The heart in neurofibromatosis type 1:

An echocardiographic study
Michele Adolfo Tedesco, MD, PhD,a Giovanni Di Salvo, MD,a Francesco Natale, MD,a Valeria Pergola, MD,a
Elvira Calabrese, MD,b Carolina Grassia, MD,b Gennaro Ratti, MD, PhD,a Diana Iarussi, MD,a
Aldo Iacono, MD, FESC,a Raffaele Calabrò, MD,a and Giuliana Lama, MDb Naples, Italy

Background Comprehensive data are unavailable for cardiac abnormalities in patients with neurofibromatosis type
1 (NF1). The goal of this study was to evaluate the prevalence of cardiovascular abnormalities with echocardiography
with color Doppler scan (ECHO) in a large, consecutive series of patients with NF1.
Methods We studied 48 patients with NF1 (mean age, 10 years). Thirty healthy subjects comparable for age and
sex served as the control group. All ECHO studies were performed by the same cardiologist and reviewed by a second
cardiologist blinded to the physical findings of the subjects.
Results Cardiac abnormalities were found in 13 of the 48 young patients (27%). A secundum atrial septal defect with
a left to right shunt was found in 2 children. ECHO evidence of mild left pulmonary artery stenosis was found in 1 partici-
pant. A moderate coarctation of the thoracic aorta was found in 1 patient. ECHO criteria for mitral valve prolapse and
evidence of trivial mitral regurgitation with myxomatous mitral valve was present in 1 case. Mild mitral regurgitation was
found in 2 patients. A regurgitant mild flow signal was detected from the aortic valve in 2 subjects. Atrial septal aneurysm
was found in 2 patients without patent foramen ovale. Two patients had septal to posterior left ventricular free wall ratio
greater than 1.5, suggesting hypertrophic cardiomyopathy.
Conclusion This is the first attempt to evaluate the prevalence of cardiovascular abnormalities in patients with NF1
with ECHO. The study’s most striking finding is the high prevalence of cardiovascular abnormalities. Congenital lesions
have potential long-term hemodynamic consequences that justify an early diagnosis. Thus, a cardiologic assessment at
regular intervals, including ECHO study, is mandatory for patients with NF1. (Am Heart J 2002;143:883-8.)

Neurofibromatosis regroups at least 2 different auto-
somal dominant genetic disorders: neurofibromatosis
type 1 (NF1) and neurofibromatosis type 2. NF1 repre-
sents 95% of neurofibromatosis cases, with an inci-
dence rate of 1 in 3500 newborns and a prevalence
rate of 1 in 4500 newborns.1-5 NF1 is characterized by
its cutaneous manifestations, cafe au lait spots, lentigi-
nes, and neurofibromas with a variable clinical expres-
sion. Nearly 50% of the cases have NF1 as the result of
a new gene mutation.6,7 Neurofibromin, NF1 protein
product, normally acts to modulate epithelial-mesen-
chymal transformation and proliferation in the devel-
oping heart by downregulating ras activity.8 In the ab-
sence of neurofibromin, mouse embryo hearts develop
From the aMedical Surgical Department of Cardio-Thoracic Sciences, and the bDepart-
ment of Pediatrics, Second University of Naples.
Submitted June 27, 2001; accepted December 3, 2001.
Reprint requests: Michele Adolfo Tedesco, MD, PhD, Salita Due Porte 14, 80136 Na-
ples, Italy.
E-mail: tedesco@napoli.pandora.it
© 2002 Mosby, Inc. All rights reserved.
0002-8703/2002/$35.00 ⫹ 0 4/1/122121
doi:10.1067/mhj.2002.122121
overabundant endocardial cushions as the result of
hyperproliferation and lack of normal apoptosis.9
These observations suggest the involvement of the car-
diovascular system in NF1. Many case reports have
shown cardiac involvement in NF1.10-14 Conversely, a
recent study15 showed that the prevalence rate of car-
diovascular abnormalities in patients with NF1 is low
(2.3%). However, estimates of the prevalence of car-
diac disease in a population are dependent on the
methods used to detect and diagnose cardiac lesions,16
and unfortunately, in Lin et al’s15 series, there was a
lack of echocardiographic data because only a small
percentage of the study population underwent echo-
cardiography. There is currently some disagreement
about the value of routine echocardiography for pa-
tients with NF1.15 Thus, because of the potential
pathogenetic significance of NF1-associated cardiovas-
cular alterations,17-19 the aim of our study was to evalu-
ate the prevalence of cardiac involvement with
M-mode, 2-dimensional echocardiography and color
Doppler scan in a relatively large, consecutive series of
young patients with NF1.
 American Heart Journal
884 Tedesco et al
May 2002

