Characteristic facial features that change with age
In the postnatal period the forehead is broad and high, there is hypertelorism, epicanthic folds and downward slanting palpebral fissures, low-set posteriorly rotated ears with a thick helix, high arched palate, micrognathia, and a short neck with excess nuchal skin and a low posterior hairline. The contour of the face becomes more triangular with age and in childhood the face often appears coarse or myopathic, with prominent eyes and (unilateral or bilateral) ptosis, and thick lips with prominent nasolabial folds. In the adolescent and young adult, the eyes are less prominent and the neck appears less short. Sometimes there is marked webbing or prominent trapezius. Typically, older adults have prominent nasolabial folds, a high anterior hair line, thick hooded eyelids and wrinkled skin [
1,
4]. The facial features can be subtle, especially at old age.
The most common congenital
heart defect is pulmonary valve stenosis with dysplastic leaflets (50%–62%) [
5,
6]. Hypertrophic obstructive cardiomyopathy (HOCM) with asymmetrical septum hypertrophy is present in 20% of patients. Atrial septal defects occur in 6%–10% of cases, ventricular septal defects occur in 5% of cases and persistent ductus arteriosus occurs in 3% of cases [
3,
4]. Other congenital heart defects more often seen in NS are atrioventricular canal defect (AVCD) associated with subaortic obstruction and structural anomalies of the mitral valve [
7].
Electrocardiograms (ECG) from NS patients display wide QRS complexes with a predominantly negative pattern in the left precordial leads (62%). They also display left axis deviation and giant Q waves [
5,
8].
Weight and length are usually normal at birth. Birth weight can be high due to subcutaneous oedema. In such cases, marked weight loss occurs in the first week of life. Neonatal feeding difficulties and failure to thrive are present in 63% of patients [
4]. In general, these feeding problems resolve spontaneously later in infancy. Mean prepubertal growth parallels the 3rd centile for height and weight. Onset of puberty is delayed by approximately two years and the pubertal growth spurt is often reduced or absent. The average bone age is also delayed by two years. Mean adult height is 162.5 cm in males and 152.7 cm in females. Both values are below the 3rd centile. Noonan-specific growth curves were designed in 1988 [
9]. Growth hormone (GH) levels are in the normal range. Somatomedin levels are elevated in some cases. GH treatment in pharmacological doses can be used to accelerate growth during the first years of life. Initial reports on the long-term effects of this treatment show a beneficial effect [
10,
11]. NS patients with a mutation in the
PTPN11 gene respond less efficiently to GH than NS patients without a mutation in
PTPN11 [
12].
Characteristic
chest deformities consist of pectus carinatum superiorly and pectus excavatum inferiorly. These sternal abnormalities are present in 70%–95% of cases. The thorax is broad and the internipple distance is large. About 15% of patients develop thoracic scoliosis. The shoulders are often rounded with scapula alata. Other common orthopaedic features include cubitus valgus (50%), radioulnar synostosis (2%), clinobrachydactyly (30%), joint hyperextensibility (50%) and talipes equinovarus (12%) [
3,
4]. Giant cell lesions of the jaw, similar to those seen in cherubism, have been reported in several patients [
13].
Undescended testicles at birth are common in male patients (77%). Increased luteinizing hormon (LH) and follicle stimulating hormone (FSH) levels are present in prepubertal boys [
14]. High FSH levels and poor quality semen have been found in adults, suggesting a failure of spermatogenesis in patients with testicular maldescent [
15]. In both sexes, pubertal development is delayed. The mean age of menarche in female patients is 14.6 years [
4]. However, fertility is not impaired in females with NS.
Urinary tract malformations are present in 10% of cases, mostly pyelo-ureteric stenosis and/or hydronephrosis [
4,
16].
