Article

Bilateral semilunar valve disease in a child with partial deletion of the Williams-Beuren syndrome region is associated with elastin haploinsufficiency

University of Nevada, Las Vegas, Las Vegas, Nevada, United States
The Journal of heart valve disease (Impact Factor: 0.75). 06/2006; 15(3):352-5.
Source: PubMed
ABSTRACT
Elastin is an extracellular matrix protein that is the primary component of elastic fibers, and is expressed in the great vessels as well as the semilunar and atrioventricular valves. Elastin haploinsufficiency, resulting from mutation or deletion of the elastin gene, is an important clinical problem that is typically characterized by arteriopathy. Herein is described a patient with elastin haploinsufficiency due to partial deletion of the Williams-Beuren syndrome region, resulting in bilateral semilunar valve disease and arteriopathy. Histochemical analysis of the aortic valve revealed decreased and disorganized elastin with loss of the normal trilaminar cusp organization. These findings suggest that elastin has a role in the pathogenesis of semilunar valve disease.

Full-text

Available from: Colleen A Morris, Sep 04, 2014
Bilateral Semilunar Valve Disease in a Child with Partial
Deletion of the Williams-Beuren Syndrome Region is
Associated with Elastin Haploinsufficiency
Robert B. Hinton, Jr.
1
, Gail H. Deutsch
2
, Jeffrey M. Pearl
3
, Holly H. Hobart
4
, Colleen A. Morris
4
,
D. Woodrow Benson
1
Divisions of
1
Cardiology,
2
Pathology and
3
Cardiothoracic Surgery, Cincinnati Children’s Hospital, Cincinnati, Ohio,
4
Division of Human Genetics, University of Nevada School of Medicine, Las Vegas, Nevada, USA
Elastin is an extracellular matrix (ECM) protein that
maintains structural integrity in many vertebrate tis-
sues including large arteries, lung, skin, tendon, and
cartilage. Mutation or deletion of the elastin gene
results in elastin haploinsufficiency, which has been
established as the cause of autosomal dominant
supravalvar aortic stenosis (SVAS; MIM 185500) and
Williams-Beuren syndrome (WBS; MIM 194050) (1-3),
as well as partial deletion of the WBS region (4). The
cardiovascular manifestations of elastin haploinsuffi-
ciency are often referred to as arteriopathy, and typi-
cally include supravalvar aortic stenosis, branch
pulmonary artery hypoplasia, coronary artery ostial
stenosis, and coarctation of the aorta. Elastin is a pri-
mary component of both the semilunar and atrioven-
tricular valves (5,6). Moreover, valve defects including
bicuspid aortic valve, aortic stenosis, pulmonary
stenosis and mitral valve prolapse have been identified
in 10-20% of cases (7,8).
Herein is described an infant with elastin haploin-
sufficiency due to partial deletion of the WBS region
who had bilateral semilunar valve disease and arteri-
opathy. Histochemical analysis of the explanted aortic
valve revealed decreased and disorganized elastin
with loss of the normal layered ECM organization.
Case report
Neonatal echocardiography of a baby girl to evaluate
cyanosis identified supravalvar aortic stenosis, branch
pulmonary artery hypoplasia, coronary artery ostial
stenosis and coarctation of the aorta. In addition, both
the aortic and pulmonary valves were dysplastic and
stenotic (Fig. 1). The family history revealed five other
affected individuals (Fig. 2).
Balloon valvuloplasty was performed on the first
day of life for critical pulmonary stenosis. The patient
underwent surgical aortic valvuloplasty at the age of
four months, and a homograft root replacement with
annulus enlargement at age ten months. The Ross pro-
cedure was contraindicated due to the pulmonary
valve anatomy. Operative findings included a diffuse-
ly dysplastic and thickened aortic valve. At the time of
aortic root replacement, aortic valve tissue was
obtained; histochemical analysis revealed reduced
elastin expression and disorganized ECM proteins (9)
(Fig. 3). Fluorescent in-situ hybridization analyses
identified an 800-kb deletion on the long arm of chro-
mosome 7 that included the elastin gene (4).
This study was approved by the Cincinnati
Children’s Hospital Institutional Review Board.