graphic equipment (Mountain View, Calif). Examinations

Table I. Characteristics of NF1 patients and healthy subjects
were carried out by the same trained physician. All echocar-
NF1 Healthy diograms were recorded on videotape. After the first exami-
patients subjects nation, a second cardiologist, blinded to the physical findings
(n ⴝ 48) (n ⴝ 30) P and to the clinical history of the subjects, reviewed all 78
echocardiographic examination results. Disagreements were
Male (%) 46 57 .48 resolved with consensus.
Age (y) 10 ⫾ 6 11 ⫾ 3 .39 Echocardiography was performed with the subjects in partial
Weight (kg) 35 ⫾ 17 42 ⫾ 11 .16 left decubitus. A variable frequency phased-array transducer
Height (cm) 127 ⫾ 20 135 ⫾ 22 .1 (2.5, 3.5 MHz) was used for all M-mode, 2-dimensional, and
Body mass index (kg/m2) 19 ⫾ 4 19 ⫾ 2 .99
Doppler scan imaging. Two-dimensional guided M-mode quanti-
Systolic blood pressure (mm Hg) 103 ⫾ 12 98 ⫾ 10 .06
Diastolic blood pressure (mm Hg) 64 ⫾ 7 69 ⫾ 7 .07
tative left ventricular (LV) analysis was performed in parasternal
Heart rate (beats/min) 90 ⫾ 23 88 ⫾ 10 .64 short-axis view according to the recommendations of the Ameri-
can Society of Echocardiography. Endocardial fractional shorten-
Values are expressed as means ⫾ SD. ing was calculated as: LV internal diastolic dimension - LV inter-
nal systolic dimension/LV internal diastolic dimension ⫻ 100. All
color Doppler scan echocardiographic recordings were ob-
Table II. Echocardiographic characteristics of NF1 tained during normal respiration with methods previously de-
patientsand healthy subjects scribed.21 The degree of mitral, aortic, pulmonary, and tricuspid
regurgitation was assessed with color Doppler scan in multiple
NF1 Healthy views. Technical inability to evaluate 1 valve did not preclude
patients subjects examination of the remaining valves. Severity of mitral regurgita-
(n ⴝ 48) (n ⴝ 30) P
tion was visually rated as none, physiologic, mild, moderate,
severe, or not able to be evaluated.22 Severity of aortic regurgita-
Left ventricular diastolic
tion was visually rated as none, trace, mild, moderate, or not
dimension (mm) 39 ⫾ 7 37 ⫾ 7 .22
able to be evaluated.23 Isolated asymptomatic patent foramen
Septal diastolic thickness (mm) 7⫾1 7⫾1 .99
Posterior wall diastolic ovale, physiologic mitral, tricuspidal, and pulmonary regurgitant
thickness (mm) 6⫾2 7⫾3 .08 flows were not included as cardiac abnormalities in this report.
Fractional shortening (%) 37 ⫾ 5 37 ⫾ 3 .99
Left ventricular mass (g) 78 ⫾ 22 85 ⫾ 23 .18
Left atrial size (mm) 31 ⫾ 5 31 ⫾ 4 .99 Reader variability
E peak velocity (cm/s) 90 ⫾ 18 96 ⫾ 13 .12 Random samples of 20 additional echocardiograms were
A peak velocity (cm/s) 54 ⫾ 11 57 ⫾ 10 .23 read by 2 readers to evaluate interobserver agreement, and
E/A ratio 1.7 ⫾ 0.5 1.7 ⫾ 0.3 .99 each reader reread a random sample of echocardiograms to
Deceleration time (ms) 125 ⫾ 40 131 ⫾ 29 .45 evaluate intrareader agreement.
Isovolumic relaxation time (ms) 54 ⫾ 11 63 ⫾ 8 ⬍.001
Cardiovascular abnormalities (%) 27 0 .001
Statistical analysis
Values are expressed as means ⫾ SD. E/A, Early-to-atrial wave ratio.
Statistical analysis was carried out with Stat View software
(SAS Institute, Cary, NC). The Student t test for unpaired data
was used to estimate the difference between mean values.
Qualitative data were expressed as percentage and were
Methods compared with a Fisher exact test (2-tailed). The data are ex-
Study population pressed as mean ⫾ standard deviation. A P value of ⬍ .05
We studied 48 consecutive patients with NF1 (22 male and was considered statistically significant. Kappa statistics and
26 female), with a mean age of 10 years (range, 4 to 19 percent concordance were used to assess interreader and
years), and 30 control subjects chosen for comparable age intrareader variability for echocardiographic parameters.
and sex. The diagnosis of NF1 was on the basis of the guide-
lines reported by the 1988 National Institutes of Health Con-
sensus Statement Conference (NIH).20 All patients were clas- Results
sified according to 4 levels of severity established by the
The clinical findings from the study population are
Baylor Program.6 Each patient underwent a physical examina-
tion in the outpatient clinic. Standard electrocardiogram was
shown in Table I. Cardiac abnormalities were found in
performed, and all patients were in sinus rhythm without 13 of the 48 patients (27%), on the basis of 2-dimen-
abnormalities. Parents of patients and controls aged ⬍18 sional echocardiogram and color Doppler scan study
years or patients aged 18 years gave their written informed results, and patients with NF1 showed an isovolumic
consent to participate in the study. relaxation time shorter than healthy subjects (P ⬍
.001; Table II). No cardiac abnormalities were found in
Echocardiographic study the control group (Table II). All of the subjects were
Complete 2-dimensional echocardiograms and Doppler term-born without complications, and none had a his-
scan studies were obtained with Sequoia Acuson echocardio- tory of rheumatic fever. There were no significant dif-
American Heart Journal
Tedesco et al 885
Volume 143, Number 5

