Between 1981 and 1997, in the Departments of Orthopaedic Surgery
and Pediatrics of our children’s hospital, sixty patients,
from the South Korean population of about forty-eight million, were
diagnosed as having Noonan syndrome. Four patients were first diagnosed
as having Noonan syndrome during their visit to our hospital for
the treatment of spinal deformities. Growth disturbance or any delay
in developmental milestones was documented. Characteristic features of
the face, neck, chest, extremities, and back were also recorded.
Spinal deformities were evaluated on 14 36-in (35.6 ¥ 91.4-cm)
posteroanterior and lateral standing radiographs of the spine. Thoracic
lordosis was measured as the angle formed by lines drawn from the
maximally tilted cephalad thoracic end vertebra and the end vertebra
in the thoracolumbar area on the standing lateral radiograph. Magnetic resonance
imaging of the spine was performed in five patients: two (Cases
5 and 12) with congenital spinal deformity, one (Case 16) with a
left thoracic scoliosis, and two (Cases 13 and 17) of the remaining
fifteen patients. The prevalence of spinal deformities and the patterns
and severity of the curves were analyzed.
Four patients with <20° of scoliosis were observed.
Braces were prescribed to treat scoliosis in the immature children who
had a curve of >25° and a high risk of progression. Spinal
arthrodesis was recommended for progressive scoliosis of >45°
in an immature growing child and for scoliosis of >50° in
a mature adolescent (Case 13). For patients in whom thoracic lordosis
was associated with scoliosis, we recommended surgery regardless
of the degree of scoliosis. Overall, surgery was recommended to
eleven of the eighteen patients, for the treatment of scoliosis
in eight and for the treatment of associated thoracic lordosis in
three.
All patients had a normal karyotype
(46XX or 46XY). There was a slight preponderance of girls (thirty-five
girls and twenty-five boys). The average age at the time of diagnosis
of Noonan syndrome was 7.0 years (range, 0.5 to seventeen years),
and the average duration of follow-up was 6.4 years (range,
two to seventeen years).
General Appearance
Most patients had the characteristic facial features of Noonan syndrome,
such as ocular hypertelorism, down-slanting palpebral fissures,
ptosis, low-set ears, and a high-arched palate. Four
patients had malformed ear lobes. Forty-two (70%) of the
sixty patients had a webbed neck, and forty (67%) had a low-set
posterior hairline. Seventeen patients (28%) had deformity
of the chest wall, which included a shield-like chest,
a funnel chest, or a combination of these deformities. Congenital
heart disease was confirmed with an echocardiogram in sixteen patients
(27%); pulmonary artery stenosis was the most common cardiopulmonary
abnormality (seven patients). Nine (36%) of the twenty-five
male patients had cryptorchidism or hypoplastic testicles. Cubitus
valgus (a carrying angle of >15°) was the most common deformity
in the upper extremities and was seen in twenty-seven patients (45%).
The average carrying angle of these twenty-seven patients was 24.2°
(range, 17° to 37°). Various hand anomalies were the second most
common problem. They were seen in twenty-two patients (37%)
and included hypoplastic fourth and fifth metacarpals (twelve patients),
partial syndactyly (six), and clinodactyly (two).
Of fifty patients whose height measurements were available, thirty-six
(72%) were under the third percentile of the population.
Of forty-five patients whose weight measurements were available,
twenty-two (49%) were under the third percentile. Delay
in developmental milestones was noted for twenty-nine patients (48%).
Mental retardation was present in thirty-five patients (58%).
Spinal Deformities
Spinal deformity was present in eighteen (30%) of the
sixty patients. Eight boys and ten girls had spinal deformity, and
the ages at which the deformity was first detected ranged from two
to fifteen years (mean, nine years). In seven patients, the deformity
was detected before the age of seven years.
Of the eighteen patients, two (Cases 5 and 12) had congenital spinal
deformity and were treated in a standard way (Table II). Of the sixteen
patients without congenital spinal deformity, nine had a single
thoracic curve (range, 16° to 125°); four, a single thoracolumbar
curve (range, 23° to 69°); and three, a double major curve (range,
17° to 77°). Of the nine single thoracic curves, three were <20°
and six ranged from 40° to 125°. Two of the patients with a single
thoracic curve had an associated thoracic lordosis, which was 15°
in one (Case 14) and 8° in the other (Case 18). Surgery was recommended
for the six patients with a single thoracic curve of 40°, including the
two with an associated thoracic lordosis.
Of the four patients with a single thoracolumbar curve, two (Cases
6 and 7) were treated with a brace. One (Case 6) wore a thoracolumbosacral
orthosis between the ages of nine and fourteen years and had only
minimal progression of the curve, from 26° to 32°, at the last follow-up
evaluation. The other patient (Case 7) wore a Milwaukee brace from
the age of four years. Four years later, the curve had progressed
from 28° to 36°. One patient (Case 13) had scoliosis of 69°, and
surgery was recommended. The fourth patient (Case 17) had a thoracolumbar
scoliosis of 23° but had an associated thoracic lordosis of 18°,
and surgery was recommended, primarily to treat the lordosis.
Observation was recommended for one patient (Case 4) with a double
major curve. Surgery was recommended for the other two patients
with a double major curve because the scoliosis measured 77° (thoracic)
and 73° (lumbar) in one (Case 8) and 50° (thoracic) and 47° (lumbar)
in the other (Case 16).
