|Year : 2014 | Volume
| Issue : 1 | Page : 22-25
Bilateral branch pulmonary artery stenosis and Mitral valve prolapse in a patient with Noonan syndrome: A case report
Meenakshi Kadiyala, Viswanathan Thangavelu, Kannan Radhakrishnan
Department of Cardiology, Madras Medical College, Chennai, Tamil Nadu, India
|Date of Web Publication||3-Mar-2014|
Department of Cardiology, Madras Medical College, Chennai, Tamil Nadu - 600 003
Source of Support: None, Conflict of Interest: None
Rasopathy syndromes are a class of phenotypically similar, but genetically distinct multiple anomaly syndromes caused by germ line mutations in genes that encode protein components of the Ras/mitogen activated protein kinase (MAPK) pathway. Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome are part of this group of developmental syndromes and have similar cardiac abnormalities. A 19-year-old male presented with complaints of exertional breathlessness class I for 6 months. Clinical examination revealed characteristic facial features, skeletal abnormalities, growth and neurocognitive problems reported in patients with Noonan syndrome. There was evidence of severe pulmonary hypertension. Trans-thoracic echocardiography revealed right atrial and right ventricular enlargement, severe pulmonary hypertension, no intra cardiac shunt, prolapse of anterior mitral leaflet with mild mitral regurgitation. CT pulmonary angiogram revealed bilateral branch pulmonary artery stenosis. A final diagnosis of Noonan syndrome was made.
Keywords: Branch pulmonary artery stenosis, mitral valve prolapse, noonan syndrome
|How to cite this article:|
Kadiyala M, Thangavelu V, Radhakrishnan K. Bilateral branch pulmonary artery stenosis and Mitral valve prolapse in a patient with Noonan syndrome: A case report. Heart India 2014;2:22-5
|How to cite this URL:|
Kadiyala M, Thangavelu V, Radhakrishnan K. Bilateral branch pulmonary artery stenosis and Mitral valve prolapse in a patient with Noonan syndrome: A case report. Heart India [serial online] 2014 [cited 2018 Dec 15];2:22-5. Available from: http://www.heartindia.net/text.asp?2014/2/1/22/127977
| Introduction|| |
Noonan syndrome is part of Rasopathy syndromes and has characteristic phenotypic features and cardiac abnormalities namely congenital heart diseases, hypertrophic cardiomyopathy and arrhythmia.  The other syndromes - cardiofaciocutaneous syndrome and Costello syndrome despite numerous overlapping features exhibit unique phenotypic features.
Noonan syndrome occurs in 1 per 1000 to 1 per 2500 live births characterized by a characteristic facial appearance (triangular shaped facies, ptosis, hypertelorism, low set ears, low posterior hairline), webbed neck, pectus excavatum, learning disabilities, bleeding diathesis, cryptorchidism, lymphatic problems, strabismus, refractive errors and variable intellectual disability.  It is genetically heterogeneous with at least 7 causative genes identified (PTPN 11, SOS1, KRAS, RAF1, NRAS, BRAF and SHOC2). , Approximately 50% of the patients with Noonan syndrome have a mutation in PTPN 11.  Most cases of Noonan syndrome are sporadic, although a pattern of autosomal dominant inheritance is well-known.
Approximately 80% of patients with Noonan syndrome have a cardiovascular abnormality  (60% congenital heart disease and 20% hypertrophic cardiomyopathy). Pulmonary valve stenosis with an atrial septal defect is the most common (25 to 35 %) overall and most commonly associated with PTPN 11 mutations.  Various additional congenital heart defects have also been described. 
