Last updated:
2/6/2024
Years published: 2024
NORD gratefully acknowledges Amanda J, Grieco, PhD and Gioconda Alyea, Brazilian MD, MS, National Organization for Rare Disorders, for the preparation of this report.
Summary
Multicentric osteolysis nodulosis and arthropathy spectrum is a group of rare congenital skeletal disorders characterized by progressive bone loss, joint disease and bumps under the skin. People with these conditions have a loss of bone tissue, especially in the hands and feet; pain, swelling, stiffness and loss of motion in joints located in the hands, feet, knees, wrists, ankles and elbows; and firm, round bumps under the skin of the palms and soles. Other signs and symptoms include coarse facial features, skin abnormalities and heart defects. These conditions are caused by changes (variants) in the MMP2 gene or MMP14 gene that are typically inherited in a recessive pattern. Treatment is supportive and can include physical therapy, pain management and mobility aids.
Introduction
In the most recent nomenclature of skeletal dysplasias, multicentric osteolysis nodulosis and arthropathy spectrum was the name given to the conditions formerly called Torg syndrome, Torg-Winchester syndrome, Winchester syndrome and multicentric osteolysis nodulosis and arthropathy (MONA). Winchester syndrome is also known as MMP14-related multicentric osteolysis, nodulosis, and arthropathy. MONA is also known as MMP2-related multicentric osteolysis, nodulosis, and arthropathy.
Individuals affected by these conditions have skeletal changes that involve thinning or weakening of the bone (multifocal osteoporosis), progressive loss of bone tissue (osteolysis) and low bone mineral density (osteopenia) which lead to degenerative changes in bones of the hands, feet, elbows, shoulders, knees, hips and spine. Loss of bone tissue and density can lead to a short stature and brittle bones that can lead to frequent bone fractures. In some individuals, spine degeneration can cause a sideways curvature of the spine (scoliosis) and forward rounding of the spine (kyphosis).
Almost all individuals affected by these conditions have joint abnormalities. Bone destruction can lead to progressive joint disease (arthropathy) that includes pain, swelling, stiffness and a reduced range of motion in the joints (contracture). Small joints of the hands and feet are the most commonly affected, but other sites near bone destruction can be involved including knees, wrists, ankles and elbows.
Skin abnormalities typically occur in individuals with these conditions. Firm, round bumps can appear under the skin (subcutaneous nodules) in the palms and soles of feet. These nodules may or may not be painful.
Some individuals have skin thickening, excessively dark patches of skin (hyperpigmentation) with or without damage to the skin (lesions) and folds of extra skin in the hands and feet where destruction of underlying bone has occurred.
Most affected individuals have coarse facial features that can include a large and round tip of the nose (bulbous nose); misalignment of the eyes where one eye aligns inward toward the nose or outward away from the nose while the other eye remains focused (strabismus); and bulging of one or both eyes (proptosis). Some individuals have large and inflamed gums (hypertrophic gums). A few individuals may have clouding of the clear front covering of the eye (corneal opacity).
About one third of affected children are born with heart defects. These may include transposition of the great arteries, atrial septal defect, ventricular septal defect, bicuspid valves or mitral valve prolapse.
Multicentric osteolysis nodulosis and arthropathy spectrum disorders are caused by variants in the MMP2 gene or MMP14 gene.
Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein that is created may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many parts of the body.
The MMP2 and the MMP14 genes code for proteins (enzymes) that break down the extracellular matrix, the protein framework that provides structural support for cells in tissues. The breakdown of the extracellular matrix is a normal process in tissue remodeling and when disturbed, may lead to diseases such as arthritis. Loss in activity of either the MMP2 or MMP14 gene results in a spectrum of skeletal abnormalities with osteolysis. However, it is still being investigated whether these genes act alone in causing disease and how the specific symptoms and signs of the spectrum are produced.
