A Unique Case of a 12-Year-Old Boy With Noonan Syndrome Combined With Noncompaction of the Ventricular Myocardium Xiao-Lin Sun,1 PhD, Jian-xun Zhao,1 PhD, Xiao-jing Chen,1 PhD, Zhi Zeng,1 MD, Yu-cheng Chen,1 MD, and Qing Zhang,1 MD

Summary A 12-year-old Chinese boy was admitted with dyspnea after exercise. Based on his clinical features, echocardiogra- phy tests, and family history, he was diagnosed with Noonan syndrome (NS) combined with noncompaction of the ven- tricular myocardium (NVM). Noonan syndrome (NS) is a common syndrome, but to the best of our knowledge, our case is the first reported case of NS combined with NVM. In our case, the detected mutated genes may be inherited and unre- ported genes caused NS or NVM. Our research may enrich our knowledge about NS and contribute to furthering our un- derstanding of the pathogenesis and treatment. In summary, we present a unique case of NS combined with NVM. (Int Heart J 2016; 57: 258-261)

Key words: Congenital heart disease, Noncompaction , Gene

oonan syndrome (NS) is an autosomal dominant in- ents were not consanguineous. Other relatives had no related herited disorder with an estimated prevalence of symptoms. N 1/1000–2500 live births.1) The clinical symptoms of The patient was 131 cm tall (< 3rd percentile) and NS are complex and vary with age, but it has some cardinal weighed 29 kg (< 3rd percentile). He had distinctive facial fea- features including characteristic facies, , congeni- tures (including a wide forehead, , , micro- tal heart defects, skeletal abnormalities, mild mental retarda- gnathia, and low-set posteriorly rotated ears), a , tion, and variable development delay.1) The congenital heart webbed fingers (Figure 1), a generalized body rash, and scolio- defect is the second most common feature of NS, and more sis. A systolic murmur in the II–III intercostal region on the than 80% of the patients with NS have a cardiovascular abnor- left sternal border was found during physical examination. mality.2) Noncompaction of the ventricular myocardium Electrocardiography displayed wide and high P waves (NVM) is a relatively rare cardiomyopathy, which is character- and QRS complexes indicative of a complete right bundle ized by prominent ventricular trabeculae and deep intertrabec- branch block (RBBB). Transthoracic echocardiography re- ular recesses communicating with the ventricular cavity. It re- vealed normal systolic function of both ventricles, normal ven- sults from arrest of the normal compaction process of the tricular wall thickness, an enlarged right atrium and ventricle, developing myocardium in the process of myocardial morpho- slightly smaller left ventricle, two atrial septal defects (ASD; genesis.3,4) NVM is very heterogeneous in its clinical presenta- 13 × 19 mm and 5 mm) with multiple left–right shunts, and tion, and can be isolated or associated with other cardiomyopa- mild tricuspid regurgitation. There were also heavy prominent thies, congenital heart diseases, and complex syndromes trabeculae in the left and right ventricles, predominantly in the involving the heart. This is a unique case of a 12-year-old boy apex, and blood flow within the deep intertrabecular recesses diagnosed with Noonan syndrome and having typical echocar- suggestive of noncompaction of the ventricular myocardium diographic imaging of NVM. (NVM). Left ventricular contrast echocardiography also con- firmed the diagnosis of NVM by conventional transthoracic echocardiography (Figure 2). Case Report analysis revealed a normal male 46, XY kary- otype with a normal chromosome microarray. Gene testing A 12-year-old boy presented to our department with dys- was performed. Next generation sequencing (NGS) platform- pnea after exercise (decreased exercise tolerance). His mother ion torrent was utilized to perform exome analysis of the and elder brother were healthy. According to his mother, his genes. The candidate genes were associated with all of the in- father had a webbed neck and webbed toes and had died of herited cardiovascular-related diseases, which were selected congenital heart disease (further details unavailable). His par- according to Online Mendelian Inheritance in Man (OMIM).

