Winchester syndrome

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Winchester syndrome or Torg-Winchester syndrome or Multicentric Osteolysis, Nodulosis, and Arthropathy
Other namesTorg-Winchester syndrome [1] Multicentric Osteolysis, Nodulosis, and Arthropathy [2]
PBB Protein MMP2 image.jpg
Matrix Metalloproteinase 2

Winchester syndrome is a rare hereditary connective tissue disease described in 1969, [3] of which the main characteristics are short stature, marked contractures of joints, opacities in the cornea, coarse facial features, dissolution of the carpal and tarsal bones (in the hands and feet, respectively), and osteoporosis. Winchester syndrome was once considered to be related to a similar condition, multicentric osteolysis, nodulosis, and arthropathy (MONA). [4] [5] However, it was discovered that the two are caused by mutations found in different genes; however they mostly produce the same phenotype or clinical picture. [4] Appearances resemble rheumatoid arthritis. Increased uronic acid is demonstrated in cultured fibroblasts from the skin and to a lesser degree in both parents. Despite initial tests not showing increased mucopolysaccharide excretion, the disease was regarded as a mucopolysaccharidosis. [3] Winchester syndrome is thought to be inherited as an autosomal recessive trait.

Contents

Symptoms

Symptoms of Winchester or MONA syndrome begin with the deterioration of bone within the hands and feet. This loss of bone causes pain, pathological fractures and limited mobility. The abnormalities of the bone spread to other areas of the body, mostly the joints. This causes arthropathy: stiffening of the joints (contractures) and swollen joints. Many people develop osteopenia and osteoporosis throughout their entire body. The bone and joint manifestations characteristically start in the hands and feet then spread to the larger joints eventually like elbows and shoulders in the upper extremities and knees and hips in the lower extremities. Due to the damage to the bones, many affected individuals suffer from bone fractures, arthritis and occasionally short stature. [4] [6] [7]

Many individuals experience leathery skin where the skin appears dark and thick. Excessive hair growth is known to be found in these darker areas of the skin (hypertrichosis). The eyes may develop a white or clear covering the cornea (corneal opacities) which can cause problems with vision. [5]

Mechanism

Winchester syndrome is believed to be inherited through autosomal recessive inheritance. [8] [4] It believed that this disease is caused by a nonlysosomal connective-tissue disturbance. The protein inactivation mutation is found on the matrix metalloproteinase 2 gene (MMP2). [4] [9] MM2 is responsible for bone remodeling. Bone remodeling is the process in which old bone is destroyed so that new bone can be created to replace it. This mutation causes a multicentric osteolysis and arthritis syndrome. It is hypothesized that the loss of an upstream MMP-2 protein activator MT1-MMP, results in decreased MMP-2 activity without affecting MMP2. The inactivating homoallelic mutation of MT1-MMP can be seen at the surface of fibroblasts. It was determined that fibroblasts lacking MT1-MMP lack the ability to degrade type I collagen which leads to anomalous function. [9]

Diagnosis

In 1989, a set of diagnostic criteria were created for the diagnosing of Winchester syndrome. [10] The typical diagnosis criteria begin with skeletal radiological test results and two of the defining symptoms, such as short stature, coarse facial features, hyperpigmentation, or excessive hair growth. [10] The typical tests that are performed are x-ray and magnetic resonance imaging. A complete skeletal radiographic survey is mandatory for diagnosis of Winchester or MONA syndrome together with a detailed musculoskeletal examination and craniofacial morphology assessment. [4] It appears that Winchester syndrome is more common in women than men. [6] Winchester syndrome is very rare. There have only been a few individuals worldwide who were reported to have this disorder. [5]

Treatment

There is no known cure for Winchester syndrome; however, there are many therapies that can aid in the treatment of symptoms. [6] Such treatments can include medications: anti-inflammatories, muscle relaxants, and antibiotics. Many individuals will require physical therapy to promote movement and use of the limbs affected by the syndrome. Bisphosphonates have been used to improve bone quality and density or at least halt the progression of bone damages or osteolysis. [11] Genetic counseling is typically prescribed for families to help aid in the understanding of the disease. There are a few clinical trials available to participate in. The prognosis for patients diagnosed with Winchester syndrome is positive. It has been reported that several affected individuals have lived to middle age; however, the disease is progressive and mobility will become limited towards the end of life. Eventually, the contractures will remain even with medical intervention, such as surgery. [6]

Research

In 2005, a patient with Winchester syndrome was shown to have mutations in the matrix metalloproteinase 2 (MMP2) gene. [12] A 2006 study showed other mutations found in the MMP2 gene. This has led to the belief that there are many similar diseases within this family of mutations. [13] As of 2007, it was found that these mutations are also found in Torg and Nodulosis-arthropathy-osteolysis syndrome (NAO). This means that Torg, NAO, and Winchester syndrome are allelic disorders. [4] [12] In 2014, a new case of Winchester syndrome was reported. [14] According to a recently published article, it was discovered that multicentric osteolysis, nodulosis, and arthropathy (MONA) and Winchester syndrome are different diseases. Mutations in MMPS and MT1-MMP result in similar but distinctly different "vanishing bone" syndromes. [8]

See also

Related Research Articles

Juvenile idiopathic arthritis (JIA) is the most common, chronic rheumatic disease of childhood, affecting approximately 16 to 150 out of 100,000 children. Juvenile, in this context, refers to disease onset before 16 years of age, while idiopathic refers to a condition with no defined cause, and arthritis is inflammation within the joint.