Frequently associated are pulmonary valvular stenosis, secundum atrial septal defects (ASD), hypertrophic cardiomyopathy (HCM) and partial atrio ventricular canal defects (AVCD). Aortic valvular stenosis, pulmonary hypertension, supravalvular pulmonary stenosis, patent ductus arteriosus (PDA), branch pulmonary artery stenosis, bicuspid aortic valve (BCAV), ventricular septal defects (VSD), Tetralogy of Fallot (TOF) and coarctation of aorta (COA) occur occasionally.  Rarely reported defects are aortic dissection, dilated cardiomyopathy, mitral valve anomalies, pulmonary atresia, aortic root dilation, restrictive cardiomyopathy, Ebstein's anomaly of tricuspid valve and coronary artery abnormalities. ,
Costello syndrome and cardio facio cutaneous syndrome (CFC) are distinguishable from Noonan syndrome in the older child but can be similar in infants and very young children. Children with CFC syndrome also have relative macrocephaly, hypertelorism and ptosis but tend to have coarser facial features. HCM is more common (about 60%) in Costello syndrome.  We report a patient with clinical Noonan phenotype and cardiovascular manifestations, a probable Rasopathy syndrome.
| Case Report|| |
A 19-year-old male born to non-consanguineous parents was brought with complaints of exertional breathlessness class I for 6 months.
There was global developmental delay in childhood milestones predominantly with mentation. The scholastic performance was poor. The other sibling was normal. He had dysmorphic triangular facies, hypertelorism, deep set eyes, down slanting palpebral fissures, low set ears, mild prognathia, and deep philtrum, prominent lower lip and low posterior hairline. There was webbing of the neck, pectus excavatum, scoliosis, increased carrying angle at the elbow, large great toes. He was short-statured (151 cms) for his age. The development of secondary sexual characters was not delayed (Tanner's stage 3-4). The testes were descended.
The jugular venous pressure was elevated with dominant a wave. Clinically there was evidence of severe pulmonary hypertension. There was a grade 3/6 ejection systolic murmur in the left and right second intercostal spaces.
Complete hemogram, thyroid function tests, renal parameters and ultra sound abdomen were normal. Electro cardiogram showed features of right atrial enlargement, right ventricular hypertrophy and right axis deviation. X-ray chest showed right atrial enlargement, Right ventricle type of apex, oligemic lung fields and scoliosis.
Echocardiogram showed right atrial and right ventricular enlargement, with features of severe pulmonary hypertension, severe tricuspid regurgitation with a peak gradient of 163 mmHg, flattened interventricular septum during both systole and diastole [Figure 1]. The pulmonary valve was not dysplastic. There was prolapse of anterior mitral leaflet with mild mitral regurgitation with a posterior eccentric jet [Figure 2]. Panel A and B]. The aortic valve was normal. Left ventricular function was normal. CT pulmonary angiogram [Figure 3] showed enlarged right atrium. There was focal out pouching with narrowing followed by distal dilatation in Right descending lobar pulmonary artery. Left descending pulmonary artery showed narrowing with dilatation.
|Figure 1: Trans-thoracic echo (TTE) short axis view at aortic level showing severe tricuspid regurgitation with a peak gradient of 161 mmHg|
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|Figure 2: Echocardiogram – Parasternal long axis view showing anterior mitral leaflet prolapse (Panel A) with posteriorly directed eccentric jet (Panel B)|
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|Figure 3: CT pumonary angiogram showing Right descending lobar pulmonary artery with focal out pouching and narrowing followed by distal dilatation. Left descending pulmonary artery shows narrowing with dilatation (white arrows)|
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| Discussion|| |
Noonan syndrome was first recognized as a unique entity in 1962 when Noonan and Ehmke described a series of patients with unusual facies and multiple malformations, including congenital heart disease. Diagnostic criteria for Noonan syndrome were developed by Van der Burgt [Table 1].
Facial and musculoskeletal features most often lead to the diagnosis of Noonan syndrome. Diagnostic criteria were developed by van der Burgt in 1997.  The characteristic features are more prominent in the childhood and adolescence and become more subtle with adulthood. Our patient had many characteristic features including triangular facies, hypertelorism, deep set eyes, down slanting palpebral fissures, low set ears, mild prognathia, deep philtrum, webbing of neck, wooly hair and a low-posterior hairline. A characteristic pectus deformity of the chest has been described and scoliosis has been reported in 10-15% of the cases.  Our patient had pectus excavatum, scoliosis, and increased carrying angle at the elbow and large great toes.
Definitive Noonan syndrome Criterion 1 A + One of 2A-6A /Two of 2B-6B OR Criterion 1 B + Two of 2A-6A/Three of 2B-6B
This patient had one major (facial features) along with 4 A (pectus excavatum), 2B (other cardiac defect), 3B (height <10 th centile ) and 6B fulfilling the criteria for definitive Noonan syndrome.
