Hypoplastic Left Heart Syndrome 1st Edition
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Dedication
This book is dedicated to the patients with hypoplastic left heart
syndrome, their courageous parents, and their supportive
families and friends.
TABLE OF CONTENTS
List of Contributors ............................................................................ ix
Foreword ............................................................................................. xi
Chapters
1 Epidemiology and Genetics ................................... .., ................ 1
Elizabeth Goldmuntz, MD.
2 Fetal Development and Prenatal Evaluation .......................... 9
Meryl S. Cohen, M.D.
3 Delivery and Obstetrical Issues ........................................... 29
Samuel Parry, MD. and Sara J. Marder, MD.
4 Echocardiographic Imaging ................................................... 39
Jack Rychik, MD.
5 Pre-Operative Management ................................................. 69
Sarah Tabbutt MD., Ph.D. and Gil Wernovsky MD.
6 Stage I Reconstruction .......................................................... 89
Thomas L. Spray, MD.
7 Stage I Postoperative Management ................................... 105
Gil Wernovsky, MD, DoffB. McElhinney, MD,
and Sarah Tabbutt MD, PhD
8 The Bidirectional Cavopulmonary Shunt ............................ 129
Tom R. Karl, MS., MD.
9 The Fontan Operation and Modifications .......................... 149
J. William Gaynor, MD.
10 Anesthetic Management for HLHS .................................... 167
James M Steven, MD., and Susan C. Nicolson, MD.
11 Cardiac Catheterization ....................................................... 193
Jacqueline Kreutzer, MD., and Jonathan J. Rome, MD.
12 Nursing Care ........................................................................ 229
Rhonda Foltz, R.N. and Kathryn M Dodds R.N., MS.N., c.P.N.P.
13 Infant Heart 1ransplantation .............................................. 241
Timothy M Hoffman, MD., and Thomas L. Spray, MD.
viii Hypoplastic Left Heart Syndrome
14 NeurologicaJ Issues ............................................................. 251
Robert Ryan Clancy, MD.
15 Feeding Issues and Somatic Growth ................................... 273
Mitchell 1. Cohen MD
16 Cardiac Structure and Function .......................................... 289
William Mahle, MD
17 Arrhythmias After Surgery ................................................. 307
Ronn E. Tanel, MD. and Larry A. Rhodes, MD.
18 Exercise Physiology and Capacity ...................................... 329
Steven Paridon, MD.
19 Complications After the Fontan .......................................... 347
Jack Rychik, MD.
20 Decision Analysis Strategies .................................. .., .......... 361
Bernard J. ClarkIIL M.D.
21 What the Pediatrician Needs to Know ................................ 379
Marie M Gleason, MD.
22 The Personal Perspective ................. 00 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
Stephen Klein, Anna Jaworski, and Kristen Aversa
23 Financial Implications ................. u ....................................... 407
William J. Greeley, MD., MB.A.
Epilogue .................................................................................................... 417
Index ..................................................... 8 ••••••••••••••••••••• 0 ••••••••••••••••••••• 419
Editors
Jack Rychik, M.D., Associate Professor, Department of Pediatrics, University of
Pennsylvania School of Medicine; Director, Non-Invasive Cardiovascular
Laboratories and the Fetal Heart Program, Division of Cardiology, The
Children's Hospital of Philadelphia.
[email protected] Gil Wernovsky, M.D., Associate Professor, Department of Pediatrics, University
of Pennsylvania School of Medicine; Staff Cardiologist, Cardiac Intensive
Care Unit; Director of Program Developement, The Cardiac Center, The
Children's Hospital of Philadelphia.
[email protected]Contributors
Kristen Aversa, M.D.
