Case Report: Biventricular hypertrophic obstructive cardiomyopathy in Patient with Noonan syndrome

doi:10.21203/rs.3.rs-2350188/v1

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Case Report

Case Report: Biventricular hypertrophic obstructive cardiomyopathy in Patient with Noonan syndrome

https://doi.org/10.21203/rs.3.rs-2350188/v1

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Background: Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphology, and congenital heart defects. The incidence of NS is estimated to be between 1:1000 and 1:2500 live births. The syndrome is transmitted as an autosomal dominant trait. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the non-receptor protein tyrosine phosphatase SHP-2 protein

Case summary: We reported 17-year-old male patient known case of Noonan syndrome with a mutation in PTPN11 gene with HOCM, started to follow up at pediatric cardiology due to murmur, diagnosed as non-obstructive HCM 13 years ago, A year ago he started to follow up at adult cardiology and found to have biventricular obstructive cardiomyopathy.

Noonan Syndrome

Hypertrophic obstructive cardiomyopathy

We herein present the case of a 17-year-old male patient, who first presented for a cardiologic examination at the age of 5 years, due to a murmur. That time he was diagnosed with “non-obstructive hypertrophic cardiomyopathy” by echocardiography. He gives a history of operation for undescended testis at the age of 7 years. He was asymptomatic, following up regularly since then till he reached 15 years old in the pediatric cardiology clinic; afterward, he continued his follow up in adult cardiology clinic. He was completely asymptomatic till 3 months back when he started to complain of occasional rapid regular palpitations that are increased with exertion and relieved by rest, with gradual onset and offset and not associated with chest pain or syncope. He denied chest pain, lightheadedness, orthopnea, pedal edema, a history of hypertension, or a family history of cardiac disease or sudden death.

Physical examination revealed a healthy-appearing, comfortable young man with pulse 76 beats/min and blood pressure 102/60 mmHg. Pectus excavatum was apparent during the inspection of the precordium. A grade 3/6 harsh mid-systolic murmur could be heard at the left upper sternal border, with radiation to the apex but not to the neck. The intensity of this systolic murmur diminished to grade 2/6 with inspiration, squatting, and passive leg raising. The intensity of the murmur increased to grade 4/6 with Valsalva maneuver and standing. Normal S1, Single S2 in addition to S4 were noticed during auscultation. The remainder of the physical examination, including jugular venous pressure and carotid upstroke, was unremarkable. ECG showed diffuse T wave inversion (figure 1)

The echocardiography showed asymmetrical septal hypertrophy (22 mm thickness), systolic anterior motion of anterior mitral leaflet (as shown in figure2-A) with biventricular obstructive HCM, with a peak gradient of 140 mmHg in the left ventricular outflow tract (LVOT) (as shown in figure 2-B), gross hypertrophy of free wall of the right ventricle (7 mm). Colour Doppler imaging revealed turbulence across the mid RV cavity with a peak gradient of 22 mmHg (as shown in Figure 3-A), and peak gradient of 22 mmHg in the mid RV cavity (as shown in figure 3-B). Pulmonary valve was normal and there was no additional gradient across, severe mitral regurgitation was also found.

CMR was done and confirmed the echocardiography results of biventricular hypertrophic obstructive cardiomyopathy (as shown in figure 4).

The patient did not agree for further evaluation. He received beta-blockers which gave partial relief of his symptoms.

The legal guardians/parents of the pediatric patient agreed to the publication of her data and the institution where the patient had been admitted, approved the publication of the case.

Noonan Syndrome (NS) is an autosomal dominant disorder characterized by short stature, typical face dysmorphology, and congenital heart defects. NS is a clinical diagnosis. Establishing a diagnosis can be very difficult, especially in adulthood. There is great variability in expression and the phenotype becomes less pronounced with increasing age1. Several scoring systems have been devised to help the diagnostic process. The most recent scoring system was developed in 19942(Table 1).

Table 1: Scoring system for Noonan syndrome (NS)

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy worldwide with a prevalence of 0.16% to 0.29% in the general population.3 Although the ESC definition of HCM 4 is based on left ventricular (LV) wall thickness criteria (≥15mmin one or more myocardial segments that are not explained solely by loading conditions), right ventricular (RV) involvement can be noteworthy, as it is not rare and can affect the prognosis of the disease.

RV involvement consists of structural changes toward the hypertrophic phenotype and also of functional alterations. In contrast to diagnostic criteria for LV hypertrophy (LVH), the definition of RV hypertrophy (RVH) is not standardized. McKenna et al. classified RVH as mild (6-8 mm), moderate (9-12 mm), and severe (>12 mm) 4 and Maron et al. defined RVH as end-diastolic RV anterior, free, or apical wall thickness ≥5 mm, and if ≥ 10 mm, it is extreme/severe RVH 5.