Discussion
Histochemical analysis of the aortic valve in a pedi-
atric patient with elastin haploinsufficiency demon-
strated decreased elastin and disorganization of the
Address for correspondence:
D. Woodrow Benson MD, PhD, Division of Cardiology, ML 7042,
Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue,
Cincinnati, Ohio 45229-3039, USA
e-mail: Woody.Benson@cchmc.org
© Copyright by ICR Publishers 2006
Elastin is an extracellular matrix protein that is the
primary component of elastic fibers, and is expressed
in the great vessels as well as the semilunar and
atrioventricular valves. Elastin haploinsufficiency,
resulting from mutation or deletion of the elastin
gene, is an important clinical problem that is typical-
ly characterized by arteriopathy. Herein is described
a patient with elastin haploinsufficiency due to par-
tial deletion of the Williams-Beuren syndrome
region, resulting in bilateral semilunar valve disease
and arteriopathy. Histochemical analysis of the aortic
valve revealed decreased and disorganized elastin
with loss of the normal trilaminar cusp organization.
These findings suggest that elastin has a role in the
pathogenesis of semilunar valve disease.
The Journal of Heart Valve Disease 2006;15:352-355
Page 1
ECM proteins; to the present authors’ knowledge, this
is the first such report. These findings identify a role
for elastin haploinsufficiency in the pathogenesis of
semilunar valve disease. Elastin haploinsufficiency
causes arteriopathy, which has been characterized
most notably as supravalvar aortic stenosis; less com-
mon manifestations include isolated aortic, mitral and
pulmonary valve disease. Bilateral semilunar valve
disease has been reported infrequently in the context
of polyvalvular disease (10,11), a condition character-
ized by marked valvar dysplasia with or without dys-
function, usually in patients with Trisomy 18 (10,12).
Although approximately one-third of polyvalvular
disease cases involve all four valves, the majority
involve only two or three valves (11-13). In case series
reporting polyvalvular disease in patients with no
known genetic syndrome, there were no cases of bilat-
eral semilunar valve disease, which suggests that this
entity might be distinct from polyvalvular disease.
During cardiac morphogenesis, semilunar valve and
great artery development is closely coordinated, and
elastin is highly expressed in these structures as well as
the atrioventricular valves (14). In the great arteries,
elastin has been shown to function as both a structural
protein and a signaling molecule (15), but the function
of elastin in valves has not been clearly defined.
Findings by these authors suggested that elastin has a
signaling role in addition to a structural role in the
development and maintenance of semilunar valves.
Mice homozygous for a null mutation of the elastin
gene (absent gene product) demonstrated arterial
obstruction reminiscent of SVAS (16). Mice heterozy-
gous for the null mutation (deletion of one copy of the
elastin gene) demonstrate decreased elastin content
(15) and alterations in the autocrine regulation of
smooth muscle cells (17) that result in systemic hyper-
tension (18). The valve phenotype of these mice has
not been characterized. In the human valve studied
herein, elastin haploinsufficiency would be expected to
result in decreased elastin, though the presence of frag-
mented elastin would suggest that additional mecha-
nisms may be contributing to pathogenesis.
While valve disease is an important clinical problem,
its genetic basis and pathogenesis remain largely
unknown. ECM proteins - including elastin - play a
central role in both valve architecture and develop-
mental signaling pathways. Human genetic and devel-
opmental studies should provide a better
understanding of the regulatory mechanisms control-
ling semilunar and atrioventricular valve develop-
ment, and promise to facilitate advances in valve
disease therapy.
Acknowledgements
These studies were supported in part by grants from
the National Institute of Neurological Disorders and
Stroke NS-35102 (C.A.M. and H.H.H.), and National
Institutes of Health HD43005 (R.B.H.), HL69712 and
HL74728 (D.W.B.).
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Valve disease and elastin
R. B. Hinton et al.
353
J Heart Valve Dis
Vol. 15. No. 3
May 2006
Figure 1: Parasternal short axis two-dimensional
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and tricuspid valves were normal (not shown). Arrows
indicate the valve cusps. LA: Left atrium; MPA: Main
pulmonary artery; RA: Right atrium; RV: Right ventricle.
Page 2
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Valve disease and elastin
R. B. Hinton et al.
J Heart Valve Dis
Vol. 15. No. 3
May 2006
Figure 2: Pedigree analysis was consistent with autosomal dominant inheritance. All affected individuals have supravalvar
aortic stenosis (SVAS), two have complex congenital heart disease (CHD) (IV-2, IV-3), and at least three have the WBS
cognitive profile (WSCP) (II-2, III-2, III-6), a common neurologic manifestation of WBS that would not be expected in SVAS.