Robert Ryan Clancy, M.D., Professor, Department of Pediatrics, University of
Pennsylvania School of Medicine; Division of Neurology, The Children's
Hospital of Philadelphia
Bernard J. Clark III, M.D., Associate Professor, Department of Pediatrics,
University of Pennsylvania School of Medicine; Division of Cardiology, The
Children's Hospital of Philadelphia
Meryl S. Cohen, M.D., Assistant Professor, Department of Pediatrics, University
of Pennsylvania School of Medicine; Division of Cardiology, The Children's
Hospital of Philadelphia
Mitchell I. Cohen M.D., Associate Cardiologist, Arizona Pediatric Cardiology
Consultants
Kathryn M. Dodds R.N., M.S.N., C.P.N.P., Pediatric Nurse Practitioner, Cardiac
Intensive Care Unit, Children's Hospital of Philadelphia
Rhonda Foltz, R.N., Pediatric Nurse Practitioner, Cardiac Intensive Care Unit,
Children's Hospital of Philadelphia
J. William Gaynor, M.D., Associate Professor of Surgery, University of
Pennsylvania School of Medicine; Division of Cardiothoracic Surgery,
Children's Hospital of Philadelphia
Marie M. Gleason, M.D., Assistant Professor, Department of Pediatrics, University
of Pennsylvania School of Medicine; Division of Cardiology, The Children's
Hospital of Philadelphia
Elizabeth Goldmuntz, M.D., Assistant Professor, Department of Pediatrics,
University of Pennsylvania School of Medicine; Division of Cardiology, The
Children's Hospital of Philadelphia
William J. Greeley, M.D., M.B.A., John J. Downes Professor, Departments of
Anesthesiology and Pediatrics, University of Pennsylvania School of
Medicine; Chairman, Department of Anesthesia, Children's Hospital of
Philadelphia
x Hypoplastic Left Heart Syndrome
Timothy M. Hoffman, M.D., Assistant Professor of Pediatrics, The Ohio State
University College of Medicine; Medical Director, Heart Transplant Program,
Columbus Children's Hospital
Anna Jaworski
Tom R. Karl, M.S., M.D., Professor of Surgery, University of California-San
Francisco School of Medicine; Chief of Pediatric Cardiothoracic Surgery,
Children's Hospital of the University of California San Francisco
Stephen Klein
Jacqueline Kreutzer, M.D., Assistant Professor, Department of Pediatrics,
University of Pennsylvania School of Medicine; Division of Cardiology, The
Children's Hospital of Philadelphia
William Mahle, M.D., Sibley Heart Center, Children's Healthcare of Atlanta
Sara J. Marder, M.D., Assistant Professor, Obstetrics and Gynecology, Division
of Maternal-Fetal Medicine, Washington University Medical Center
Doff B. McElhinney, MD, Fellow in Cardiology, Boston Children's Hospital
Susan C. Nicolson, M.D., Professor, Departments of Anesthesiology and Pediatrics,
University of Pennsylvania School of Medicine; Chair, Division of Cardiac
Anesthesia, Children's Hospital of Philadelphia
Steven Paridon, M.D., Associate Professor, Department of Pediatrics, University
of Pennsylvania School of Medicine; Division of Cardiology, The Children's
Hospital of Philadelphia
Samuel Parry, M.D., Assistant Professor, Division of Maternal-Fetal Medicine,
Department of Obstetrics and Gynecology, Hospital of the University of
Pennsylvania
Larry A. Rhodes, M.D., Associate Professor, Department of Pediatrics, University
of Pennsylvania School of Medicine; Division of Cardiology, The Children's
Hospital of Philadelphia
Jonathan J. Rome, M.D., Assistant Professor, Department of Pediatrics, University
of Pennsylvania School of Medicine; Division of Cardiology, The Children's
Hospital of Philadelphia
Thomas L. Spray, M.D., Professor of Surgery, University of Pennsylvania School
of Medicine; Chief, Division of Cardiothoracic Surgery, Children's Hospital of
Philadelphia
James M. Steven, M.D., Professor, Departments of Anesthesiology and Pediatrics,
University of Pennsylvania School of Medicine; Chair, Division of Cardiac
Anesthesia, Children's Hospital of Philadelphia
Sarah Tabbutt M.D., Ph.D., Assistant Professor, Department of Pediatrics,
University of Pennsylvania School of Medicine; Divisions of Cardiology and
Critical Care Medicine, The Children's Hospital of Philadelphia
Ronn E. Tanel, M.D., Assistant Professor, Department of Pediatrics, University of
Pennsylvania School of Medicine; Division of Cardiology, The Children's
Hospital of Philadelphia
FOREWORD
Despite approximately 50 years of progress in the management of com-
plex congenital heart disease, hypoplastic left heart syndrome (HLHS) has
been one of the last cardiac malformations to yield to effective surgical treat-
ment. The surgical therapies for hypoplastic left heart syndrome have evolved
by two quite disparate routes. One approach has been the staged reconstruc-
tion operations utilizing an initial operation pioneered by many but developed by
Dr. William Norwood and subsequently modified by many other investigators.
The first stage reconstruction operation has been refined and standardized such
that the majority of infants now proceed to second and third stage reconstruc-
tive operations culminating in a Pontan Kreutzer single ventricle physiology.
