeks and lateral part of upper eyelids. B : Cutis laxa with redundant axillary skin folds (arrows). C : Chest roentgenogram (Antero-posterior view) – aortic enlargement evident as mediastinal widening. Dilated descending aortic shadow seen in right hemithorax just above the level of the diaphragm. D : Echocardiogram showing dilated descending thoracic aorta (AoDt) compressing upon the left heart structures (LA – left atrium, LV – left ventricle). [Figures  1A-1D belong to Proband 5]. E and   F : Orcein-stained skin biopsies from an age-matched control and proband 10 respectively, showing the abundant, dark stained elastic fibers in the control and severely deficient and fragmented elastic fibers in patient.
Figure 2
Figure 2
Cardiovascular imaging.A- F : 64-slice cardiac CT images showing characteristic aneurysmal enlargement and tortuosity of aorta and arch branches. Note the narrow aortic isthmus (*) ( A, C, D, E), abdominal aortic stenosis ( D- F). AoAs – Ascending Aorta, AoDt- Descending Thoracic Aorta, AoAb – Abdominal Aorta.
Figure 3
Figure 3
Natural history and outcomes.Ai and Aii : Serial 64-slice CT scans done in Proband 4 after an interval of 11 months showing progressive enlargement and tortuosity of descending aorta. Bi and Bii : Graphs showing the increase in the absolute dimensions and the respective Z-scores, of Ascending Aorta, Aortic Root and Main Pulmonary Artery in serial 64-slice CT scans in Proband 4 (at interval of 11 months) and Proband 5 (at interval of 6 months). C: Kaplan Meier Survival Graph for the homozygous mutant patients. D : Scatter diagram for the entire cohort, showing the ages at death. Currently surviving probands are encircled.
Figure 4
Figure 4
Sequence alignment of fibulin-4 and location of mutations.A: Multiple sequence alignment of fibulin-4 protein sequence from (1) Homo sapiens, (2) Pan troglodytes*, (3) Canis lupus familiaris*, (4) Bos taurus, (5) Mus musculus, (6) Danio rerio ; sequences from species marked * were computationally predicted. cbEGF4 sequence is enclosed in the rectangular box. Substitutions within the domain are encircled. Arrow marks the position of aspartate 203 in human fibulin-4. Conservation of amino acid identity of this aspartate across species and its sequence position at start of the cbEGF4 domain, indicates its functional significance. All patients had identical missense mutation at this crucial position. B : Schematic representation of domains, based on Swiss-Prot annotation [Swiss-Prot:O95967]. The types of domain are listed on the left. Amino acid position in fibulin 4 sequence is noted at start and end positions of the protein, the atypical cbEGF domain and the region containing 5 tandem cbEGF domains. Mutations listed on the right are found in human disease with the exception of I259V*. The D203A mutation (bold) is the one found in all patients in our cohort. Mutations shown in italics occurred in compound heterozygotes. References are shown in brackets.
Figure 5
Figure 5
Map of India. Political map of India showing the state of Kerala (panel inset) and the Malabar region (encircled). Source : Wikimedia.
See this image and copyright information in PMC

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