Spondylocarpotarsal synostosis syndrome is a disorder that affects the development of bones throughout the body. Newborns with this disorder are of approximately normal length, but impaired growth of the torso results in short stature over time. The bones of the spine (vertebrae) are misshapen and abnormally joined together (fused). The vertebral abnormalities may result in an abnormally curved lower back (lordosis) and a spine that curves to the side (scoliosis).

People with spondylocarpotarsal synostosis syndrome have abnormalities and fusion of the bones of the wrist (carpal bones) and ankle (tarsal bones). They may also have inward- and upward-turning feet (clubfeet). Characteristic facial features include a round face, a large forehead (frontal bossing), and nostrils that open to the front rather than downward (anteverted nares).

Some people with spondylocarpotarsal synostosis syndrome have an opening in the roof of the mouth (a cleft palate), hearing loss, thin tooth enamel, flat feet, or an unusually large range of joint movement (hypermobility). Individuals with this disorder can survive into adulthood. Intelligence is generally unaffected, although mild developmental delay has been reported in some affected individuals.

Mutations in the FLNB gene cause spondylocarpotarsal synostosis syndrome. The FLNB gene provides instructions for making a protein called filamin B. This protein helps build the network of protein filaments (cytoskeleton) that gives structure to cells and allows them to change shape and move. Filamin B attaches (binds) to another protein called actin and helps the actin to form the branching network of filaments that makes up the cytoskeleton. It also links actin to many other proteins to perform various functions within the cell, including the cell signaling that helps determine how the cytoskeleton will change as tissues grow and take shape during development.

Filamin B is especially important in the development of the skeleton before birth. It is active (expressed) in the cell membranes of cartilage-forming cells (chondrocytes). Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone (a process called ossification), except for the cartilage that continues to cover and protect the ends of bones and is present in the nose, airways (trachea and bronchi), and external ears. Filamin B appears to be important for normal cell growth and division (proliferation) and maturation (differentiation) of chondrocytes and for the ossification of cartilage.

FLNB gene mutations that cause spondylocarpotarsal synostosis syndrome result in the production of an abnormally short filamin B protein that is unstable and breaks down rapidly. Loss of the filamin B protein appears to result in out-of-place (ectopic) ossification, resulting in fusion of the bones in the spine, wrists, and ankles and other signs and symptoms of spondylocarpotarsal synostosis syndrome.

A few individuals who have been diagnosed with spondylocarpotarsal synostosis syndrome do not have mutations in the FLNB gene. Researchers are working to identify and confirm additional genetic changes that can cause this disorder.

Normal Function

The FLNB gene provides instructions for making a protein called filamin B. This protein helps build the network of protein filaments (cytoskeleton) that gives structure to cells and allows them to change shape and move. Filamin B attaches (binds) to another protein called actin and helps the actin to form the branching network of filaments that makes up the cytoskeleton. It also links actin to many other proteins to perform various functions within the cell, including the cell signaling that helps determine how the cytoskeleton will change as tissues grow and take shape during development.

Filamin B is involved in the development of the skeleton before birth. It is active (expressed) in many cells and tissues of the body, including cartilage-forming cells called chondrocytes. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone (a process called ossification), except for the cartilage that continues to cover and protect the ends of bones and is present in the nose, airways (trachea and bronchi), and external ears. Filamin B appears to be important for normal cell growth and division (proliferation) and maturation (differentiation) of chondrocytes and for the ossification of cartilage.

Health Conditions Related to Genetic Changes

Atelosteogenesis type 1

At least seven FLNB gene mutations have been identified that cause atelosteogenesis type 1, a disorder that affects the development of bones throughout the body. The mutations change single protein building blocks (amino acids) in the filamin B protein or delete a small section of the protein sequence, resulting in an abnormal protein. This abnormal protein appears to have a new, atypical function that interferes with normal proliferation or differentiation of chondrocytes, impairing ossification and leading to the signs and symptoms of atelosteogenesis type 1.

Atelosteogenesis type 3

At least six FLNB gene mutations have been identified that cause atelosteogenesis type 3, a disorder that affects the development of bones throughout the body. These mutations change single amino acids in the filamin B protein or delete a small section of the protein sequence, resulting in an abnormal protein. This abnormal protein appears to have a new, atypical function that interferes with normal proliferation or differentiation of chondrocytes, impairing ossification and leading to the signs and symptoms of atelosteogenesis type 3.

Boomerang dysplasia

At least two FLNB gene mutations have been identified that cause boomerang dysplasia, a disorder that affects the development of bones throughout the body. These mutations change single amino acids in the filamin B protein or delete a small section of the protein sequence, resulting in an abnormal protein. This abnormal protein appears to have a new, atypical function that interferes with normal proliferation or differentiation of chondrocytes, impairing ossification and leading to the signs and symptoms of boomerang dysplasia.

Larsen syndrome

At least 13 FLNB gene mutations have been identified that cause Larsen syndrome, a disorder that affects the development of bones throughout the body. These mutations change single amino acids in the filamin B protein or delete a small section of the protein sequence, resulting in an abnormal protein. This abnormal protein appears to have a new, atypical function that interferes with normal proliferation or differentiation of chondrocytes, impairing ossification and leading to the signs and symptoms of Larsen syndrome.

It is not clear why similar mutations in the FLNB gene can result in four different disorders: atelosteogenesis type 1, atelosteogenesis type 3, boomerang dysplasia, or Larsen syndrome. Certain mutations in regions of the FLNB gene known as exons 2 through 5 seem to have the most harmful effects, usually resulting in the more severe disorders, atelosteogenesis type 1 and boomerang dysplasia. Atelosteogenesis type 3 and Larsen syndrome, which are less severe, are usually caused by apparently milder mutations in exons 2 through 5 or by mutations in exons 27 through 33. In a few cases, the same mutation has been associated with more than one of these disorders in different people.

Spondylocarpotarsal synostosis syndrome

At least five FLNB gene mutations have been identified that cause spondylocarpotarsal synostosis syndrome, a disorder that affects the development of bones throughout the body. These mutations, which may occur in any region of the gene, result in the production of an abnormally short filamin B protein that is unstable and breaks down rapidly. Loss of the filamin B protein appears to result in out-of-place (ectopic) ossification, resulting in fusion of the bones in the spine, wrists, and ankles and other signs and symptoms of spondylocarpotarsal synostosis syndrome.

Other disorders

Several common variations (polymorphisms) in the FLNB gene have been associated with low bone mineral density (osteoporosis), which weakens the bones and makes them prone to fracture. FLNB gene variations may affect the maintenance of bone structure throughout the lifespan and result in differences in bone mineral density.

Other Names for This Gene

• ABP-278
• ABP-280 homolog
• actin binding protein 278
• actin-binding-like protein
• beta-filamin
• FH1
• filamin B, beta
• filamin homolog 1
• filamin-3
• filamin-B
• FLN-B
• FLN1L
• FLNB_HUMAN
• LRS1
• TABP
• TAP
• thyroid autoantigen
• truncated ABP
• truncated actin-binding protein

Genomic Location

Spondylocarpotarsal synostosis syndrome caused by FLNB gene mutations is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

In a few individuals with signs and symptoms similar to those of spondylocarpotarsal synostosis syndrome but without FLNB gene mutations, the condition appears to have been inherited in an autosomal dominant pattern. Autosomal dominant means one copy of the altered gene in each cell is sufficient to cause the disorder.

Spondylocarpotarsal synostosis syndrome is a rare disorder; its prevalence is unknown. At least 25 affected individuals have been identified.