Noonan syndrome in a premature infant with hypertrophic cardiomyopathy and death in infancy

We report an extremely premature infant with Noonan syndrome who developed rapidly progressive obstructive hypertrophic cardiomyopathy, which contributed to the death of the infant. The complications of prematurity combined with progressive, severe hypertrophic cardiomyopathy associated with Noonan syndrome lead to a poor prognosis.     

Hypertrophic obstructive cardiomyopathy as a manifestation of a cardiocutaneous syndrome (Noonan syndrome)

Summary The case of a 50-year-old patient with hypertrophic obstructive cardiomyopathy is reported. The patient demonstrated somatic signs of the Turner phenotype, but a cytogenetically normal karyotype was shown. These findings were compatible with the diagnosis of Noonan syndrome. The most commonly diagnosed cardiac disease in this syndrome is pulmonary stenosis, followed by hypertrophic cardiomyopathy. The patient's prognosis is limited by the natural history or the typical complications of the underlying cardiac lesion.Abbreviations EC echocardiography - H(O)CM hypertrophic (obstructive) cardiomyopathy - NS Noonan syndrome - SAM systolic anterior motion - MRT magnetic resonance tomogram - LH luteinizing hormone - FSH follicle-stimulating hormone     

Isolated right ventricular hypertrophic obstructive cardiomyopathy

Two cases of isolated hypertrophic cardiomyopathy of right ventricle without any involvement of interventricular septum or left ventricle are reported. Two cases reported in literature are also reviewed. In these cases symptoms are those of left ventricular hypertrophic obstructive cardiomyopathy. Right ventricular dominance on clinical examination and electrocardiogram and inspiratory increase in intensity of murmur are helpful clues. 2-Dimensional echocardiography with Doppler evaluation can confirm the diagnosis noninvasively.     

Sustained arrhythmias in hypertrophic obstructive cardiomyopathy

Patients with hypertrophic obstructive cardiomyopathy are subject to syncope and sudden death. Ambulatory monitoring discloses frequent and complex ventricular ectopy in many of these patients, and the occurrence of ventricular tachycardia suggests an increased risk of sudden death. We prospectively evaluated whether induced sustained arrhythmia could explain episodes of cerebral dysfunction in hypertrophic cardiomyopathy. Seven consecutive symptomatic patients (six of whom had an intraventricular gradient of 40 to 130 mm Hg) were subjected to atrial and ventricular stimulation. An electrophysiologic abnormality that would explain the symptoms was identified in every patient: supraventricular tachycardia was present in two, sustained ventricular tachycardia in three, ventricular fibrillation in one, and a prolonged QT interval and dispersion of ventricular refractoriness in one. Antiarrhythmic drugs were selected on the basis of the response to electrophysiologic testing. There has been no recurrence of symptoms in 120 patient-months of follow-up. This experience suggests that arrhythmias are the principal cause of syncope or sudden death in obstructive cardiomyopathy and that electrophysiologic study may be useful in selecting prophylactic therapy.     

Pathological features of hypertrophic obstructive cardiomyopathy

The macroscopic features of hypertrophic obstructive cardiomyopathy are variable. The most easily recognized picture is of disproportionate and asymmetrical left ventricular hypertrophy with a small ventricular volume. Symmetrical ventricular hypertrophy also occurs and dilatation of the ventricular cavity may lead to a configuration more usually associated with congestive cardiomyopathy. Papillary muscle involvement leads to a bullet shape, often retained even when the ventricle dilates. Eighteen of the hearts showed a distinctive band of fibrous thickening below the aortic valve. This was a mirror image of the free edge of the anterior mitral cusp, had the microscopic features of an endocardial friction lesion, and was clearly the morphological expression of the systolic contact between cusp and septum seen on cineangiography. This band is characteristic of hypertrophic obstructive cardiomyopathy; it was more common in older patients and is of particular diagnostic value in cases with symmetrical hypertrophy, including those with dilated ventricular cavities.Sudden death was the commonest presentation in the younger cases but in several cases over 60 years at death hypertrophic obstructive cardiomyopathy was an incidental necropsy finding.     

