Stiff skin syndrome

Stiff skin syndrome (SSS) is a genetic syndrome caused by changes (mutations) in the FBN1 gene.^[1] This gene gives the body instructions to make a large protein called fibrillin-1. This protein works in the spaces between the cells (the extracellular matrix) to help form elastic fibers which enable the skin, ligaments, and blood vessels to stretch. This protein is also important for providing support to bones and the tissues that support the nerves, muscles, and lenses of the eye.^[2]

Mutations in the FBN1 gene that cause SSS affect the fibrillin-1 protein, which is thought to cause abnormal associations between fibrillin and another protein called elastin. When these two proteins interact abnormally in the extracellular matrix, this leads to the development of features of SSS.^[1]

Mutations in the FBN1 gene are also associated with a different genetic syndrome called Marfan syndrome. The changes that cause SSS occur in a different part of a gene than the changes that cause Marfan syndrome.^[1][3] It is possible that some cases of stiff skin syndrome occur in people without mutations in FBN1. More research will be necessary to determine if all cases of stiff skin syndrome are due to mutations in FBN1.^[4] 

Stiff skin syndrome (SSS) is primarily considered to be a connective tissue disease, rather than an autoimmune disease. Connective tissue is the structural tissue that gives strength to joints, tendons, ligaments, and blood vessels.

In autoimmune diseases, inflammation and the immune response result in tissue damage which may affect various tissues and organs in the body.^[5] Autoimmune diseases affect a significant portion of the population and are typically thought to be multifactorial (caused by a combination of genetic and environmental factors). Autoimmune diseases due to mutations in single genes are rare.^[6] SSS is now known to be caused by mutations in the FBN1 gene (rather than a faulty immune response), which is responsible for a key component of connective tissue and is known to cause various other connective tissue disorders.^[7]

There are disorders that are considered both autoimmune diseases and connective tissue diseases. Sometimes they are referred to as autoimmune disorders of connective tissue, or as autoimmune rheumatic disorders. These conditions result from the immune system mistakenly attacking components of connective tissues.

Scleroderma is an example of an autoimmune disorder of connective tissue (of unknown cause).^[7] SSS is sometimes described as an inherited, congenital form of scleroderma or a scleroderma-like disorder, because of overlapping features. It appears that in both conditions, the same process malfunctions and causes a similar end result of "stiff skin" or fibrosis.^[8] However, the triggers for this process appear to differ (an FBN1 gene mutation affecting skin development and maintenance, vs a faulty immune response). In this case, SSS is a connective tissue disorder that resembles scleroderma, which is autoimmune in nature.^[9]