An alternative surgical approach has been the development of neonatal and
infant heart transplantation for HLHS. This approach also has had a signifi-
cant impact on the treatment of HLHS and other cardiac malformations and
has been associated with good intermediate term results. Both of the thera-
peutic approaches devised for treatment of hypoplastic left heart syndrome
have been effective and the outcomes are continuing to improve with each.
The present monograph summarizes our current level of knowledge of treat-
ment of HLHS and its variants based largely on the extensive experience at
The Children's Hospital of Philadelphia in over 1,000 consecutive infants with
this form of complex congenital heart disease. The knowledge gained from
experience with this large number of patients and the contributions from many
other centers have created a large body of new information on the anatomy,
diagnosis, management and longterm follow-up of children with HLHS. Nev-
ertheless, the rapid recent improvements in outcome in children with HLHS
has meant that the majority of survivors are only now reaching their early
childhood years, so that additional developmental and neurologic testing can
now begin. In addition, the oldest patients with staged reconstruction are now
entering their teenage years and early adulthood and the effects on longterm
function can only now begin to be evaluated. Certainly, as these children con-
tinue to grow we will learn more about potential late complications and their
management.
xii Hypoplastic Left Heart Syndrome
Although resources that have been committed to treatment of HLHS have
been extensive over the past two decades, the impact of these resources on
total health care expenditures has been relatively small compared to the great
effect on the development of successful therapy for HLHS and on the surgical
reconstructive techniques, critical care, and cardiologic management of many
other forms of congenital heart disease. Continued challenges in management
will occur as more children survive into young adulthood and onward. As in
other areas of progress, new unforeseen problems will certainly arise which
will continue to challenge medical and surgical knowledge and skills.
The current success with surgical repair for children with HLHS could not
have occurred without the dedication and persistence of countless medical,
surgical, and nursing teams, but most of all, without the hope, compassion and
support of the parents.
Thomas L. Spray, M.D.
Chief, Division of Cardiothoracic Surgery,
Executive Director, The Cardiac Center
The Children 50 Hospital of Philadelphia
Alice Langdon Warner Professor of Surgery
University of Pennsylvania School of Medicine
Acknowledgements
Although there are countless physicians, nurses, and allied professionals who
have contributed to the advances in the treatment of hypoplastic left heart
syndrome, we wish to acknowledge the insight, perseverance and inestimable
contributions of the following pediatric cardiovascular surgeons - Leonard Bailey,
Marc de Leval, Francis Fontan, Guillermo Kreutzer, William Glenn, and William
Norwood - and pediatric cardiologists Peter Lang and John Murphy.
We would like to express our gratitude to all the authors who contributed to this
book. Each produced a clear synthesis of their research and clinical experience of
HLHS, and on editing the chapters we realized how fortunate we were to find
ourselves among such a dedicated group of contributors and colleagues.
This text was completed thanks to the hard work and enthusiasm of David Reese,
who spent many hours editing and formatting 24 distinct chapters into this final
version. This project would have been impossible without him.
- J.R. and G. W.
I would like to thank my mentors and colleagues, the cardiologists, surgeons and
staff at The Children's Hospital of Philadelphia. These exceptional people have
demonstrated to me that through hard work, logic, and compassion, one can
make a major difference in the lives of children with heart disease. I would espe-
cially like to thank Bill Norwood, Marshall Jacobs, John Murphy and Alvin Chin
who contributed heavily to my thinking about complex heart disease. In addition,
I would like to thank my parents Hana and Harry Rychik, who taught me the
importance of self-sacrifice and education in life. Lastly, I would like to thank my
wife Susan, and my children Jordana, Leora, and Tali for providing me with the
daily support and encouragement I need to do the things I do. Without them,
nothing would get done.
- J.R.
I would first like to thank three pediatric cardiologists who have been role models
as compassionate physicians, investigators and teachers: Peter Lang, Jane
Newburger, and David Wessel. I would also like to thank Dr. Aldo R. Castaneda,
who, in addition to his brilliance as a cardiovascular surgeon, taught me the value
of a collaberative approach to patient care among medicine, surgery, and nursing.
I would especially like to thank my wife Lauren, and my children Simon and
Jenna for their continued support and encouragement through the rigors of
academic pediatric cardiology. Finally, I would like to dedicate this book to the
memory of my parents, Louis and Janet, who, with great foresight, would not let
me become a musician .. ,
- G.w.
