Five out of six patients with a pathogenic mutation in
FLNA from our database show a combination of cardiac disease and bilateral cerebral PNH. Four patients presented to a cardiologist before or at the time of their neurological workup. Neurological signs were absent or mild at that time and the diagnosis of bilateral PNH was made later due to epileptic seizures (case 4), hypotonia (case 2) or during the workup of non-related complaints. This suggests that the cardiologist had the first opportunity to recognize these patients. Recently also X-linked mitral valvular dystrophy without neurological signs or symptoms of epilepsy was found to be caused by mutations in
FLNA, however, brain imaging was not reported [
10]. The cardiological phenotype is not always this specific. FLNA knock out mice show midline skeletal defects and early male lethality due to cardiac malformations in atrioventricular septal and outflow tract development [
11]. Human patients also show abnormalities in the outflow tract ranging from patent ductus arteriosus, mitral or aortic valvular abnormalities to coarctation of the aorta, and ascending aorta aneurysm [
12‐
14]. Cerebral PNH in
FLNA patients is caused by impaired migration of later born neurons due to disrupted cell adhesion and abnormal ventricular ependymal function [
15]. This shows that pathways involved in cell adhesion can both affect the neuro-epithelium and vascular development. Apart from cerebral and cardiovascular developmental defects
FLNA mutations can also cause connective tissue abnormalities, and autopsy studies show abnormal glomeruloid microvascular proliferations in the brain [
9,
15]. A combination of PNH and Ehlers-Danlos syndrome with joint hyperlaxity and aorta aneurysms caused by a mutation in
FLNA has been described in females [
16]. Neurological phenotypes associated with PNH are diverse and range from epilepsy and normal development to patients with multiple congenital anomalies and mental retardation. In males mutations are often prenatal lethal. Less severe mutations with residual filamin A function are found in males with PNH. One male patient has been described with PNH and a lethal complex cardiac malformation, including atrial and ventricular septal defect and persistent left superior caval vein [
12]. Interestingly, gain of function mutations of FLNA are associated with syndromes with craniofacial and skeletal abnormalities, including otopalatodigital syndrome types 1 and 2, Melnick-Needles syndrome (MNS) and frontometaphyseal dysplasia [
17]. In these syndromes several male patients have been described with heart defects, cryptorchidism and umbilical hernia, but no PNH [
17]. The combination of mitral and/or aortic regurgitation and skeletal abnormalities with hyperlaxity is also found in autosomal dominant Marfan syndrome (OMIM 154700), in the allelic Shprintzen-Goldberg syndrome (OMIM 182212) and in Loeys-Dietz syndrome type 1A and B (OMIM 609192 and 610168). Some neuromuscular abnormalities are described in these patients, but no cerebral cortical developmental abnormalities.
Although we did not find any cases, cardiac defects are reported to be associated with some other cerebral PNH phenotypes. Patients with Williams syndrome, caused by a microdeletion of chromosome 7q11.22-23, have distinctive facial dysmorphias, ‘elfin face’, and often cardiac defects, such as supravalvular aortic stenosis, mitral or pulmonary valve abnormalities, and atrial or ventricular septum defect. One case has been described with associated PNH [
18]. In chromosome 6q terminal deletion syndrome, brain MRI commonly shows hypoplasia of the corpus callosum, and a few patients have been described with associated PNH [
19]. About half of 6q terminal deletion patients are reported to have cardiac abnormalities, primarily ventricular or atrial septum defect. Distal duplications of chromosome 5p have been associated with PNH in two patients, one of which also had atrial septum defect and mitral and tricuspid valve prolapse [
20]. Genetic factors related to similar cardiac malformations without PNH are being widely investigated, but still only few genes are known to cause a developmental defect of the atrioventricular septum and the outflow tract in humans [
21‐
23].