From the 1 Department of , West China Hospital, Sichuan University, Chengdu, China. Address for correspondence: Qing Zhang, MD, Department of Cardiology, West China Hospital, Sichuan University, No.37, Guoxue Road, Chengdu 610041, Sichuan, China. E-mail: [email protected] Received for publication August 31, 2015. Revised and accepted October 17, 2015. Released in advance online on J-STAGE March 11, 2016. All rights reserved by the International Heart Journal Association. 258 Vol 57 No 2 NOONAN SYNDROME AND VENTRICULAR NONCOMPACTION 259

Figure 1. A: Webbed neck. B: Webbed fingers.

Figure 2. A: Apical echocardiogram in 4-chamber view demonstrating heavy prominent trabeculations in the left and right ventricles. B: Short-axis view demonstrating noncompaction of the left ventricular apex. C, D: Massive trabeculations are shown to have increased significantly in the right ventricular free wall and apex as well as the left ventricular apex on left ventricular contrast echocardiography.

The gene testing results revealed in the SH3 and PX cardiac catheterization and implanted a 28 mm ASD occluder domains of 2B (SH3PXD2B, c.970G > A), Bardet-Biedl syn- (Starway Medical Technology, Inc., Beijing). Before occlusion drome 2 (BBS2, c.865T > C, and c.1297-1296insertion G), and the mean pulmonary artery pressure was 44/25/15 mmHg. titin (TTN, c.53149G > A, c.44726T > A, and c.52151A > G) Pulmonary hypertension was excluded by both Doppler genes as well as some single nucleotide polymorphic varia- echocardiography and cardiac catheterization. After the cardiac tions such as COQ2, MLYCD, AGL, and LRPPRC. catheterization, transthoracic echocardiography showed an In order to relieve his declined exercise tolerance, we per- echo of occluder in the middle of the atrial septum without at- formed percutaneous atrial septal defect closure. We performed tached thrombus and residual shunt around it, microscale tri- Int Heart J 260 SUN, ET AL March 2016 cuspid regurgitation; LV end-diastolic dimension (EDD) at 36 pate in the RAS-MAPK pathway.16) How- mm, LV end-diastolic volume (EDV) at 54 mm, and LV ejec- ever, these mutations can only explain 60–75% of molecular tion fraction (EF) at 68%. NS causes.17) Similarly, many different gene mutations have been reported in patients with NVM, such as DTNA, ZASP, ACTC, TNNT2, MYH7, and G4.5 (TAZ). These genes are asso- Discussion ciated with mitochondrial, cytoskeletal, Z-line, and sarcomeric proteins.18) Because of the patient’s clinical features, karyotype and Although our patient was negative for known NS- or family history, he was definitively diagnosed with NS accord- NVM-related mutations, many mutated genes were presented ing to the NS scoring system developed by van der Burgt.5) in his gene testing results. However, these mutations may be The description of transthoracic echocardiography met echo­ the new variable sites associated with NS or NVM. SH3PXD2B cardiographic diagnostic criteria for NVM.6,7) As such, the pa- encodes an adapter protein, and mutations in this gene are as- tient’s final diagnosis was NS and NVM. To the best of our sociated with Frank-ter Haar syndrome (FTHS). BBS2 is a knowledge, this is the first reported clinical case of NS com- member of the BBS gene family, mutations of which may bined with NVM. However, NS combined with NVM has cause Bardet-Biedl syndrome (BBS). The 3 mutations of these been observed by Nakamura, et al in a mouse model of NS.8) two genes are all heterozygous mutations in this case, which Their study provides a credible basis for our conjecture that might not cause the FTHS and BBS (autosomal recessive in- NS may lead to NVM. herited disorder). TTN encodes a large abundant protein of stri- A broad spectrum of cardiac abnormalities have been re- ated muscle, which spans in a spring-like fashion from the Z- ported due to NS, such as pulmonary stenosis (50–60%), disc to the M-band as a single molecule. Mutations in this gene hypertrophic cardiomyopathy (HCM, 16-20%), and ASDs (6– are associated with cardiac and skeletal myopathies, and trun- 10%).2) Our patient had two ASDs which were NS associated cation mutations are a common cause of dilated cardiomyopa- cardiac defects, and maybe the major reasons for the decreased