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Systemic scleroderma
Systemic scleroderma is an autoimmune disorder that affects the skin and internal
organs. Autoimmune disorders occur when the immune system malfunctions and
attacks the body's own tissues and organs. The word "scleroderma" means hard skin
in Greek, and the condition is characterized by the buildup of scar tissue (fibrosis) in
the skin and other organs. The condition is also called systemic sclerosis because the
fibrosis can affect organs other than the skin. Fibrosis is due to the excess production
of a tough protein called collagen, which normally strengthens and supports connective
tissues throughout the body.
The signs and symptoms of systemic scleroderma usually begin with episodes of
Raynaud phenomenon, which can occur weeks to years before fibrosis. In Raynaud
phenomenon, the fingers and toes of affected individuals turn white or blue in response
to cold temperature or other stresses. This effect occurs because of problems
with the small vessels that carry blood to the extremities. Another early sign of
systemic scleroderma is puffy or swollen hands before thickening and hardening
of the skin due to fibrosis. Skin thickening usually occurs first in the fingers (called
sclerodactyly) and may also involve the hands and face. In addition, people with
systemic scleroderma often have open sores (ulcers) on their fingers, painful bumps
under the skin (calcinosis), or small clusters of enlarged blood vessels just under the
skin (telangiectasia).
Fibrosis can also affect internal organs and can lead to impairment or failure of the
affected organs. The most commonly affected organs are the esophagus, heart,
lungs, and kidneys. Internal organ involvement may be signaled by heartburn, difficulty
swallowing (dysphagia), high blood pressure (hypertension), kidney problems,
shortness of breath, diarrhea, or impairment of the muscle contractions that move food
through the digestive tract (intestinal pseudo-obstruction).
There are three types of systemic scleroderma, defined by the tissues affected in the
disorder. In one type of systemic scleroderma, known as limited cutaneous systemic
scleroderma, fibrosis usually affects only the hands, arms, and face. Limited cutaneous
systemic scleroderma used to be known as CREST syndrome, which is named for
the common features of the condition: calcinosis, Raynaud phenomenon, esophageal
motility dysfunction, sclerodactyly, and telangiectasia. In another type of systemic
scleroderma, known as diffuse cutaneous systemic scleroderma, the fibrosis affects
large areas of skin, including the torso and the upper arms and legs, and often involves
internal organs. In diffuse cutaneous systemic scleroderma, the condition worsens
quickly and organ damage occurs earlier than in other types of the condition. In the third
type of systemic scleroderma, called systemic sclerosis sine scleroderma ("sine" means
without in Latin), fibrosis affects one or more internal organs but not the skin.
 Approximately 15 percent to 25 percent of people with features of systemic scleroderma
also have signs and symptoms of another condition that affects connective tissue, such
as polymyositis, dermatomyositis, rheumatoid arthritis, Sjögren syndrome, or systemic
lupus erythematosus. The combination of systemic scleroderma with other connective
tissue abnormalities is known as scleroderma overlap syndrome.

Frequency
The prevalence of systemic scleroderma is estimated to range from 50 to 300 cases
per 1 million people. For reasons that are unknown, women are four times more likely to
develop the condition than men.

Causes
Researchers have identified variations in several genes that may influence the risk of
developing systemic scleroderma. The most commonly associated genes belong to a
family of genes called the human leukocyte antigen (HLA) complex. The HLA complex
helps the immune system distinguish the body's own proteins from proteins made by
foreign invaders (such as viruses and bacteria). Each HLA gene has many different
normal variations, allowing each person's immune system to react to a wide range of
foreign proteins. Specific normal variations of several HLA genes seem to affect the risk
of developing systemic scleroderma.
Normal variations in other genes related to the body's immune function, such as
IRF5 and STAT4, are also associated with an increased risk of developing systemic
scleroderma. Variations in the IRF5 gene are specifically associated with diffuse
cutaneous systemic scleroderma, and a variation in the STAT4 gene is associated with
limited cutaneous systemic scleroderma. The IRF5 and STAT4 genes both play a role
in initiating an immune response when the body detects a foreign invader (pathogen)
such as a virus.
It is not known how variations in the associated genes contribute to the increased risk
of systemic scleroderma. Variations in multiple genes may work together to increase
the risk of developing the condition, and researchers are working to identify and confirm
other genes associated with increased risk. In addition, a combination of genetic and
environmental factors seems to play a role in developing systemic scleroderma.

