SEPTEMBER, 1974

NEUROFIBROMATOSIS AND CONGENITAL

HEART DISEASE*
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By HARVEY L. NEIMAN, M.D., ERNESTO MENA, M.D., JOHN F. HOLT, MI).,

AARON M. STERN, M.l).,f and BURTON L. PERRY, M.D.t
ANN ARBOR, MICHIGAN

T HE cutaneous, osseous and central

ic girl
CASE III.
with
(PjR)
multiple
This 4
caf#{233}
au
year old
lait
asymptomat-
spots on the
nervous system manifestations of neu-
rofibromatosis have been widely recognized abdomen and chest was the sister of Case n.

for many years.4”#{176}”” Less attention has Blood pressure in the right arm was 360/90 and
right leg 90 ‘84 mm. Hg. The femoral pulses
been given to the cardiovascular abnor-
were delayed and weaker than the radial pulse.
malities which may also occur. The most
A Grade 2/6 harsh systolic ejection murmur
frequently described abnormality is renal was best heard at the right sternal border in
artery stenosis and secondary hypertension, the secolid interspace. Chest roentgenogram
especi ally in children.’ ‘ ‘ ‘ Hypertension demonstrated rib notching. Cardiac catheteri-
secondary to pheochromocytorna has been zation revealed a high grade coarctation of the
described in adults.8 Cardiac anomalies jn aorta just distal to the origin of the left sub-
neurofibromatosis, however, have only re- clavian artery with prominent collaterals (Fig.
cently been described.’2 1, A and B). She also has mental retardation
A review of all cases of neurofibromatosis and a Turner phenotype.
seen at the University of Michigan Medical
CASE P/. (LLR) This patient is the mother
Center during the past 20 years (1951-
of Case 11 and Case III (Fig. 2). She was 12
‘97’) disclosed 78 children with this condi- years old when first seen with a history of easy
tion, of whom 6 also had congenital heart fatigability, multiple caf#{233}au lait spots, mental
disease. The purpose of this report is to retardation , velopharyngeal insufficiency, a
describe these 6 cases and to emphasize the Turner phenotype and a harsh systolic murmur
increased incidence of congenital heart dis- best heard in the pulmonic area. Cardiac
ease in patients with neurofibromatosis. catheterization in 1943 demonstrated pulmonic
valvular stenosis. A transventricular pulmonary
REPORT OF CASES valvulotomy was carried out. Six years later she
CASE I. (HG) This 9 month old male with had recurrent symptoms and subsequently had
caf#{233}
au lait spots and a family history of neuro- a pulmonary valvulotomy using cardiopul-
fibromatosis was noted to have a Grade 3/6 monary bypass.
systolic murmur at the left sternal border and
mild cyanosis. A cardiac catheterization re- CASE v. (RC) This 6 year old boy with mul-
vealed a high ventricular septal defect. At the tiple caf#{233}
au lait spots over the trunk and ex-
age of 5 years he underwent repair of the defect. tremities and probably a left forehead subcu-
However, 3 years later he was re-operated on taneous neurofibroma was evaluated because of
for closure of a residual defect. progressive easy fatigability and a Grade 3/6
systolic murmur heard over the entire pre-
CASE (RLR) II. This 23 month old male with cordium. Cardiac catheterization revaled an
caf#{233}
au lait spots, xanthoma of the
scalp, mental atrial septal defect which was subsequently
retardation and veloph aryn geal in su flicien c y repaired.
was noted to have a Grade 4/6 systolic murmur
radiating to the left axilla. Cardiac catheteriza- CASE VI. (BC) This patient with multiple
tion revealed pulmonic valve stenosis (26 mm. caf#{233} ati lait spots over the abdomen and ex-
Hg systolic gradient) and peripheral pulnionic tremities and multiple cutaneous neurofibro-
stenosis at the origin of the right and left pul- mata was first seen at the age of c years, when
monary arteries (io mm. Hg gradients). she was noted to have sinus bradycardia with

* From the Department of Radiology and I)epartment of Pediatrics and Communicable Diseases,f University of Michigan Medical
Center, Ann Arbor, Michigan.

146
 VOL. 122, No. I Neurofibromatosis and Congenital Heart Disease ‘47

second degree A-V block. At the age of 17

years she was found to have complete heart

block. Cardiac catheterization demonstrated no
abnormality except generalized cardiac enlarge-
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men t.