Multicentric osteolysis nodulosis and arthropathy spectrum are inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one gene variant e for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
The exact number of people who have these disorders is unknown. Onset is usually between ages six months and six years but can range from birth to 11 years of age.
To date, in 2023, 51 people from 31 families have been tested and confirmed to have variants in the MMP2 gene that cause these conditions. So far, it is not known how many people have variants in the MMP14 gene, but it is believed to be less than a dozen.
A diagnosis of multicentric osteolysis nodulosis and arthropathy spectrum is based upon identification of characteristic clinical features, a detailed patient and family history and thorough clinical testing that can include molecular genetic testing and an evaluation of enzyme activity.
Several clinical findings may lead to a suspected diagnosis of multicentric osteolysis nodulosis and arthropathy spectrum. These include pain, swelling or a limited range of motion (contractures) in joints of the hands and feet in early childhood; firm, round bumps under the skin (subcutaneous nodules) in the palms and soles of feet; coarse facial features and large and inflamed gums (hypertrophic gums). Findings on X-rays can include thinning and degeneration of bones, especially in the hands, feet, spine and long bones. A diagnosis may also be suspected if another family member has been diagnosed with a condition in this spectrum.
A diagnosis can be confirmed by molecular genetic testing or an evaluation of enzyme activity. Molecular genetic testing can determine if an individual has two disease-causing variants in the MMP2 gene or MMP14 gene. Enzyme activity tests can be performed on body fluid, tissue or cells and can detect a lack of matrix metalloproteinase-2 enzyme activity.
Clinical Testing and Work-up
Patients should undergo evaluations of body systems typically affected by these conditions, including screenings for back abnormalities, joint disease and congenital heart defects. Meeting with a clinical geneticist and/or genetic counselor may also be helpful. Skeletal and joint evaluations should be repeated annually by a rheumatologist and/or orthopedic surgeon. Heart defects should be evaluated at intervals recommended by a cardiologist and may include ongoing surveillance of the heart through EKG (electrocardiogram) testing.
Treatment
Treatments are supportive and directed toward lessening symptoms. Supplements of vitamin D and calcium can be taken daily to help support remaining bone health. Spine abnormalities may be managed by an orthopedist. Reducing physical trauma may reduce the risk of fractures. Physical therapy may slow the onset of joint contractures and help prolong mobility. Mobility aids, like wheelchairs and walking aids, may be needed to facilitate mobility. Pain medications recommended by a rheumatologist or pain clinic may relieve some types of pain. Surgical release of contractures may be possible to increase joint mobility. Medical or surgical treatments for heart defects may be needed.
Bisphosphonates should be considered in osteopenia and osteoporosis. The use of disease-modifying antirheumatic drugs should be avoided. Molecular analysis is also recommended to aid in developing crucial molecules for targeted therapy. Other future treatment may include targeted enzyme therapy with MMP-2 because MMP 2 deficiency is found in these patients, or the use of TGF-β because MMP 2 activates TGF-β.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Imam SK, Alnaqeb D, Bedaiwi M, Khouj EM. Multicentric osteolysis nodulosis arthropathy syndrome simulating juvenile idiopathic arthritis in an adult female: a case report and a literature review. Cureus. 2023;15(9):e45152. Published 2023 Sep 13. doi:10.7759/cureus.45152
Unger S, Ferreira CR, Mortier GR, et al. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191(5):1164-1209. doi:10.1002/ajmg.a.63132
Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, et al. Nosology of genetic skeletal disorders: 2023 revision. American Journal of Medical Genetics Part A. 2023;191(5): 1164–1209. https://doi.org/10.1002/ajmg.a.63132
INTERNET
Bhavani GSL, Shah H, Shukla A, et al. Multicentric Osteolysis Nodulosis and Arthropathy. 2016 Jul 14. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK373578/. Accessed Jan 25, 2024.
Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 259600: 01/08/2024. Available at: https://www.omim.org/entry/259600. Accessed Jan 20, 2024.
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