ferences in age, sex, height, sexual maturity, level of Table III. Clinical characteristics of NF1 patients with and
NF1 severity established with the Baylor Program, sys- without cardiovascular abnormalities
tolic and diastolic blood pressure, and heart rate
among the 13 patients with cardiac abnormalities and NF1 with NF1
CA without CA
the remaining 35 without cardiac abnormalities (Table (n ⴝ 13) (n ⴝ 35) P
III). No significant clinical or cardiac differences were
found between genders. Only 6 of the 13 patients Male (%) 54 36 .34
(43%) had abnormal cardiovascular findings on a physi- Age (y) 11 ⫾ 6 9⫾6 .29
cal examination performed by a cardiologist who at Body mass index (kg/m2) 20 ⫾ 6 18 ⫾ 3 .10
Systolic blood pressure (mm Hg) 101 ⫾ 9 103 ⫾ 13 .61
the time of the examination was aware of the echocar-
Diastolic blood pressure (mm Hg) 62 ⫾ 10 61 ⫾ 7 .68
diographic results. Catheterization or surgery were per- Heart rate (beats/min) 93 ⫾ 28 88 ⫾ 21 .49
formed in 2 children, and 11 to date have had no addi- III-IV Baylor scale degree (%) 15 17 .99
tional procedures. All 13 patients need continuing
Values are expressed as means ⫾ SD. CA, Cardiovascular abnormalities.
follow-up examination with a cardiologist.