Chapterl
THE EPIDEMIOLOGY AND GENETICS OF
HYPOPLASTIC LEFT HEART SYNDROME
Elizabeth Goldmuntz, M.D.
Division of Cardiology, The Children's Hospital of Philadelphia
Hypoplastic left heart syndrome (HLHS) is a common major congenital
malformation, but very little is known about its etiology. Some hypothesize and
animal models indicate that diminished blood flow through the left side of the
fetal heart results in retarded growth and consequent hypoplasia of the left-
sided structures (see Chapter 2 for further discussion). However, the primary
mechanisms that cause this diminution of flow, whether they are structural or
functional alterations, have not been defined and are likely to be heteroge-
neous. Epidemiologic studies point to a genetic component in the etiology of
HLHS, as do reports offamilies with multiple affected members and its consis-
tent association with specific genetic syndromes. These studies also demon-
strate that, in some cases, HLHS is likely to represent a continuum of disease
with other left-sided lesions ofthe heart including coarctation of the aorta and
aortic valve stenosis. However, it has been particularly difficult to identify the
genetic etiology of HLHS given the rarity of large families with multiple af-
fected members for which a linkage analysis could be performed to identify a
chromosomal disease locus. In addition, very few candidate genes from animal
models have been identified that could be tested as disease-related in humans.
In the following sections, the epidemiology of HLHS and the current under-
standing of its genetic etiology will be reviewed.
EPIDEMIOLOGY
Perhaps the best data on the epidemiology of CHD comes from the Balti-
more-Washington Infant Study (BWIS), a prospective, case-control study de-
signed to identify intrinsic and extrinsic risk factors for CHD. The strength of
this investigation stems from its design as a population-based study with com-
plete ascertainment of affected cases, consistency of pathologic classification,
and use of echocardiography to identify and define anatomy accurately. How-
ever, even this study's results may have been affected by the advent of fetal
echo cardiography and the possible termination of abnormal pregnancies. The
2 Hypoplastic Left Heart Syndrome
BWIS found a prevalence of4.9 cases ofCHD per 1,000 livebirths overall, and
1.8 cases ofHLHS per 10,000 livebirths in particular [21 J. Thus, in this study,
HLHS is the eighth most common cardiac defect accounting for 3.8% of all
CHD.
Of interest, the BWIS and other studies have consistently found that males
are more frequently affected with HLHS than females [9J. However, the preva-
lence ofHLHS does not appear to vary by race. Non-cardiac anomalies have
been identified in 12-37% of HLHS cases in clinical and autopsy series, and
will be discussed further below [18J.
The BWIS is the largest study that systematically attempted to identify en-
vironmental exposures that might contribute to the etiology of HLHS. They
found an association with maternal diabetes, paternal exposure to general an-
esthesia six months prior to surgery, and exposure to various solvents by univariate
analysis [9J. The association with maternal diabetes became insignificant by
multivariate analysis. Thus, few if any environmental exposures have been
identified as risk factors for HLHS.
ETIOLOGY: EVIDENCE FOR A GENETIC
COMPONENT
Reports of unique families: an inherited disorder
Athough HLHS is often considered a sporadic disease, many investigators
have reported unique families with multiple affected members with left-sided
cardiac defects, some of whom have HLHS. These reports are consistent with
variable modes of inheritance including autosomal dominant, autosomal reces-
sive and multifactorial or polygenic inheritance. In addition, they demonstrate
that left-sided cardiac defects most likely share common genetic etiologies. For
example, Menahem reported one family whose father had mild aortic valve
stenosis and whose three offspring had aortic valve stenosis, HLHS and coarc-
tation respectively [16]. This family history is consistent with an autosomal
dominant mode of inheritance. Shokeir reported five unrelated families with
unaffected parents each with more than one child with HLHS, consistent with
autosomal recessive inheritance [25]. Consanguinity was demonstrated in three
of the families. Finally, Van Egmond and colleagues reported two siblings and
one cousin with HLHS consistent with multifactorial inheritance [27J. These
reports and others provide evidence for an inherited, genetic contribution to the
etiology ofHLHS.
