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Digilio MC, Marino B. Clinical manifestations of Noonan syndrome. Images Paediatr Cardiol 2001;7:19-30 |
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Medical Genetics and Pediatric Cardiology, Bambino Gesù Hospital, Rome |
| MeSH | ||
| Noonan syndrome | clinical genetics | heart defects, congenital |
| genetic counselling |
There is a wide range of variability in the phenotypical expression of Noonan syndrome, with some affected subjects having minimal features.18,19 Noonan syndrome affects both males and females, and the karyotype is normal. Autosomal dominant inheritance with variable expressivity has been documented in many families.19-21 A gene for Noonan syndrome has been mapped by linkage analysis in several families to the long arm of chromosome 12.22 Nevertheless, the gene has not yet been cloned therefore the diagnosis of Noonan syndrome is purely clinical with no "diagnostic" test available.
Clinical features
The main phenotypical features of Noonan syndrome and their occurrence
in our series of 190 children are listed in Table 1.
| Clinical finding |
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| Short stature |
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| Macrocephaly |
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| Facial anomalies |
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| Hypertelorism |
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| Downslanted palpebral fissures |
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| Ptosis |
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| Epicanthal folds |
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| Low-set ears |
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| Dysmorphic ears |
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| Short neck / Webbed neck |
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| Cardiac defect |
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| Sternal anomalies |
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| Wide-set nipples |
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| Elbow anomalies |
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| Cryptorchidism |
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| Developmental delay |
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| Nevertheless, the phenotypical expression is highly variable
and may change with age (fig. 2a,b,c).18,19, 21,23
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| Facial anomalies can often be difficult to recognise in the newborn (fig. 3). In fact, the mean age at diagnosis from the literature is nine years, and the delay in recognising the distinctive characteristics probably reflects the evolving phenotype.1,23 In particular, ocular and nasal bridge anomalies become less evident with increasing age. |
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Congenital heart defect
The prevalence of congenital heart defect in Noonan syndrome varies
from 50 to 80% in the reported series from the literature.4-9
The percentage of occurrence of the different types of cardiac defect in
our experience is shown in Table 2. Pulmonary stenosis and hypertrophic
cardiomyopathy are generally the most common congenital heart defects found
in Noonan syndrome.
| Cardiac defect |
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| Pulmonary valve stenosis |
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| Atrioventricular septal defect |
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| Coarctation of the aorta |
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| Hypertrophic cardiomyopathy |
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| Atrial septal defect (ostium secundum type) |
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| Left atrioventricular valve anomalies |
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| Ventricular septal defect |
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| Tetralogy of Fallot |
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| Patent ductus arteriosus |
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| Pulmonary atresia/intact ventricular septum |
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| Partial anomalous pulmonary venous return |
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| Dilated ascending aorta |
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Hypertrophic cardiomyopathy involves predominantly the ventricular septum as asymmetric septal hypertrophy, but may also affect the ventricular free walls. Left ventricular outflow tract obstruction may occasionally be produced.
Atrial septal defect, patent ductus arteriosus and tetralogy of Fallot are also found in Noonan syndrome. In our experience, left-sided obstructive lesions and atrioventricular septal defect are also frequently diagnosed. Left-sided anatomic obstruction can occur at the valvular or supravalvular level,9 in the subaortic position as a result of left atrioventricular valve abnormalities,11-12, or as coarctation of the aortic.13-15. Interestingly, the subgroup of patients with Noonan syndrome and aortic coarctation demonstrates male preponderance, and physical manifestations overlapping with those of Turner syndrome, so that the involvement of putative lymphogenic genes located on sex chromosomes has been suggested in these patients.24 The atrioventricular septal defect of subjects with Noonan syndrome is generally "partial" and frequently associated (25% of the cases in our series) with subaortic stenosis.16 The structural abnormalities causing subaortic stenosis include accessory fibrous tissue and/or anomalous insertion of the left atrioventricular valve and anomalous papillary muscle of the left ventricle. Interestingly, the anomalies of the left atrioventricular valve leaflets and of the subvalvular apparatus in patients with atrioventricular septal defect are similar to those reported in patients with hypertrophic cardiomyopathy.25,26
The pathogenesis of cardiac defects in Noonan syndrome has been attributed to a defect of cardiac jelly and extracellular matrix, in some cases,27 and the same mechanism is probably involved in the pathogenesis of the atrioventricular septal defect.28 Additionally, the development of leaflets and papillary muscles of the left atrioventricular valve is related to the morphogenesis of the left ventricular outflow tract and the atrioventricular and interventricular septations.29-32 Thereafter, in some patients with Noonan syndrome, the developmental mechanism of the left ventricular myocardium and the left atrioventricular valve may be altered.
Rare cardiac defects occurring in Noonan syndrome are pulmonary atresia with intact ventricular septum, which should be considered in the spectrum of pulmonary valve stenosis with dysplasia of the leaflets,33,34 and dilated ascending aorta.35
Neck anomalies
| An obvious and evident webbing of the neck (fig. 4a,b) is generally
present in only one fourth of the cases, while an apparent neck shortening
with redundant skin on the neck and low posterior hairline are more commonly
noted.
