Stiff skin syndrome (SSS)is a rare syndrome characterized by hard, thick skin, usually on the entire body. The thickening of the skin can limit joint mobility and causes joints to be stuck in a bent position (flexion contractures). The onset of signs and symptoms can range from presenting at birth through childhood. Other signs and symptoms may include excessive hair growth (hypertrichosis), loss of body fat (lipodystrophy), scoliosis, muscle weakness, slow growth, and short stature. Weakness or paralysis of the eye muscles have also been reported.

Stiff skin syndrome is caused by mutations (changes) in the FBN1gene and is inherited in an autosomal dominant manner. Diagnosis is based on a clinical evaluation that is consistent with stiff skin syndrome, and the diagnosis can be confirmed with genetic testing. Treatment is based on the symptoms of each individual and may include physical therapy to improve or maintain joint movement.

Normal Function

The FBN1 gene provides instructions for making a large protein called fibrillin-1. 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, molecules of fibrillin-1 attach (bind) to each other and to other proteins to form threadlike filaments called microfibrils. Microfibrils form elastic fibers, which enable the skin, ligaments, and blood vessels to stretch. Microfibrils also provide support to more rigid tissues such as bones and the tissues that support the nerves, muscles, and lenses of the eyes.

Microfibrils store a protein called transforming growth factor beta (TGF-β), a critical growth factor. TGF-β affects development by helping to control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (motility), and the self-destruction of cells (apoptosis). Microfibrils help regulate the availability of TGF-β, which is turned off (inactivated) when stored in microfibrils and turned on (activated) when released.

Health Conditions Related to Genetic Changes

Acromicric dysplasia

At least nine FBN1 gene mutations have been identified in people with acromicric dysplasia. This condition is characterized by severely short stature, short limbs, stiff joints, and distinctive facial features.

FBN1 gene mutations that cause acromicric dysplasia are located in an area of the gene called exons 41 and 42, and change single protein building blocks (amino acids) in a region of the fibrillin-1 protein called TGF-β binding-protein-like domain 5. The mutations result in a reduction and disorganization of the microfibrils. Without enough normal microfibrils to store TGF-β, the growth factor is abnormally active. These effects likely contribute to the physical abnormalities that occur in acromicric dysplasia, but the mechanisms are unclear.

It is unknown why the FBN1 gene mutations that cause acromicric dysplasia lead to short stature, while certain other FBN1 gene mutations that also increase TGF-β activity cause a disorder called Marfan syndrome (see below), which is characterized by tall stature.

Isolated ectopia lentis

More than 30 mutations in the FBN1 gene have been found to cause isolated ectopia lentis. In this condition, the lens in one or both eyes is off-center (displaced), which leads to vision problems. Most of the FBN1 gene mutations that cause this condition change single amino acids in the fibrillin-1 protein. As a result, the production of normal fibrillin-1 protein is reduced, leading to a decrease in microfibril formation or the formation of impaired microfibrils. Without enough functional microfibrils to anchor the lens in its central position at the front of the eye, the lens becomes displaced, resulting in isolated ectopia lentis and related vision problems.

Ectopia lentis is classified as isolated when it occurs alone, without signs and symptoms affecting other body systems. However, some people initially diagnosed with isolated ectopia lentis caused by FBN1 gene mutations later develop additional features typical of a condition called Marfan syndrome (described below), such as abnormalities of the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). In these cases, the diagnosis often changes from isolated ectopia lentis to Marfan syndrome.

Marfan syndrome

Researchers have identified more than 1,300 FBN1 gene mutations that cause Marfan syndrome, a disorder that affects the connective tissue supporting the body's joints and organs. Abnormalities in the connective tissue lead to heart and eye problems in people with this disorder. In addition, affected individuals are usually tall and slender with elongated fingers and toes and other skeletal abnormalities.

Most of the mutations that cause Marfan syndrome change a single amino acid in the fibrillin-1 protein. The remaining FBN1 gene mutations result in an abnormal fibrillin-1 protein that cannot function properly. FBN1 gene mutations that cause Marfan syndrome reduce the amount of fibrillin-1 produced by the cell, alter the structure or stability of fibrillin-1, or impair the transport of fibrillin-1 out of the cell. These mutations lead to a severe reduction in the amount of fibrillin-1 available to form microfibrils.

