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Parietal foramina (PFM) are defects of the human skull vault, characterised by symmetrical, oval defects in the parietal bone situated on each side of the sagittal suture and separated from each other by a narrow bridge of bone. Size decreases with age and an intrafamilial variability is seen (OMIM 168500). It is thought to be a normal variant of skull development and, consequently, a benign entity.1 Currently, loss of function mutations in two genes encoding homeobox containing transcription factors, MSX2 and ALX4, have been detected in patients with PFM.2,3 Parietal foramina is classified as type I, caused by MSX2 mutations, and type II, which is caused by ALX4 mutations.
Herein, we report a family with PFM type II in which two members had epilepsy and discuss the importance of neuroimaging findings to determine its possible cause. In addition, we study the variations of clinical expression, with regard to the severity of the epilepsy, in different generations.
The first patient, a boy, was referred at the age of 3 months because of a large bone defect (PFM) identified on physical examination. The mother (22 years old), aunt (25 years old), and grandfather (55 years old) also had PFM, but smaller than the child’s, showing an age related size variation. Molecular analysis, reported elsewhere,4 showed that this family had an ALX4 mutation (PFM type II). History, neurological examination, and neuroimaging evaluations were obtained from three relatives. The aunt refused further analysis. Electroclinical investigation consisted of a detailed clinical history, review of charts, and video electroencephalogram (V-EEG) monitoring. Neuroimaging evaluation consisted of helical computed tomography scans of the head (with post-processing three dimensional views of the cranial vault), 1.5T magnetic resonance imaging (MRI) at three orthogonal planes with conventional SE (before and after intravenous paramagnetic contrast administration), and magnetic resonance venography.
At the age of 4 years, the patient was referred to our laboratory for elucidation of paroxysmal events, described as brief periods of “blindness”. He was born at term, by caesarian section after an uneventful pregnancy. During follow up, physical and neurological examinations revealed normal neurological development and physical growth. Seizure semiology was highly suggestive of an occipital origin; seizures were characterised by visual phenomena (blackouts), progressing to loss of contact and forced eye and head deviation to the left, followed by vomiting and headache. Onset occurred during infancy, at 8 months, and up to the latest evaluation, a total of six seizures had occurred. Carbamazepine was replaced by valproate in an attempt to improve seizure control.
The mother had a history of epilepsy with the same characteristics as those seen in the child, although the seizures were shorter. Onset occurred later, during puberty, at 15 years. She had four stereotyped seizures, controlled with phenobarbital (50 mg/day), which was taken for two years. Her past and current medical history was normal, including neurological examination.
Electroencephalographic tracings showed frequent, sharp waves over the left posterior quadrant in the child (fig 1A). Although V-EEG was done, we did not register his seizures because of their sporadic nature. The mother had a normal current EEG, but previous EEG reports described the same abnormality as in her child.
The grandfather had no current neurological or cognitive deficits. He denied a history of seizures, syncope, migraine, or other paroxysmal events. His EEG was normal.
Neuroimaging investigation with 1.5T MRI showed a malformation of occipital infolding, suggestive of a polymicrogyric cortex over the posterior regions in all three patients, although this was more prominent in the child (fig 1B).
This family had the classic phenotype for PFM, in this case type II (ALX4 mutation), including age related expression with regard to the size of the foramina. In contrast to the current idea that PFM is not associated with neurological disorders, the child and his mother had epilepsy with occipital lobe seizures. Reviewing previous studies, Kyte5 described one patient with identical epilepsy and EEG features as seen in our patients, including the age related improvement. An important issue in this family, not previously reported, is the earlier onset and higher frequency of events in the child. Analysis of this family showed an intrafamilial variability, with a more severe and earlier presentation of epilepsy in the youngest member. Our findings suggest a generation related modulation of the clinical picture, which may explain why some patients may present with a clinical condition whereas others remain asymptomatic.
Our family had an ALX4 mutation, but there is no evidence of phenotype–genotype differences between patients with PFM type I (MSX2 mutation) and II (ALX4 mutation). In an experimental study, Satokata et al described Msx-2 mutant mice with seizures accompanied by abnormal development of the cerebellar cortex,6 which suggested a structural malformation as the cause of seizures, as seen in our patients. The association of cortical anomalies and epilepsy is well known and the neuroimaging study in our family showed the coexistence of a cortical malformation on the posterior region in the three relatives with PFM, including the asymptomatic member. Reddy et al described cortical and vascular anomalies,7 corroborating that these findings may not be uncommon, and are now being identified because of advances in neuroimaging.
Malformations of cortical development are seen in some syndromes found with other diseases that have a well known genetic basis. Polymicrogyria seems to result from genetic or environmental factors, or both. In our patients, although a genetic anomaly was found, the abnormal cortex overlies vascular territories. This may seem contradictory, but it is possible that the cortical anomalies in this family are the consequence of a vascular abnormality which, in turn, could have been caused by the genetic anomaly.
In conclusion, we suggest that some cases of PFM are not as benign as thought previously. From a practical point of view, the documentation of a family with neurological symptoms because of cortical abnormalities indicates that more extensive neuroimaging is recommended for patients with PFM, in addition to the investigation of families, especially when patients are symptomatic.
The authors thank Dr S Blaser for reviewing the manuscript and her important contribution to the neuroimaging analysis.
Competing interests: none declared
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