Approximately 50% to 70% of individuals with NS have short stature. Puberty is typically delayed for both boys and girls with Noonan syndrome and is characterized by a diminished pubertal growth spurt 5. Although short-statured (<10 th centile), there was no delay in secondary sexual character development (Tanner's stage 3-4) in our patient
Cryptorchidism is reported in up to 80% and renal anomalies (solitary kidney, renal pelvis dilation, and duplicated collecting system) occur in 10% to 11%. Thyroid antibodies are commonly found. This patient had normally descended testes, no renal anomalies and normal thyroid function.
Most people with Noonan syndrome have normal intelligence, but 10% to 40% require special education. Our patient had global developmental delay in milestones predominantly with mentation and mild mental retardation. A broad spectrum of cardiac abnormalities has been reported in Noonan syndrome.  This patient had right and left descending pulmonary artery narrowing which has been reported to occur only occasionally. The patient also had anterior mitral leaflet prolapse with mild mitral regurgitation which also has been rarely reported to occur. Sznajer y et al., reported an incidence of peripheral pulmonary artery stenosis in 15% of 274 patients.  However, branch pulmonary artery stenosis with mitral valve prolapse in Noonan syndrome has been rarely reported in literature. 
Among the mutated genes that account for NS, many different genotype/phenotype correlations have been made.  No phenotypic features are found exclusively among one genotype, probably because of genetic and epigenetic factors that inﬂuence both penetrance and expressivity. PTPN11 mutations have been consistently associated with the presence of a pectus deformity, the characteristic facial appearance, and short stature  and pulmonary valvular stenosis.  SHOC 2 mutations are associated with over representation of mitral valve prolapse and septal defects.  Our patient showed an overlap of features which could not be ascribed to any specific gene mutation which is usually the case with sporadic forms (as was probably in our case). We did not embark on genetic studies because the patient could not afford it. Trans-catheter management with balloon pulmonary angioplasty (BPA) and or endovascular stenting is generally considered the procedure of choice for most patients with branch pulmonary artery stenosis. Stenoses at the branch pulmonary arteries bifurcation as in this patient are better dealt with at surgery.  The patient is presently on follow-up with cardiothoracic surgery department.
| Conclusion|| |
Noonan syndrome is genetically heterogeneous with at least seven causative genes identified. A high index of suspicion is necessary to recognize these patients when typical features are not present. Gene testing may be needed to differentiate from other phenotypically similar syndromes (Costello, cardiofaciocutaneous syndrome) in childhood. This case is presented because of its sporadic nature and its association with less common cardiac defects.
| References|| |
|1.||Tidyman WE, Rauen KA. Noona, Costello and cariofacio cutaneous syndromes: Dysregulation of the Ras -MAPK pathway. Expert Rev Mol Med 2008;10:e37. |
|2.||Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, et al. Noonan syndrome: Clinical features, diagnosis, and management guidelines. Pediatrics 2010;126:746-59. |
|3.||Lin AE, Alexander ME, Colan SD, Kerr B, Rauen KA, Noonan J, et al. Clinical, pathological and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome. Am J Med Genet A 2011;155:486-507. |
|4.||Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y. The RAS/MAPK syndromes: Novel roles of the RAS pathway in human genetic disorders. Hum Mutat 2008;29:992-1006. |
|5.||Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, et al. PTPN11 mutations in Noonan syndrome: Molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002;70:1555-63. |
|6.||DYSCERNE - Noonan Syndrome Guideline Development Group: Management of Noonan Syndrome: A Clinical Guideline, Version 1,2010;03-04. |
|7.||Sznajer Y, Keren B, Baumann C, Pereira S, Alberti C, Elion J, et al. The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene. Pediatrics 2007;119: e1325-31. |
|8.||Zenker M. Genetic and pathogenetic aspects of Noonan syndrome and related disorders. Horm Res 2009;72 Suppl 2:57-63. |
|9.||Bacha EA, Kreutzer J. Comprehensive management of branch pulmonary artery stenosis. J Interv Cardiol 2001;14:367-75. |
[Figure 1], [Figure 2], [Figure 3]