Without enough microfibrils, excess TGF-β growth factors are activated and elasticity in many tissues is decreased, leading to overgrowth and instability of tissues and the signs and symptoms of Marfan syndrome.

Weill-Marchesani syndrome

Mutations in the FBN1 gene have also been identified in Weill-Marchesani syndrome. One of the identified mutations deletes part of the gene, leading to the production of an unstable version of the fibrillin-1 protein. The unstable protein likely interferes with the assembly of microfibrils. Abnormal microfibrils weaken connective tissue, which causes the eye, heart, and skeletal abnormalities associated with Weill-Marchesani syndrome.

Familial thoracic aortic aneurysm and dissection

MedlinePlus Genetics provides information about Familial thoracic aortic aneurysm and dissection

Geleophysic dysplasia

MedlinePlus Genetics provides information about Geleophysic dysplasia

Shprintzen-Goldberg syndrome

MedlinePlus Genetics provides information about Shprintzen-Goldberg syndrome

Other disorders

Mutations in the FBN1 gene can cause a condition called stiff skin syndrome. This condition is characterized by very hard, thick skin covering most of the body. The abnormal skin limits movement and can lead to joint deformities called contractures that restrict the movement of certain joints. The signs and symptoms of stiff skin syndrome usually become apparent in infancy to mid-childhood.

Mutations in the FBN1 gene can cause another condition called MASS syndrome. This condition involves abnormalities in several parts of the body, including the mitral valve (one of the valves that controls blood flow through the heart), the aorta (a large blood vessel that distributes blood from the heart to the rest of the body), the skeleton, and the skin.

It is unknown why different mutations in the FBN1 gene cause such a variety of disorders.

Other Names for This Gene

• FBN
• FBN1_HUMAN
• fibrillin 1 (Marfan syndrome)
• MFS1
• SGS

Genomic Location

Stiff skin syndrome (SSS) is inherited in an autosomal dominant manner. This means that having a change in only one copy of the FBN1 gene will cause symptoms of stiff skin syndrome. We inherit one copy of each of our genes from our mother and the other from our father.

Some people with stiff skin syndrome have a parent who has the syndrome as well. In this case, the affected individual inherited the syndrome from their affected parent. In other cases, a person with stiff skin syndrome is the first person in the family to have the syndrome, and neither parent is affected. In these cases, the mutation in FBN1 is new in the affected person, which is called a de novo mutation.

When a person with stiff skin syndrome has children, for each child there is a:

• 50% chance that the child will inherit the mutation in FBN1, which means they will have stiff skin syndrome
• 50% chance that the child will not inherit the mutation in FBN1, which means they will not have stiff skin syndrome.

Researchers have proposed that, in some cases, people with stiff skin syndrome may only have a mutation in FBN1 in some cells of the body. This could cause a less severe form of stiff skin syndrome that is called segmental stiff skin syndrome because it only affects certain parts of the body.

At this time, no specific therapies are available to reverse the symptoms of stiff skin syndrome (SSS). The recommended therapies aim to address issues moving the joints that may develop as a symptom of SSS. Regular physical therapy and exercise may be recommended to improve or maintain joint movement. A number of treatments have been tried in individual cases, including steroids, immunosuppressant drugs, psoralens (light-sensitizing medications), and light therapy. These treatments have not been helpful in slowing or stopping symptoms of SSS.

Some study findings on animal models have indicated potential future therapeutic options. In one study, mice with stiff skin syndrome were treated by blocking certain antibodies (integrin binding and TGF-beta antibodies). This prevented new skin lesions and reversed existing ones.

Another recent paper discussed the possibility of using a medication that suppresses the immune system called mycophenolate mofetil in combination with physical therapy to treat individuals with stiff skin syndrome. Although this treatment has only been used for a couple of affected individuals, the doctors noted an improvement in symptoms. However, these individuals had the segmental form of stiff skin syndrome. It is not known whether this treatment would work for every person with the segmental form of stiff skin syndrome, and it is not known if it will work at all for people with the classic form of stiff skin syndrome.