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Causes of OSMED, Homozygous
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Homozygous OSMED is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Some individuals with homozygous OSMED have parent who were closely related. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Homozygous OSMED appears to occur as a result of changes or disruptions (mutations) of the collagen XI, apha-2 polypeptide (COL11A2) gene located on the short arm (p) of chromosome 6 (6p21.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 6p21.3” refers to band 21.3 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The COL11A2 gene is involved in the formation (synthesis) of collagen, specifically type XI collagen. Collagen is the body's major structural protein forming an essential part of connective tissues and is the main component of ligaments, tendons and cartilage. Collagen is also found in bone. Type XI collagen is usually found in cartilage, the specialized tissue that serves as a buffer or cushion for bones at joints. The COL11A2 gene encodes for proteins that are essential to the development and function of type XI collagen. Mutations to this gene result in abnormalities in the production of collagen XI which in turn affects the proper formation and development of cartilage and bone.
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Causes of OSMED, Homozygous. Homozygous OSMED is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females. Some individuals with homozygous OSMED have parent who were closely related. All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Homozygous OSMED appears to occur as a result of changes or disruptions (mutations) of the collagen XI, apha-2 polypeptide (COL11A2) gene located on the short arm (p) of chromosome 6 (6p21.3). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 6p21.3” refers to band 21.3 on the short arm of chromosome 6. The numbered bands specify the location of the thousands of genes that are present on each chromosome.The COL11A2 gene is involved in the formation (synthesis) of collagen, specifically type XI collagen. Collagen is the body's major structural protein forming an essential part of connective tissues and is the main component of ligaments, tendons and cartilage. Collagen is also found in bone. Type XI collagen is usually found in cartilage, the specialized tissue that serves as a buffer or cushion for bones at joints. The COL11A2 gene encodes for proteins that are essential to the development and function of type XI collagen. Mutations to this gene result in abnormalities in the production of collagen XI which in turn affects the proper formation and development of cartilage and bone.
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OSMED, Homozygous
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nord_914_3
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Affects of OSMED, Homozygous
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Homozygous OSMED affects males and females in equal numbers. The disorder was first described in the medical literature in 1970. Homozygous OSMED may be referred to as a type XI collagen disorder (collagenopathy). Type XI collagenopathies are disorders that involve abnormalities with type XI collagen and include heterozygous OSMED and Stickler syndrome type II.
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Affects of OSMED, Homozygous. Homozygous OSMED affects males and females in equal numbers. The disorder was first described in the medical literature in 1970. Homozygous OSMED may be referred to as a type XI collagen disorder (collagenopathy). Type XI collagenopathies are disorders that involve abnormalities with type XI collagen and include heterozygous OSMED and Stickler syndrome type II.
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OSMED, Homozygous
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nord_914_4
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Related disorders of OSMED, Homozygous
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Symptoms of the following disorders can be similar to those of OSMED. Comparisons may be useful for a differential diagnosis.Heterozygous OSMED (also known as Weissenbacher-Zweymuller syndrome or Stickler syndrome type III) is a rare genetic disorder characterized by skeletal malformations resulting in shortening of the upper limbs and thighs and short stature (rhizomelic dwarfism). Additional symptoms include distinctive facial features and delays in psychomotor development. After an initial period of growth deficiency, affected individuals experience gradual improvement in bone growth that leads to normal physical development by early childhood. Mental and motor development is also normal by early childhood. In some cases, affected individuals develop hearing loss. Heterozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene and is inherited as an autosomal dominant trait. (For more information on this disorder, choose “heterozygous OSMED” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of disorders of the connective tissue that involves several of the body's organ systems such as the eye, skeleton, inner ear, and/or the head and face. Connective tissue is made up of a protein known as collagen that develops into the several varieties found in the body. It is the tissue that physically supports many organs in the body and may act like glue or an elastic band that allows muscles to stretch and contract. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), and the ends of the bones that make up the joints of the body (epiphysis). Most authorities agree that there are four types of Stickler syndrome, of which three are reasonably well differentiated and a fourth remains not well understood. Stickler syndrome type I (STL1) is responsible for about 75% of reported cases and presents with a full array of symptoms (eye, ear, jaw and cleft, joints); Stickler syndrome type II; (STL2) also presents with a full array of symptoms; Stickler syndrome type III (STL3) presents with a “Stickler-like” syndrome that affects the joints and hearing without involving the eyes. Some researchers believe that this form is the same disorder as heterozygous oto-spondylo-megaepiphyseal dysplasia (OSMED). (For more information on this disorder, choose “Stickler syndrome” as your search term in the Rare Disease Database.)Kniest dysplasia is one of several forms of dwarfism that is caused by a change (mutation) in a gene known as COL2A1. This gene is involved in the production of a particular protein that forms type II collagen, which is essential for the normal development of bones and other connective tissue. Changes in the composition of type 2 collagen lead to abnormal skeletal growth and, thus, to a variety of dwarfing conditions known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other characteristics may not appear for two or three years. (For more information on this disorder, choose “Kniest dysplasia” as your search term in the Rare Disease Database.)Marshall syndrome is a rare genetic disorder. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes (hyperterlorism), nearsightedness, cataracts and moderate to severe hearing loss. Affected individuals experience degeneration of the thick fluid that fills the center of the eye and the membrane (retina) that lines the back of the eye (vitreoretinal degeneration). Malformation of certain bones of the arms (e.g., bowing of the arm bones) may also occur. Affected individuals may also have Pierre-Robin sequence. Pierre-Robin sequence consists of an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and, in some cases, incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Marshall syndrome is inherited as an autosomal dominant trait. The site of the gene for Marshall syndrome is the same as the site of the gene for Stickler syndrome type II. (For more information choose “Marshall syndrome” as your search term in the Rare Disease Database.)Congenital spondyloepiphyseal dysplasia is a rare genetic disorder characterized by growth deficiency before birth (prenatally), spinal malformations, and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency eventually results in short stature (dwarfism) due, in part, to a disproportionately short neck and trunk, and a hip deformity in which the thighbone is angled toward the center of the body (coxa vara). In most cases, affected individuals may have diminished muscle tone (hypotonia), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), abnormal inward curvature of the spine (lumbar lordosis), and/or unusual protrusion of the breast bone (sternum), a condition known as pectus carinatum. Affected individuals also have abnormalities affecting the eyes including nearsightedness (myopia) and, in approximately 50 percent of cases, detachment of the nerve-rich membrane lining the eye (retina). Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant trait. (For more information on this disorder, choose “spondyloepiphyseal dysplasia” as your search term in the Rare Disease Database.)
