Last updated:
02/01/2024
Years published: 1993, 1998, 2002, 2005, 2021, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Hayley Bottino and Shabri Patel, Master of Science in Human Genetics and Genetic Counseling (MSGC) students, NORD Editorial Interns from the Keck Graduate Institute and Emily Quinn, MS, CGC, Assistant Professor of Genetics at the Keck Graduate Institute, for assistance in preparation of this report.
Summary
Winchester syndrome is an extremely rare congenital connective tissue and bone disorder. Winchester syndrome is characterized most frequently by short stature, wearing down of bone and tissue, dark skin patches and coarse facial features. The main feature of this syndrome is short stature due to changes in the vertebrae of the backbone and long bones of the limbs that get worse over time (degenerative). Other symptoms commonly include arthritis-like symptoms, loss of bone tissue (osteolysis), reduced bone density (osteoporosis), nodules under the skin (subcutaneous), coarse facial features and abnormalities of the eyes and teeth. The most commonly affected joints are those of the hands, feet, knees, shoulders, elbow and hip. Winchester syndrome is caused by changes (variants or mutations) in the MMP14 gene and it is inherited in a recessive manner.
Introduction
Winchester syndrome is now considered to be part of a spectrum of diseases called multicentric osteolysis nodulosis and arthropathy spectrum. In the most recent nomenclature of skeletal dysplasias, Winchester syndrome was named MMP14-related multicentric osteolysis, nodulosis, and arthropathy.
The primary signs of Winchester syndrome are skeletal changes that involve thinning or weakening of the bone (multifocal osteoporosis), loss of bone tissue (progressive osteolysis), low bone mineral density (osteopenia) and joint issues (arthropathy) which encompass degenerative changes in the hands, feet, elbows, shoulders, knees, hips and spine. Due to loss of bone tissue and density, fractures may be more prevalent. Age of onset varies from 3 months to 22 years. Typically, the syndrome becomes apparent around the age of two years. The beginning signs of this syndrome are osteolysis particularly of the hands and feet which causes pain and limited movement. The accumulation of these skeletal abnormalities leads to short stature in the affected individual.
In addition to skeletal alterations, other symptoms include coarse facial features, congenital heart defects, cloudy covering of the cornea (corneal opacities) and skin findings. Coarse facial features can include a large head; flat, broad nose with a fleshy tip; large lips; large tongue (macroglossia); and irregularly spaced teeth or extra teeth. Patients also have large, inflamed gums, also known as hypertrophic gums. About one third of those affected with Winchester syndrome are born with a heart defect; these heart defects may include transposition of the great arteries, atrial septal defect, ventricular septal defect, bicuspid valves or mitral valve prolapse. There should be ongoing surveillance of the heart through EKG (electrocardiogram) as heart murmurs may occur. Clouding of the cornea may be observed in those affected with this syndrome and can cause vision problems or vision loss. Lastly, skin findings include thickened hyperpigmentation such as thick and darkened patches of skin and/or over growth of hair on the skin (hirsutism). Most individuals with Winchester syndrome have normal intelligence.
Winchester syndrome is caused by mutations in the MMP14 gene (also known as MT1-MMP).
In all known individuals affected with Winchester syndrome, two copies of the gene are altered, leading to disease. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body. In the case of Winchester syndrome, the parts of the body that are affected the most are the bones and skin.
The MMP14 gene provides instructions for making a protein called matrix metallopeptidase 14, which is found on the surface of cells, and helps modify and break down various components of 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 disease processes such as arthritis.
The matrix metallopeptidase 14 protein also turns on (activates) another protein called matrix metallopeptidase 2. The activity of matrix metallopeptidase 2 appears to be important for a variety of body functions, including bone remodeling, which is a normal process in which old bone is broken down and new bone is created to replace it.
Variants in the MMP14 gene result in less of the enzyme that is available to break down components of the extracellular matrix and activate matrix metallopeptidase 2 and may result in the signs and symptoms of Winchester syndrome with a spectrum of skeletal abnormalities with osteolysis.
Winchester syndrome is inherited in a recessive manner. 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 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.
All individuals carry a few gene variants. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry variants in the same gene, which increases the risk to have children with a recessive genetic disorder.
Since the original description of this syndrome in 1969, only about a dozen affected individuals have been described in the medical literature. Those identified with the syndrome to date have included individuals of Mexican, Puerto Rican and Iranian descent. More recently, multiple affected individuals of South Asian (India and Pakistan) and East Asian (Korean and Japanese) ancestry have been reported. Between 1969-2001, only 12 affected individuals with Winchester syndrome were reported worldwide. It appears that Winchester is more common in females than males with a female to male ratio of 3:1 (nine females, three males). Additional affected individuals may be undiagnosed or misdiagnosed.
A diagnosis of Winchester syndrome can be made in one of two ways. There are established clinical criteria and there is clinical genetic testing that can identify variants in the MMP14 gene.
The main clinical findings needed for a diagnosis of Winchester syndrome are the skeletal findings including osteoporosis, osteolysis and degenerative changes in the vertebral, carpal and tarsal bones. Skeletal findings need to be accompanied by two of the following symptoms: short stature, progressive fusion of the joints (contractures), corneal clouding (cataracts), thickened patches of skin (hyperpigmentation) or growth of hair on the skin (hirsutism), gum enlargement/hypertrophy and coarse facial features.