Noonan syndrome or new autosomal dominant condition with coarctation of the aorta,hypertrophic cardiomyopathy,and minor anomalies

This is a report on a father and his two children with an apparent autosomal dominant condition characterized by craniofacial anomalies, coarctation of the aorta, hypertrophic cardiomyopathy, and other structural heart abnormalities with normal psychomotor development. Some clinical features are reminiscent of Noonan syndrome. Alternatively, this family may have a previously undescribed genetic condition. The family history is suggestive of a new autosomal dominant mutation in the father.     

Noonan syndrome or new autosomal dominant condition with coarctation of the aorta,hypertrophic cardiomyopathy,and minor anomalies

This is a report on a father and his two children with an apparent autosomal dominant condition characterized by craniofacial anomalies, coarctation of the aorta, hypertrophic cardiomyopathy, and other structural heart abnormalities with normal psychomotor development. Some clinical features are reminiscent of Noonan syndrome. Alternatively, this family may have a previously undescribed genetic condition. The family history is suggestive of a new autosomal dominant mutation in the father. © 2002 Wiley‐Liss, Inc.     

Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant

We report on a patient with Noonan syndrome due to SHOC2 missense mutation predicting p.Ser2Gly, recently described in association with Noonan syndrome. The male infant presented with fetal distress requiring premature delivery at 32 weeks and was noted to have dysmorphic features, edema, hepatosplenomegaly, leukocytosis, thrombocytopenia, and respiratory distress following birth. An echocardiogram revealed hypertrophic cardiomyopathy with left ventricular outflow tract obstruction. The infant's cardiac lesion rapidly progressed, and he was discharged home for palliative care. Clinical testing of genes causative of Noonan syndrome and related disorders detected the previously reported, pathogenic, de novo SHOC2 missense mutation predicting p.Ser2Gly. The patient's cardiac findings and features were not typical for those individuals previously reported with this SHOC2 mutation and thus expand the clinical phenotype.     

Succesful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome

Infants with Noonan Syndrome and hypertrophic cardiomyopathy have a poor prognosis and a high mortality especially when diagnosed before six months of age. As for the majority of the RASopathies, no medical treatment has been approved for Noonan Syndrome. Meanwhile, several approved agents targeting the same RAS/MAPK signaling pathway are used in cancer treatment. In this case report we describe a child with Noonan Syndrome caused by a pathogenic RIT1 variant, who developed severe early-onset hypertrophic cardiomyopathy and pulmonary valve stenosis. She received off-label treatment with the MEK-inhibitor trametinib which resulted in complete remission of the cardiac hypertrophy and a significant improvement of the pulmonary valve stenosis. Our case emphasizes the potential of existing cancer agents targeting the RAS/MAPK signaling pathway as successful treatment for RASopathy manifestations.     

External carotid pulse recordings in hypertrophic obstructive cardiomyopathy

External carotid pulse tracings were examined in 15 patients with hypertrophic obstructive cardiomyopathy (HOCM), the diagnosis being confirmed by catheterization of the left heart. Of 12 patients with intraventricular gradients at rest, 9 had a typical bifid pulse with midsystolic dipping. In one patient without a gradient at rest, midsystolic dipping occurred only in beats following extrasystoles (Brockenbrough phenomenon). The upstroke of the pulse wave was rapid in all the patients, a finding that distinguishes them from patients with valvular aortic stenosis. There was a correlation between the length of the left ventricular ejection time and the intraventricular gradient (r = 0.71) but as more than half the patients had normal or shortened ejection times, the diagnosis of HOCM cannot be based on measurements of this parameter. It is concluded that carotid pulse registrations are of considerable diagnostic value in patients suspected of having HOCM. As the pulse changes are correlated to the degree of left ventricular outflow obstruction, it is suggested that repeated pulse tracings may be used as a means for controlling the degree of obstruction once the diagnosis has been established in the individual patient.     