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Related disorders of OSMED, Homozygous. Symptoms of the following disorders can be similar to those of OSMED. Comparisons may be useful for a differential diagnosis.Heterozygous OSMED (also known as Weissenbacher-Zweymuller syndrome or Stickler syndrome type III) is a rare genetic disorder characterized by skeletal malformations resulting in shortening of the upper limbs and thighs and short stature (rhizomelic dwarfism). Additional symptoms include distinctive facial features and delays in psychomotor development. After an initial period of growth deficiency, affected individuals experience gradual improvement in bone growth that leads to normal physical development by early childhood. Mental and motor development is also normal by early childhood. In some cases, affected individuals develop hearing loss. Heterozygous OSMED occurs because of disruptions or changes (mutations) to the COL11A2 gene and is inherited as an autosomal dominant trait. (For more information on this disorder, choose “heterozygous OSMED” as your search term in the Rare Disease Database.)Stickler syndrome refers to a group of disorders of the connective tissue that involves several of the body's organ systems such as the eye, skeleton, inner ear, and/or the head and face. Connective tissue is made up of a protein known as collagen that develops into the several varieties found in the body. It is the tissue that physically supports many organs in the body and may act like glue or an elastic band that allows muscles to stretch and contract. Stickler syndrome often affects the connective tissue of the eye, especially in the interior of the eyeball (vitreous humor), and the ends of the bones that make up the joints of the body (epiphysis). Most authorities agree that there are four types of Stickler syndrome, of which three are reasonably well differentiated and a fourth remains not well understood. Stickler syndrome type I (STL1) is responsible for about 75% of reported cases and presents with a full array of symptoms (eye, ear, jaw and cleft, joints); Stickler syndrome type II; (STL2) also presents with a full array of symptoms; Stickler syndrome type III (STL3) presents with a “Stickler-like” syndrome that affects the joints and hearing without involving the eyes. Some researchers believe that this form is the same disorder as heterozygous oto-spondylo-megaepiphyseal dysplasia (OSMED). (For more information on this disorder, choose “Stickler syndrome” as your search term in the Rare Disease Database.)Kniest dysplasia is one of several forms of dwarfism that is caused by a change (mutation) in a gene known as COL2A1. This gene is involved in the production of a particular protein that forms type II collagen, which is essential for the normal development of bones and other connective tissue. Changes in the composition of type 2 collagen lead to abnormal skeletal growth and, thus, to a variety of dwarfing conditions known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other characteristics may not appear for two or three years. (For more information on this disorder, choose “Kniest dysplasia” as your search term in the Rare Disease Database.)Marshall syndrome is a rare genetic disorder. Major symptoms may include a distinctive face with a flattened nasal bridge and nostrils that are tilted upward, widely spaced eyes (hyperterlorism), nearsightedness, cataracts and moderate to severe hearing loss. Affected individuals experience degeneration of the thick fluid that fills the center of the eye and the membrane (retina) that lines the back of the eye (vitreoretinal degeneration). Malformation of certain bones of the arms (e.g., bowing of the arm bones) may also occur. Affected individuals may also have Pierre-Robin sequence. Pierre-Robin sequence consists of an unusually small jaw (micrognathia), downward displacement or retraction of the tongue (glossoptosis), and, in some cases, incomplete closure of the roof of the mouth (cleft palate). Cleft palate may also occur as an isolated finding. Marshall syndrome is inherited as an autosomal dominant trait. The site of the gene for Marshall syndrome is the same as the site of the gene for Stickler syndrome type II. (For more information choose “Marshall syndrome” as your search term in the Rare Disease Database.)Congenital spondyloepiphyseal dysplasia is a rare genetic disorder characterized by growth deficiency before birth (prenatally), spinal malformations, and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency eventually results in short stature (dwarfism) due, in part, to a disproportionately short neck and trunk, and a hip deformity in which the thighbone is angled toward the center of the body (coxa vara). In most cases, affected individuals may have diminished muscle tone (hypotonia), abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis), abnormal inward curvature of the spine (lumbar lordosis), and/or unusual protrusion of the breast bone (sternum), a condition known as pectus carinatum. Affected individuals also have abnormalities affecting the eyes including nearsightedness (myopia) and, in approximately 50 percent of cases, detachment of the nerve-rich membrane lining the eye (retina). Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant trait. (For more information on this disorder, choose “spondyloepiphyseal dysplasia” as your search term in the Rare Disease Database.)
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OSMED, Homozygous
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nord_914_5
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Diagnosis of OSMED, Homozygous
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A diagnosis of homozygous OSMED is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including x-rays. X-ray studies reveal characteristic skeletal malformations associated with homozygous OSMED. Genetic testing is also available to scan for mutations of genes coding for collagen XI.
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Diagnosis of OSMED, Homozygous. A diagnosis of homozygous OSMED is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including x-rays. X-ray studies reveal characteristic skeletal malformations associated with homozygous OSMED. Genetic testing is also available to scan for mutations of genes coding for collagen XI.
