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Association Between Fetal Lymphedema and Congenital Cardiovascular Defects in Turner Syndrome

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Abstract

Turner syndrome (TS) is associated with congenital cardiovascular defects (CCVDs), most commonly bicuspid aortic valve (BAV) and aortic coarctation (COARC), congenital renal anomalies, and fetal lymphedema. It has been theorized that compressive or obstructive effects of fetal lymphedema may actually cause cardiovascular and renal dysmorphogenesis in TS. The objective of this study was to determine whether there is a specific association between a history of fetal lymphedema and CCVDs in monosomy X, or TS, independent of karyotype or general severity of the phenotype. This was a prospective study of 134 girls and women who have TS (mean age: 30 years) and were clinically evaluated for evidence of fetal lymphedema, classified as central (signified by the presence of neck webbing) or peripheral (current or perinatal, or dysplastic fingernails). The presence of BAV and/or COARC was detected by magnetic resonance imaging combined with echocardiography, and renal anomalies were determined by ultrasound. There is a strong association between developmental central lymphedema, signified by neck webbing, and the presence of BAV (chi2 = 10) and COARC (chi2 = 8). The association between webbed neck and CCVDs was independent of karyotype. There was, in contrast, no significant association between renal anomalies and webbed neck or CCVDs. The strong, statistically significant association between neck webbing and the presence of BAV and COARC in TS suggests a pathogenetic connection between fetal lymphatic obstruction and defective aortic development. The presence of neck webbing in TS should alert the clinician to the possibility of congenital cardiovascular defects.
Association Between Fetal Lymphedema and Congenital Cardiovascular Defects
in Turner Syndrome
Melissa L. Loscalzo, Phillip L. Van, Vincent B. Ho, Vladimir K. Bakalov, Douglas R.
Rosing, Carol A. Malone, Harry C. Dietz and Carolyn A. Bondy
Pediatrics 2005;115;732-735
DOI: 10.1542/peds.2004-1369
This information is current as of April 14, 2006
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/115/3/732
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Association Between Fetal Lymphedema and Congenital Cardiovascular
Defects in Turner Syndrome
Melissa L. Loscalzo, MD*; Phillip L. Van, MS‡; Vincent B. Ho, MD§; Vladimir K. Bakalov, MD‡;
Douglas R. Rosing, MDI; Carol A. Malone, PA-CI; Harry C. Dietz, MD*¶; and Carolyn A. Bondy, MD‡
ABSTRACT. Objectives. Turner syndrome (TS) is as-
sociated with congenital cardiovascular defects (CCVDs),
most commonly bicuspid aortic valve (BAV) and aortic
coarctation (COARC), congenital renal anomalies, and
fetal lymphedema. It has been theorized that compres-
sive or obstructive effects of fetal lymphedema may ac-
tually cause cardiovascular and renal dysmorphogenesis
in TS. The objective of this study was to determine
whether there is a specific association between a history
of fetal lymphedema and CCVDs in monosomy X, or TS,
independent of karyotype or general severity of the phe-
notype.
Methods. This was a prospective study of 134 girls
and women who have TS (mean age: 30 years) and were
clinically evaluated for evidence of fetal lymphedema,
classified as central (signified by the presence of neck
webbing) or peripheral (current or perinatal, or dysplas-
tic fingernails). The presence of BAV and/or COARC was
detected by magnetic resonance imaging combined with
echocardiography, and renal anomalies were determined
by ultrasound.
Results. There is a strong association between devel-
opmental central lymphedema, signified by neck web-
bing, and the presence of BAV (
X
2
= 10) and COARC (
X
2
= 8). The association between webbed neck and CCVDs
was independent of karyotype. There was, in contrast, no
significant association between renal anomalies and
webbed neck or CCVDs.
Conclusions. The strong, statistically significant associ-
ation between neck webbing and the presence of BAV and
COARC in TS suggests a pathogenetic connection between
fetal lymphatic obstruction and defective aortic develop-
ment. The presence of neck webbing in TS should alert the
clinician to the possibility of congenital cardiovascular
defects. Pediatrics 2005;115:732–735; X-chromosome, aortic
coarctation, bicuspid aortic valve, lymphedema.