Molecular genetic testing can confirm a diagnosis of Winchester syndrome when disease-causing variants in the MMP14 gene are identified.
Treatment
At this point in time, there is no effective cure for Winchester syndrome. Treatments involve supportive measures to lessen the effect of symptoms. Both physical therapy and analgesic therapy are important for individuals with Winchester syndrome. Physical therapy may aid in slowing down the onset of joint contractures, which will help prolong mobility. Surgical treatments involving joint contracture release may be available, but outcomes have been inconsistent. Analgesic therapy refers to therapy that involves drugs that assist in the relief of pain; this may include anti-inflammatories, skeletal muscle relaxants and antibiotics. In addition to physical and analgesic therapies, physiotherapy and hydrotherapy may be beneficial for those experiencing movement difficulties.
To support bone health, supplements of calcium and vitamin D may be incorporated on a daily basis. Recent studies have reported success with bisphosphonate treatments in individuals with inherited osteolysis like those affected with Winchester syndrome. Bisphosphonate therapy includes dosing of two drugs, pamidronate or soledronate, to aid in the prevention of loss of bone density. Early initiation of this therapy when symptoms first appear can provide a better quality of life for those with Winchester syndrome.
Individuals with an initial diagnosis of Winchester syndrome should receive a complete skeletal survey, cardiac evaluation which includes an ultrasound of the heart (echocardiogram) and an eye examination. Referrals to an orthopedic surgeon, rheumatologist, physical therapist, clinical geneticist and/or genetic counselor are also necessary. After the initial diagnosis, individuals should receive annual check-ups by a rheumatologist and/or orthopedic surgeon for pain and joint assessment.
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Some current clinical trials also are posted on the following page on the NORD website:
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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/
TEXTBOOK
Chen H, & Chen H. Winchester Syndrome. In: Atlas of Genetic Diagnosis and Counseling 2017; 2995-3000.
JOURNAL ARTICLES
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
de Vos JHM, Tao EY, Ong SLM, et al, Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype. Human Molecular Genetics. 2018 Aug 15;27(16):2775-2788.
Park PG, Kim KH, Hyun HS, et al. Three cases of multicentric carpotarsal osteolysis syndrome: a case series. BMC medical genetics. 2018 Sep 12;19(1):164.
Mathew M, Thomas P, Roshni PR, & Kumar N M. A case report on Winchester syndrome. National Journal of Physiology, Pharmacy and Pharmacology 2017; 7(10):1137.
Rappaport N, Twik M, Plaschkes I, Nudel R, Iny Stein T, Levitt J, Gershoni M, Morrey CP, Safran M, and Lancet D. MalaCards: an amalgamated human disease compendium with diverse clinical and genetic annotation and structured search, Nucleic Acids Research 2017 Jan 4;45(D1):D877-D887
Pichler K, Karall D, Kotzot D, et al. Bisphosphonates in multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder–an alternative therapeutic approach. Scientific reports 2016; 6:34017.
Stelzer G, Rosen R, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Iny Stein T, Nudel R, Lieder I, Mazor Y, Kaplan S, Dahary D, Warshawsky D, Guan – Golan Y, Kohn A, Rappaport N, Safran M, and Lancet D. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analysis, Current Protocols in Bioinformatics 2016 Jun 20;54:1.30.
Ekbote AV, Danda S, Zankl A, et al.Patient with mutation in the matrix metalloproteinase 2 (MMP2) gene – a case report and review of the literature. J Clin Res Pediatr Endocrinol. 2014; 6:40–46.
Vanatka R, Rouzier C, Lambert J, Leroux C, & Coussement A. Winchester syndrome: The progression of radiological findings over a 23-year period. Skeletal Radiology 2011; 40(3), 347-51. doi:10.1007/s00256-010-1033-y
Seon-Yong J, Bo-Young K, & Hyon J. A novel homozygous mmp2 mutation in a patient with torg-winchester syndrome. Journal of Human Genetics / Japan Society of Human Genetics 2010;55(11): 764-766.
Lee SJ, Whitewood C, & Murray KJ. Inherited multicentric osteolysis: case report of three siblings treated with bisphosphonate. Pediatric Rheumatology 2010; 8(1): 12.
Grover S, Grewal RS, Verma R, et al. Winchester syndrome: a case report. International Journal of Dermatology 2009; 48:175-177. doi:10.1111/j.1365-4632.2009.03872.x
Rouzier C, Vanatka R, Bannwarth S, et al.A novel homozygous mmp2 mutation in a family with winchester syndrome. Clinical Genetics. 2006; 69(3): 271-276. doi:10.1111/j.1399-0004.2006.00584.x
Ravel TJ. Idiopathic multicentric osteolysis presents early and is not linked to chromosome 18q21.1. Journal of Medical Genetics 2000; 37(11). doi:10.1136/jmg.37.11.e34
INTERNET
Bhavani GSL, Shah H, Shukla A, et al. Multicentric Osteolysis Nodulosis and Arthropathy. 2016 Jul 14 [Updated 2023 Mar 30]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK373578/ Accessed Feb 1, 2024.
Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, Baltimore, MD. MIM Number: 277950: 01/31/2024. Available at: https://www.omim.org/entry/277950 Accessed Feb 1, 2024.
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