Congenital contractural arachnodactyly is a disorder that affects many parts of the body. People with this condition typically are tall with long limbs (dolichostenomelia) and long, slender fingers and toes (arachnodactyly). They often have permanently bent joints (contractures) that can restrict movement in their hips, knees, ankles, or elbows. Additional features of congenital contractural arachnodactyly include underdeveloped muscles, a rounded upper back that also curves to the side (kyphoscoliosis), permanently bent fingers and toes (camptodactyly), ears that look "crumpled," and a protruding chest (pectus carinatum). Rarely, people with congenital contractural arachnodactyly have heart defects such as an enlargement of the blood vessel that distributes blood from the heart to the rest of the body (aortic root dilatation) or a leak in one of the valves that control blood flow through the heart (mitral valve prolapse). The life expectancy of individuals with congenital contractural arachnodactyly varies depending on the severity of symptoms but is typically not shortened.

A rare, severe form of congenital contractural arachnodactyly involves both heart and digestive system abnormalities in addition to the skeletal features described above; individuals with this severe form of the condition usually do not live past infancy.

Mutations in the FBN2 gene cause congenital contractural arachnodactyly. The FBN2 gene provides instructions for producing the fibrillin-2 protein. Fibrillin-2 binds to other proteins and molecules to form threadlike filaments called microfibrils. Microfibrils become part of the fibers that provide strength and flexibility to connective tissue that supports the body's joints and organs. Additionally, microfibrils regulate the activity of molecules called growth factors. Growth factors enable the growth and repair of tissues throughout the body.

Mutations in the FBN2 gene can decrease fibrillin-2 production or result in the production of a protein with impaired function. As a result, microfibril formation is reduced, which probably weakens the structure of connective tissue and disrupts regulation of growth factor activity. The resulting abnormalities of connective tissue underlie the signs and symptoms of congenital contractural arachnodactyly.

Normal Function

The FBN2 gene provides instructions for making a large protein called fibrillin-2. This protein is transported out of cells into the extracellular matrix, which is an intricate lattice of proteins and other molecules that forms in the spaces between cells. In this matrix, fibrillin-2 binds to other proteins to form threadlike filaments called microfibrils. Microfibrils become part of elastic fibers which enable the skin, ligaments, and blood vessels to stretch. Researchers have suggested that fibrillin-2 plays a role in directing the assembly of elastic fibers during embryonic development. Microfibrils also contribute to more rigid tissues that support the lens of the eye, nerves, and muscles. Additionally, microfibrils hold certain growth factors called transforming growth factor-beta (TGF-beta) proteins, which keeps them inactive. When released from microfibrils, TGF-beta growth factors are activated and affect the growth and repair of tissues throughout the body.

Health Conditions Related to Genetic Changes

Congenital contractural arachnodactyly

More than 20 mutations in the FBN2 gene have been found to cause congenital contractural arachnodactyly. Most of these mutations change one protein building block (amino acid) in the fibrillin-2 protein, usually replacing the amino acid cysteine with a different amino acid. The substitution of another amino acid for cysteine can alter the structure or function of fibrillin-2. Most other FBN2 mutations disrupt the way the FBN2 gene's instructions are used to make the fibrillin-2 protein. All of these mutations reduce the amount of fibrillin-2 available to form microfibrils. Decreased microfibril formation probably weakens the elastic fibers and causes overactivation of TGF-beta growth factors, which leads to the signs and symptoms of congenital contractural arachnodactyly.

Other Names for This Gene

• CCA
• DA9
• FBN2_HUMAN
• fibrillin 2 (congenital contractural arachnodactyly)

Genomic Location

• Marfan-like appearance (tall and slender with arm span longer than the person's height)
• Arachnodactyly (long slender fingers and toes)
• "Crumpled" ears
• Contractures of major joints from birth (particularly knees, elbows, fingers, toes, and hips)
• Bowed long bones
• Muscular hypoplasia (underdeveloped muscles)
• Kyphosis/scoliosis
• Aortic root dilation
• Craniofacial abnormalities (such as micrognathia; high arched palate; scaphocephaly (premature fusion of the sagittal suture of the skull leading to a long, narrow head); brachycephaly (premature fusion of the coronal suture, leading to a short skull); and frontal bossing).