thy.19) Recently, some research has indicated that titin expres- exercise tolerance. NVM is the specific cardiac disorder in our sion is regulated by MAPK/ERK signaling.20-22) Although TTN patient compared to other reported patients with NS. The clini- may be implicated in MAPK/ERK signaling that is associated cal symptoms of NVM patients are wide and nonspecific, and with 60–75% of NS, we could not determine whether the mu- they may have no symptoms or only chest pain, arrhythmias, tations of TTN had a relationship with the NS in our case. In and even heart failure. Following the progress of the disease, one case, an asymptomatic 5-year-old girl presented with the systolic function of the patients gradually decreases, and bradycardia, and her echocardiogram and cardiac MRI sug- more than 50% of patients ultimately develop heart failure.9) In gested left NVM; this patient was positive for a TTN mutation our case, systolic function was normal in both ventricles, but (Lys4455Arg).23) Thus, it is possible that TTN mutations are RBBB may have resulted from NVM.10) closely associated with NVM. From the limited genetic data, it Cardiovascular abnormality is the most serious threat to is difficult to ascertain a correlation between these mutated the survival of NS patients. The progression of NVM can re- genes and the phenotype of our patient. However, given the sult in fatal complications, such as embolic events, arrhythmi- suggestive NS of our patient’s father and the inheritance pat- as, and sudden death.9) In this patient, NS-associated ASD tern of NS and NVM (predominantly autosomal dominant in- combined with NVM was a serious disadvantage. In fact, heritance), these mutated genes, especially the TTN, may be NVM may be the most important prognostic factor for this pa- inherited, and cause NS or NVM. This topic requires further tient. However, there is currently no specific therapy validated research. for NS and NVM. Early correction of the cardiac defects may greatly improve prognosis. In this case, ASD closure was rec- ommended for our patient with multiple left–right shunts and References an enlarged right atrium and ventricle. We performed percuta- neous closure and prevented the development of right heart 1. Mendez HM, Opitz JM. Noonan syndrome: a review. Am J Med failure and pulmonary hypertension caused by the ASD.11) Gene 1985; 21: 493-506. (Review) A retrospective study in children with NVM reported that 2. Prendiville TW, Gauvreau K, Tworog-Dube E, et al. Cardiovascu- lar disease in Noonan syndrome. Arch Dis Child 2014; 99: 629- high left ventricular (LV) end-diastolic diameter at the time of 12) 34. diagnosis might be associated with a poorer prognosis. In 3. Jenni R, Oechslin EN, van der Loo B. Isolated ventricular non- this case, our patient had no LV enlargement, heart failure, compaction of the myocardium in adults. Heart 2007; 93: 11-5. ventricular wall thickening, or thromboembolic events, mean- (Review) ing that he may have a relatively better prognosis. However, 4. Weiford BC, Subbarao VD, Mulhern KM. Noncompaction of the regular follow-up care will be necessary not only during his ventricular myocardium. Circulation 2004; 109: 2965-71. (Re- childhood but also throughout his adulthood to enable early di- view) 5. van der Burgt I. Noonan syndrome. Orphanet J Rare Dis 2007; 2: 4. agnosis and timely treatment and to prevent serious complica- (Review) tions. 6. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann Both NS and NVM are genetically heterogeneous disor- PA. Echocardiographic and pathoanatomical characteristics of iso- ders with sporadic and familial forms.13,14) In recent years, mu- lated left ventricular non-compaction: a step towards classification tations in PTPN11, KRAS, SOS1, NRAS, RAF1, BRAF, as a distinct cardiomyopathy. Heart 2001; 86: 666-71. SHCO2, CBL, MAP2K1, MAP2K2, HRAS, NF1, and SPRED1 7. Zuccarino F, Vollmer I, Sanchez G, Navallas M, Pugliese F, Gayete A. Left ventricular noncompaction: imaging findings and have been identified in patients with NS or NS-like syn- diagnostic criteria. AJR Am J Roentgenol 2015; 204: W519-30. dromes.15,16) The proteins encoded by all of these genes partici- Vol 57 No 2 NOONAN SYNDROME AND VENTRICULAR NONCOMPACTION 261

