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Disease Profile

Stiff skin syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Childhood

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ICD-10

L98.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Categories

Congenital and Genetic Diseases; Skin Diseases

Summary

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).[1] The onset of signs and symptoms can range from presenting at birth through childhood.[2] 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.[2][3]

Stiff skin syndrome is caused by mutations (changes) in the FBN1 gene and is inherited in an autosomal dominant manner.[1][3] 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.[1]

Symptoms

The signs and symptoms associated with stiff skin syndrome (SSS) include hard, thickened skin, especially affecting the buttocks, thighs, and shoulders. Other symptoms may include excessive hair growth (hypertrichosis), loss of body fat (lipodystrophy), scoliosis, muscle weakness, slow growth, and short stature.[1] Some people with SSS may have restrictive pulmonary changes and a narrow chest cavity that cause trouble breathing. Many individuals with SSS walk on their tiptoes.[4]

The thickening of the skin associated with stiff skin syndrome can result in difficulty moving joints, as they become stuck in the bent position (flexion contractures). This typically affects the larger joints, such as the shoulders, elbows, and knees. The ability to flex the joints of the fingers may also be affected, as individuals with this syndrome may develop nodules on the skin of the fingers. SSS is a slowly progressive syndrome, meaning that the signs and symptoms worsen as individuals get older.[4]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Lack of skin elasticity
0100679
Limitation of joint mobility
Decreased joint mobility
Decreased mobility of joints
Limited joint mobility
Limited joint motion

[ more ]

0001376
Thickened skin
Thick skin
0001072
5%-29% of people have these symptoms
Abnormal circulating lipid concentration
0003119
Aplasia/Hypoplasia of the skin
Absent/small skin
Absent/underdeveloped skin

[ more ]

0008065
Glaucoma
0000501
Hypertension
0000822
Impaired pain sensation
Decreased pain sensation
0007328
Lipoatrophy
Loss of fat tissue in localized area
0100578
Lipodystrophy
Inability to make and keep healthy fat tissue
0009125
Midface retrusion
Decreased size of midface
Midface deficiency
Underdevelopment of midface

[ more ]

0011800
Muscle weakness
Muscular weakness
0001324
Nephrolithiasis
Kidney stones
0000787
Peripheral neuropathy
0009830
Retinal detachment
Detached retina
0000541
Sensorineural hearing impairment
0000407
Short stature
Decreased body height
Small stature

[ more ]

0004322
Strabismus
Cross-eyed
Squint
Squint eyes

[ more ]

0000486
Subcutaneous nodule
Firm lump under the skin
Growth of abnormal tissue under the skin

[ more ]

0001482
Type II diabetes mellitus
Noninsulin-dependent diabetes
Type 2 diabetes
Type II diabetes

[ more ]

0005978
Percent of people who have these symptoms is not available through HPO
Autosomal dominant inheritance
0000006
Flexion contracture
Flexed joint that cannot be straightened
0001371
Stiff skin
0030053

Cause

Stiff skin syndrome (SSS) is a genetic syndrome caused by changes (mutations) in the FBN1 gene.[3] 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.[5]

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.[3]

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.[3][6] 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.[7] 

Diagnosis

A diagnosis of stiff skin syndrome (SSS) can be made based on a clinical evaluation that is consistent with the signs and symptoms of the syndrome. A healthcare provider may observe that a child has features of stiff skin syndrome. In some cases, biopsies of the skin can be used to determine if the skin has certain characteristics when viewed under a microscope.[2] In some cases, genetic testing of the FBN1 gene may be used to confirm the diagnosis.[4] 

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    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.[2]

    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.[8] You can read more about this discovery through the following link to the Scleroderma Research Society: https://www.srfcure.org/research/funded-research/3301-interrogation 

    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.[9]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      In-Depth Information

      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Stiff skin syndrome. Click on the link to view a sample search on this topic.

        References

        1. Chamney S, Cartmill B, Earley O, McConnell V, and Willoughby CE. The ocular phenotype of stiff-skin syndrome. Eye (Lond). January 2016; 30(1):156-159. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709530/.
        2. Amorim AG, Aide MK, Duraes SM, and Rochael MC. Stiff skin syndrome--case report. An Bras Dermatol. 2011 Jul-Aug; 86(4 Suppl 1):S178-81. https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0365-05962011000700046&lng=en&nrm=iso&tlng=en.
        3. Stiff Skin Syndrome, SSKS. Online Mendelian Inheritance of Man (OMIM). June 8, 2016; https://omim.org/entry/184900.
        4. Stiff skin syndrome. Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2833. Accessed 9/10/2017.
        5. FBN1 gene. Genetics Home Reference. March 2015; https://ghr.nlm.nih.gov/gene/FBN1.
        6. Eckes B, Wang F, Moinzadeh P, Hunzelmann N, and Krieg T. Pathophysiological Mechanisms in Sclerosing Skin Diseases. Frontiers in Medicine. 2017; 4:120. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563304/.
        7. Myers KL, Mir A, Schaffer JV, Meehan SA, Orlow SJ, and Brinster NK. Segmental stiff skin syndrome (SSS): A distinct clinical entity. Journal of the American Academy of Dermatology. July 2016; 75(1):163-168. https://www.ncbi.nlm.nih.gov/pubmed/26944597.
        8. Gerber EE, Gallo EM, Fontana SC, Davis EC, Wigley FM, Huso DL, and Dietz HC. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature. November 7, 2013; 503(7474):126-30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992987/.
        9. Kurtzman DJB, Wright NA, Patel M, and Vleugels RA. Segmental stiff skin syndrome (SSS): Two additional cases with a positive response to mycophenolate mofetil and physical therapy. Journal of the American Academy of Dermatology. December 2016; 75(6):237-239. https://www.ncbi.nlm.nih.gov/pubmed/27846975.

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