Post on 06-Jul-2016
Case report
Anaesthetic implications of LEOPARD syndrome
JAVIER TORRES M DM D, PIERANTONIO RUSSO M DM D AND
JOSEPH D. TOBIAS M DM D
The Departments of Child Health, Anesthesiology and Cardiothoracic Surgery, The Division ofPediatric Critical Care/Pediatric Anesthesiology, The University of Missouri, Columbia, MO,USA
SummaryLEOPARD syndrome is a neuroectodermal disorder presumed to
result from an abnormality in neural crest cells. The acronym
‘LEOPARD’ is derived from the clinical features which include
multiple lentigines, electrocardiographic abnormalities, ocular hyper-
telorism, pulmonary stenosis, abnormal genitalia, retarded growth,
and deafness. Given the multisystem nature of the disease process,
several issues may affect the perioperative care of these patients. Of
primary importance are associated conditions of the cardiovascular
system including congenital heart disease, conduction disturbances,
and progressive hypertrophic obstructive cardiomyopathy. The
authors present a 4-year old boy who presented for anaesthetic care
for repair of a ventricular septal defect and pulmonary valvotomy for
congenital pulmonary stenosis. The potential perioperative implica-
tions of LEOPARD syndrome are discussed.
Keywords: LEOPARD syndrome; congenital heart disease; cardio-
myopathy; lentigines: craniofacial abnormality; anaesthesia
Introduction
LEOPARD syndrome, also known as Moynahan
syndrome, is classified as a cardiocutaneous syn-
drome of neural crest origin (1). The acronym ‘LEO-
PARD’ coined by Gorlin et al. in the 1960s is derived
from the clinical features which include multiple
lentigines, electrocardiographic abnormalities, ocular
hypertelorism, pulmonary stenosis, abnormal geni-
talia, retarded growth and deafness (2). The disorder
is transmitted as an autosomal dominant trait with
high penetrance and significant variation in clinical
expression. Several potential theories have been
proposed to explain the pathogenesis of the syn-
drome. The unifying feature of these theories is an
abnormality of neural crest cell. The cells derived
from the neural crest form spinal and autonomic
ganglion cells, Schwann cells of peripheral nerves, as
well as sympathetic terminations in the cardiac
ventricles. Neural crest cells also give rise to melano-
cytes thereby explaining the associated lentigines.
Patients with LEOPARD syndrome most fre-
quently present for evaluation and treatment of
their cardiac disease which may include rhythm
disturbances, congenital structural lesions, or a
Correspondence to: Joseph D. Tobias, Vice-Chairman, Departmentof Anesthesiology, Director, Pediatric Critical Care/PediatricAnesthesiology, Professor of Anesthesiology and Child Health,Department of Anesthesiology, The University of Missouri,3W40H, One Hospital Drive, Columbia, MO 65212, USA(email: Tobiasj@health.missouri.edu).
Pediatric Anesthesia 2004 14: 352–356
352 � 2004 Blackwell Publishing Ltd
hypertrophic obstructive cardiomyopathy (HOCM).
Given the multisystem involvement of the disorder,
several perioperative implications may exist. We
present a 6-year old boy with LEOPARD syndrome
who required cardiopulmonary bypass (CPB) for
closure of a ventricular septal defect (VSD) and
pulmonary valvotomy. The anaesthetic implications
of the disorder are reviewed.
Case report
The patient was a 4-year old, 17 kg boy who
presented for closure of a VSD and pulmonary
valvotomy. His past medical history was positive for
a diagnosis of LEOPARD syndrome made at
18 months of age based on the findings of congenital
heart disease, abnormal external genitalia (bilateral
cryptorchidism), hypertelorism, short stature, deaf-
ness, and multiple lentigines. His past history was
positive for one previous surgical procedure (bilat-
eral orchiopexy/herniorrhaphy) during general
anaesthesia without complications. Previous renal
ultrasonography had demonstrated normal anatomy
of the kidneys and collecting systems. Speech and
fine motor skills were delayed. The patient was on
no medication.
Physical examination revealed a cooperative
4-year old with the previously mentioned lentigines,
ocular hypertelorism, and short stature. The airway
was a Mallampati class II. Cardiac auscultation
revealed a grade III/VI holosystolic murmur. Car-
diac catheterization demonstrated the VSD, a gradi-
ent of 60–70 mmHg across the pulmonary valve, and
normal ventricular function. Preoperative electro-
cardiogram revealed a first degree AV block with a
prolonged PR interval. Preoperative laboratory eval-
uation revealed a haemoglobin of 12.6 gÆdl)1, haem-
atocrit 38.4% and a platelet count of 264 · 109 ll)1.
Coagulation parameters, electrolytes, blood urea
nitrogen and creatinine were within normal limits.