(Review) 16. Jorge AA, Malaquias AC, Arnhold IJ, Mendonca BB. Noonan 8. Nakamura T, Colbert M, Krenz M, et al. Mediating ERK 1/2 sign- syndrome and related disorders: a review of clinical features and aling rescues congenital heart defects in a mouse model of Noo- mutations in genes of the RAS/MAPK pathway. Horm Res 2009; nan syndrome. J Clin Invest 2007; 117: 2123-32. 71: 185-93. (Review) 9. Lofiego C, Biagini E, Pasquale F, et al. Wide spectrum of presen- 17. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinical- tation and variable outcomes of isolated left ventricular non-com- ly related disorders. Best Pract Res Clin Endocrinol Metab 2011; paction. Heart 2007; 93: 65-71. 25: 161-79. (Review) 10. Iio C, Ogimoto A, Nagai T, et al. Association between genetic var- 18. Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere iation in the SCN10A gene and cardiac conduction abnormalities protein genes in left ventricular noncompaction. Circulation 2008; in patients with hypertrophic cardiomyopathy. Int Heart J 2015; 117: 2893-901. 56: 421-7. 19. Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing 11. Fujino T, Yao A, Hatano M, et al. Targeted therapy is required for dilated cardiomyopathy. N Engl J Med 2012; 366: 619-28. management of pulmonary arterial hypertension after defect clo- 20. Du MR, Zhou WH, Yan FT, et al. Cyclosporine A induces titin ex- sure in adult patients with atrial septal defect and associated pul- pression via MAPK/ERK signalling and improves proliferative monary arterial hypertension. Int Heart J 2015; 56: 86-93. and invasive potential of human trophoblast cells. Hum Reprod 12. Ozgur S, Senocak F, Orun UA, et al. Ventricular non-compaction 2007; 22: 2528-37. in children: clinical characteristics and course. Interact Cardiovasc 21. Nir R, Grossman R, Paroush Z, Volk T. Phosphorylation of the Thorac Surg 2011; 12: 370-3. Drosophila melanogaster RNA-binding protein HOW by MAPK/ 13. Croonen EA, Nillesen W, Schrander C, et al. Noonan syndrome: ERK enhances its dimerization and activity. PLoS Genet 2012; 8: comparing mutation-positive with mutation-negative dutch pa- e1002632. tients. Mol Syndromol 2013; 4: 227-34. 22. Zhong L, Chiusa M, Cadar AG, et al. Targeted inhibition of ANK- 14. Oechslin E, Jenni R. Left ventricular non-compaction revisited: a RD1 disrupts sarcomeric ERK-GATA4 signal transduction and distinct phenotype with genetic heterogeneity? Eur Heart J 2011; abrogates phenylephrine-induced cardiomyocyte hypertrophy. 32: 1446-56. (Review) Cardiovasc Res 2015; 106: 261-71. 15. Aoki Y, Niihori T, Banjo T, et al. Gain-of-function mutations in 23. Egan KR, Ralphe JC, Weinhaus L, Maginot KR. Just sinus brady- RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. cardia or something more serious? Case Rep Pediatr 2013; 2013: Am J Hum Genet 2013; 93: 173-80. 736164.