Patients with neurofibromatosis type 1 in whom

procedure was recommended (n ⫽ 4)
A secundum atrial septal defect with a left to right
shunt greater than 2:1 was found in 2 children. In
both cases, typical auscultatory findings were present,
consisting of a widely and fixedly split second heart
sound, a systolic ejection murmur in the left upper
sternal border, and diastolic rumble at the right lower
sternal border. A transcatheter device closure was rec-
ommended, but to date both patients are still unde-
cided.
Echocardiographic and Doppler scan evidence of left
pulmonary artery stenosis of moderate degree (mean
gradient, 37 mm Hg) was found in 1 participant. With
auscultation, a systolic ejection murmur was audible in
the left sternal border, radiating to the lungs. The pa-
tient underwent cardiac catheterization, which con-
firmed the echocardiographic diagnosis. Conservative
follow-up examination was recommended. Coarctation
of the thoracic aorta of moderate degree was found in
1 patient, cardiac catheterization confirmed echocar-
diographic diagnosis, and surgical management was
scheduled.
Patients with neurofibromatosis type 1 in whom
procedure was not recommended (n ⫽ 9)
A regurgitant flow signal, defined as mild, was de-
tected as originating from the aortic valve in 2 subjects
(Figure 1A). Echocardiographic criteria for mitral valve
prolapse in both long axis and apical 4 chamber views
and color Doppler scan evidence of mild mitral regur-
gitation with myxomatous mitral valve were present in
1 case (Figure 1B). Bicuspid aortic valve was diag-
nosed in no participants. Antibiotic prophylaxis for
bacterial endocarditis was started in these 3 patients.
Mild mitral regurgitation was found in 2 patients. Atrial
septal aneurysm, defined as a bulging ⬎15 mm beyond
the plane of atrial septum with a basal width ⬎15 mm,
both type 1B, according to Hanley’s diagnostic criteria,
was found in 2 patients without patent foramen
ovale.24 Two patients (1 male and 1 female) had a sep-
tal to posterior LV free wall ratio greater than 1.5, sug-
gesting hypertrophic cardiomyopathy (Figure 1C).
However, neither patient showed obstruction of LV
outflow tract estimated with continuous wave Doppler
scan imaging with basal conditions nor history of hy-
pertension and family history of hypertrophic cardio-
myopathy.
Intraobserver and interobserver variability
There was complete agreement between the 2 read-
ers on the presence of valvular regurgitation and other
cardiac alterations. When evaluating the degree of val-
vular regurgitation, the concordance was good (kap-
pa ⫽ 0.77). For intraobserver variability, there was an
89% concordance (kappa ⫽ 0.71).
Discussion
This is the first attempt to evaluate the prevalence of
cardiovascular abnormalities in young patients with
NF1 with M-mode, 2-dimensional echocardiography
and color Doppler scan. The study’s most striking find-
ing is the higher prevalence rate of cardiovascular ab-
normalities in patients with NF1 (27%) compared with
our control group and a large population of healthy
adolescents (3.6%).16
Neurofibromatosis type 1 and cardiovascular
abnormalities
Many case reports of congenital heart disease associ-
ated with NF1 appear in the literature.10-14 The lesions
reported include valvular pulmonary stenosis, branch
peripheral pulmonary stenosis, atrial and ventricular
septal defects, coarctation of the aorta, and hypertro-
phic cardiomyopathy. However, the only prevalence
study of cardiovascular abnormalities in patients with
NF1, not only including patients with definite disease,
was on the basis of clinical, radiographic, and electro-