A spinal arthrodesis was recommended for eleven of the eighteen
patients with spinal deformity, and seven of the eleven patients
underwent the procedure (Table III). One of them (Case 12) had congenital
scoliosis. Among the eleven patients, there was a preponderance
of girls (eight girls and three boys). Eight of these patients had
scoliosis only (mean, 68.5°; range, 45° to 125°) (Figs. 1-A and 1-B), and the other
three (Cases 14, 17, and 18) had an associated thoracic lordosis
(15°, 18°, and 8°). Of the seven patients who were treated with
spinal arthrodesis, six were operated on for scoliosis and one (Case
14), for an associated thoracic lordosis. An in situ spinal arthrodesis
was performed in one patient (Case 12) with congenital scoliosis.
The other six patients were treated with a posterior and/or
anterior spinal arthrodesis with instrumentation. The patient with
excessive (15°) thoracic lordosis (Case 14) was treated with an
anterior release and posterior spinal arthrodesis with segmental
sublaminar wiring to achieve thoracic kyphosis (14°) (Figs. 2-A, 2-B, and 2-C).
Four patients had not had the recommended operation at the time
of writing. The parents of one patient (Case 15) refused to allow
the operation, and two patients were to undergo surgical correction
at a future date. Surgery was postponed in another patient (Case
18) because malignant hyperthermia developed during the induction
of anesthesia. The preoperative serum creatine phosphokinase level
in this patient was 224 U/L (normal range, 20 to 270 U/L).
During induction of anesthesia, the patient was noted to have generalized
muscle rigidity and a rapidly rising body temperature to 40°C with
a severe metabolic acidosis (pH 7.18).
Pulmonary function tests were performed preoperatively in two
patients (Cases 14 and 18) of the three with an associated thoracic
lordosis. Both patients showed restricted lung function, with a
forced vital capacity of 61% of the predicted value in
one (Case 14) and 55% in the other (Case 18). Seven (39%) of
the eighteen patients with spinal deformity had cardiopulmonary
problems such as congenital heart disease (Cases 4, 9, and 16) and
agenesis of the lung (Case 5). Magnetic resonance imaging of the
spinal cord was performed in only five patients (Cases 5, 12, 13,
16, and 17), and the findings were normal in all five.
The incidence of Noonan syndrome has been estimated to be between
one in 1000 and one in 2500 live births11.
The published reports about spinal deformities in Noonan syndrome
have been inconsistent, not only regarding the prevalence of the
deformities but also about their characteristics. Noonan2 commented briefly about spinal deformities
in three of nineteen patients; two had scoliosis and one, kyphosis.
Sharland et al.14 reported that
a thoracic scoliosis was detected in twenty (13%) of 151
patients but none required medical or surgical treatment. Nora et
al.13 and Allanson11 noted scoliosis and kyphosis in
20% and 25% of their patients, respectively, but
gave no details about the nature of the spinal deformities.
We believe that our study involved one of the largest series
of patients with Noonan syndrome with a detailed analysis of spinal
deformities. The prevalence of spinal deformities in our study was
relatively high (eighteen [30%] of sixty
patients). The prevalence of severe scoliosis of 45° or of scoliosis
with associated thoracic lordosis requiring surgical correction (eleven
of eighteen patients) was also higher than reported previously15-18. Spinal deformities in Noonan
syndrome develop early in life. Seven of our patients had detectable
spinal deformity before the age of seven years. Nine of our patients
had a curve of >40° (mean, 62.7°; range, 45° to 94°) at
their first visit to our department, suggesting an early age of
onset of scoliosis.
Thoracic lordosis was associated with scoliosis in three of our patients.
To our knowledge, this finding has not been described previously
in the literature. Excessive thoracic lordosis results in pulmonary
dysfunction19,20, as demonstrated
by restricted lung function in two of our three patients with thoracic
lordosis. Therefore, when a patient with Noonan syndrome presents
with thoracic lordosis, cardiopulmonary function needs to be assessed.
Malignant hyperthermia developed in one patient (Case 18) during
the induction of anesthesia for the performance of spinal arthrodesis.
There are a few reports describing malignant hyperthermia in patients
with Noonan syndrome4,11,21-23.
The exact pathophysiology of malignant hyperthermia is not understood
well. Hunter and Pinsky21 studied
the risk of malignant hyperthermia developing in patients with Noonan
syndrome and recommended that clinical and laboratory assessment
be performed in such patients, especially when there is evidence
of a myopathy or an elevated serum creatine phosphokinase level.
We believe that all patients with Noonan syndrome should be considered
to be at risk for malignant hyperthermia developing during anesthesia even
when preoperative clinical and laboratory findings are normal, as
these findings were normal in our patient in whom malignant hyperthermia
developed.
Although we have only limited experience with the use of magnetic
resonance imaging in patients with Noonan syndrome and spinal deformity,
we believe that magnetic resonance imaging is not necessary unless
there are abnormal neurological and radiographic findings.
Our study showed that spinal deformities, including scoliosis and
scoliosis associated with thoracic lordosis, are frequently seen
in patients with Noonan syndrome. Since the deformities tend to
develop early and are relatively severe, clinical and, if necessary,
radiographic assessment of the spine with careful follow-up
should be performed for early detection and treatment of spinal
deformity in these patients.