The incidence of RV involvement in patients with HCM varies greatly according to the criteria and the method used. The first observations come from postmortem and then catheterization studies. Cardiac magnetic resonance (CMR) studies identify RVH in 30% 5, whereas echocardiography identifies RVH in 44% of patients with HCM.4 Severe RVH is relatively rare, with a prevalence of 1.3% in the overall HCM population 6.

Three possible locations of obstruction have been recognized: outflow tract, apex, and mid-base. RV outflow tract obstruction (RVOTO) has been defined as a pressure gradient exceeding 25 mmHg under resting conditions12 or as 16 mmHg by Shimizu et al 7.

Interestingly RV involvement in HCM is associated with an increased incidence of supraventricular and ventricular arrhythmias in 70% and 47% of the patients with RVH, respectively 8.

RVH is a qualitative and a quantitative risk factor that augments significantly the risk of SCD over and above the risk calculated by the SCD risk score. Although RV wall thickness (RVWT) is not currently included in the SCD risk score, as is the case for late gadolinium enhancement of the LV, for example, RVH is correlated with an increased SCD risk score 9 through 3 potential mechanisms: a) independent relationship with the presence of ventricular arrhythmias,9 b) increased percentage of myocardial fibrosis,10 and c) accumulation of more than one HCM mutation, 6.

Noonan syndrome is a rare disease, which can be very difficult to diagnose, especially based on features other than lentigines, and identification of Noonan syndrome in young can represent a challenge. Cardiac involvement in Noonan syndrome can be progressive and requires multiple medical and surgical interventions.

The detailed study of the right ventricle should be an integral part of the assessment and follow-up of patients with HCM to identify as early as possible its involvement, to clarify its modifying role in the natural history of the disease, and most importantly, to reduce with appropriate measures the risk of heart failure and SCD.

NS (Noonan Syndrome), HCM(Hypertrophic cardiomyopathy), ECG(Electrocardiogram), LVOT(Left ventricular outflow tract obstruction), RV(Right ventricle), LV (Left ventricle), CMR (cardiac magnetic resonant), RVH(Right ventricular hypertrophy), SCD(sudden cardiac death).

[1] Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD: Noonan syndrome: the changing phenotype. Am J Med Genet 1985, 21:507-514.

[2] Van der Burgt I, Berends E, Lommen E, van Beersum S, Hamel B, Mariman E: Clinical and molecular studies in a large Dutch family with Noonan syndrome. Am J Med Genet 1994, 53:187-191.

[3] Marian AJ, Braunwald E. Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res. 2017 Sep 15;121(7): 749e770.

[4] McKenna WJ, Kleinebenne A, Nihoyannopoulos P, Foale R. Echocardiographic measurement of right ventricular wall thickness in hypertrophic cardiomyopathy: relation to clinical and prognostic features. J Am Coll Cardiol. 1988;11: 351e358.

[5] Maron MS, Hauser TH, Dubrow E, Horst TA, Kissinger KV, Udelson JE, et al. Right ventricular involvement in hypertrophic cardiomyopathy. Am J Cardiol. 2007;100:1293e1298.

[6] Guo X, Fan C, Tian L, Liu Y, Wang H, Zhao S, et al. The clinical features, outcomes, and genetic characteristics of hypertrophic cardiomyopathy patients with severe right ventricular hypertrophy. PLoS One. 2017;12(3):e0174118.

[7] Shimizu M, Kawai H, Yokota Y, Yokoyama M. Echocardiographic assessment of right ventricular obstruction in hypertrophic cardiomyopathy. Circ J. 2003;67: 855e860.

[8] McKenna WJ, Kleinebenne A, Nihoyannopoulos P, Foale R. Echocardiographic measurement of right ventricular wall thickness in hypertrophic cardiomyopathy: relation to clinical and prognostic features. J Am Coll Cardiol. 1988;11: 351-358.

[9] Ros¸ ca M, C_alin A, Beladan CC, et al. Right ventricular remodeling, its correlates, and its clinical impact in hypertrophic cardiomyopathy. J Am Soc Echocardiogr. 2015 Nov;28(11):1329e1338.

[10] Ho CY, Lόpez B, Coelho-Filho OR, Lakdawala NK, Cirino AL, Jarolim P, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med. 2010;363:552-563.

No competing interests reported.

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Case Report: Biventricular hypertrophic obstructive cardiomyopathy in Patient with Noonan syndrome

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