Lacrimo-atrio-dento-digital syndrome ... (Lacrimo-atrio-dento-digital syndrome -LADD-) - Genes FGFR2, FGFR3, or FGF10.
The lacrimo-atrio-dento-digital syndrome (LADD) is a genetic disorder that primarily affects the eyes, ears, mouth and hands. As the name suggests, LADD syndrome is characterized by defects in the lacrimal system, ear problems, dental abnormalities and deformities of the digits.
Malformations of the lacrimal system may include an underdeveloped or absent tear duct opening in the punctum and nasolacrimal duct obstruction. These lacrimal system malformations may result epiphora, dacryocystitis, keratoconjunctivitis, or an inability to produce tears. For its part, the ears are usually low - set and cup - shaped, often accompanied by hearing loss from mild to severe may be due to sensorineural hearing loss, conductive hearing loss or mixed hearing loss. In addition, people with LADD syndrome may have underdeveloped or absent salivary glands that can cause xerostomia and increased susceptibility to decay, small and underdeveloped teeth with thin enamel incisors and peg - shaped.
Other signs of the disease may include abnormally small or absent thumbs. Alternatively, the thumb can be duplicated, fused with the index finger, abnormally placed, or have three bones rather than the normal two. Abnormalities of digits include syndactyly the second and third fingers, extra or missing fingers, and fifth finger clinodactyly. Sometimes the forearm is also affected and may be shorter with an abnormal wrist joint development which limits the movement of the elbow. People with LADD syndrome may also have other signs and symptoms as nephrosclerosis and hydronephrosis, recurrent urinary tract infections and genitourinary abnormalities. In addition, some people have cleft palate with or without cleft lip. Signs and symptoms of this disease are highly variable, even among members of the same family affected.
This process is due to mutations in, FGFR2, FGFR3 and FGF10 gene.
FGFR2 gene, located on the long arm of chromosome 10 (10q26) encodes a protein called receptor fibroblast growth factor 2. This protein is part of a family of receptors of fibroblast growth factor that share similar structures and functions. These proteins play a role in several important cellular processes, including the regulation of growth and cell division, determining the cell type, the formation of blood vessels, wound healing and development before birth. The FGFR2 protein across the cell membrane, so that one end of the protein remains on the outer surface of the cell. This positioning allows the protein interacts with specific growth factors outside the cell and receives signals that help the cell to respond to its environment. The FGFR2 protein plays an important role in bone growth particularly during embryonic development. There are several isoforms of FGFR2 protein. Specific patterns of these isoforms are found in the tissues of the body, and these patterns may change over growth and development.
They have identified at least two mutations in FGFR2 gene associated with syndrome lacrimo-atrio-dento-digital (LADD). These mutations reduce the ability of FGFR2 receptor protein to trigger chemical reactions within the cells when bound to its growth factor, leading to a decrease in cellular signaling. A mutation that occurs in some people with LADD syndrome replaces the amino acid alanine by threonine at amino acid position 628 of FGFR2 receptor protein (Ala628Thr or A628T). These defects in cell signaling alter cell maturation and development, resulting in the abnormal formation in the eyes and mouth, ears and skeleton in people with LADD syndrome.
FGFR3 gene, located on the short arm of chromosome 4 (4p16.3) encodes a protein called receptor fibroblast growth factor 3. This protein is part of a family of receptors of fibroblast growth factor sharing structures and functions Similar. These proteins play a role in several important cellular processes, including the regulation of growth and cell division, determining the cell type, the formation of blood vessels, wound healing and development before birth. The FGFR3 protein across the cell membrane, so that one end of the protein remains inside the cell and the other end remains on the outer surface. This positioning of the protein allows it to interact with specific growth factors outside the cell and receive signals that control growth and development. When these growth factors bind to the FGFR3 protein, protein triggers a cascade of chemical reactions within the cell that instruct to perform certain changes, such as maturation to take specialized functions. From the FGFR3 gene, various isoforms of the FGFR3 protein, found in various tissues of the body and interact with a variety of growth factors are encoded. Many isoforms are found in the cells that form bones. It is believed that bone cells, the protein FGFR3 regulates bone growth by ossification, particularly in the long bones. One particular isoform of FGFR3 protein is specifically in epithelial cells, including the cells that form the epidermis.
It has identified at least one mutation in the FGFR3 gene in people with digital-atrio-dento-lacrimo syndrome (LADD). The identified genetic change the amino acid aspartic acid replaces the amino acid asparagine at position 513 of the protein FGFR3 (Asp513Asn or D513N). It is likely that this mutation reduces the ability of the protein FGFR3 receptor to trigger chemical reactions within the cells when bound to its growth factor. These defects in cell signaling alter cell maturation and development, resulting in the abnormal formation of the glands in the eyes and mouth, ears, and skeleton in people with LADD syndrome.
The FGF10 gene, located on the short arm of chromosome 5 (5p13-p12), encodes a protein called fibroblast growth factor 10 (FGF10). This protein is part of a family of proteins called growth factors fibroblasts which are involved in important processes such as cell division, regulation of cell growth and maturation, the formation of blood vessels, wound healing, and development before birth. By joining another protein, the FGF10 protein triggers a cascade of chemical reactions within the cell that causes the cell to undergo certain changes, such as maturation to take specialized functions. During development before birth, signals activated by the FGF10 protein appear to stimulate the cells to form structures that make up the ears, skeleton, organs and glands in the eyes and mouth.
They have been described at least three mutations in the FGF10 gene responsible digital-atrio-dento-lacrimo syndrome (LADD). These genetic changes reduce the amount and activity of the FGF10 protein, so there is less growth factor available to bind to the receptors, thus decreasing the signaling within cells. A decrease in cell signaling disrupts cell development and maturation, causing the abnormal formation of the glands in the eyes and mouth, ears, and skeleton in people with LADD syndrome.
This disease is inherited as an autosomal dominant pattern, meaning that a mutation in one copy 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 the detection of mutations associated with syndrome lacrimo-atrio-dento-digital (LADD), by complete PCR amplification of the exons of FGFR2, FGFR3 and FGF10, respectively, 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).