Novel Genetic Microvascular Dysplasia Causing Hypoperfusion of Cardiac, Renal, and Cerebral Circulation

Background: Microvascular disorders represent an uncommon site of tissue hypo-perfusion and damage. Various genetic and acquired causes can be involved. A 65-year-old man was admitted because of refractory angina, which he had had since the age of 30 years, micro-hematuria, and recurrent transitory ischemic attacks from the age of 64. Methods: Hematochemical studies, ECG, Holter monitoring, 2D-echo, cardiac magnetic resonance (CMR), CTA of cerebral vessels, endomyocardial coronary angiography, and kidney biopsy processes were undertaken. Gene mutation analysis was conducted using next-generation sequencing, which included more than 5000 genes associated with inherited diseases. Results: Hematochemical findings were unremarkable. The ECG, Holter, 2D-echo, and CTA of brain vessels were normal. Cerebral magnetic resonance showed the presence of multiple small foci of ischemia. Coronary and ventricular angiography showed normal arteries with remarkably slow flow and multiple biventricular micro-aneurysms. At the endomyocardial biopsy, five of seven arterioles presented severe lumen obstruction due to hypertrophy and disarray of the muscular coat. Similarly, obstructed pre-glomerular arteries with glomerular sclerosis were seen at the renal biopsy. Genetics identified mutations in the ABCC6, MMP2, and XYLT1 genes, which play pivotal roles in the extracellular matrix. Conclusion: This study described a new genetic microvascular obstructive disease causing progressive hypo-perfusion of the human brain, heart, and kidney

Prevalence, Type, and Molecular Spectrum of NF1 Mutations in Patients with Neurofibromatosis Type 1 and Congenital Heart Disease

The aim of this study was to assess the prevalence and type of congenital heart disease (CHD) and the associated mutation spectrum in a large series of patients with neurofibromatosis type 1 (NF1), and correlate the mutation type with the presence and subgroups of cardiac defects. The study cohort included 493 individuals with molecularly confirmed diagnosis of NF1 for whom cardiac evaluation data were available. CHD was reported in 62/493 (12.6%) patients. Among these patients, 23/62 (37.1%) had pulmonary valve stenosis/dysplasia, 20/62 (32.3%) had mitral valve anomalies, and 10/62 (16.1%) had septal defects. Other defects occurred as rare events. In this NF1 subcohort, three subjects carried a whole-gene deletion, while 59 were heterozygous for an intragenic mutation. A significantly increased prevalence of non-truncating intragenic mutations was either observed in individuals with CHD (22/59, 37.3%) or with pulmonary valve stenosis (13/20, 65.0%), when compared to individuals without CHD (89/420, 21.2%) (p = 0.038) or pulmonary valve stenosis (98/459, 21.4%) (p = 0.002). Similarly, patients with non-truncating NF1 mutations displayed two- and six-fold higher risk of developing CHD (odds ratio = 1.9713, 95% confidence interval (CI): 1.1162–3.4814, p = 0.0193) and pulmonary valve stenosis (odds ratio = 6.8411, 95% CI: 2.6574–17.6114, p = 0.0001), respectively. Noteworthy, all but one patient (19/20, 95.0%) with pulmonary valve stenosis, and 18/35 (51.4%) patients with other CHDs displayed Noonan syndrome (NS)-like features. Present data confirm the significant frequency of CHD in patients with NF1, and provide further evidence for a higher than expected prevalence of NF1 in-frame variants and NS-like characteristics in NF1 patients with CHD, particularly with pulmonary valve stenosis