ABBREVIATIONS. CCVD, congenital cardiovascular defect; BAV,
From the *McKusick-Nathans Institute of Genetic Medicine and ¶Howard
Hughes Medical Institute, Johns Hopkins University School of Medicine,
Baltimore, Maryland; ‡Developmental Endocrinology Branch, National In-
stitute of Child Health, National Institutes of Health, Bethesda, Maryland;
§Diagnostic Radiology Department, Warren G. Magnuson Clinical Center,
National Institutes of Health, and Department of Radiology, Uniformed
Services University of the Health Sciences, Bethesda, Maryland; INational
Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda,
Maryland.
Dr Loscalzo and Mr Van contributed equally to this work.
Accepted for publication Jul 26, 2004.
doi:10.1542/peds.2004-1369
No conflict of interest declared.
Reprint requests to (C.A.B.) Building 10/10N262, National Institutes of
Health, 10 Center Dr, Bethesda, MD 20892. E-mail: bondyc@mail.nih.gov
PEDIATRICS (ISSN 0031 4005). Published in the public domain by the
American Academy of Pediatrics.
bicuspid aortic valve; COARC, coarctation; TS, Turner syndrome.
C
ongenital cardiovascular defects (CCVDs), in-
cluding most commonly bicuspid aortic valve
(BAV) and coarctation of the aorta (COARC),
are well-known features of Turner syndrome (TS).
1–3
It is unknown whether these defects are attributable
to haploinsufficiency for X-chromosome gene(s) in-
volved in cardiovascular development or secondary
to other features of the syndrome, such as massive
fetal lymphedema interfering with heart and major
vessel formation. This latter possibility was sug-
gested by observations of an apparent increased
prevalence of CCVD in individuals with TS and neck
webbing
4
—the postnatal residua of nuchal cystic hy-
gromas caused by obstructed jugular lymphatics in
utero. On the basis of this observation, Clark
4
pro-
posed that jugular lymphatic obstruction led to com-
pression of the ascending aorta, resulting in reduced
flow and left-sided cardiovascular outflow tract
anomalies. This view was supported by further epi-
demiologic observations in a study of 120 infants
with neck webbing reported in the Iowa Birth De-
fects registry, among which 66% were found to have
flow-related defects.
5
This hypothesis obtained addi-
tional support from studies of 45,X embryos ascer-
tained because of cystic hygromas, with the majority
demonstrating left-sided defects, from left heart hy-
poplasia to aortic valve defects, aortic hypoplasia,
and/or coarctation.
6,7
Moreover, these studies docu-
mented the presence of dilated lymphatics in the
vicinity of the developing heart and great vessels.
The original observations associating neck web-
bing with CCVDs came from a retrospective review
of published cardiology clinic cases,
4
suggesting a
likely bias toward the most severely affected individ-
uals. Likewise, the pathologic studies certainly fo-
cused on the most severely affected fetuses, raising
the possibility that the association between CCVDs
and neck webbing simply reflects the most severe
phenotype in 45,X individuals rather than a specific
connection between these 2 phenotypic features of
X-chromosome deletion. In the present study, we
revisit the issue of association between signs of fetal
lymphedema and the presence of CCVDs in a pro-
spective study of 134 volunteers with TS, not selected
for cardiovascular disease, who underwent physical
examination and cardiovascular evaluation by MRI
and echocardiography in a tertiary clinical research
center.
