Frontometaphyseal dysplasia

Frontometaphyseal dysplasia is a disorder involving abnormalities in skeletal development and other health problems. It is a member of a group of related conditions called otopalatodigital spectrum disorders, which also includes otopalatodigital syndrome type 1, otopalatodigital syndrome type 2, 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 bony abnormalities involving various areas of the skeleton.

Frontometaphyseal dysplasia is distinguished from the other otopalatodigital spectrum disorders by the presence of joint deformities called contractures that restrict the movement of certain joints. People with frontometaphyseal dysplasia may also have bowed limbs, an abnormal curvature of the spine (scoliosis), and abnormalities of the fingers and hands.

Characteristic facial features may include prominent brow ridges; wide-set and downward-slanting eyes; a very small lower jaw and chin (micrognathia); and small, missing, or misaligned teeth. Some affected individuals have hearing loss.

In addition to skeletal abnormalities, individuals with frontometaphyseal dysplasia may have obstruction of the ducts between the kidneys and bladder (ureters), heart defects, or constrictions in the passages leading from the windpipe to the lungs (the bronchi) that can cause problems with breathing.

There are three types of frontometaphyseal dysplasia, known as type 1, type 2, and type 3. The three types differ in their genetic cause and the way they are inherited.

Frontometaphyseal dysplasia is a rare disorder; over a hundred cases have been reported worldwide.

Variants (also called mutations) in the FLNA gene cause frontometaphyseal dysplasia type 1. Variants in the MAP3K7 gene cause frontometaphyseal dysplasia type 2, and TAB2 gene variants cause type 3.

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 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.

Variants in the FLNA gene have been identified in people with frontometaphyseal dysplasia. These mutations 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 think that the mutations 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 frontometaphyseal dysplasia.

When frontometaphyseal dysplasia is caused by variants in the FLNA gene, it is inherited in an X-linked dominant pattern. The FLNA gene  is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a variant in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a variant in the only copy of the gene in each cell causes the disorder. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. Males with frontometaphyseal dysplasia type 1 generally have more severe signs and symptoms of the disorder than do females, who may show only the characteristic facial features.

When frontometaphyseal dysplasia is caused by variants in the MAP3K7 or TAB2 gene, it is inherited in an autosomal dominant pattern. Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder.