Noonan syndrome (NS) is a genetic disorder caused by mutations altering proteins relevant to RAS/mitogen-activated protein kinase signal transduction. Cardiac involvement is common, most prevalently pulmonary valve stenosis and hypertrophic cardiomyopathy. Because abnormal mitogen-activated protein kinase signaling contributes to the aortopathy in Marfan syndrome and with rare reports of aortic aneurysm in NS, we undertook a retrospective study of ascending aortic anatomy in 37 patients with NS and without confounding medical conditions. Age ranged from 0.6 to 32 years. Based on the most recent echocardiogram, the aortic annulus and root were dilated in the cohort (mean z scores of 1.14 and 0.98, respectively, p <0.005) but the sinotubular junction and ascending aorta were not (mean z scores of 0.05 and 0.19, respectively). The aortic root was aneurysmal (>2 z scores) in 8 subjects (21.6%). PTPN11 mutations were present in 14 subjects, whose aortic status was similar to the cohort overall. Comparison of age and z scores revealed a modest tendency for the aortic annulus and root to dilate over time. Among 13 subjects with multiple imaging studies over an average of 6.8 years, the average z score increased to 0.78 and 0.39 for the aortic annulus and root, respectively. Multivariate analysis revealed that age accounted for 7.0% and 11.0% of the variance in the aortic annular and root diameters, respectively. In conclusion, we found that aortic annular dilation and aortic root aneurysm are prevalent in NS, often presenting during childhood and progressing over time. Further study is needed to identify potential risks associated with these abnormalities.
Noonan syndrome (NS) is a genetically heterogenous, pleomorphic, autosomal dominant disorder. NS with multiple lentigines (formerly LEOPARD syndrome), Costello syndrome, and cardiofaciocutaneous syndrome are closely related phenotypically. Gene mutations underlying NS and the related disorders, termed the RASopathies, alter several proteins involved in the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. In NS, 80% to 90% of affected patients exhibit cardiovascular involvement, comprising morphologic defects, particularly pulmonary valve stenosis, and early-onset hypertrophic cardiomyopathy. Marfan syndrome, an unrelated genetic disorder caused by FBN1 mutations, is associated with aortic aneurysm, a result of excess transforming growth factor β signaling. In a mouse model of Marfan syndrome, the MAPK, Erk1/2, is hyperactivated in aortic aneurysm, and inhibition of RAS pathway is therapeutic. Because the RASopathies are characterized by excessive signaling through ERK1/2, we questioned whether aortic aneurysm is an unrecognized part of the phenotype. A literature review revealed a few case reports of aortic aneurysm at the aortic root or ascending aorta in NS ( Table 1 ). For the other rarer RASopathies, 1 case of aortic root aneurysm in an adolescent with Costello syndrome was identified. The combination of clinically relevant aortic issues in several patients with NS and evidence suggesting the involvement of MAPK pathways in the development of aortic aneurysms led us to investigate the prevalence of aortic dilation in patients with NS using a retrospective study design.
| Age (yrs) | Gender | Aortic Pathology | Treatment | Genotype | Reference |
|---|---|---|---|---|---|
| 8 | F | Root, annulus | Atenolol | PTPN11 R501K | Jefferies et al |
| Adult | M | Ascending, dissection | — | — | Kretschmar and Witkowski |
| 42 | M | Root | — | — | Lin et al |
| 18 | F | Ascending (aortitis) | Surgical replacement | None for PTPN11 , KRAS , BRAF | Menon et al |
| 42 | M | Root | — | — | Morgan et al |
| 8 | M | Root | — | PTPN11 E76D | Power et al |
| 49 | M | Root | Surgical replacement | — | Purnell et al |
| Adult | M | Ascending, dissection | Surgical replacement | — | Shachter et al |
| 41 | M | Ascending; abdominal, dissection | Surgical replacement | — | Tousimis and Deshmukh |
Methods
With Institutional Review Board approval, medical records and echocardiographic data were reviewed retrospectively for all patients with NS at the Icahn School of Medicine at Mount Sinai. Cases were identified through searches of an echocardiographic database covering 1993 to present, and a clinical database for the Cardiovascular Genetics Program in which affected patients are frequently assessed and followed. The inclusion criterion was any patient diagnosed with NS clinically, generally using established criteria, or through genetic testing. The exclusion criteria were aortic valve disease, subaortic stenosis, and previous surgery with aortic cannulation.
Echocardiographic data were extracted from reports, which routinely included z scores normalized for body surface area for the diameters of the aortic annulus, aortic root, sinotubular junction, and ascending aorta. The sites for those measurements were as previously described. z scores for those echocardiographic parameters from each subject’s most recent study were compared statistically using t testing to the population norm. For subjects with ≥2 echocardiographies performed over time, multivariate regression models were constructed with aortic root or annulus diameter z score as the dependent variable and ln (age) and dummy variables for patients as the independent variables using SPSS Statistics 20 (IBM, Armonk, New York).
Results
We identified 37 patients with NS who fit our inclusion and exclusion criteria. Among those, the underlying mutation was known in 16 cases, 14 altering PTPN11 . The remaining 2 were mutations in SOS1 and SHOC2 . The ages of the subjects ranged from 0.6 to 32 years (mean 10.7, median 7.0) and 57% were men.
The mean z scores from the subjects’ most recent echocardiogram for the aortic annulus and root were 1.14 and 0.98, respectively, which were significantly greater than the population norm (p <0.005). The distribution of z scores for the aortic annulus and root ( Figure 1 ) were similar to the expected normal distribution but shifted toward larger values. Of the 37 patients with NS, 10 (27.0%) had aortic annulus z scores >2, the threshold for declaring annular dilation. Similarly, 8 patients (21.6%) had aortic root z scores >2, qualifying as aortic root aneurysm. The numbers of patients with z scores >2 were significantly more than expected (p <0.01 and <0.05, respectively).
The mean z scores for the sinotubular junction and ascending aortic diameters were 0.05 and 0.19, respectively, which were not different from the general population. The distribution of z scores for these aortic anatomic sites was similar to the expected normal distribution ( Figure 1 ). No patient had dilation of the sinotubular junction, and 2 patients (5.4%) had ascending aortic z scores >2, not significantly more than the expected 2.5%.
The 14 subjects with a PTPN11 mutation had average aortic annulus and aortic root diameter z scores of 1.103 and 0.86, respectively, which were significantly greater than the population (p <0.05) but not different from the NS cohort overall. The mean z scores for the sinotubular junction and ascending aortic diameters were −0.07 and 0.20, respectively, which were not different from the general population or the NS cohort as a whole.
Next, we sought to determine if the aortic dilation was progressive in NS. To do that, we first looked at the effect of age on aortic annular and root sizes. As shown in Figure 2 , there was a modest tendency for z scores to increase with age. Similar effects were seen for the sinotubular junction and ascending aortic z scores. More strikingly, we studied subjects who had undergone ≥2 echocardiographies ( Figure 3 ). Among 13 such patients in our cohort, 5 (38.5%) had progressive aortic annular dilation and 7 (53.8%) had progressively dilating aortic roots over an average follow-up interval of 6.8 years. The average increases in z score for the aortic annulus and root were 0.78 and 0.39, respectively. Multivariate models of z scores in subjects who had undergone ≥2 echocardiographies revealed that ln (age) accounted for 11.0% of the variation in the aortic root z score (p = 0.002) and for 7.0% of the variation in the aortic annulus z score (p = 0.001).