732 PEDIATRICS Vol. 115 No. 3 March 2005
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METHODS
Individuals with TS were recruited for this clinical study
mainly through notices posted on Internet web sites (eg, http://
turners.nichd.nih.gov/). Study participants signed informed as-
sents/consents that were approved by the National Institute of
Child Health and Human Development Institutional Review
Board. Karyotype analysis of G-banded chromosomes in 50 lym-
phocytes was performed for all study participants. Diagnosis of TS
was based on X-monosomy or X- or Y-deletion/rearrangement
affecting 70% of cells. Participants with 30% normal cells were
excluded from the study. A total of 134 girls and women with TS
(mean age: 30; range: of 7– 60 years) were studied. Adult partici-
pants underwent MRI that included contrast-enhanced, 3-dimen-
sional MR angiography
8
; girls who were younger than 18 years
had noncontrast MRI. All participants also had 2-D echocardiog-
raphy with Doppler and renal ultrasound examination. MR im-
ages were evaluated by a single cardiovascular radiologist
(V.B.H.), and echocardiograms were evaluated by a single cardi-
ologist (D.R.R.). There was complete concordance for the 2 imag-
ing methods for diagnosis of BAV, but echo was unable to define
the aortic valve in 34 cases. MRI, however, was able to define the
valve in all but 9 of these 34 patients, so the total for evaluation of
BAV was 125. The diagnosis of COARC was by MRI or by history
of surgical COARC repair.
Each study participant underwent a full physical examination
and clinical cardiac evaluation. The presence of neck webbing was
distinguished from a simply short neck by the finding of skin folds
flaring from the lateral base of the skull to the mid- or lateral
shoulder. The findings reported on physical examination were
confirmed by review of neck photographs in anterior, lateral, and
posterior views. A few participants had a history of surgical
correction of webbing, verified by residual webbing and surgical
scars.
Associations between phenotypic features were evaluated by
X
2
analysis with Yate’s correction and forward stepwise regression in
a linear model (SigmaStat, version 2.0; SPSS Inc, Chicago, IL).
RESULTS
We found that 26 (21%) of 125 of our study par-
ticipants had a BAV, and 16 (12%) of 134 had CO-
ARC, with 9 individuals having both. Forty-seven
(35%) of 134 had a webbed neck. The association of
webbed neck and these specific CCVDs was assessed
by
X
2
analyses (Table 1). BAV was significantly asso-
ciated with neck webbing, with a P < .002. COARC
was also significantly associated with neck webbing,
as was the presence of either COARC or BAV (Table
1). Of note, the presence of COARC was highly as-
sociated with BAV (
X
2
= 15.8, P = .0001). Nine
participants had both COARC and BAV, and 5 had
COARC with a normal, tricuspid valve (1 had an
aortic valve that was not defined by MR angiography
or echocardiography).
It is often assumed that the more severe pheno-
typic features of TS may be associated simply be-
cause they are more frequently found in individuals
with a 45,X karyotype. We found a strong statistical
association between the presence of a webbed neck
and the 45,X karyotype (P < .001) and a weaker but
significant association between BAV and the 45,X
karyotype (P = .014). However, in a forward step-
wise regression in a linear model with independent
variables karyotype and webbed neck, only a
webbed neck was a significant predictor of BAV (P <
.0001). Likewise, in the same type of regression anal-
ysis, webbed neck but not karyotype was signifi-
cantly associated with COARC (P < .002). We also
investigated the relationship between CCVDs and
peripheral lymphedema, which was identified in 2
ways: by a history of perinatal peripheral lymphed-
ema and/or current peripheral lymphedema and by
the presence of dysplastic fingernails. These diag-
noses, each including 30% to 35% of study partici-
pants, were not associated with BAV, COARC, or
webbed neck.
To clarify the specificity of the association between
webbed neck and cardiovascular anomalies, we in-
vestigated the association between webbed neck and
renal anomalies. Renal anomalies, including horse-
shoe kidney, single kidney, and duplicated collecting
systems, were found in 28 (21%) of 134; 11 of these
had a webbed neck, and 17 did not (
X
2
= 0.385, P =
.65). There was no association between the presence
of BAV or COARC and renal anomalies (BAV:
X
2
=
0.24, P = .99; COARC:
X
2
= 1.8, P = .2). The presence
of renal anomaly, however, was significantly associ-
ated with the 45,X karyotype (P < .02).