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OSMED, Homozygous
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Therapies of OSMED, Homozygous
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TreatmentThe treatment of homozygous OSMED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists), orthopedic surgeons, specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Hearing aids may be used to treat hearing loss. Surgery may be necessary to correct certain skeletal malformations and abnormalities such as cleft palate. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of OSMED, Homozygous. TreatmentThe treatment of homozygous OSMED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat abnormalities of the skeleton, joints, muscles, and related tissues (orthopedists), orthopedic surgeons, specialists who asses and treat hearing problems (audiologists), and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment.Hearing aids may be used to treat hearing loss. Surgery may be necessary to correct certain skeletal malformations and abnormalities such as cleft palate. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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OSMED, Homozygous
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nord_915_0
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Overview of Osteochondritis Dissecans
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SummaryOsteochondritis dissecans is a joint condition that occurs when a piece of cartilage and the thin layer of bone beneath it separate from the underlying bone. It may be asymptomatic during the early stages of the disease. People with symptoms may experience pain, catching and/or decreased range of motion in the affected joint, especially if the cartilage and bone break off into the joint space. Osteochondritis dissecans can affect people of all ages, but it is usually diagnosed in children between the ages of 10 and 15 years. Osteochondritis dissecans mostly affects the knees, elbows or ankles of young patients who are heavily involved in sports at a young age. It mostly affects only one joint and only one side of the body but may be found on both sides of the body, such as in both knees or both elbows. The disease process is characterized by abnormal alteration of bone in joints that may lead to disruption and separation of the overlying cartilage.Treatment for the condition varies depending on many factors, including the age of the affected person, stage of the lesion and the severity of the symptoms, but may include rest, weight bearing restriction, brace for unloading or immobilization or surgery and/or physical therapy. If improperly treated, osteochondritis dissecans may cause premature osteoarthritis.IntroductionIn 1840 a scientist named Paré was the first to describe the removal of loose bodies (osteochondral fragments) from a joint. In 1870, another scientist by the name Paget described the disease process as “quiet necrosis” due to formation of loose, dead osteochondral (joint bone and cartilage) fragments on articular (joint) surfaces. In 1888, another scientist named König described a condition that led to loose body formation which he called “arthrophytes” in a patient without known trauma. It was believed that inflammation of bone and cartilage followed by tissue death and separation (of bone and cartilage from the underlying bone) was the underlying mechanism of the disease.Though this theory has been questioned, it was the basis for the term osteochondritis dissecans which is derived from “osteochondritis” meaning inflammation of the joint surface and “dissec” meaning to separate.
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Overview of Osteochondritis Dissecans. SummaryOsteochondritis dissecans is a joint condition that occurs when a piece of cartilage and the thin layer of bone beneath it separate from the underlying bone. It may be asymptomatic during the early stages of the disease. People with symptoms may experience pain, catching and/or decreased range of motion in the affected joint, especially if the cartilage and bone break off into the joint space. Osteochondritis dissecans can affect people of all ages, but it is usually diagnosed in children between the ages of 10 and 15 years. Osteochondritis dissecans mostly affects the knees, elbows or ankles of young patients who are heavily involved in sports at a young age. It mostly affects only one joint and only one side of the body but may be found on both sides of the body, such as in both knees or both elbows. The disease process is characterized by abnormal alteration of bone in joints that may lead to disruption and separation of the overlying cartilage.Treatment for the condition varies depending on many factors, including the age of the affected person, stage of the lesion and the severity of the symptoms, but may include rest, weight bearing restriction, brace for unloading or immobilization or surgery and/or physical therapy. If improperly treated, osteochondritis dissecans may cause premature osteoarthritis.IntroductionIn 1840 a scientist named Paré was the first to describe the removal of loose bodies (osteochondral fragments) from a joint. In 1870, another scientist by the name Paget described the disease process as “quiet necrosis” due to formation of loose, dead osteochondral (joint bone and cartilage) fragments on articular (joint) surfaces. In 1888, another scientist named König described a condition that led to loose body formation which he called “arthrophytes” in a patient without known trauma. It was believed that inflammation of bone and cartilage followed by tissue death and separation (of bone and cartilage from the underlying bone) was the underlying mechanism of the disease.Though this theory has been questioned, it was the basis for the term osteochondritis dissecans which is derived from “osteochondritis” meaning inflammation of the joint surface and “dissec” meaning to separate.
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Osteochondritis Dissecans
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nord_915_1
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Symptoms of Osteochondritis Dissecans
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Symptoms of osteochondritis dissecans are often vague and occur on and off especially in early stages of the condition but may increase with activities such as climbing stairs or throwing. As the condition progresses and more loose bits of cartilage and bone are found in the joint, there may be catching (partial inhibition of movement), locking, (total inhibition of movement) or a sense of giving way of the joint and there may also be the sensation of loose fragments within the joint. Additionally, there may be pain and swelling of the affected joint.When a doctor evaluates a person with osteochondritis dissecans, the findings are often vague. There may be a grating sound or sensation which is produced by friction between bone and cartilage (crepitus), joint swelling (effusion) or tenderness (pain with pressing). Tenderness is often poorly localized early in the condition but has more definite locations later. In the knee and ankle, patients may even take on an abnormal gait (walking motion) to avoid pain or joint dysfunction. In the ankle, there may be crepitus, tenderness, swelling and inflammation like in the knee, but there may also be pain with compression of the ankle (tibiotalar joint). Osteochondritis dissecans of the elbow is associated with pain, swelling, stiffness and limited range of motion. Although most people with this disease have joint pain and swelling, these symptoms are also associated with many other disorders which can make it difficult to narrow a diagnosis.
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Symptoms of Osteochondritis Dissecans. Symptoms of osteochondritis dissecans are often vague and occur on and off especially in early stages of the condition but may increase with activities such as climbing stairs or throwing. As the condition progresses and more loose bits of cartilage and bone are found in the joint, there may be catching (partial inhibition of movement), locking, (total inhibition of movement) or a sense of giving way of the joint and there may also be the sensation of loose fragments within the joint. Additionally, there may be pain and swelling of the affected joint.When a doctor evaluates a person with osteochondritis dissecans, the findings are often vague. There may be a grating sound or sensation which is produced by friction between bone and cartilage (crepitus), joint swelling (effusion) or tenderness (pain with pressing). Tenderness is often poorly localized early in the condition but has more definite locations later. In the knee and ankle, patients may even take on an abnormal gait (walking motion) to avoid pain or joint dysfunction. In the ankle, there may be crepitus, tenderness, swelling and inflammation like in the knee, but there may also be pain with compression of the ankle (tibiotalar joint). Osteochondritis dissecans of the elbow is associated with pain, swelling, stiffness and limited range of motion. Although most people with this disease have joint pain and swelling, these symptoms are also associated with many other disorders which can make it difficult to narrow a diagnosis.
