Otopalatodigital syndrome type 2 is a disorder primarily involving abnormalities in skeletal development. It is a member of a group of related conditions called otopalatodigital spectrum disorders, which also includes otopalatodigital syndrome type 1, frontometaphyseal dysplasia, Melnick-Needles syndrome, and terminal osseous dysplasia. In general, these disorders involve hearing loss caused by malformations in the tiny bones in the ears (ossicles), problems in the development of the roof of the mouth (palate), and skeletal abnormalities involving the fingers or toes (digits). Otopalatodigital syndrome type 2 also tends to cause problems in other areas of the body, such as the brain and heart.

People with otopalatodigital syndrome type 2 have characteristic facial features including wide-set and downward-slanting eyes; prominent brow ridges; a broad, flat nose; and a very small lower jaw and chin (micrognathia). Affected individuals often have abnormalities of the fingers and toes, such as unusual curvature of the fingers (camptodactyly) and shortened or absent thumbs and big toes. People with otopalatodigital syndrome type 2 usually have short stature, abnormally curved (bowed) bones in the arms and legs, and other abnormal or absent bones. Underdeveloped ribs can cause problems with breathing in affected individuals. Some people with this condition have an opening in the roof of the mouth (a cleft palate) or hearing loss.

In addition to skeletal abnormalities, individuals with otopalatodigital syndrome type 2 may have developmental delay, increased fluid in the center of the brain (hydrocephalus), protrusion of the abdominal organs through the navel (omphalocele), heart defects, chest abnormalities, obstruction of the ducts between the kidneys and bladder (ureters), and, in males, opening of the urethra on the underside of the penis (hypospadias).

Males with otopalatodigital syndrome type 2 generally have much more severe signs and symptoms compared to affected females. Males with this condition typically do not survive past infancy because of respiratory failure due to an underdeveloped rib cage.

Otopalatodigital syndrome type 2 is caused by mutations in the FLNA gene. The FLNA gene provides instructions for producing the protein filamin A, which helps build the network of protein filaments (cytoskeleton) that gives structure to cells and allows them to change shape and move. Filamin A binds to another protein called actin, and helps the actin to form the branching network of filaments that make up the cytoskeleton. Filamin A also links actin to many other proteins to perform various functions within the cell.

The FLNA gene mutations that cause otopalatodigital syndrome type 2 all result in changes to the filamin A protein in the region that binds to actin. The mutations are described as "gain-of-function" because they appear to lead to a protein with an increased ability to bind to actin. Researchers believe that the mutations impair the stability of the cytoskeleton and disrupt cellular processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of otopalatodigital syndrome type 2.

Normal Function

The FLNA gene provides instructions for producing the protein filamin A, which helps build cells' extensive internal network of protein filaments called the cytoskeleton. The cytoskeleton gives structure to cells and allows them the flexibility to change shape. The cytoskeleton is also important for certain processes inside the cells, such as the movement of proteins within the cell and the breakdown of unneeded proteins. Filamin A primarily attaches (binds) to another protein called actin and helps it form the branching network of filaments that make up the cytoskeleton.

Filamin A can also bind to many other proteins in the cell to carry out various functions, including the attachment of cells to one another (cell adhesion), cell movement (migration), determination of cell shape, the relay of signals within cells, and cell survival. These numerous functions involving filamin A have been found to play roles in regulating skeletal and brain development, the formation of heart tissue and blood vessels, blood clotting, skin elasticity, the maintenance of lung tissue, and the function of the digestive system.

Filamin A is also involved in the organization of the extracellular matrix, which is the lattice of proteins and other molecules outside the cell. Filamin A binds to proteins called integrins, which span the cell membrane and anchor cells to the extracellular matrix. Through this binding, cells are correctly positioned and signals can be exchanged between the cell and the extracellular matrix.

Health Conditions Related to Genetic Changes

Frontometaphyseal dysplasia

Variants (also known as mutations) in the FLNA gene have been identified in people with frontometaphyseal dysplasia. This condition is a member of a group of related conditions called otopalatodigital spectrum disorders, which also includes otopalatodigital syndrome type 1, otopalatodigital syndrome type 2, frontometaphyseal dysplasia, and Melnick-Needles syndrome (described below). Frontometaphyseal dysplasia involves abnormalities in skeletal development, particularly involving the joints, and other health problems, including kidney, heart, and airway defects.

FLNA gene variants that cause frontometaphyseal dysplasia are described as "gain of function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Different variants in the FLNA gene appear to produce specific changes in the protein, resulting in particular signs and symptoms that are classified as individual FLNA-related disorders. Researchers suspect that the variants involved in frontometaphyseal dysplasia may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of the condition.

Intestinal pseudo-obstruction

Several variants in the FLNA gene have been identified in people with intestinal pseudo-obstruction, a condition characterized by impairment of the muscle contractions that move food through the digestive tract (peristalsis).

The FLNA gene variants that cause intestinal pseudo-obstruction include deletions or duplications of genetic material. The variants are thought to reduce levels of the filamin A protein or impair its function; this type of variant is called "loss of function." Research suggests that decreased filamin A function may affect the shape of cells in the smooth muscles of the gastrointestinal tract during development before birth, causing abnormalities in the layering of these muscles. Smooth muscles line the internal organs; they contract and relax without being consciously controlled. Abnormal layering of these muscles may interfere with these musclar movements that move food through the digestive tract.

Deletions or duplications of genetic material can affect all or part of the FLNA gene, and may also include nearby genes on the X chromosome. Changes in these additional genes may account for some of the other signs and symptoms, such as neurological abnormalities and unusual facial features, that occur in some affected individuals.