The prevalence of congenital BAV or COARC by
TS karyotype is shown in Table 2. This table is pro-
vided primarily as a reference for meta-analyses to
accumulate data on genotype-phenotype correla-
tions in larger numbers of subjects, because there are
clearly too few individuals in genotype groups other
than 45,X to allow any statistically meaningful infer-
ences from this study alone. It is worth noting, how-
ever, that a relatively large percentage of 45,X/46,XY
individuals have CCVDs. Adding our data to that
previously reported, summarized by Sybert,
3
the
prevalence of CCVDs in 45,X/46,XY is 14 (50%) of 28,
substantially higher than the 30% to 40% typically
noted in 45,X. To facilitate the localization of the
CCVD locus on the X chromosome, we listed sepa-
rately individuals with virtually complete deletions
of Xp or Xq. We found BAV in 1 of 7 participants
with 46,XiXq—which, combined with the 3 of 27
reported by Sybert for a prevalence of 12%, is signif-
icantly above that of the normal population, whereas
to our knowledge, there are no reported congenital
heart defects in subjects with 46,XXq-.
TABLE 1. Association Between Webbed Neck and Cardiac Anomalies in TS
Webbed Neck Aortic Valve COARC BAV or COARC
BAV TAV Total COARC+ COARC- Total Either Neither Total
Web+ 16 28 44 11 36 47 18 26 44
Web- 10 71 81 5 82 87 15 67 82
Total 26 99 125 16 118 134 33 93 126
X
2 10.0 9.05 8.5
P .002 .003 .004
OR (95% CI) 4.1 (1.6–10.0) 5.0 (1.6–15.5) 3.3 (1.5–7.4)
OR indicates odds ratio; CI, confidence interval.
ARTICLES 733
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TABLE 2. Genotype and Congenital Cardiovascular Defects (BAV or COARC)
45X 45X/46XX* 45X/46XXp
del
46X,Xp
del
45X/46XY 46X,Xq
del
45X/46XXq
del
Total
N 83 21 14 8 5 2 2 134
No with cardiac defects 27 0 2 1 3 0 1 34
Incidence of cardiac defects, % 33 0 14 13 60 0 50 25
X* indicates a normal X, ring X, or X with partial q or p deletions.
Xp
del
-includes only the most proximal small arm deletions (<11.3) and iXq.
DISCUSSION
of low flow, and specific right-sided defects such as
The present observations in a large group of par-
persistent left superior vena cava, anomalous pulmo-
ticipants with TS not selected for cardiovascular dis-
nary venous return, and dilated right atrium as a
ease confirms a significant association between cen-
result of back-pressure from obstruction to forward
tral fetal lymphedema, signaled by neck webbing,
flow. The Clarke hypothesis seems plausible and
BAV, and COARC. We have also shown that the
does include the constellation of CCVDs most com-
association between neck webbing and CCVDs is not
monly found in TS, but after 20 years, it remains
merely a reflection of a more severe phenotype in
hypothetical, without direct proof. Although ana-
45,X individuals but is a statistically significant con-
tomic evidence shows that dilated lymphatics are
nection independent of karyotype and parental im-
observed in the vicinity of developing aorta, no cor-
printing and specific for cardiovascular but not renal
relation has been observed between the presence of
anomalies. Our study confirms the modern observa-
dilated lymphatic and aortic defects.
4,6,7
The present
tion of Mazzanti et al
2
that COARC is significantly
study provides a significant correlation between the
associated with neck webbing and extends the find-
presence of CCVDs and centralized fetal lymphed-
ing to BAV as well. This highly significant associa-
ema but obviously cannot establish cause and effect.
tion between central lymphedema during fetal de-
An alternative explanation for the association be-
velopment and CCVDs could reflect a cause and
tween neck webbing and CCVDs in TS is that hap-
effect relation between these 2 features.
loinsufficiency for an X-chromosome gene indepen-
One study suggested that defective cardiovascular
dently causes fetal lymphedema (webbed neck) and
development may be a primary feature in TS, with
congenital heart defects. Haploinsufficiency for an
impaired lymphatic development and generalized
autosomal gene (FOXC2;16q) causes widespread
hydrops as consequences.
9
This proposition seems
lymphedema and occasional cardiac defects in the
unlikely for a number of reasons. The anatomic de-
lymphedema-distichiasis syndrome,
12
but targeted
fects associated with fetal lymphedema in TS are
deletion of this gene in mice results in abnormal
decreased numbers of lymphatics and dilated lym-
aortic arch development in the absence of obvious
phatic channels that end in distended sacs, lacking
lymphedema.