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Osteochondritis Dissecans
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nord_915_2
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Causes of Osteochondritis Dissecans
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KneeThe origin of osteochondritis dissecans in the knee is unknown, but many causes have been suggested. It is probably due to many factors that could include some or all the following: inflammation, genetics, poor blood flow (ischemia), defective bone formation (ossification) or repetitive trauma.The trauma causing osteochondritis dissecans is not due to direct trauma like a car accident, but rather indirect trauma such as repetitive joint movements or overuse. This mechanism is similar to that of shin splints (bone injuries) which runners get after running excessively long distances or on hard surfaces. This theory of repetitive trauma is supported by the increasing incidence of osteochondritis dissecans in younger patients with increasing participation in sports at a young age, specialization in a single sport and increasing rates of childhood obesity (which puts more strain on joints). Alternatively, the increased number of cases could be due to greater awareness and greater ability to detect the condition through improved imaging tests (x-ray, CT, MRI). Individual differences in a person’s joint structures (anatomic variations) may increase the risk of developing osteochondritis dissecans from repetitive trauma.Regarding the possibility of poor blood flow, some scientists have suggested that poor blood flow may make certain areas of the cartilage and bone in joints more susceptible to separation from the underlying bone. The underlying mechanism is that this area of bone and cartilage gets injured, does not heal well and accumulates injuries over time. Eventually, the bone is damaged and some of the overlying bone and cartilage separate and may fall into the joint space as a flap or as loose bodies.The theory about abnormal bone formation (ossification) in younger patients suggests that bones may fail to properly harden, leading to separation under stress. This separation may initially be partial but after a cycle of repeated trauma, partial reattachment and accumulation of damage, the layers may fully separate.Researchers have studied genetic causes of osteochondritis dissecans but have found only small effects from family history and genetic predispositions.Ankle & Elbow Osteochondritis dissecans of the ankle and elbow are even more strongly related to trauma than osteochondritis of the knee. In the ankle, osteochondritis dissecans lesions that are more lateral (towards the outside edge) are strongly associated with trauma while those that are more medial (towards the centerline) are less associated with trauma. In the elbow, osteochondritis dissecans is highly associated with repetitive trauma and has a relatively high rate in throwing activities such as baseball or racquet sports.
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Causes of Osteochondritis Dissecans. KneeThe origin of osteochondritis dissecans in the knee is unknown, but many causes have been suggested. It is probably due to many factors that could include some or all the following: inflammation, genetics, poor blood flow (ischemia), defective bone formation (ossification) or repetitive trauma.The trauma causing osteochondritis dissecans is not due to direct trauma like a car accident, but rather indirect trauma such as repetitive joint movements or overuse. This mechanism is similar to that of shin splints (bone injuries) which runners get after running excessively long distances or on hard surfaces. This theory of repetitive trauma is supported by the increasing incidence of osteochondritis dissecans in younger patients with increasing participation in sports at a young age, specialization in a single sport and increasing rates of childhood obesity (which puts more strain on joints). Alternatively, the increased number of cases could be due to greater awareness and greater ability to detect the condition through improved imaging tests (x-ray, CT, MRI). Individual differences in a person’s joint structures (anatomic variations) may increase the risk of developing osteochondritis dissecans from repetitive trauma.Regarding the possibility of poor blood flow, some scientists have suggested that poor blood flow may make certain areas of the cartilage and bone in joints more susceptible to separation from the underlying bone. The underlying mechanism is that this area of bone and cartilage gets injured, does not heal well and accumulates injuries over time. Eventually, the bone is damaged and some of the overlying bone and cartilage separate and may fall into the joint space as a flap or as loose bodies.The theory about abnormal bone formation (ossification) in younger patients suggests that bones may fail to properly harden, leading to separation under stress. This separation may initially be partial but after a cycle of repeated trauma, partial reattachment and accumulation of damage, the layers may fully separate.Researchers have studied genetic causes of osteochondritis dissecans but have found only small effects from family history and genetic predispositions.Ankle & Elbow Osteochondritis dissecans of the ankle and elbow are even more strongly related to trauma than osteochondritis of the knee. In the ankle, osteochondritis dissecans lesions that are more lateral (towards the outside edge) are strongly associated with trauma while those that are more medial (towards the centerline) are less associated with trauma. In the elbow, osteochondritis dissecans is highly associated with repetitive trauma and has a relatively high rate in throwing activities such as baseball or racquet sports.
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Osteochondritis Dissecans
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nord_915_3
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Affects of Osteochondritis Dissecans
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Osteochondritis dissecans is estimated to be 2-3x more common in males and more common in people aged 10-15 (average = 11.3-13.4 years). It affects fewer than 30 people per 100,000. It is rarer for patients older than 50 or younger than 10 to develop this condition. While OCD most commonly affects the knees, boys tend to have a higher risk of developing osteochondritis dissecans in the knees or elbows whereas girls have a higher risk of developing it in the ankles.There are two main populations to consider when discussing those affected by osteochondritis dissecans. Younger patients (age 5-15) with open growth plates and older patients with closed growth plates. Younger patients with open growth plates have the “juvenile” form of osteochondritis dissecans and are most commonly young male athletes. Older patients with closed growth plates have the “adult” form of osteochondritis dissecans. Osteochondritis dissecans is rarely seen in patients <10 or >50 years. Adults with a new diagnosis likely had it for years without symptoms.KneeJuvenile osteochondritis dissecans of the knee is generally diagnosed in early adolescent or teen years. Diagnosis in adults is more variable and may occur at any age but is generally before age 40.AnkleMost people with osteochondritis dissecans of the ankle are diagnosed in early adulthood. Osteochondritis dissecans of the lateral ankle is associated with trauma and may have more persistent symptoms. Osteochondritis dissecans of the medial ankle is often not associated with trauma and is frequently asymptomatic.ElbowPatients with osteochondritis dissecans of the elbow are often adolescents who participate in throwing sports like baseball.
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Affects of Osteochondritis Dissecans. Osteochondritis dissecans is estimated to be 2-3x more common in males and more common in people aged 10-15 (average = 11.3-13.4 years). It affects fewer than 30 people per 100,000. It is rarer for patients older than 50 or younger than 10 to develop this condition. While OCD most commonly affects the knees, boys tend to have a higher risk of developing osteochondritis dissecans in the knees or elbows whereas girls have a higher risk of developing it in the ankles.There are two main populations to consider when discussing those affected by osteochondritis dissecans. Younger patients (age 5-15) with open growth plates and older patients with closed growth plates. Younger patients with open growth plates have the “juvenile” form of osteochondritis dissecans and are most commonly young male athletes. Older patients with closed growth plates have the “adult” form of osteochondritis dissecans. Osteochondritis dissecans is rarely seen in patients <10 or >50 years. Adults with a new diagnosis likely had it for years without symptoms.KneeJuvenile osteochondritis dissecans of the knee is generally diagnosed in early adolescent or teen years. Diagnosis in adults is more variable and may occur at any age but is generally before age 40.AnkleMost people with osteochondritis dissecans of the ankle are diagnosed in early adulthood. Osteochondritis dissecans of the lateral ankle is associated with trauma and may have more persistent symptoms. Osteochondritis dissecans of the medial ankle is often not associated with trauma and is frequently asymptomatic.ElbowPatients with osteochondritis dissecans of the elbow are often adolescents who participate in throwing sports like baseball.
