Noonan's syndrome is a genetic disease with an autosomal dominant transmission, with mutation of the PTPN11 gene found in from one-third to half of all cases.1–3 Congenital cardiac malformations are frequent, with pulmonary valvar stenosis and hypertrophic myocardiopathy typically present.4 Aortic stenosis is rarely reported, and its association with mutation of the PTPN11 gene, as far as we know, has never been described. We have now encountered a patient with familial Noonan's syndrome and severe aortic valvar stenosis, finding a mutation of the PTPN11 gene in his father.
Case report
F. was the first child, born at full term of a normal pregnancy. The apgar score was 10 out of 10 the first minute, and his birth weight was 3.150 kilograms. At the age of 1 month, he started to be short of breath when suckling. Cardiac auscultation revealed a systolic murmur, graded at 2 from 6, at the aortic position, with normal femoral pulses and blood pressure. He had marked craniofacial abnormalities including hypertelorism, an antimongoloïd slant of the palpebral fissures, short neck, and retrognathism. He had a history of bilateral cryptorchidism and a horseshoe kidney. The electrocardiogram showed left axis deviation, with the QRS axis at – 120° (Fig. 1). Cross-sectional and Doppler echocardiography showed severe aortic valvar stenosis, with maximal and mean gradients respectively of 120 and 70 millimetres of mercury. The aortic valve was trifoliate, but with dysplastic and markedly thickened leaflets (Fig. 2). The left ventricle was also markedly thickened, with concentric myocardial hypertrophy. The pulmonary valve was slightly thickened, albeit without significant stenosis. From these findings, we suspected the diagnosis of Noonan's syndrome.
Figure 1. Electrocardiogram showing left QRS axial deviation at –120°, typical for Noonan's syndrome.
Figure 2. Cross-sectional echocardiography of the aortic valve. The long axis plane (left) shows dysplastic aortic leaflets and hypertrophic myocardiopathy. The short axis plane (right) shows markedly thickened free edges of the three valvar leaflets.
Surgery was performed on account of the severity of the aortic valvar stenosis, with commissurotomy achieved after a period of aortic clamping of 56 minutes. The peroperative views confirmed the extent of the thickening of the valve. At the end of the surgical procedure, however, there was severe biventricular failure culminating in death.
Screening of the family showed that the father had typical signs of Noonan's syndrome, with craniofacial abnormalities, left axis on the electrocardiogram, surgical correction of bilateral cryptorchidism, and hypertrophic septal myocardiopathy. The physical examination of his mother, however, failed to reveal the typical signs of Noonan's syndrome. Venous blood was drawn from the father for extraction of genomic deoxyribonucleotide after obtaining informed consent. Screening was carried out for any mutation of the PTPN 11 gene, using methods previously described.5 Direct sequencing showed the mutation A922G (N308D), which is among the most frequent mutations found in Noonan's syndrome. The parents have now requested genetic counselling with a view to a future pregnancy.
Discussion
First described in 1963, Noonan's syndrome is a polymalformation syndrome characterised by distinct facial abnormalities, light to severe mental retardation in up to three-quarters of cases, short stature, thoracic deformity, cryptorchidism, and cardiac malformations in from half to four-fifths of cases.4 The most frequent cardiac lesions are pulmonary valvar stenosis, found in up to three-quarters of afflicted patients, hypertrophic myocardiopathy seen in up to one-fifth, and deficiencies within the oval fossa. The syndrome is an autosomal dominant disorder, with mutations of the PTPN11 gene found in from one-third to half of the affected individuals.1–3 This gene maps to chromosome 12q24, and encodes the protein tyrosine phosphatase (SHP-2). Zenker et al.,6 in a study involving 57 patients which explored genotype-phenotype correlations, showed that patients having the mutation had a higher prevalence of congenital cardiac defects, with greater frequency of pulmonary stenosis compared to those without the mutation, but fewer with cardiomyopathy, and also atrial or ventricular septal defects. The findings reported by Zenker et al.6 did not achieve statistical significance, but similar results with statistical significance had previously been found by Tartaglia et al.,2 who studied 119 patients. Sarkozy et al.1 also found that, among their patients with the mutation, pulmonary stenosis was the most common congenital heart defect, being found in two-thirds, and being associated with a codon 308 mutation hot spot, while cardiomyopathy was found in one-sixth of the individuals with congenital cardiac malformations.
Left-sided obstructions are less common, but their prevalence is significant, although probably underestimated. Marino et al.,7 for example, discovered aortic coarctation in almost one-tenth of their series of 136 patients. Anomalies of the mitral valve, detected in 8 patients, were responsible for subaortic stenosis. Interestingly, atrioventricular septal defect with common atrioventricular junction, but separate valves for the right and left ventricles, the so-called “ostium primum defect”, was detected in 21 patients, being associated with subaortic obstruction in 5 of those 21 patients.
Aortic valvar stenosis, however, is seldom described in Noonan's syndrome, with no cases reported in the cited studies.1–3 We have found only 2 individual case reports.8, 9 Chen et al.,10 however, have worked on mice which had a homozygous mutation for the Egfr wa2/wa2 gene. This gene encodes for a protein involved in development of the arterial, but not atrioventricular, valves, and particularly in the transformation of endocardial into mesenchymal cells. The aortic and pulmonary valvar leaflets were thickened compared to heterozygous mutant mice.
Concerning the effects of genetic mutation on left-sided structures, Sarkosy et al.,1 report, on one hand, the case of a patient with mutation of exon 3 of the PTPN11 gene having dysplastic mitral valvar leaflets, and on the other hand, 2 patients without the mutation but with mitral valvar anomalies without dysplastic leaflets. Moreover, none of the patients with the mutation was associated with aortic coarctation, whereas this was found in 4 of those without the mutation. These findings suggest that the PTPN11 gene may also play a role in the development of atrioventricular valves, albeit that this needs to be proven, and that there might be a different genetic background causing aortic coarctation in patients with Noonan's syndrome.