Further evidence that HLHS could be an inherited disorder with a genetic
etiology comes from a study by Brenner and colleagues [4]. They evaluated
first degree relatives of children with HLHS in 14 families for the presence of
a bicuspid aortic valve (BAV) using echocardiograms. Cardiac abnormalities
EPIDEMIOLOGY AND GENETICS 3
were not found in the first-degree relatives of three HLHS patients who also
had extracardiac abnormalities. In contrast, 5 of 41 (12.2%) first degree rela-
tives of 11 probands with isolated HLHS, including 4 parents and one sibling,
were found to have a BAV. The proportion of relatives with a BAV in this study
is far greater than that in the general population (1-2%). None of the parents
were aware that they had a heart defect prior to the study. These findings
support the hypothesis that, in some cases, HLHS is the result of an inherited
trait and that it is only one lesion in the spectrum of related left-sided cardiac
defects.
Risk of recurrence
Several studies have estimated the risk of recurrence for HLHS, or the risk
that a family would have a second child with CHD having had one child with
HLHS. Nora and Nora initially calculated a recurrence risk of 2.2% if there
was only one affected sibling and suggested a recurrence risk of 6% if there
were two affected siblings [20]. However, the BWIS calculated the precurrence
rate for HLHS, or the rate with which first-degree relatives had CHD in those
families with one affected child. They found a precurrence rate of 13.5% (5/38
siblings of cases with HLHS had CHD), which was higher than that for other
groups of CHD [2]. In addition, they found a high concordance rate among
affected relatives, meaning that left-sided lesions clustered together within fami-
lies. The high precurrence rate and the high concordance of lesions within a
family support the hypothesis that there is a genetic component to the develop-
ment ofHLHS in particular, and left-sided lesions in general.
Non-cardiac associations
Many extra-cardiac abnormalities, both chromosomal and structural organ
defects, have been reported in association with HLHS. Approximately 11-37%
of HLHS patients have been found to have non-cardiac anomalies [18]. The
wide range of affected patients most likely reflects the investigative method.
Some of the studies were based on clinical findings alone while others were
based on complete autopsies where the detection rate of anomalies is expected
to be higher. In particular, the BWIS found that 15% (24/162) had non-cardiac
anomalies based on clinical observations [9]. Natowicz and colleagues, in a
review of complete autopsies, found that 28% (23/83) ofHLHS subjects had
non-cardiac anomalies (Table 1) [18].
Chromosome abnormalities
A wide array of chromosomal abnormalities has been reported in patients
with HLHS, though several appear to be specifically associated. The most
4 Hypoplastic Left Heart Syndrome
Table 1. Non-cardiac anomalies
Category BWIS (%) Natowicz (%)
Chromosome abnormalities 5.6 11
Syndromes 4.9
Mendelian 2.5 5
Non-Mendelian 2.5
Multiple, non-classified 0.6 12
Single organ defec1s 3.7
No associated abnormalities 85.2 72
Table 2. Common chromosomal abnormalities/syndromes
Syndrome BWIS (#) (n=162) Natowicz (#) (n=83)
Turner (XO) 3 3
Trisomy 18 2 3
Trisomy 13 2 1
Trisomy21 1 1
other del1q del2q
common chromosomal defects and syndromes, as identified by N atowicz et al.
(1988) and the BWIS, are listed in Table 2 [9, 18].
Turner's syndrome (or the Ullrich-Turner syndrome) is caused by complete
or partial monosomy ofthe X chromosome (45,X) and is clinically character-
ized by dysmorphic facial features, webbed neck, neonatal lymphedema, CHD,
short stature and amenorrhea. The clinical features are highly variable, may
not be apparent in the neonate, and may only be diagnosed in the adolescent
female presenting with short stature and/or amenorrhea. CHD occurs in 20-
50% of cases with Turner's syndrome and most commonly includes coarcta-
tion of the aorta and/or bicuspid aortic valve [11,26]. However, more recent
reports have identified the association of HLHS with Turner's syndrome as
well. Recent reports have identified several cases of Turner's syndrome in
large series of patients examined with HLHS [19]. It may be that in the past
patients with HLHS and Turner's syndrome were not identified given the uni-
form mortality ofHLHS in the neonatal period and the variable presentation of
Turner's syndrome. However, with the relatively recent improvement in sur-
vival of infants with HLHS, the diagnosis of Turner's syndrome may now be
more readily recognized and thus appear more frequent now than in earlier
series.