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Osteochondritis Dissecans
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nord_915_4
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Related disorders of Osteochondritis Dissecans
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Osteochondritis dissecans may be part of an inherited condition such as genetic forms of short stature (dwarfism), bow-legging (tibia vara), Legg-Calvé-Perthes disease and Stickler's syndrome.
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Related disorders of Osteochondritis Dissecans. Osteochondritis dissecans may be part of an inherited condition such as genetic forms of short stature (dwarfism), bow-legging (tibia vara), Legg-Calvé-Perthes disease and Stickler's syndrome.
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Osteochondritis Dissecans
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nord_915_5
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Diagnosis of Osteochondritis Dissecans
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As mentioned above, the physical exam findings in a person with osteochondritis dissecans are often not specific enough to confirm a diagnosis. Therefore, diagnosis is mostly reliant on imaging. Initial imaging of the joint is usually conducted with x-rays that may show transparency of subchondral bone, separation of bone fragments from underlying bone, evidenced by a dark (radiolucent) line, or loose osseous bodies. On further imaging such as an magnetic resonance imaging (MRI), physicians may be able to better characterize the state of the bone and cartilage, determine the degree of displacement of those pieces and monitor treatment progress or restoration of vascular supply. Studies have shown that MRI and arthroscopy (surgical visualization of the inside of the joint with a camera) are the best tools to determine disease diagnosis and progression.In addition to identification of disease, MRI and arthroscopy may help determine the stage of the disease. Ultrasound may also be used but tends to be less reliable. An imaging technique called scintigraphy was once used in diagnosis and evaluation of treatment response but has been increasingly phased out due to increased use of MRI.
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Diagnosis of Osteochondritis Dissecans. As mentioned above, the physical exam findings in a person with osteochondritis dissecans are often not specific enough to confirm a diagnosis. Therefore, diagnosis is mostly reliant on imaging. Initial imaging of the joint is usually conducted with x-rays that may show transparency of subchondral bone, separation of bone fragments from underlying bone, evidenced by a dark (radiolucent) line, or loose osseous bodies. On further imaging such as an magnetic resonance imaging (MRI), physicians may be able to better characterize the state of the bone and cartilage, determine the degree of displacement of those pieces and monitor treatment progress or restoration of vascular supply. Studies have shown that MRI and arthroscopy (surgical visualization of the inside of the joint with a camera) are the best tools to determine disease diagnosis and progression.In addition to identification of disease, MRI and arthroscopy may help determine the stage of the disease. Ultrasound may also be used but tends to be less reliable. An imaging technique called scintigraphy was once used in diagnosis and evaluation of treatment response but has been increasingly phased out due to increased use of MRI.
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Osteochondritis Dissecans
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Therapies of Osteochondritis Dissecans
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TreatmentTreatment for osteochondritis dissecans has evolved over the past 150 years. The original treatment was either non-operative treatment or simple open removal of loose fragments (arthrotomy), but modern therapy is a combination of both non-surgical and more advanced surgical treatments. Though definitive treatment guidelines have not firmly been established, there are well-established trends, recommendations and indications for both surgical and non-surgical treatments. Conservative, nonoperative treatment is preferred in early stages of the disease or in young patients with open growth plates. In later stages or in older patients, improved imaging techniques like MRI, treatment options (arthroscopy) and understanding of joint bone-cartilage healing allow for more accurate assessment of disease stage, progression and treatment response.MRI helps determine the best treatment choice by detecting the degree of disease progression, growth plate closure and stability of the OCD lesion.Young patients with open growth plates, minimal symptoms, intact joint surfaces and those with less unstable joints often can be treated with simple weight bearing restrictions and physical therapy as osteochondritis dissecans will frequently heal without surgery. Weight bearing restrictions may involve the use of off-loading braces or crutches to prevent further joint damage and allow for proper healing. Often patients will have these activity limitations until they are symptom free, or a series of MRIs shows significant healing. If after 3 months of conservative treatment, patients remain symptomatic or imaging shows little healing, surgery may be needed.In contrast, patients with closed growth plates, severe or persistent symptoms or unstable joints often require surgery due to the low chance of healing without surgical treatment. Improper treatment carries the risk of joint disease progression to premature and potentially irreversible osteoarthritis. Regardless of type, patient symptoms may be best managed with acetaminophen (Tylenol).The nonoperative treatments for the knee are highly variable among institutions, but may generally be broken down into 3 phases.Phase 1 includes 4-6 weeks of knee immobilization with crutch-assisted partial weight bearing gait.Phase 2 includes 6-8 weeks of weight bearing without immobilization plus initiation of a rehabilitation program focused on knee range of motion and low impact strengthening of the quadriceps and hamstring muscles. Patients should continue to avoid sports or repetitive-impact activities during this phase.Phase 3 consists of supervised jumping, running and cutting (quick directions changing) sport activities. A gradual increase in activity intensity and return to sports is permitted if the patient remains pain free. At this stage an MRI should be repeated to assess for healing. If images show recurrence of lesions or patients again become symptomatic, repeated non-surgical treatment may be advised.Surgical treatment of osteochondritis dissecans is indicated in patients with any of the following: symptomatic loose bodies, disease progression or persistence during conservative/non-surgical treatment, and detection of a displaced or completely separated fragment in the joint. Most adults with osteochondritis dissecans are treated surgically due to a high rate of joint instability and low rate of spontaneous healing.The goals of surgery include restoring the continuity (smoothness) of joint surfaces, enhancement/restoration of blood supply to fragments, rigid fixation of salvageable fragments and removal of loose fragments that cannot be restored to their proper location (approximated). After surgery patients should begin to use a walker or crutches as permitted by their doctor to help maintain range of motion and strength. Surgeons use minimally invasive techniques such as arthroscopy to restore the joint surface, promote blood vessel growth and smooth out any rough bone or cartilage. Simply removing all the bone fragments or trying to put them all back in place is not recommended due to the risk of creating an irregular joint surface. Thus, replacement of larger fragments to their proper location and removal of smaller ones that cannot be properly replaced is key to helping reconstruct a smooth joint surface. The larger fragments are then fixed in place with pins, wires, screws or pegs that may be biodegradable. If the joint surface is unsalvageable, the surgeon may need to take some bone or cartilage from a different, non-weight bearing joint surface or from a cadaver donor to reconstruct the deformed joint. If patients are older and have significant joint disease, they may be referred for treatment with more significant surgeries such as a total or partial knee replacement.In the ankle, early-stage lesions are treated conservatively without surgery, while late-stage lesions are treated with surgery. All very late-stage lesions, regardless of location, are treated with minimally invasive arthroscopic surgery as listed above.In the elbow, like in other joints, treatment can be either non-surgical or surgical based on the disease stage, size of the lesion, patient skeletal maturity, patient symptoms or imaging findings. Surgical treatment may consist of only removing loose fragments with drilling to help stimulate blood vessel growth in bone, but the preference is to salvage the fragment with fixation. Transplanting a plug of cartilage and subchondral bone from a different part of the body or from a cadaver donor is another treatment option. Loss of elbow motion is one of the most common complications after surgery.