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| Skeletal anomalies
Thoracic deformities include the classic sternal changes of Noonan syndrome, often associated with shield chest (Figure 5). Kyphosis and thoracic scoliosis are frequently found, although medical or surgical treatment are rarely required. Bilateral elbow deformity is a frequent upper limb abnormality. |
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Developmental anomalies
The majority of children with Noonan syndrome (65% to 85% according
to different series) have normal mental capacities and attend regular schools.1,21,23,37
Early delay in motor milestones could probably be explained by the
presence of hypotonia and hyperextensibility in the younger child.
A recent study, investigating patterns of cognitive functioning in school-aged children, showed that Noonan syndrome is not associated with substantial deficits at the level of intellectual functioning.37 However, the correlation between phenotypic and cognitive expression revealed that a severe Noonan syndrome phenotype, i.e. more severe cardiac defect, more evident facial and skeletal anomalies, was associated with a specific pattern of deficits and capacities in cognitive functioning.37 Generally, patients with Noonan syndrome are at risk for speech delay,38,39 which could be related to hearing loss or recurrent otitis media that frequent occurs in this syndrome. Tests for hearing are recommended in children with Noonan syndrome, as are tests for vision, because of the association of strabismus and refractive errors in this syndrome.23
Growth
Growth retardation is an important feature of Noonan syndrome, and
short stature is found in 50-70% of cases in previously reported series.21,23,40
In our experience (Table 1), the percentage of subjects with height
below the 3rd percentile is lower. We believe that in older series, patients
with a more complete expression of the syndrome may have been enrolled,
while the more recent reports include also patients with milder phenotype
Noonan syndrome such that the impact of growth abnormalities may be less
evident.
The pattern of growth is similar in males and females, and weight-height ratio is normal. A delayed pubertal growth spurt has been documented in both sexes. Bone age is also usually delayed. The mean adult height reaches, in general, the lowest level of the normal percentiles.
Non-cyanotic heart defects are not found to have any major impact on overall growth patterns.
Coagulation factor deficiencies
Easy bruising after minor trauma and abnormal bleeding are frequently
reported in patients with Noonan syndrome, and a variety of coagulation
factor deficiencies have been detected.41 The most common abnormality
is a partial factor XI deficiency, but VIII and XII factor anomalies have
also been described. Combined coagulation factor deficiencies may also
occur. The involvement of several factors, and the possible presence of
combined abnormalities implies that anomalies in regulatory factors of
the coagulation system, which is under chromosome genetic control may be
the cause.
Familial transmission
Approximately half of the patients are sporadic cases in the families
and may represent new mutations. In the remaining 50% of cases, Noonan
syndrome is familial, with most of the pedigrees being consistent with
autosomal dominant inheritance.2,3,15,19,22,42 A mild or subtle
phenotype must be searched for in parents of affected children.
A predominance of maternal transmission is noted in familial cases. This has been thought to be due to infertility in affected males, which may be related to cryptorchidism.36
Molecular studies
The result of a linkage analysis of a three-generation family with
eight affected individuals and 20 two-generation families performed by
Jamieson et al.22 localised a gene for Noonan syndrome to chromosomal
region 12q22qter. Nevertheless, the gene is at present not cloned, so that
a laboratory test to confirm a clinical diagnosis of Noonan syndrome is
not yet available. In searching the gene for Noonan syndrome, it would
be interesting to look at candidate genes that might explain cardiac defects,
particularly valvular abnormalities and cardiac hypertrophy.
Prenatal diagnosis
Prenatal diagnosis by molecular testing is not possible. Nevertheless
ultrasonographic findings can suggest the diagnosis in utero. Reported
sonographic signs include cystic hygroma, hydrothorax, polyhydramnios,
and congenital heart defect.43 However, Noonan syndrome has
an evolving phenotype, since early nuchal region findings can regress in
later pregnancy and detectability of characteristic cardiac defects of
Noonan syndrome can be low, since pulmonary stenosis can be difficult to
diagnose in utero and asymmetric septal hypertrophy is a progressive anomaly
that becomes more evident postnatally. The variability of the phenotype
must also be taken in consideration, since patients with mild phenotypic
expression have only subtle sonographic manifestations, which can be overlooked.
Conversely, it has been noted that second-trimester manifestations may
predict a severe postnatal course.
Conclusions
Noonan syndrome is a genetic condition with characteristic phenotypic
anomalies, but a wide range of clinical expression. Cardiac malformations
are also heterogeneous. At present, it is not known whether clinical variability
reflects variable expression of the same genetic defect or, on the contrary,
genetic heterogeneity may be involved by causing similar phenotypes due
to different genetic entities.
It is important to point out that clinical aspects and associated malformations of Noonan syndrome can be early identified and favourably treated. Patients with Noonan syndrome can have good physical health and a normal grade of intelligence, with a positive integration in social life.
Although a gene for Noonan syndrome has been mapped by linkage analysis
to chromosome 12q, the gene or genes of the syndrome have not been yet
identified. The association of Noonan syndrome with peculiar types of cardiac
defects could be used to address the search for the gene of Noonan syndrome
to specific cardiac candidate genes. It is hopful that the rapidly evolving
progresses in genetic mapping and identification could lead also to the
understanding of the pathogenetic mechanism of this peculiar and fascinating
syndrome.
References
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