Increased bruising or bleeding is frequent, especially in childhood. Up to 55% of cases have a mild-to-moderate bleeding tendency. Severe haemorrhage occurs in 3% of cases. Coagulation studies reveal prolonged bleeding times, factor VIII, XI and XII deficiencies, thrombocytopaenia and platelet function defects. These manifestations appear individually or in combination [
4,
17]. For NS patients, there is no correlation between the results of coagulation tests and a history of easy bruising. Thus, these tests may not be predictive of bleeding risk in NS patients. Since many patients undergo one or more operations, special care is required to prevent intraoperative or postoperative haemorrhage. Suitable blood products should be made readily accessible in case such complications arise [
18].
Acute leukaemia and myeloproliferative disorders (MPD) have been described in some patients. The 218C>T mutation in the
PTPN11 gene is associated with a predisposition to an MPD, which most often resolve spontaneously [
19]. In rare cases, individuals with NS can develop fatal MPD, typically juvenile myelomonocytic leukaemia (JMML). However, the prognosis for NS patients with JMML is better than that for non-NS patients with JMML [
19,
20].
Lymphatic vessel dysplasia, hypoplasia, or aplasia are common findings in NS (20%). They lead to generalised lymphoedema, peripheral lymphoedema, pulmonary lymphangiectasia or intestinal lymphangiectasia. The most common manifestation is dorsal limb lymphoedema, which usually disappears during childhood. Varying degrees of oedema or hydrops are present during intrauterine life. Ultrasound examination may reveal a cystic hygroma in early pregnancy. This swelling subsequently regresses and results in excess nuchal skin and pterygium colli after birth. Other features, which may be due to disruption of normal tissue migration or organ placement by foetal oedema, are cryptorchidism, wide-spaced nipples, low-set posteriorly rotated ears, hypertelorism and downward slanting palpebral fissures [
21,
22]. Spontaneous chylothorax may occur in childhood and chylous effusion is a known complication of cardiac surgery and surgery for thoracic deformity [
23,
24].
Abnormalities of pigmentation in NS include pigmented naevi (25%),
cafe-au-lait spots (10%) and lentigines (3%). Ulerythema ophryogenes (
keratosis pilaris atrophicans faciei) is present in 14% of cases and may lead to a lack of eyebrows. NS is also often accompanied by keratosis pilaris on the upper arms [
4,
25]. Approximately one-third of the patients have thick curly hair, and 10% have thin sparse hair. Foetal pads on fingers and toes are common (67%) [
4].
Frequent
ophthalmic abnormalities are strabismus (48%–63%), refractive errors (61%) and amblyopia (33%). Anterior segment changes (63%) and fundal abnormalities (20%) may be present, nystagmus is seen in 10% of NS patients [
26,
27].
Hearing loss due to otitis media is a frequent complication (15%–40%). Sensorineural hearing loss is less common, but involves the low frequency range in 10% of patients and the high frequency range in 25% of patients [
28]. Structural anomalies of the inner ear have occasionally been reported [
29,
30] and vestibular abnormalities have been described in a single case [
31].
Hepatosplenomegaly unrelated to cardiac failure is often present in infancy (26%–51%). It is less frequent with higher age. There are no reports of hepatic and/or splenal dysfunctions being associated with the organomegaly [
4,
19].
In general, children with NS demonstrate
mild motor delay, which may be partly attributed to the muscular hypotony that is often present in early childhood. Mean age for sitting is 10 months, that for walking alone is 21 months, and that for talking is 31 months [
4]. Articulation abnormalities are frequent (72%). Mental retardation is present in 15%–35% of cases and is usually mild. It is characterised by specific visual-constructional problems and verbal performance discrepancy. Mean full scale intelligence quotient (IQ) is 85, but there is a wide range in the level of intelligence [
32,
33]. Prominent behavioural problems are clumsiness, eating problems, fidgety or stubborn spells, echolalia and irritability. Social problems and attention deficit have also been noted. In spite of this wide range of reported behavioural problems, most authors state that children with NS can be raised with parental support alone, without any specialised intervention [
34].