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Therapies of Osteochondritis Dissecans. TreatmentTreatment for osteochondritis dissecans has evolved over the past 150 years. The original treatment was either non-operative treatment or simple open removal of loose fragments (arthrotomy), but modern therapy is a combination of both non-surgical and more advanced surgical treatments. Though definitive treatment guidelines have not firmly been established, there are well-established trends, recommendations and indications for both surgical and non-surgical treatments. Conservative, nonoperative treatment is preferred in early stages of the disease or in young patients with open growth plates. In later stages or in older patients, improved imaging techniques like MRI, treatment options (arthroscopy) and understanding of joint bone-cartilage healing allow for more accurate assessment of disease stage, progression and treatment response.MRI helps determine the best treatment choice by detecting the degree of disease progression, growth plate closure and stability of the OCD lesion.Young patients with open growth plates, minimal symptoms, intact joint surfaces and those with less unstable joints often can be treated with simple weight bearing restrictions and physical therapy as osteochondritis dissecans will frequently heal without surgery. Weight bearing restrictions may involve the use of off-loading braces or crutches to prevent further joint damage and allow for proper healing. Often patients will have these activity limitations until they are symptom free, or a series of MRIs shows significant healing. If after 3 months of conservative treatment, patients remain symptomatic or imaging shows little healing, surgery may be needed.In contrast, patients with closed growth plates, severe or persistent symptoms or unstable joints often require surgery due to the low chance of healing without surgical treatment. Improper treatment carries the risk of joint disease progression to premature and potentially irreversible osteoarthritis. Regardless of type, patient symptoms may be best managed with acetaminophen (Tylenol).The nonoperative treatments for the knee are highly variable among institutions, but may generally be broken down into 3 phases.Phase 1 includes 4-6 weeks of knee immobilization with crutch-assisted partial weight bearing gait.Phase 2 includes 6-8 weeks of weight bearing without immobilization plus initiation of a rehabilitation program focused on knee range of motion and low impact strengthening of the quadriceps and hamstring muscles. Patients should continue to avoid sports or repetitive-impact activities during this phase.Phase 3 consists of supervised jumping, running and cutting (quick directions changing) sport activities. A gradual increase in activity intensity and return to sports is permitted if the patient remains pain free. At this stage an MRI should be repeated to assess for healing. If images show recurrence of lesions or patients again become symptomatic, repeated non-surgical treatment may be advised.Surgical treatment of osteochondritis dissecans is indicated in patients with any of the following: symptomatic loose bodies, disease progression or persistence during conservative/non-surgical treatment, and detection of a displaced or completely separated fragment in the joint. Most adults with osteochondritis dissecans are treated surgically due to a high rate of joint instability and low rate of spontaneous healing.The goals of surgery include restoring the continuity (smoothness) of joint surfaces, enhancement/restoration of blood supply to fragments, rigid fixation of salvageable fragments and removal of loose fragments that cannot be restored to their proper location (approximated). After surgery patients should begin to use a walker or crutches as permitted by their doctor to help maintain range of motion and strength. Surgeons use minimally invasive techniques such as arthroscopy to restore the joint surface, promote blood vessel growth and smooth out any rough bone or cartilage. Simply removing all the bone fragments or trying to put them all back in place is not recommended due to the risk of creating an irregular joint surface. Thus, replacement of larger fragments to their proper location and removal of smaller ones that cannot be properly replaced is key to helping reconstruct a smooth joint surface. The larger fragments are then fixed in place with pins, wires, screws or pegs that may be biodegradable. If the joint surface is unsalvageable, the surgeon may need to take some bone or cartilage from a different, non-weight bearing joint surface or from a cadaver donor to reconstruct the deformed joint. If patients are older and have significant joint disease, they may be referred for treatment with more significant surgeries such as a total or partial knee replacement.In the ankle, early-stage lesions are treated conservatively without surgery, while late-stage lesions are treated with surgery. All very late-stage lesions, regardless of location, are treated with minimally invasive arthroscopic surgery as listed above.In the elbow, like in other joints, treatment can be either non-surgical or surgical based on the disease stage, size of the lesion, patient skeletal maturity, patient symptoms or imaging findings. Surgical treatment may consist of only removing loose fragments with drilling to help stimulate blood vessel growth in bone, but the preference is to salvage the fragment with fixation. Transplanting a plug of cartilage and subchondral bone from a different part of the body or from a cadaver donor is another treatment option. Loss of elbow motion is one of the most common complications after surgery.
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Osteochondritis Dissecans
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Overview of Osteogenesis Imperfecta
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Osteogenesis imperfecta (OI) is a rare disease affecting the connective tissue and is characterized by extremely fragile bones that break or fracture easily (brittle bones). The abnormal growth of bones is often referred to as a bone dysplasia. The specific symptoms and physical findings associated with OI vary greatly from person to person. The severity of OI also varies greatly, even among individuals in the same family. OI may be a mild disorder or result in severe complications.Four main types of OI (the collagen types) have been identified based on clinical features and severity. These types account for 85-90 percent of OI cases and are caused by mutations (changes) in the COL1A1 or COL1A2 genes. These genes code for type 1 collagen, the most abundant collagen in the human body. It is found in bones, tendons and ligaments. OI type I is the most common and the mildest form of the disorder. OI type II is the most severe of the collagen types. OI types V through XXI (the non-collagen types), as well as unclassified types, make up the remaining 10-15 percent of OI cases. These types are caused by changes in genes that code for proteins that interact with collagen.