<span class="mw-page-title-main">Arthrogryposis</span> Medical condition

Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning "curving of joints".

A connective tissue disease (collagenosis) is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds together, and protects organs. These tissues form a framework, or matrix, for the body, and are composed of two major structural protein molecules: collagen and elastin. There are many different types of collagen protein in each of the body's tissues. Elastin has the capability of stretching and returning to its original length—like a spring or rubber band. Elastin is the major component of ligaments and skin. In patients with connective tissue disease, it is common for collagen and elastin to become injured by inflammation (ICT). Many connective tissue diseases feature abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one's own body tissues (autoimmunity).

<span class="mw-page-title-main">Otospondylomegaepiphyseal dysplasia</span> Medical condition

Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive disorder of bone growth that results in skeletal abnormalities, severe hearing loss, and distinctive facial features. The name of the condition indicates that it affects hearing (oto-) and the bones of the spine (spondylo-), and enlarges the ends of bones (megaepiphyses).

Farber disease is an extremely rare, progressive, autosomal recessive lysosomal storage disease caused by a deficiency of the acid ceramidase enzyme. Acid ceramidase is responsible for breaking down ceramide into sphingosine and fatty acid. When the enzyme is deficient, this leads to an accumulation of fatty material in the lysosomes of the cells, leading to the signs and symptoms of this disorder.

<span class="mw-page-title-main">Jackson–Weiss syndrome</span> Medical condition

Jackson–Weiss syndrome (JWS) is a genetic disorder characterized by foot abnormalities and the premature fusion of certain bones of the skull (craniosynostosis), which prevents further growth of the skull and affects the shape of the head and face. This genetic disorder can also sometimes cause intellectual disability and crossed eyes. It was characterized in 1976.

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<span class="mw-page-title-main">MMP2</span> Protein-coding gene in the species Homo sapiens

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

<span class="mw-page-title-main">MMP14</span> Protein-coding gene in the species Homo sapiens

Matrix metalloproteinase-14 is an enzyme that in humans is encoded by the MMP14 gene.

Interstitial collagenase, also known as fibroblast collagenase, and matrix metalloproteinase-1(MMP-1) is an enzyme that in humans is encoded by the MMP1 gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. MMP-1 was the first vertebrate collagenase both purified to homogeneity as a protein, and cloned as a cDNA. MMP-1 has an estimated molecular mass of 54 kDa.

<span class="mw-page-title-main">MMP10</span> Protein-coding gene in the species Homo sapiens

Stromelysin-2 also known as matrix metalloproteinase-10 (MMP-10) or transin-2 is an enzyme that in humans is encoded by the MMP10 gene.

<span class="mw-page-title-main">Melorheostosis</span> Medical condition

Melorheostosis is a medical developmental disorder and mesenchymal dysplasia in which the bony cortex widens and becomes hyperdense in a sclerotomal distribution. The condition begins in childhood and is characterized by thickening of the bones. Pain is a frequent symptom and the bone can have the appearance of dripping candle wax.

<span class="mw-page-title-main">Pycnodysostosis</span> Genetic disease

Pycnodysostosis, is a lysosomal storage disease of the bone caused by a mutation in the gene that codes the enzyme cathepsin K. It is also known as PKND and PYCD.

<span class="mw-page-title-main">Coarse facial features</span> Medical condition

Coarse facial features is a constellation of facial features that are present in many inborn errors of metabolism.

<span class="mw-page-title-main">MMP27</span> Protein-coding gene in the species Homo sapiens

Matrix metallopeptidase 27 also known as MMP-27 is an enzyme which in humans is encoded by the MMP27 gene.

<span class="mw-page-title-main">MMP15</span> Protein-coding gene in the species Homo sapiens

Matrix metalloproteinase 15 also known as MMP15 is an enzyme that in humans is encoded by the MMP15 gene.

Haim–Munk syndrome is a skin disease caused, like Papillon-Lefevre Syndrome, by a mutation in the cathepsin C gene. One of its features is thick curved finger and toenails.

<span class="mw-page-title-main">Parastremmatic dwarfism</span> Medical condition

Parastremmatic dwarfism is a rare bone disease that features severe dwarfism, thoracic kyphosis, a distortion and twisting of the limbs, contractures of the large joints, malformations of the vertebrae and pelvis, and incontinence. The disease was first reported in 1970 by Leonard Langer and associates; they used the term parastremmatic from the Greek parastremma, or distorted limbs, to describe it. On X-rays, the disease is distinguished by a "flocky" or lace-like appearance to the bones. The disease is congenital, which means it is apparent at birth. It is caused by a mutation in the TRPV4 gene, located on chromosome 12 in humans. The disease is inherited in an autosomal dominant manner.