13
These observations suggest that the
connections with the venous system.
4,6,10,11
The de-
heart defects and lymphedema found in the human
velopmental delay is particularly pronounced in the
disorder may be independent effects of the same
axillojugular lymphatics,
10
which drain the upper
gene. Noonan syndrome may be another instance in
half of the body. The nuchal cystic hygromas are
which lymphedema and cardiac defects occur as in-
loculated collections of lymph associated with blind-
dependent effects of the same gene mutation/dele-
ended jugular lymphatics. Central lymphatic ob-
tion. Heart defects are more common and include
struction is apparent in fetuses with TS as early as 10
predominantly right-sided lesions in Noonan syn-
to 12 weeks but resolves during the latter half of
drome compared with TS.
14
Also in contrast to TS,
gestation and is detected at birth only by the redun-
Noonan syndrome manifests few abnormal features
dant skin folds of the neck. It is difficult to imagine
during early fetal development, with cystic hygroma
how delayed or defective lymphatic development
being a rare finding and residual stigmata of fetal
could be caused by heart failure as shown in the Barr
lymphedema are less common in Noonan syn-
and Oman-Ganes study.
9
It is equally difficult to
drome.
15–17
Attempts to correlate webbed neck and
reconcile this notion with the observation of many
cardiovascular lesions in this syndrome have been
individuals who have TS with neck webbing, with or
conflicting.
5,18
A specific gene mutation that is re-
without CCVDs, but no sign of heart failure. It seems
sponsible for 50% of Noonan syndrome cases has
more likely that severe lymphatic obstruction early
only recently been identified
19
; thus, the earlier stud-
in fetal development may cause heart failure from
ies that attempted to associate CCVDs and lymphed-
compression and/or impaired filling of developing
ema may have included genetically heterogeneous
cardiovascular structures, leading to fetal hydrops
populations.
and demise, as was the case for most of the cases
The role of fetal lymphedema in the pathogenesis
examined in the Barr and Oman-Ganes study.
9
Thus,
of CCVDs in TS may be resolved when the genes that
if there were a cause-and-effect relation between fetal
are responsible for lymphedema are identified, al-
lymphedema and CCVDs in TS, then it would seem
lowing experimental studies to elucidate its function
most likely that the lymphedema is primary.
in developing lymphatic and cardiovascular sys-
Clarke
4
suggested that centrally localized dis-
tems. With this goal, a recent study has suggested
tended lymphatics compress the developing aortic
that the “critical region” for the TS lymphedema
root, resulting in specific left-sided defects, including
gene lies at Xp11.4.
20
The careful phenotypic charac-
hypoplastic left heart, BAV, and COARC as a result terization of additional patients with TS and infor-
734 CONGENITAL CARDIOVASCULAR DEFECTS IN TURNER SYNDROME
Downloaded from www.pediatrics.org at Natl Inst Of Hlth Library on April 14, 2006
mative X-chromosome deletions will further advance
this effort, aided by newly available X-chromosome
sequence information.
ACKNOWLEDGMENTS
We are grateful to Eileen Lange, RN, and the nurses of the
National Institutes of Health Clinical Center for excellent care of
our patients. We also acknowledge the important role of the
Turner Syndrome Society, USA, in publicizing the study.
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Association Between Fetal Lymphedema and Congenital Cardiovascular Defects
in Turner Syndrome
Melissa L. Loscalzo, Phillip L. Van, Vincent B. Ho, Vladimir K. Bakalov, Douglas R.
Rosing, Carol A. Malone, Harry C. Dietz and Carolyn A. Bondy
Pediatrics 2005;115;732-735
DOI: 10.1542/peds.2004-1369
This information is current as of April 14, 2006
& Services
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... A significant association between the presence of pterygium colli and cardiovascular defects in TS has been reported in several studies [88][89][90]. Cystic hygromas are malformations commonly detected in fetuses with the 45,X karyotype. These multiloculated flu-id-filled sacs are thought to arise from a failure of the lymphatic system to communicate with the venous system in the fetal neck, often progressing to hydrops fetalis. ...
