Parietal foramina enlarged (parietal foramina Enlarged) - Genes ALX4 and MSX2  

Parietal foramina enlarged is an inherited developmental abnormality skull, characterized by foramina in the parietal bones of the skull. This alteration is due to problems with the formation of the parietal bones. The openings are symmetrical and circular, with a variable size from a few millimeters to several centimeters wide.

The area covers the parietal foramen is soft to the touch. The pressure applied to the openings can cause severe headaches. Usually, people with the disease have no medical problems related to alteration, but have been observed scalp defects, seizures and structural brain abnormalities in a small percentage of those affected. The risk of brain damage may increase if any injury occurs in the area of the openings. There are two ways parietal foramina enlarged, designated type 1 and type 2, which differ in their genetic cause.

This process is due to mutations in the ALX4 (ALX homeobox 4) and MSX2 (msh homeobox 2) genes, which result in type 1 and 2, respectively. Mutations in the gene ALX4 are responsible for 60% of cases, while mutations in the gene have been identified MSX2 40%. These genes encode proteins transcription factors, which are necessary for proper development of the whole organism. Transcription factors bind to specific DNA regions and help control the activity of particular genes. The ALX4 and MSX2 proteins are involved in regulating genes that are required in various cellular processes in early development.

The gene ALX4 (ALX homeobox 4), located on the short arm of chromosome 11 (11p11.2), encoding a protein family member of homeobox proteins. These proteins direct the formation of body structures in early embryonic development. Protein is needed for normal development of the head and face, particularly the formation of the nose, which begins around the fourth week of development. This protein is also involved in the formation of skin layers, but its role in this process is poorly understood. Protein controls the activity of genes that regulate the growth, proliferation and migration, ensuring that the cells grow and stop growing at specific times and that are located correctly during development.

The MSX2 gene (msh homeobox 2), located on the long arm of chromosome 5 (5q35.2), encoding a protein that is necessary for proper development in the whole organism. The MSX2 protein is part of a pathway known as chemical signaling path bone morphogenetic protein (BMP). This signaling pathway regulates many cellular processes and is implicated in cell growth, including new bone cells. The presence of the protein appears to be particularly critical for the full development of the skull. Protein controls the activity of genes that regulate the growth, proliferation, differentiation and cell survival.

They have identified at least eight mutations in the gene ALX4 and 10 mutations in the gene MSX2 in people with enlarged parietal foramina. Mutations involved include nucleotide changes coding for amino acids in the protein and deletions of one or more nucleotides of the DNA of the gene. These genetic changes lead to an unstable protein which can not bind DNA, altering the regulation of cell proliferation, cell maturation and differentiation and the balance of cell survival and self - destruction in certain areas of the skull. The cells involved in the development of the skull appear to be particularly sensitive to these disruptions. There seems no difference in the size of the openings between types 1 and 2.  

This disease is inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to cause the alteration. In most cases, an affected person has a parent with the disorder. A small number of cases may be due to new mutations in the gene that occur in people with no history of disease in your family.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with parietal foramina enlarged by the complete PCR amplification of the exons of ALX4 and MSX2 respectively and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).