DISCUSSION

Neurofibromatosis is an uncommon but

certainly not rare disease, probably due to
a mesodermal and ectodermal dysplasia

hG. 2. Photograph of Cases ii, III, and iv.

neurofibromata are visible on LLR (Case iv).

that can affect tnv system of the body. The

protean manifestations have generally been
well documen ted.4’ ‘ ‘ ‘ ‘ ‘ ‘‘ Cardiovascular
system manifestations are less frequently
observed, however, and it was only in 1965
that the relationship ofrenal artery stenosis
and hpertension in children with neuro-
fibrornatosis was described.9 The associa-
tion of pheochromocytorna with neuro-
fibromatosis or other of the neurocutaneous
syndromes is well known, with some esti-
mates of a io to 20 per cent incidence.8
Carol et al.,3 and Glenn et al.7 have each
described a case of coarctation of the aorta
and neurofibromatosis.
Kaufman et al.’2 recently presented evi-

I
dence that congenital heart disease, espe-
cially pulmonic valvular stenosis, may be
ii’ part of the vascular manifestations of lieu-
rofibromatosis. The found ,#{231}
cases of Inll-
IflOfliC valvular stenosis among I 9 families
affected with this condition. An additional
member of one family had supravalvular
aortic stenosis. Crowe et al.,4 however,
FIG. . Case III. (A) Chest roentgenogram demon- found in 223 cases only i patient with pos-
strates prominent rib notching shown by cinecar- sible congenital heart disease; presumably
diography to be due to collateral circulation rather
an atrial septal defect.
than to neurofibromas of intercostal nerves. (B)
\Ve have reviewed all the cases of neuro-
Cinecardiogram demonstrates coarc tation of the
aorta (arrow) with markedly enlarged internal fibromatosis seen at the University of
mammary arteries. Michigan Medical Center in the years
 148 Neiman et al. SEPTEMBER, 5974

TABLE I
SUMMARY OF CASES

Age at Time of .
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. .
Name Sex . Congenital Heart Disease Associated Abnormalities
Evaluation

HG M 9 mo. Ventricular septal defect -

RLR M 2! mo. Pulmonic valvular stenosis Mental retardation

Velopharyngeal insufficiency

PJR F 4 yr. 6 mo. Coarctation of upper thoracic aorta Mental retardation

Bicuspid aortic valve Turner phenotype

LLR F 12 yr. 4 mo. Pulmonic valvular stenosis Mental retardation

‘I’urner phenotype

RC M 6 yr. 2 mo. Atrial septal defect -

BC F yr. Complete heart block -

1951-1971 and found 78 children with this A previous report in 1940 described the
diagnosis. In this group there were 6 cases association of coarctation of the upper
with congenital heart disease. Three were thoracic aorta and neurofibromatosis in a
males and 3 females, ranging in age from 7 year old boy.3 Glenn et al.7 described a
9 months to I 2 years. Generally, the patient case of coarctation of the lower thoracic
presented because of the cardiac sympto- aorta in a patient with neurofibromatosis.
matology (Table ). Therefore, our case is only the third demon-
The incidence of congenital heart disease stration of this association. These cases are
has been found to be from 0.32 to 0.64 per particularly interesting from a roentgeno-
cent of live births.2”3 Our series, therefore, graphic standpoint in that both coarctation
indicates a definite increased incidence of and neurofibromatosis can produce rib
congenital heart disease and neurofibroma- notching.’#{176} In our case, however, collateral
tosis (7.7 per cent). The exact incidence, vessels secondary to the coarctation are the
however, is uncertain since 3 of our cases proven cause for the notching. Congenital
are from the same family and since the heart block has not been previously re-
diagnosis of neurofibromatosis is often not ported in neurofibromatosis.
made until the second or third decade. The increased incidence of congenital
Particularly, there is an increased incidence anomalies ofthe heart in patients with neu-
of pulmonic valvular stenosis and neuro- rofibromatosis may be based on the fact
fibromatosis in view of the cases of that the heart embryologically has a meso-
Kaufman et al.’2 and
of our 6 cases. Addi- 2 dermal origin and therefore is likely to be
tionally, et al.16 described
Rosenquist a involved in this dysplasia.
child with neurofibromatosis who developed
SUMMARY
stenosis of the pulmonary outflow tract,
but who had a normal appearing pulmonic A review 0178 cases of neurofibromatosis
valve. It is of particular interest that the in children disclosed 6 with congenital heart
association of pigmentary cutaneous dis- disease. This included 2 cases of pulmonic
orders and pulmonic valvular stenosis has valvular stenosis and i case each of coarcta-
also been reported to occur in the multiple tion of the thoracic aorta, atrial septal de-
lentigines syndrome and the Watson syn- fect, ventricular septal defect and con-
drome.’2 genital heart block.
 VoL. 122, No. i Neurofibromatosis and Congenital Heart Disease ‘49

This material, therefore, further empha- celiac axis. Surg., Gynec. & Obst., 1952, 94,
sizes the increased incidence of congenital 561-569.
8. GLUSHEIN, A. S., MANSUY, M. M., and LITTMAN,
heart disease in patients with neurofibro-
D. S. Pheochromocytoma: its relationship to
matosis.
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neurocutaneous syndromes. Am. 7. Med.,

1953, 14,318-327.
John F. Holt, M.D.
9. HALPERN, M., and CURRARINO, G. Vascular
C. S. Mott Children’s Hospital
. lesions causing hypertension in neurofibroma-
University of Michigan Medical Center
Ann Arbor, Michigan 48104
tosis. New England 7. Med., 1965, 273, 248-
252.

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