... Redirection of intracardiac blood flow would lead to flow-related congenital heart diseases such as bicuspid aortic valve, coarctation of the aorta, hypoplastic left heart, patent ductus arteriosus, aortic atresia or hypoplasia, aortic valve anomalies, persistent left superior vena cava, and anomalous pulmonary venous return [88]. This hypothesis is supported by several studies [88,90,[92][93][94]. Although this association arose from retrospective studies and may reflect the most severe phenotype in 45,X individuals, suggesting a likely bias, a prospective study with a large cohort of subjects with TS not selected for cardiovascular disease confirmed this significant association independent of karyotype and parental imprinting [90]. ...
... This hypothesis is supported by several studies [88,90,[92][93][94]. Although this association arose from retrospective studies and may reflect the most severe phenotype in 45,X individuals, suggesting a likely bias, a prospective study with a large cohort of subjects with TS not selected for cardiovascular disease confirmed this significant association independent of karyotype and parental imprinting [90]. ...
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Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally abnormal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.
... A significant association between the presence of pterygium colli and cardiovascular defects in TS has been reported in several studies [88][89][90]. Cystic hygromas are malformations commonly detected in fetuses with the 45,X karyotype. These multiloculated flu-id-filled sacs are thought to arise from a failure of the lymphatic system to communicate with the venous system in the fetal neck, often progressing to hydrops fetalis. ...
... Redirection of intracardiac blood flow would lead to flow-related congenital heart diseases such as bicuspid aortic valve, coarctation of the aorta, hypoplastic left heart, patent ductus arteriosus, aortic atresia or hypoplasia, aortic valve anomalies, persistent left superior vena cava, and anomalous pulmonary venous return [88]. This hypothesis is supported by several studies [88,90,[92][93][94]. Although this association arose from retrospective studies and may reflect the most severe phenotype in 45,X individuals, suggesting a likely bias, a prospective study with a large cohort of subjects with TS not selected for cardiovascular disease confirmed this significant association independent of karyotype and parental imprinting [90]. ...
... This hypothesis is supported by several studies [88,90,[92][93][94]. Although this association arose from retrospective studies and may reflect the most severe phenotype in 45,X individuals, suggesting a likely bias, a prospective study with a large cohort of subjects with TS not selected for cardiovascular disease confirmed this significant association independent of karyotype and parental imprinting [90]. ...
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Turner syndrome (TS) is a chromosomal disorder that is caused by a missing or structurally ab-normal second sex chromosome. Subjects with TS are at an increased risk of developing intrauterine growth retardation, low birth weight, short stature, congenital heart diseases, infertility, obesity, dyslipidemia, hypertension, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases (stroke and myocardial infarction). The underlying pathogenetic mechanism of TS is unknown. The assumption that X chromosome-linked gene haploinsufficiency is associated with the TS phenotype is questioned since such genes have not been identified. Thus, other pathogenic mechanisms have been suggested to explain this phenotype. Morphogenesis encompasses a series of events that includes cell division, the production of migratory precursors and their progeny, differentiation, programmed cell death, and integration into organs and systems. The precise control of the growth and differentiation of cells is essential for normal development. The cell cycle frequency and the number of proliferating cells are essential in cell growth. 45,X cells have a failure to proliferate at a normal rate, leading to a decreased cell number in a given tissue during organogenesis. A convergence of data indicates an association between a prolonged cell cycle and the phenotypical features in Turner syndrome. This review aims to examine old and new findings concerning the relationship between a prolonged cell cycle and TS phenotype. These studies reveal a diversity of phenotypic features in TS that could be explained by reduced cell proliferation. The implications of this hypothesis for our understanding of the TS phenotype and its pathogenesis are discussed. It is not surprising that 45,X monosomy leads to cellular growth pathway dysregulation with profound deleterious effects on both embryonic and later stages of development. The prolonged cell cycle could represent the beginning of the pathogenesis of TS, leading to a series of phenotypic consequences in embryonic/fetal, neonatal, pediatric, adolescence, and adulthood life.