The patient was fasted for 6 h and transported
to the operating room after oral premedication
with midazolam (0.7 mgÆkg)1) in acetaminophen
(15 mgÆkg)1). Routine monitors were placed and
inhalation induction accomplished with increasing
concentrations of sevoflurane in 100% oxygen.
Following induction, two peripheral intravenous
cannulas were placed and tracheal intubation faci-
litated with cis-atracurium (0.2 mgÆkg)1). An arterial
cannula was placed in the left radial artery. Tem-
perature was monitored from both a nasopharyngeal
and urinary catheter probe. Maintenance anaesthesia
consisted of our usual practice including fentanyl
(10–12 lgÆkg)1) administered over the first 10–
15 min of the case, desflurane (inspired concentra-
tion adjusted according to need) in a 50% oxygen/
air mixture, and intermittent doses of cis-atracurium
administered according to train-of-four monitoring.
Intravenous fluids consisted of lactated Ringer’s and
blood glucose was monitored every 60–90 min
throughout the procedure. Anticoagulation was
provided with heparin (initial dose of 300 unitsÆkg)1)
with incremental doses to maintain the activated
clotting time above 400 s. Following the initiation of
CPB, the surgical procedure consisted of patch
closure of the VSD and pulmonary valvotomy. Total
CPB time was 98 min with an aortic cross-clamp
time of 48 min. The patient was weaned from CPB
without difficulty. Postoperatively, the gradient
across the pulmonary valve was measured directly
to be 8–10 mmHg. Following CPB, residual heparin
effect was reversed with protamine. At the comple-
tion of the surgical procedure, residual neuromus-
cular blockade was reversed with neostigmine and
glycopyrrolate. After return of protective airway
reflexes, demonstration of adequate spontaneous
ventilation, and purposeful movements, the
patient’s trachea was extubated. The patient was
transported with supplemental oxygen to the Pedi-
atric Intensive Care Unit. The remainder of the
postoperative course was uncomplicated and the
patient was discharged home on postoperative day 4.
Discussion
Given the multisystem involvement of LEOPARD
syndrome, several issues may be of concern during
the perioperative period. The problem that most
frequently requires medical care of these patients
relates to various patterns of cardiac involvement.
These may include electrocardiographic abnormal-
ities with rhythm disturbances, congenital structural
defects, or alterations in myocardial function. Var-
ious electrocardiogram (ECG) abnormalities have
been reported in LEOPARD syndrome (Table 1)
(3–10). In many cases, these problems are benign and
relatively asymptomatic including nonspecific find-
ings such as left axis deviation, the most commonly
LEOPARD SYNDROME 353
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noted ECG finding, which is present in approxi-
mately 30% of patients. However, several reports
document more problematic conduction or rhythm
disturbances including complete heart block, ven-
tricular conduction delays, incomplete bundle
branch block, prolonged P–R and QRS intervals,
bradycardia, paroxysmal atrial fibrillation or ven-
tricular fibrillation with sudden death (9,10). The
latter has been reported in patients who develop a
HOCM in association with the syndrome (see
below). Given these issues, we would suggest
preoperative ECG testing in all patients, use of a
five lead ECG intraoperatively, consideration for
postoperative monitoring in patients with preexist-
ing conduction or rhythm abnormalities, and the
ready availability of transcutaneous pacing capabil-
ities in patients with significant conduction defects.
An additional theoretical concern relates to the
administration of anaesthetic agents (droperidol,
sevoflurane) or other medications which may affect
repolarization and thereby prolong the QT interval
in patients with preexisting QT prolongation or
abnormalities of ventricular repolarization.
As demonstrated by our patient, congenital and
acquired structural cardiac defects may also occur in
association with LEOPARD syndrome. Valvular or
infundibular pulmonary stenosis represents the
most commonly noted structural lesion, occurring
in up to 40% of patients (11,12). Outflow tract
obstruction of the right or left ventricle may be
related to congenital structural defects or may be a
consequence of a HOCM that has more recently been
recognized as a significant associated disorder in
this group of patients. HOCM may progress with
age or present later in life than the other clinical
findings. It frequently involves the septum which
may lead to obstruction of either the left or right
ventricular outflow tracts. HOCM may be associated
with ECG changes and arrhythmias with the poten-
tial for ventricular fibrillation and sudden death (10).
It represents the major cause of early mortality in
this population of patients.
In addition to HOCM, left atrial myxomas have
been reported in association with LEOPARD syn-
drome (13–15). Although the association was first
reported in 1973 (15), there remains some contro-
versy as to whether the myxomas are actually a
clinical manifestation of LEOPARD syndrome or if
their presence suggests a separate disorder which
shares similar phenotypic expression (lentigines)
with LEOPARD syndrome (16,17). Carney’s com-
plex is a unique autosomal dominantly transmitted
multisystem disorder characterized by myxomas
(heart, skin and breast), spotty skin pigmentation
(lentigines and blue naevi), endocrine tumours
(adrenal, testicular, thyroid and pituitary), and
peripheral nerve tumours (Schwannomas). The most
prevalent manifestation is spotty skin pigmentation,
followed by skin and cardiac myxomas, Cushing
syndrome and acromegaly. As Carney’s complex
shares cutaneous and cardiac manifestations with
LEOPARD syndrome, separation of the two disor-
ders may be difficult.