Melnick-Needles syndrome

Several variants in a region of the FLNA gene called exon 22 have been identified in people with Melnick-Needles syndrome. This condition is typically the most severe of the otopalatodigital spectrum disorders (described above). It involves abnormalities in skeletal development, causing short stature, abnormal curvature of the spine, partial dislocation of joints, and other health problems. The FLNA gene variants associated with Melnick-Needles syndrome are described as "gain of function" because they appear to enhance the activity of the filamin A protein or give the protein a new, atypical function. Researchers believe that the variants involved in Melnick-Needles syndrome may change the way the filamin A protein helps regulate processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of the condition.

Otopalatodigital syndrome type 1

Several variants in the FLNA gene have been found to cause otopalatodigital syndrome type 1. This condition is typically the mildest of the otopalatodigital spectrum disorders (described above). It is characterized by hearing loss caused by malformations in tiny bones in the ears (ossicles), an opening in the roof of the mouth (cleft palate), and skeletal abnormalities involving the fingers or toes (digits).

The FLNA gene variants that cause otopalatodigital syndrome type 1 all result in changes to the filamin A protein in a region that binds to actin (known as the CH2 domain). Many of these variants change single amino acids in the filamin A protein. These variants are described as "gain-of-function" because they appear to lead to a protein with an increased ability to bind to actin. Researchers believe that the FLNA gene variants impair the stability of the cytoskeleton and disrupt cellular processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of otopalatodigital syndrome type 1.

Otopalatodigital syndrome type 2

Several variants in the FLNA gene have been found to cause otopalatodigital syndrome type 2, which is part of the otopalatodigital spectrum (described above). This condition is similar to otopalatodigital syndrome type 1 (described above) and is characterized by hearing loss caused by malformations in the ossicles, a cleft palate, and skeletal abnormalities involving the digits. These abnormalities in skeletal development are typically more severe than in otopalatodigital syndrome type 1.

The FLNA gene variants that cause otopalatodigital syndrome type 2 all result in changes to the filamin A protein in a region that binds to actin (known as the CH2 domain). Most of these variants change single amino acids in the filamin A protein. These variants are described as "gain-of-function" because they appear to lead to a protein with an increased ability to bind to actin. Researchers believe that the FLNA gene variants impair the stability of the cytoskeleton and disrupt cellular processes involved in skeletal development, but it is not known how changes in the protein relate to the specific signs and symptoms of otopalatodigital syndrome type 2.

Periventricular heterotopia

Hundreds of FLNA gene variants have been identified in individuals with periventricular heterotopia, a condition in which nerve cells (neurons) do not move (migrate) properly during the early development of the fetal brain leading to seizures and other neurological problems. Most of these variants result in a lack of filamin A protein, which makes the cytoskeleton disorganized and impairs the attachment (adhesion) of cells to one another. Impaired adhesion alters cells that line the fluid-filled cavities near the center of the brain (the ventricles), which is where neurons develop. Disruption of this lining prevents the movement of neurons to the surface of the brain. Neurons that do not migrate properly during development form clumps (nodules) around the ventricles, resulting in the signs and symptoms of periventricular heterotopia.

In some cases, variants result in the substitution of one protein building block (amino acid) for another amino acid in the protein sequence. These variants may result in the production of a partially functional protein, sometimes causing a milder form of the disorder.

Terminal osseous dysplasia

At least one variant in the FLNA gene has been found to cause terminal osseous dysplasia, which is part of the otopalatodigital spectrum of disorders (described above). Terminal osseous dysplasia is characterized by skeletal abnormalities in the hands and feet, noncancerous (benign) tumors on the fingers and toes (digits), and dark patches of skin on the face.

The FLNA gene variant that causes terminal osseous dysplasia changes a single DNA building block (nucleotide) in the gene, substituting adenine for guanine at DNA position 5217 (written as 5217G>A). This DNA change alters the way the blueprint for making the filamin A protein is put together. The version of the protein made using this blueprint is abnormally short. Researchers suspect the altered protein may not be able to interact with other molecules normally. It is thought that the inability to bind to other proteins disrupts important processes involved in skeletal development and cell growth, leading to the bone and skin abnormalities characteristic of terminal osseous dysplasia.

X-linked cardiac valvular dysplasia

Variants in the FLNA gene have been found to cause X-linked cardiac valvular dysplasia, a condition characterized by abnormally thick heart valves. Most of these variants change single amino acids in the filamin A protein. These variants likely alter the shape of the protein, impairing its ability to bind to actin and other proteins. As a result, the cell cytoskeleton is weakened and valve cells and the extracellular matrix are disorganized. The cells are not positioned properly within the valve, so the valve becomes malformed. In addition, the cells' decreased ability to change shape impairs the valves' ability to open and close when the heart pumps blood. It appears that excess proteins are produced in the abnormal extracellular matrix, causing the valves to become thickened and further impairing their ability to open and close normally.

It is unclear why the heart valves are the only tissue affected by these FLNA gene variants. The variants that cause X-linked cardiac valvular dysplasia occur in a different part of the gene than those that cause other disorders (described above). It has been suggested that the region of the filamin A protein affected by these variants is necessary for binding to other proteins that play a significant role in heart development.

FG syndrome

MedlinePlus Genetics provides information about FG syndrome

Other Names for This Gene

• ABP-280
• ABPX
• actin-binding protein 280
• DKFZp434P031
• filamin 1
• filamin A, alpha
• filamin A, alpha (actin binding protein 280)
• FLN
• FLN1
• FLNA_HUMAN

Genomic Location

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males, who have only one X chromosome, a mutation in the only copy of the gene in each cell is sufficient to cause the condition. In females, who have two copies of the X chromosome, one altered copy of the gene in each cell can lead to less severe features of the condition or may cause no signs or symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Otopalatodigital syndrome type 2 is a rare disorder, affecting fewer than 1 in every 100,000 individuals. Its specific incidence is unknown.