886 Tedesco et al
Figure 1
Examples of aortic regurgitation (A), mitral valve prolapse with valvular regurgitation (B), and thickened septum (C).
cardiographic diagnosis, reserving the echocardio-
graphic study only for few patients with definite NF1
according to NIH diagnostic criteria.15
The prevalence of cardiac disease can only be estab-
lished with detection methods and diagnosis of cardiac
lesions.16 Children with clear signs, such as cyanosis,
congestive heart failure, or audible murmurs, are easily
recognized. In contrast, cardiac disease in asymptom-
atic children with trivial physical findings may be eas-
ily missed during physical examination, despite the
significant abnormalities.
In the study from Steinberger et al,16 nearly 4% of a
randomly selected population of junior high school
students was found to have previously undetected car-
diac disease, severe enough in about half of them to
necessitate cardiac catheterization and surgery at the
time of diagnosis. It is not surprising that noncardiolo-
gists would fail to detect subtle auscultatory findings.
However, some heart disorders go undiagnosed after
physical examination by well-trained specialists, and,
as the report from Steinberger et al16 shows, only 7 of
13 patients (54%) were found to have abnormal car-
diac examination results by a pediatric cardiologist.
Our findings are in agreement with Goldberg, Don-
nerstein, and Samson,25 who showed that history and
American Heart Journal
May 2002
physical examinations performed by trained pediatric
cardiologists are accurate in only 81% of cases after an
initial evaluation and that cardiac disease can be
missed without additional diagnostic tools. Echocardi-
ography is one such tool that greatly improves the ac-
curacy of the work-up in children with mild heart dis-
ease.26,27 It is somewhat surprising that patients with
NF1 had a shorter isovolumic relaxation time than con-
trols. This finding may suggest an abnormal cardiovas-
cular compliance in these patients.18,19
Cardiovascular abnormalities and neurofibromatosis
type 1: Pathogenesis
NF1 knockout mouse homozygous mutant embry-
os28,29 die with double outlet right ventricle, a cardio-
vascular malformation attributed to abnormal migration
of ectomesenchymal cells30 derived from the cranial
neural crest.31 Furthermore, these mouse embryos
have enlarged and abnormal endocardial cushions32
that may obstruct forward blood flow in some cases.
This anomaly suggests that neurofibromin is necessary
for normal cardiac valve development. Complex devel-
opmental mechanisms in addition to neural crest mi-
gration play a role in cardiac development in NF1. The
rarity of complex cardiovascular malformations sup-
American Heart Journal
Volume 143, Number 5
ports the notion that NF1 is not a multiple malforma-
tion syndrome and may better be viewed as a multiple
dysplasia syndrome.5 However, there is no firm geno-
type-phenotype correlation with particular NF1 muta-
tions.15 Cardiovascular malformations were noted in 3
patients with large deletions.33-36 Nevertheless, there
are no commodities between our findings and those
anticipated by any single locus on the NF1 gene in the
experimental settings.28,31-32 But it is not surprising
that the type and the degree of cardiovascular involve-
ment may be completely different in patients who
most likely carry different microdeletions.
Study limitations
Because the NIH criteria remain the gold standard
for diagnosis, none of our patients with NF1 had DNA
or microdeletion studies. The number of patients may
appear to be low. However, we exclusively studied
patients with definite NF1. Thus, 48 patients are a
large sample for a genetic disorder as NF1. Our Pediat-
ric Department is the University referral center for
NF1, and thus, our patients may be a particularly se-
lected cohort with a severe degree of the disease.
However, we studied consecutive patients (35% of
NF1 population regularly followed by our department),
and the percentage of patients who fit the III to IV
degree Baylor program scale was low.
Clinical implications
Our study shows the presence of cardiac involve-
ment in patients with NF1. The heterogeneity of car-
diovascular abnormalities may be related to the hetero-
geneity of NF1. In our sample, most cardiac
abnormalities are not severe and thus, we explain the
low incidence of cardiovascular abnormalities in pa-
tients with NF1 studied exclusively with physical ex-
amination. There are several reasons why cardiac dis-
orders necessitate an early diagnosis. First, repair of
congenital lesions, such as atrial septal defect, reduces
the later risk of arrhythmias, right ventricular dysfunc-
tion, and pulmonary hypertension. Second, not only
severe, but also some mild cardiac lesions, have poten-
tial long-term hemodynamic consequences and risk
bacterial endocarditis. Not only has the skin condition
often been wrongly labeled as NF1, but the heart dis-
order has also gone undiagnosed until late. Thus, for
any patient with NF1, a cardiologic assessment includ-
ing M-mode, 2-dimensional and color Doppler scan
echocardiogram is mandatory at regular intervals.
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