... Increased nuchal translucency is often present in Turner syndrome and is seen as a forerunner of webbed neck (302). Because this external feature co-segregates with congenital heart disease in Turner syndrome, a causal relation between lymph accumulation and congenital heart disease has been proposed (302)(303)(304). ...
... Increased nuchal translucency is often present in Turner syndrome and is seen as a forerunner of webbed neck (302). Because this external feature co-segregates with congenital heart disease in Turner syndrome, a causal relation between lymph accumulation and congenital heart disease has been proposed (302)(303)(304). ...
Article
Turner syndrome is a condition in females missing the second sex chromosome (45,X) or parts thereof. It is considered a rare genetic condition and is associated with a wide range of clinical stigmata, such as short stature, ovarian dysgenesis, delayed puberty and infertility, congenital malformations, endocrine disorders, including a range of autoimmune conditions and type 2 diabetes and neurocognitive deficits. Morbidity and mortality is clearly increased compared with the general population and the average age at diagnosis is quite delayed. During recent years it has become clear that a multidisciplinary approach is necessary towards the patient with Turner syndrome. A number of clinical advances has been implemented, and these are reviewed. Our understanding of the genomic architecture of Turner syndrome is advancing rapidly, and these latest developments are reviewed and discussed. Several candidate genes, genomic pathways and mechanisms, including an altered transcriptome and epigenome are also presented.
... Rights reserved. disease leading to progressive ventricular dysfunction [18]. Further studies on protective placental mechanics and compensation with preload and afterload alterations in addition to longitudinal studies following fetuses through the interstage period are warranted. ...
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To investigate the relationship between congenital heart disease and jugular lymphatic obstruction as manifested in web neck anomaly, we used the Iowa Birth Defects Registry to determine the incidence of congenital heart defects (CHD) in infants with and without web neck. Sixty percent of infants with web neck had CHD, with a high incidence of flowrelated defects such as hypoplastic left heart, coarctation, and secundum atrial septal defect. Sixty-eight percent of infants with web neck had a genetic syndrome (37% Down syndrome, 13% Ullrich-Turner syndrome, and 5% Noonan syndrome), and 24% had dysmorphic features consistent with lymphatic obstruction sequence. When infants with Down, Ullrich-Turner, and Noonan syndrome and web neck were compared to infants with the same syndrome but without web neck, those with web neck were significantly more likely to have flow-related heart defects. Infants with Ullrich-Turner syndrome and web neck had an 11-fold higher incidence of coarctation, compared to those with a normal neck. Our data suggests web neck is associated with both flow and nonflow-related heart defects. This association implies a pathogenetic relationship and appears to be independent of causal factors. The finding of web neck or nuchal cystic hygroma on a prenatal ultrasound or newborn examination should prompt a search for CHD. © Wiley-Liss, Inc.
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To investigate the relationship between congenital heart disease and jugular lymphatic obstruction as manifested in web neck anomaly, we used the Iowa Birth Defects Registry to determine the incidence of congenital heart defects (CHD) in infants with and without web neck. Sixty percent of infants with web neck had CHD, with a high incidence of flowrelated defects such as hypoplastic left heart, coarctation, and secundum atrial septal defect. Sixty-eight percent of infants with web neck had a genetic syndrome (37% Down syndrome, 13% Ullrich-Turner syndrome, and 5% Noonan syndrome), and 24% had dysmorphic features consistent with lymphatic obstruction sequence. When infants with Down, Ullrich-Turner, and Noonan syndrome and web neck were compared to infants with the same syndrome but without web neck, those with web neck were significantly more likely to have flow-related heart defects. Infants with Ullrich-Turner syndrome and web neck had an 11-fold higher incidence of coarctation, compared to those with a normal neck. Our data suggests web neck is associated with both flow and nonflow-related heart defects. This association implies a pathogenetic relationship and appears to be independent of causal factors. The finding of web neck or nuchal cystic hygroma on a prenatal ultrasound or newborn examination should prompt a search for CHD. © Wiley-Liss, Inc.