Specificity of cellular and myofibrillar disorientation in hypertrophic obstructive cardiomyopathy

The specificity of the ultrastructural myocardial abnormalities in hypertrophic obstructive cardiomyopathy (HOCM) is undetermined. We undertook a quantitative study using myocardial biopsy specimens from the subaortic area in a patient with classical HOCM and compared them with hypertrophic left ventricular myocardium from a patient suffering from rheumatic valve disease. Myofibrillar disarray and side-to-side junctions were chosen as strictly quantifiable features. The former was seen as representing intracellular disorganization; the latter was seen as criterion for intercellular disorganization. The results showed that there is no preference for these abnormalities to occur in HOCM. Indeed, intracellular abnormalities more frequently occurred in the hypertrophic myocardium the patient without HOCM. Neither intracellular nor intercellular features can be regarded as specific for HOCM, even in a quantitative sense.     

A lethal course of hypertrophic cardiomyopathy in Noonan syndrome due to a novel germline mutation in the KRAS gene: case study

Noonan syndrome is a relatively common and heterogeneous genetic disorder, including congenital heart defect in more than half of the cases. If the defect is not large, life expectancy is normal. Here we report on a case of an infant with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene. This heterozygous unclassified missense variant in exon 3: c.179G>T (p.Gly60Val) might be associated with a lethal form of Noonan syndrome. The malignant clinical course of the disease and the lethal outcome in an infant only a few months old might be connected to RAS-mitogen-activated protein kinase pathway hyperactivation, consequently promoting cell growth and proliferation, leading to rapidly progressive hypertrophic cardiomyopathy. Further biochemical and functional studies are needed to confirm this hypothesis.Noonan syndrome (NS; http://www.omim.org/entry/163950?search=163950&highlight=163950) is a relatively common genetic disorder with an incidence of 1 per 1000-2500 live births (1). Clinically it is a very heterogeneous disorder, predominantly characterized by dysmorphic facial features, congenital heart defect (CHD), post-natal short stature, webbed neck, chest deformity, cryptorchidism in men, lymphatic dysplasia, variable bleeding disorders, and intellectual disability. CHD is present in 50 to 80% of affected individuals and it is also very heterogeneous (2). Most commonly found are pulmonary valve stenosis with or without dysplastic pulmonary valve and hypertrophic cardiomyopathy. Providing the CHD is not large, life expectancy is in the normal range (3). NS and CHD are regularly connected with germline KRAS mutations. We describe a patient with NS and rapidly progressive hypertrophic cardiomyopathy with lethal outcome, in whom we identified a novel mutation in the KRAS gene.     

Noonan syndrome

Noonan syndrome is a common autosomal dominant condition caused by multiple genes in the RasMAPK pathway. The adult phenotype can be extremely subtle, and many adults are diagnosed only after the birth of a more obviously affected child. Whether diagnosis is made in childhood or adulthood, initial and ongoing evaluation of many systems can have considerable health benefits.     

Infective endocarditis complicating hypertrophic obstructive cardiomyopathy: an unusual mural pattern

A patient with hypertrophic obstructive cardiomyopathy (HOCM) and an unusual right ventricular mural pattern of endocarditis that clinically mimicked a neoplasm is presented. To our knowledge, this is the first report of right ventricular mural endocarditis complicating HOCM.     

室间隔射频消融术在梗阻性肥厚型心肌病中的应用

目的探讨室间隔射频消融术(PIMSRA)治疗梗阻性肥厚型心肌病(HOCM)的临床效果。方法收集2019年6~8月于我院心血管内科行PIMSRA的7例HOCM患者的临床资料,回顾分析该治疗方法的手术要点、术后管理重点和随访结果。结果7例患者手术均获成功,术中、术后未出现严重并发症,术后左心室流出道压力阶差下降明显,超声显示二尖瓣前叶收缩期前向运动现象明显减轻。出院后15 d、2个月、3个月随访,7例患者生存良好,疾病症状均缓解,心功能分级均有改善。结论PIMSRA治疗HOCM安全可靠,术后即刻可降低左室流出道压力阶差,改善患者临床症状。