NORD gratefully acknowledges 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.
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 (mutations) in either the MMP14 or MMP2 gene and is inherited in a recessive manner.
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 present with 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 associated with mutations in matrix metallopeptidase genes (MMP14 or MMP2). These genes code for proteins that breakdown 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. 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 or not these genes act alone in causing disease.
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 mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular 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.
Winchester syndrome is an extremely rare disorder inherited in a recessive manner. This means that two non-working copies of the gene must be present in order for symptoms to occur.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
All individuals carry a few changes in genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same altered genes, 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 mutations in the MMP14 or MMP2 genes.
Clinical Diagnostic Criteria
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.
Clinical Testing and Workup
Molecular genetic testing can be used to confirm a diagnosis of Winchester syndrome. Molecular testing is capable of identifying genetic mistakes in the DNA code. There are currently two known genes that are associated with Winchester syndrome; MMP14 and MMP2. Molecular genetic testing of these two genes can confirm a diagnosis of Winchester syndrome.
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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