Frontonasal dysplasia (Frontonasal dysplasia) - Genes ALX1, ALX3 and ALX4.

Frontonasal dysplasia, also called syndrome half cleft face, is a disease characterized by abnormal development of head and face before birth. People with frontonasal dysplasia have at least two of the following characteristics: ocular hypertelorism, broad nasal base, slit on one or both sides of the nose, nose blunt, a central slit which may involve the nose, upper lip or palate , incomplete formation of the above bones of the skull, so that the skin only covers this stop (ocultum cranium bifidum). Additional features of the disease may include facial malformations, agenesis of the corpus callosum and intellectual disability.

Described three types of Frontonasal dysplasia are distinguished by their genetic causes and their signs and symptoms. In addition to the features described above, each type is associated with other characteristics. People with fronto dysplasia type 1 often have impaired nose, philtrum and ptosis. People with type 2 Frontonasal dysplasia may have alopecia and enlarged parietal foramina. Often, men with this form of the disease have genital abnormalities. Meanwhile, the characteristics of the frontonasal dysplasia type 3 include anophthalmia or microphthalmia and set ears rotated backwards. In general, the type 3 disease is associated with more severe facial abnormalities, but the severity of the disease varies widely, even among individuals with the same type.

The life expectancy of affected individuals depends on the severity of malformations and if surgery may or may not improve the problems associated with health such as respiratory and feeding problems caused by facial clefts.

This process is due to mutations in the ALX1, ALX3 and ALX4 genes. Mutations in the gene ALX1, located on the long arm of chromosome 12 (12q21.31), cause frontonasal dysplasia type 3. Mutations in the gene ALX3, located on the short arm of chromosome 1 (1p13.3), they are responsible 1 and mutations in the gene ALX4, located on the short arm of chromosome 11 (11p11.2), give rise to type 2 disease. These genes encode proteins family members of homeobox proteins that are necessary for normal development, especially of the head and face before birth. These proteins are transcription factors that control the activity of genes that regulate the growth and proliferation and cell migration. The ALX3 and ALX4 proteins are involved primarily in the development of the nose and surrounding tissues, while the ALX1 protein is involved in the development of the eyes, nose and mouth.

They have identified at least three mutations in the gene ALX1, seven mutations in the gene ALX3 and 4 mutations in the gene ALX4 leading to frontonasal dysplasia. Mutations in these genes reduce or eliminate the function of the respective protein. As a result, the regulation of cell organization during development of the head and face is interrupted, particularly affecting the face half. Abnormal development of the nose, philtrum and upper lip leads to facial fissures that characterize this disease. This abnormal development also interferes with proper formation of the skull and other facial structures, leading to occultum the previous bifidum skull, hypertelorism, and other characteristics of the Frontonasal dysplasia.

When the frontonasal dysplasia is caused by mutations in the ALX1 or ALX3 gene is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease. On the other hand, when the frontonasal dysplasia is caused by mutations in the gene ALX4 is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. In some cases, an affected person inherits the mutation from an affected parent. Other cases are due to new mutations in the gene and occur in people with no history of disease in your family.

Tests in IVAMI: in IVAMI perform detection of mutations associated with frontonasal dysplasia, by complete PCR amplification of the exons of ALX1, ALX4 ALX3 and genes, and subsequent sequencing.

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).