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Overview of Osteogenesis Imperfecta. Osteogenesis imperfecta (OI) is a rare disease affecting the connective tissue and is characterized by extremely fragile bones that break or fracture easily (brittle bones). The abnormal growth of bones is often referred to as a bone dysplasia. The specific symptoms and physical findings associated with OI vary greatly from person to person. The severity of OI also varies greatly, even among individuals in the same family. OI may be a mild disorder or result in severe complications.Four main types of OI (the collagen types) have been identified based on clinical features and severity. These types account for 85-90 percent of OI cases and are caused by mutations (changes) in the COL1A1 or COL1A2 genes. These genes code for type 1 collagen, the most abundant collagen in the human body. It is found in bones, tendons and ligaments. OI type I is the most common and the mildest form of the disorder. OI type II is the most severe of the collagen types. OI types V through XXI (the non-collagen types), as well as unclassified types, make up the remaining 10-15 percent of OI cases. These types are caused by changes in genes that code for proteins that interact with collagen.
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Osteogenesis Imperfecta
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Symptoms of Osteogenesis Imperfecta
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In all types of osteogenesis imperfecta, symptoms vary greatly from one individual to the next, even within the same type and the same family. Some affected individuals may not experience any bone fractures or only a few. Other affected individuals experience multiple fractures. The age of onset of fractures varies from person to person. OI is a collagen related disease, and as such, the arrangement and integrity of teeth (dentition), lung function, heart (cardiac) function, muscle strength and ligament flexibility may be affected as well. Historically, OI has been classified into four main types according to clinical features and severity. Over the past decade, many new genes have been identified in individuals who have brittle bones as a component of their disease. The classification has been expanded beyond types I through IV to include these new and rarer types of OI. Types V through XXI are classified according to the causative genetic mutation. Just like the more common types of OI, the clinical features of affected individuals vary within these rare types. The types of OI and the causative gene (shown in parentheses) are described below.Osteogenesis Type I (COL1A1)Osteogenesis type I is the most common and usually the mildest form of OI. In most people, it is characterized by multiple bone fractures, usually occurring during childhood through puberty. A child with type I OI may fracture early in life with minimal trauma (falling from a standing position or when being pulled up by a caregiver), whereas others may fracture later on when participating in higher intensity physical activity. Fractures during the newborn (neonatal) period are rare. The frequency of fractures usually declines after puberty. Repeated fractures may result in slight malformation of the bones of the arms and legs (e.g., bowing of the tibia and femur).A distinguishing feature associated with OI type I is a bluish discoloration of the whites of the eyes (blue sclera). Some individuals with OI type I may develop abnormalities affecting the middle and/or inner ears, contributing to, or resulting in hearing impairment. The incidence of hearing loss in patients with type I OI increases with age.Individuals with OI type I may have a triangular facial appearance. Height is variable and most people are below average height for age in childhood, with an adult height shorter than that of unaffected family members. Between 10 and 40 percent of patients with OI type I develop a curved spine (scoliosis). The curve is often mild and progresses minimally over time. Additional symptoms associated with OI type I include loose (hyper extensible) joints and low muscle tone (hypotonia). This may result in a predisposition to joint dislocations and ligament sprains. Some patients have skin that bruises easily. Brittle teeth (dentinogenesis) are uncommon in type I OI. Osteogenesis Type II (COL1A1 or COL1A2)OI type II is the most severe type of osteogenesis imperfecta. Affected infants often experience life-threatening complications at birth or shortly after. Infants with OI type II have low birth weight, abnormally short arms and legs and blue sclera. In addition, affected infants have extremely fragile bones and numerous fractures present at birth. The ribs and long bones of the legs are often malformed.Infants with OI type II have underdeveloped lungs and an abnormally small upper chest (thorax) that may result in life-threatening respiratory insufficiency. Some affected infants may experience congestive heart failure.Infants with OI type II may also have a small, narrow nose, small jaw (micrognathia) and abnormally large soft spots on the top of the skull (large fontanelle). Affected infants may also have thin, fragile skin and low muscle tone (hypotonia).Osteogenesis Type III (COL1A1 or COL1A2)Extremely fragile malformed bones and multiple fractures characterize OI type III. Fractures are often present at birth and x-rays may show signs of healing fractures that occurred prenatally. Progressive malformations of various bones commonly result in short stature, spinal deformity (scoliosis, thoracic kyphosis and lumbar lordosis) and malformation of the junction where the bone in the back of the skull (occipital bone) and the top of the spine meet (basilar invagination). Approximately 70 percent of children with type III OI develop scoliosis. These curves have a high risk of progression during skeletal growth. Chest wall deformities are common, resulting in a barrel shaped rib cage. Frequent fractures and bone deformities of the upper and lower extremities may require multiple surgeries for stabilization as the child grows. Adult height is severely reduced. Individuals with type III OI may become more dependent on the use wheelchairs and other mobility aids by young adulthood. Infants with OI type III may have a slight blue discoloration to the whites of the eyes at birth. In most patients, the bluish tinge fades during the first year of life. Affected infants often have a triangular facial appearance due to an abnormally prominent forehead (frontal bossing) and a small jaw (micrognathia). Hearing loss may develop during the first decade. Dentinogenesis imperfecta may also be present. Type III patients may develop pulmonary problems secondary to abnormal lung tissue and chest wall abnormalities.Osteogenesis Type IV (COL1A1 or COL1A2)The clinical severity of type IV OI (the moderate type) may resemble type I or type III. Fractures are more common before puberty. Affected individuals experience mild to moderate bone malformation and are usually shorter than average. Patients with type IV OI may also develop scoliosis.Individuals with OI type IV may have a triangular facial appearance. In most patients, the sclera are normal or pale blue during infancy. As an infant ages, the pale blue discoloration of the sclera fades. Affected individuals may also experience hearing impairment and dentinogenesis imperfecta.Osteogenesis Type V (IFITM5)OI type V is moderate in severity, with a clinical picture similar to type IV. Individuals may develop an abundance of healing bone (hypertrophic callus) at