Inheritance Pattern
Most cases of systemic scleroderma are sporadic, which means they occur in people
with no history of the condition in their family. However, some people with systemic
scleroderma have close relatives with other autoimmune disorders.
A small percentage of all cases of systemic scleroderma have been reported to
run in families; however, the condition does not have a clear pattern of inheritance.
Multiple genetic and environmental factors likely play a part in determining the risk of
developing this condition. As a result, inheriting a genetic variation linked with systemic
scleroderma does not mean that a person will develop the condition.

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Other Names for This Condition
• familial progressive scleroderma
• progressive scleroderma
• systemic sclerosis

Diagnosis & Management

Genetic Testing Information
• What is genetic testing?
/primer/testing/genetictesting
• Genetic Testing Registry: Scleroderma, familial progressive
https://www.ncbi.nlm.nih.gov/gtr/conditions/C1866983/

Research Studies from ClinicalTrials.gov

• ClinicalTrials.gov
https://clinicaltrials.gov/ct2/results?cond=%22systemic+scleroderma%22

Other Diagnosis and Management Resources

• Cedars-Sinai Medical Center
https://www.cedars-sinai.org/health-library/diseases-and-conditions/s/
scleroderma.html

Additional Information & Resources

Health Information from MedlinePlus
• Encyclopedia: Raynaud's Phenomenon
https://medlineplus.gov/ency/article/000412.htm
• Encyclopedia: Scleroderma
https://medlineplus.gov/ency/article/000429.htm
• Encyclopedia: Telangiectasia
https://medlineplus.gov/ency/article/003284.htm
• Health Topic: Connective Tissue Disorders
https://medlineplus.gov/connectivetissuedisorders.html
• Health Topic: Scleroderma
https://medlineplus.gov/scleroderma.html

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Genetic and Rare Diseases Information Center
• Localized scleroderma
https://rarediseases.info.nih.gov/diseases/7058/localized-scleroderma
• Scleroderma
https://rarediseases.info.nih.gov/diseases/10308/scleroderma
• Systemic scleroderma
https://rarediseases.info.nih.gov/diseases/9748/systemic-scleroderma

Additional NIH Resources

• National Institute of Arthritis and Musculoskeletal and Skin Diseases: Raynaud's
Phenomenon
https://www.niams.nih.gov/health-topics/raynauds-phenomenon
• National Institute of Arthritis and Musculoskeletal and Skin Diseases: Scleroderma
https://www.niams.nih.gov/health-topics/scleroderma

Educational Resources
• American College of Rheumatology
https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/
Scleroderma
• Boston Children's Hospital
http://www.childrenshospital.org/conditions-and-treatments/conditions/s/
scleroderma
• Cedars-Sinai Medical Center
https://www.cedars-sinai.org/health-library/diseases-and-conditions/s/
scleroderma.html
• MalaCards: systemic scleroderma
https://www.malacards.org/card/systemic_scleroderma

Patient Support and Advocacy Resources

• Scleroderma Foundation
http://www.scleroderma.org/site/PageServer
• Scleroderma Research Foundation
https://srfcure.org/

Scientific Articles on PubMed

• PubMed
https://www.ncbi.nlm.nih.gov/pubmed?term=%28systemic+scleroderma%5BTI
AB%5D%29+AND+english%5Bla%5D+AND+human%5Bmh%5D+AND+%22last
+1800+days%22%5Bdp%5D

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 Catalog of Genes and Diseases from OMIM
• SCLERODERMA, FAMILIAL PROGRESSIVE
http://omim.org/entry/181750

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Reprinted from Genetics Home Reference:
https://ghr.nlm.nih.gov/condition/systemic-scleroderma

Reviewed: April 2015

Published: August 20, 2019

Lister Hill National Center for Biomedical Communications

U.S. National Library of Medicine
National Institutes of Health
Department of Health & Human Services

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