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

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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

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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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