<span class="mw-page-title-main">Bruck syndrome</span> Medical condition

Bruck syndrome is characterized as the combination of arthrogryposis multiplex congenita and osteogenesis imperfecta. Both diseases are uncommon, but concurrence is extremely rare which makes Bruck syndrome very difficult to research. Bruck syndrome is thought to be an atypical variant of osteogenesis imperfecta most resembling type III, if not its own disease. Multiple gene mutations associated with osteogenesis imperfecta are not seen in Bruck syndrome. Many affected individuals are within the same family, and pedigree data supports that the disease is acquired through autosomal recessive inheritance. Bruck syndrome has features of congenital contractures, bone fragility, recurring bone fractures, flexion joint and limb deformities, pterygia, short body height, and progressive kyphoscoliosis. Individuals encounter restricted mobility and pulmonary function. A reduction in bone mineral content and larger hydroxyapatite crystals are also detectable Joint contractures are primarily bilateral and symmetrical, and most prone to ankles. Bruck syndrome has no effect on intelligence, vision, or hearing.

<span class="mw-page-title-main">Multicentric carpotarsal osteolysis syndrome</span> Medical condition

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare autosomal dominant condition. This condition is also known as idiopathic multicentric osteolysis with nephropathy. It is characterised by carpal-tarsal destruction and kidney failure.

References

  1. ↑ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Torg Winchester syndrome". www.orpha.net. Retrieved 27 April 2019.
  2. ↑ "OMIM Entry - # 259600 - MULTICENTRIC OSTEOLYSIS, NODULOSIS, AND ARTHROPATHY; MONA". omim.org.
  3. 1 2 Winchester P, Grossman H, Lim WN, Danes BS (May 1969). "A new acid mucopolysaccharidosis with skeletal deformities simulating rheumatoid arthritis". Am J Roentgenol Radium Ther Nucl Med. 106 (1): 121–8. doi:10.2214/ajr.106.1.121. PMID   4238825.
  4. 1 2 3 4 5 6 7 Elsebaie H, Mansour MA, Elsayed SM, Mahmoud S, El-Sobky TA (December 2021). "Multicentric Osteolysis, Nodulosis, and Arthropathy in two unrelated children with matrix metalloproteinase 2 variants: Genetic-skeletal correlations". Bone Rep. 15: 101106. doi:10.1016/j.bonr.2021.101106. ISSN   2352-1872. PMC   8283316 . PMID   34307793.
  5. 1 2 3 Reference, Genetics Home. "Winchester syndrome". Genetics Home Reference. Retrieved 2017-12-12.
  6. 1 2 3 4 "Winchester Syndrome - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2017-11-07.
  7. ↑ "Torg Winchester syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2017-12-12.
  8. 1 2 Evans BR, Mosig RA, Lobl M, Martignetti CR, Camacho C, Grum-Tokars V, Glucksman MJ, Martignetti JA (September 2012). "Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome". Am J Hum Genet. 91 (3): 572–6. doi:10.1016/j.ajhg.2012.07.022. PMC   3512002 . PMID   22922033.
  9. 1 2 Reference, Genetics Home. "MMP14 gene". Genetics Home Reference. Retrieved 2017-11-07.
  10. 1 2 "Winchester Syndrome Clinical Presentation: History, Physical Examination, Causes". emedicine.medscape.com. Retrieved 2017-12-12.
  11. ↑ Pichler K, Karall D, Kotzot D, Steichen-Gersdorf E, Rümmele-Waibel A, Mittaz-Crettol L, Wanschitz J, Bonafé L, Maurer K, Superti-Furga A, Scholl-Bürgi S (September 2016). "Bisphosphonates in multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder - an alternative therapeutic approach". Sci Rep. 6: 34017. doi:10.1038/srep34017. PMC   5043187 . PMID   27687687.
  12. 1 2 Zankl A, Bonafé L, Calcaterra V, Di Rocco M, Superti-Furga A (March 2005). "Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2". Clin Genet. 67 (3): 261–6. doi:10.1111/j.1399-0004.2004.00402.x. PMID   15691365. S2CID   29033013.
  13. ↑ Rouzier C, Vanatka R, Bannwarth S, Philip N, Coussement A, Paquis-Flucklinger V, Lambert JC (March 2006). "A novel homozygous MMP2 mutation in a family with Winchester syndrome". Clin Genet. 69 (3): 271–6. doi:10.1111/j.1399-0004.2006.00584.x. PMID   16542393.
  14. ↑ Ekbote AV, Danda S, Zankl A, Mandal K, Maguire T, Ungerer K (2014). "Patient with mutation in the matrix metalloproteinase 2 (MMP2) gene - a case report and review of the literature". J Clin Res Pediatr Endocrinol. 6 (1): 40–6. doi:10.4274/Jcrpe.1166. PMC   3986738 . PMID   24637309.
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