Both Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are RASopathies. Characteristic cardiac phenotypes of NS, including specific electrocardiographic changes, pulmonary valve stenosis and hypertrophic cardiomyopathy have not been completely studied in NF1. Purpose: The aims of this study were to assess: (1) similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS in asymptomatic patients with NF1, and (2) the presence of discrete myocardial dysfunction in NF1 patients using myocardial strain imaging. Methods: Fifty-eight patients with NF1 (ages 0–18 years), and thirty-one age-matched healthy controls underwent cardiac assessment including blood pressure measurements, a 12-lead ECG, and detailed echocardiography. Quantification of cardiac chamber size, mass and function were measured using conventional echocardiography. Myocardial strain parameters were assessed using 2-Dimensional (2D) Speckle tracking echocardiography. Results: Asymptomatic patients with NF1 had normal electrocardiograms, none with the typical ECG patterns described in NS. However, patients with NF1 showed significantly decreased calculated Z scores of the left ventricular internal diameter in diastole and systole, reduced left ventricular mass index and a higher incidence of cardiac abnormal findings, mainly of the mitral valve, in contrast to the frequently described types of cardiac abnormalities in NS. Peak and end systolic global circumferential strain were the only significantly reduced speckle tracking derived myocardial strain parameter. Conclusions: Children with NF1 demonstrated more dissimilarities than similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS. The role of the abnormal myocardial strain parameter needs to be explored.

Background/Objectives: Pathogenic variants in collagen type 4 α5 chain (COL4A5), responsible for X-linked Alport syndrome, are classically associated with progressive kidney disease, sensorineural hearing impairment, and ocular abnormalities. Cerebrovascular involvement is not considered part of the COL4A5-related phenotype, although rare recent reports suggest it may occur. We describe a family with cerebrovascular events across three generations, segregating in a clear X-linked pattern, and evaluate whether these events could be linked to a pathogenic COL4A5 variant identified in the proband. Methods: We report the clinical, radiological, and genetic findings in a 16-year-old heterozygous female proband, interpreted in the context of her family’s cerebrovascular history. Exome sequencing, chromosomal microarray, and familial segregation analysis were performed. Results: The proband presented with severe migraine, cerebellar microhemorrhage, and poor visualization of the left distal posterior cerebral artery (PCA) branches. Exome sequencing detected the heterozygous COL4A5 pathogenic variant c.1871G>A; p.(Gly624Asp), inherited from her hemizygous father, who has Alport syndrome. The proband’s sister, an obligate carrier of the same variant with a history of migraine, was found to have a small brain aneurysm. In the paternal line, the great-grandmother died of a cerebrovascular event in her early 40 s, the great-aunt had a stroke at around 40, and her son died of a cerebrovascular event at 35; the obligate-carrier grandmother had chronic kidney disease and migraine. Conclusions: This COL4A5 variant is usually associated with late-onset Alport syndrome and variable renal involvement, even in obligate carriers, and has not previously been linked to cerebrovascular disease. In the present family, the X-linked clustering of cerebrovascular events raises the possibility that COL4A5 may contribute to cerebrovascular fragility, with an effect that may extend beyond the kidney. These findings suggest that COL4A5 may be relevant in selected families with unexplained cerebrovascular disease, even when renal manifestations are mild or absent.