Abstracts

RATIONALE: Calvarial bone defects such as parietal foramina (PF) have been found to be caused by mutations in the MSX2 homeobox gene located on Chr 5 (PFM1). Parietal foramina also occur as part of the Chr 11p11.2 deletion syndrome, where they are caused by haploinsufficiency of the ALX4 homeobox gene (PF2). The association of malformations of cortical development (MCD) and PF have been scattered reported, however no genetic defect was described. The aim of this study is to present the neurological, imaging and eletroclinical profile of a three generation family with an ALX4 point mutation.
METHODS: Calvarial bone defect were detected in 4 patients in a three generation family. A detailed history was obtained of three patients out of these (son, mother, and grandfather). The genetic profile of these patients was previously addressed by Mavrogiannis et al.(2001) and showed an ALX4 point mutation. Neuroimaging studies consisted of evolutionary skull X-rays (PA and lateral), CT scan of the head without intravenous contrast, 3D CT bone reformatted images and MRI. The MRI data include a structural protocol and complementary MR venography imaging performed to address the full spectrum of the brain anomalies associated with this calvarial defect previously considered as of benign nature. A complete neurological follow-up was performed and EEG routine and a short-term V-EEG (4hours) was done.
RESULTS: The imaging studies of all three patients showed individual variations and expressions of the same abnormalities, which were: (i) Bones: calvarial bone defect in the gross spectrum of the parietal foramina and cranium biffidum occultum, (ii) Vascular: Persistent falcine venous sinus and an athretic straight sinus, (iii) White matter: deep white matter signal changes in the periatrial region and (iv) Gyral and cortical pattern: Unusual variation of the paramedian occipital infolding surrounded by a polymicrogyric cortex, especially located on the mesial portion of occipital lobes. We also noticed a high tentorial incisura with an enlarged posterior fossa. Two out of these patients (mother and son) presented a history of non-refractory epilepsy characterized by sporadic seizures of occipital origin, starting in infancy in the son and childhood in the mother with remission during puberty. EEGs revealed frequent low amplitude sharp waves over the posterior quadrant.
CONCLUSIONS: Parietal foramina have been largely considered a benign calvarial bone defect. However, our three generation family with PFM2 presented distinct morphostructural changes with an evolutionary aspect, involving not only the bone but also the cortical infolding, deep white matter and cerebrovascular drainage system. The straight correlation between the topographic and electroclinical alterations associated with an ALX4 point mutation could light up a new direction for researchers and gene hunters.
Mavrogiannis, L. A.; Antonopoulou, I.; Baxova, A.; et al. Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. Nature Genet. 27: 17-18, 2001.
[Supported by: University of Sao Paulo-Brazil]