The association of Turner's syndrome and left-sided lesions is of particular
interest given the proposed mechanism of disease. Clarl<: first reported that the
incidence ofCHD was significantly higher in patients with Turner's syndrome
who had a web neck as compared to those with a normal neck (30%. versus
9%) [5]. In addition, 25% ofthose with Turner's syndrome and a coarctation of
the aorta had a web neck as compared to 3% with a normal neck. Clark went
on to hypothesize that "increased lymphatic pressure associated with jugular
EPIDEMIOLOGY AND GENETICS 5
lymphatic sac obstruction distended the thoracic ducts, which compress the
ascending aorta altering intracardiac flow." Presumably, the re-direction of flow
then results in maldevelopment of the left-sided structures.
Additional studies have supported Clark's findings and hypothesis. In par-
ticular, Lacro and colleagues found left-sided lesions in 9/12 fetuses with Turner's
syndrome and nuchal cystic hygromas [14]. Berdahl and colleagues also found
a high incidence of CHD in patients with a web neck and different genetic
syndromes [1]. Of interest, though patients with Turner's syndrome predomi-
nantly had coarctation of the aorta and BAV, patients with a web neck and
different genetic syndrome had other types of CHD as well. Thus, patients
with Down syndrome and a web neck did not have left-sided cardiac defects
but those defects (common atrioventricular canal defect, secundum ASD, VSD,
and tetralogy ofF allot) commonly associated with Trisomy 21. These findings
imply either that the mechanism and consequence of the web neck varies be-
tween different genetic syndromes, or that the specific chromosomal alteration
in conjunction with the cystic hygroma dictates the pattern ofCHD observed in
thatsyndrome. These findings support the hypothesis that the etiology ofHLHS
is genetic given its association with a specific chromosomal abnormality.
HLHS has also been a feature of the three most common chromosomal
trisomy syndromes (Table 2). A multitude of other rare chromosomal alter-
ations have been reported in patients with HLHS including chromosome 22q 11
mosaic deletion [6], 12p duplication [23], partial trisomy 9 [24], and t(8,11)
(p211;p1.53) [22]. Several patients with Jacobsen syndrome have been diag-
nosed with HLHS and l1q deletions. Jacobsen syndrome is characterized by
mental retardation, microcephaly, carp mouth, trigonocephaly, depressed nasal
bridge, high vaulted or cleft palate, and CHD. The association of HLHS and
11q deletions suggests that a gene(s) for HLHS maps to this region. Investiga-
tions are underway to examine this region for disease-related genes [13].
Mendelian and non-Mendelian syndromes, non-classified organ
defects
The Online Mendelian Inheritance in Man identifies 34 entries when searching
for syndromes associated with HLHS. Thus, HLHS has been reported in nu-
merous Mendelian and non-Mendelian syndromes. The most common include
Smith-Lemli-Opitz and Holt Oram syndromes, and the VACTERL association
[9, 18]. Several infants of diabetic mothers have been reported [18]. Additional
non-classified organ system malformations reported in (l:onjunction with HLHS
include the musculoskeletal, genitourinary, renal and central nervous systems
[12]. Thus, HLHS is frequently associated with other organ system malforma-
tions.
6 Hypoplastic Left Heart Syndrome
CONCLUSIONS
Hypoplastic left heart syndrome is a common severe cardiac malformation
accounting for nearly 4% of all CHD; its etiology is nonetheless poorly under-
stood. Reports of unique families indicate that HLHS is part of a spectrum of
left-sided cardiac defects and that there is a genetic contribution to the malde-
velopment of the left-sided structures. Further evidence for a genetic compo-
nent comes from the consistent association of HLHS with specific chromo-
somal alterations such as monosomy X or 11 q deletions. Family studies provide
evidence for multiple modes of inheritance, and the association of different
genetic syndromes supports the hypothesis that the etiology is heterogeneous,
even if the final common pathway is disruption of blood flow through the left
side of the fetal heart.
Given that large families with sufficient numbers of affected members for a
parametric linkage analysis have not been identified, alternative methods will
need to be used to identify specific genetic causes. Studies of syndromes with
consistent chromosomal alterations, such as monosomy X or 11 q deletions, may
identify disease genes. In addition, genetically engineered model systems such
as mice or zebrafish are increasingly identifying genes that are critical to car-
diovascular development. These discoveries not only identify genes that may
be disease-related to human defects but also elucidate developmental path-
ways that may be interrupted to cause human disease. It is highly likely that
some of the genes identified in the animal models and subsequently studied in
the human for mutations or allelic association by non-parametric linkage analy-
ses will prove to be disease-related. These investigations will slowly begin to
unravel the heterogeneous etiology ofHLHS, and in the future help the clini-
cian understand or predict clinical outcome.
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