Given the potential perioperative morbidity asso-
ciated with either congenital structural defects or
acquired lesions (HOCM and left atrial myxomas),
preoperative echocardiography is suggested even in
the presence of a normal clinical examination.
Patients with structural defects require antibiotic
prophylaxis during ‘at risk’ procedures to prevent
bacterial endocarditis (18). The latter is particularly
relevant because of the high incidence of dental
abnormalities in LEOPARD syndrome and the
resultant potential need for repeated dental proce-
dures (see below).
Several other organ systems may be affected in
LEOPARD syndrome. Significant impairment and
associated malformations of the central nervous
system (CNS) have been identified including
mental retardation in 30% of patients, sensorineu-
ral hearing loss in 25% of patients, and an
abnormal electroencephalogram in 15% of patients
(12). As melanocytes, which are derived from
neural crest cells, participate in the formation of
the inner ear; the associated sensorineural deafness
is another feature suggestive of a neural crest
Table 1
Electrocardiographic abnormalites in Leopard syndrome
Left axis deviationProlonged PR interval or complete heart blockVentricular conduction delays or incomplete bundle branch blockRight, left, or biventricular enlargementInfarction patternsIschaemic patterns with nonspecific S-T and T wave changesIsolated ventricular ectopic beatsVentricular fibrillationBradycardiaParoxsysmal atrial fibrillation
354 J . TORRES ET AL .
� 2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 352–356
origin for the syndrome. Other occasionally repor-
ted CNS associations include seizures, nystagmus,
brain atrophy, Arnold–Chiari malformation and
agenesis of the corpus callosum (19,20). As these
latter conditions are rare, their association with
LEOPARD syndrome remains to be definitively
demonstrated; however, it has been suggested that
CNS imaging be performed in all patients with
LEOPARD syndrome (19,20).
Previously reported skeletal and craniofacial
anomalies include ocular hypertelorism, pectus
excavatum, pectus carinatum, scoliosis, fusion of
the cervical spine, and several orofacial/dental
issues. These latter associated problems may poten-
tially impact on airway management and include
mandibular prognathism, micrognathia, and abnor-
malities of dentition including supernumerary teeth,
delayed dentition plus defective formation of pri-
mary and permanent teeth (21,22). Although there
are limited data regarding anaesthetic care in
patients with LEOPARD syndrome with only one
previous report in the literature (23) to date, there
are no definite problems reported regarding airway
management or difficulties with tracheal intubation.
Likewise, there are limited data to suggest abnor-
malities of respiratory function. As previously
mentioned, skeletal abnormalities may include
scoliosis which may impact on respiratory function
with the development of restrictive lung disease
with chronic hypoxaemia leading to right sided
heart failure with pulmonary hypertension (24).
Robain et al. reported a second patient with LEO-
PARD syndrome who died of respiratory failure;
however, they attributed the aetiology of the chro-
nic lung disease to an interstitial pneumonitis from
flecainide therapy (25).
A high prevalence of genitourinary abnormalities
has been reported especially in male patients. GU
abnormalities include cryptorchidism (as demon-
strated by our patient), hypospadias, as well as
abnormalities of the kidneys and collecting systems.
Patients with a history of symptoms related to the
GU system should be considered for preoperative
renal function testing (blood urea nitrogen and
serum creatinine) or imaging (ultrasonography) to
delineate the extent of GU involvement. A minority
of patients with LEOPARD syndrome may also have
endocrine involvement including short stature,
delayed puberty and hypothyroidism.
Voron et al. have suggested the following diag-
nostic criteria (12). If the patient has multiple
lentigines, two of the following features must also
be present: cardiac abnormalities, ECG abnormalit-
ies, endocrine abnormalities, neurological deficits
including deafness, characteristic craniofacial dys-
morphism, short stature or skeletal abnormalities. If
lentigines are absent, features from three of the
above categories must be present plus an immediate
relative with LEOPARD syndrome.
In summary, we report the perioperative manage-
ment of a patient with LEOPARD syndrome. Of
primary importance is the high incidence of associ-
ated disorders of the cardiovascular system inclu-
ding congenital heart diseases, conduction
disturbances, and HOCM. Additionally, previously
undiagnosed patients may present for anaesthesia.
The preoperative evaluation of a patient with mul-
tiple cutaneous lentigines should suggest the possi-
bility of LEOPARD syndrome.
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Accepted 4 June 2003
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� 2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 352–356