A partial deletion of the WBS region was previously reported in extended family members (6). Circles indicate females;
squares indicate males; black boxes represent affected individuals.
Page 3
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Valve disease and elastin
R. B. Hinton et al.
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J Heart Valve Dis
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Figure 3: Cross-section of the aortic valve cusp using
Movat’s pentachrome stain in a 14-month-old child who
died from non-cardiac causes (A; original magnification
×20) and the proband with elastin haploinsufficiency and
bilateral semilunar valve disease at 10 months of age (B,
original magnification ×10 and C, original magnification
×20). In all panels, the arterial aspect of the cusp is
oriented upward; scale bar = 1 µm. Panel A illustrates
normal overlapping trilaminar organization with radially
oriented elastic fibers (black) and longitudinally oriented
collagen and proteoglycan. Panel B shows that the diseased
valve is thick, and trilaminar organization is lost.
Specifically, the elastin content is decreased and the elastic
fibers are fragmented (C). The pentachrome stain identifies
elastin as black, nuclei as purple, collagen as yellow,
proteoglycan as light blue, and myocardium as red. Of
note, collagen and proteoglycan in close proximity appear
teal green.
Page 4
  • Source
    • "Heart valves facilitate unidirectional blood flow during the cardiac cycle and this is largely achieved by highly organized layers of connective tissue that each offer distinct biomechanical properties to facilitate opening and closing of the valve leaflets or cusps [1], [2]. In healthy valves, connective tissue homeostasis is mediated by valve interstitial cells (VICs), which in turn are regulated by a monolayer of valve endothelial cells (VECs) that overly the valve surface. "
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    • "he interstitial cells . Disruptions in the developmental pro - cesses that lead to normal valve histomorphology and the dysfunction of the two major valve cell types have been shown to be responsible for a series of valve pathological conditions ( Rabkin et al . 2002 ; Leask et al . 2003 ; Armstrong & Bischoff 2004 ; Rabkin - Aikawa et al . 2004 ; Hinton et al . 2006 ) . As melanocyte precursors reach the heart during the early stages of valve development and per - sist into adulthood ( Brito & Kos 2008 ) , it is reasonable to expect that their dysfunction might lead to valve abnorm - alities . Deficits associated with the proper specification , differentiation and migration of neural crest cells an"
    [Show abstract] [Hide abstract] ABSTRACT: Pigmentation of murine cardiac tricuspid valve leaflet is associated with melanocyte concentration, which affects its stiffness. Owing to its biological and viscoelastic nature, estimation of the in situ stiffness measurement becomes a challenging task. Therefore, quasi-static and nanodynamic mechanical analysis of the leaflets of the mouse tricuspid valve is performed in the current work. The mechanical properties along the leaflet vary with the degree of pigmentation. Pigmented regions of the valve leaflet that contain melanocytes displayed higher storage modulus (7-10 GPa) than non-pigmented areas (2.5-4 GPa). These results suggest that the presence of melanocytes affects the viscoelastic properties of the mouse atrioventricular valves and are important for their proper functioning in the organism.
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    [Show abstract] [Hide abstract] ABSTRACT: Heart valve disease is an important cause of morbidity and mortality worldwide. Little is known about valve disease pathogenesis, but increasing evidence implicates a genetic basis for valve disease, suggesting a developmental origin. Although the cellular and molecular processes involved in early valvulogenesis have been well described, less is known about the regulation of valve extracellular matrix (ECM) organization and valvular interstitial cell (VIC) distribution that characterize the mature valve structure. Histochemistry, immunohistochemistry, and electron microscopy were used to examine ECM organization, VIC distribution, and cell proliferation during late valvulogenesis in chicken and mouse. In mature valves, ECM organization is conserved across species, and developmental studies demonstrate that ECM stratification begins during late embryonic cusp remodeling and continues into postnatal life. Cell proliferation decreases concomitant with ECM stratification and VIC compartmentalization. Explanted, stenotic bicuspid aortic valves (BAVs) from pediatric patients were also examined. The diseased valves exhibited disruption of the highly organized ECM and VIC distribution seen in normal valves. Cusps from diseased valves were thickened with increased and disorganized collagens and proteoglycans, decreased and fragmented elastic fibers, and cellular disarray without calcification or cell proliferation. Taken together, these studies show that normal valve development is characterized by spatiotemporal coordination of ECM organization and VIC compartmentalization and that these developmental processes are disrupted in pediatric patients with diseased BAVs.
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