fracture sites or where bones have been cut surgically. They may also have an abnormal bony connection between the two long bones of the forearm resulting in limitations of motion at the wrist and elbow. Osteogenesis Type VI (SERPINF1)Type VI OI is moderate in severity and affected individuals have a clinical picture similar to type IV. Children who have type OI type VI do not have fractures at birth, but develop them later. Vertebral compression fractures and scoliosis are common, as is progressive bowing of the bones in the arms and legs. Height is moderate to severely affected. The sclera of the eyes are white, teeth are normal and hearing loss has not been observed. Osteogenesis Imperfecta Type VII (CRTAP)Type VII OI is severe and affected individuals have clinical cases similar to type II. Osteogenesis Imperfecta Type VIII (LEPREI)Affected individuals have white sclera, severe growth deficiency and a clinical course similar to types either II or III.Osteogenesis Imperfecta Type IX (PPIB)Type IX OI is very rare and affected individuals have white sclera, proportionate limbs and moderate to severe clinical cases.Osteogenesis Imperfecta Type X (SERPINH1)Type X OI is extraordinarily rare and the bones are severely affected. Individuals with type X OI have a head that appears large for body size and blue sclera. Pulmonary complications, renal stones and muscle weakness have been reported.Osteogenesis Imperfecta Type XI (FKBP10)Type XI OI encompasses a spectrum of disorders that include variable severities of both brittle bones and abnormalities in joint mobility. Progressive scoliosis and kyphosis, abnormal hips and normal hearing are common features. Bruck syndrome type I is also caused by mutations in the FKBP10 gene and is characterized by severe OI and joint contractures (limited mobility). Osteogenesis Imperfecta Type XII (BMP1)Type XII OI includes several disorders that are characterized by recurrent fractures, poor bone density, muscle weakness, delayed tooth eruption, progressive hearing loss and white sclera. Bone density may be above normal.Osteogenesis Imperfecta Type XIII (SP7)Affected individuals have bone density just at or below normal and develop mild to moderate bone deformities. They have a small lower jaw, normal teeth, faint blue sclera and growth deficiency. Osteogenesis Imperfecta Type XIV (TMEM38B)The severity of symptoms in affected individuals varies widely. Some individuals have bowing of the bones in the legs and recurrent fractures, whereas others are asymptomatic. Muscle weakness and heart abnormalities have been reported in patients with type XIV OI. Osteogenesis Imperfecta Type XV (WNT1)Affected individuals have moderate to severe bowing of the long bones, scoliosis, vertebral fractures and muscle weakness. Some have blueish sclera and neurological problems have been reported.Osteogenesis Imperfecta Type XVI (CREB3L1)OI type XVI is severe. Fractures are present at the time of birth and the long bones of the upper arms and legs develop bowing. Osteogenesis Imperfecta Type XVII (SPARC)Type XVII is severe. Affected individuals have white sclera, no dental involvement, joint hypermobility and may develop scoliosisOsteogenesis Imperfecta Type XVIII (FAM46A)OI Type XVIII causes severe bony abnormalities, scoliosis, chest wall deformity and the sclera may be blue or white. OI Type XIX (MBTPS2)Type XIX OI is a severe type caused by a mutation on the X chromosome. It is characterized by prenatal fractures, growth deficiency, scoliosis and severe angulation of the lower leg bone (tibia).OI Type XX (MESD)OI type XX is severe. Features include fractures, severe bowing deformities of the long bones, and possible respiratory failure.OI Type XXI (KDELR2)Type XXI OI is moderate to severe and results in progressive bone deformities and multiple fractures. Growth deficiency and scoliosis are also reported.
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Symptoms of Osteogenesis Imperfecta. In all types of osteogenesis imperfecta, symptoms vary greatly from one individual to the next, even within the same type and the same family. Some affected individuals may not experience any bone fractures or only a few. Other affected individuals experience multiple fractures. The age of onset of fractures varies from person to person. OI is a collagen related disease, and as such, the arrangement and integrity of teeth (dentition), lung function, heart (cardiac) function, muscle strength and ligament flexibility may be affected as well. Historically, OI has been classified into four main types according to clinical features and severity. Over the past decade, many new genes have been identified in individuals who have brittle bones as a component of their disease. The classification has been expanded beyond types I through IV to include these new and rarer types of OI. Types V through XXI are classified according to the causative genetic mutation. Just like the more common types of OI, the clinical features of affected individuals vary within these rare types. The types of OI and the causative gene (shown in parentheses) are described below.Osteogenesis Type I (COL1A1)Osteogenesis type I is the most common and usually the mildest form of OI. In most people, it is characterized by multiple bone fractures, usually occurring during childhood through puberty. A child with type I OI may fracture early in life with minimal trauma (falling from a standing position or when being pulled up by a caregiver), whereas others may fracture later on when participating in higher intensity physical activity. Fractures during the newborn (neonatal) period are rare. The frequency of fractures usually declines after puberty. Repeated fractures may result in slight malformation of the bones of the arms and legs (e.g., bowing of the tibia and femur).A distinguishing feature associated with OI type I is a bluish discoloration of the whites of the eyes (blue sclera). Some individuals with OI type I may develop abnormalities affecting the middle and/or inner ears, contributing to, or resulting in hearing impairment. The incidence of hearing loss in patients with type I OI increases with age.Individuals with OI type I may have a triangular facial appearance. Height is variable and most people are below average height for age in childhood, with an adult height shorter than that of unaffected family members. Between 10 and 40 percent of patients with OI type I develop a curved spine (scoliosis). The curve is often mild and progresses minimally over time. Additional symptoms associated with OI type I include loose (hyper extensible) joints and low muscle tone (hypotonia). This may result in a predisposition to joint dislocations and ligament sprains. Some patients have skin that bruises easily. Brittle teeth (dentinogenesis) are uncommon in type I OI. Osteogenesis Type II (COL1A1 or COL1A2)OI type II is the most severe type of osteogenesis imperfecta. Affected infants often experience life-threatening complications at birth or shortly after. Infants with OI type II have low birth weight, abnormally short arms and legs and blue sclera. In addition, affected infants have extremely fragile bones and numerous fractures present at birth. The ribs and long bones of the legs are often malformed.Infants with OI type II have underdeveloped lungs and an abnormally small upper chest (thorax) that may result in life-threatening respiratory insufficiency. Some affected infants may experience congestive heart failure.Infants with OI type II may also have a small, narrow nose, small jaw (micrognathia) and abnormally large soft spots on the top of the skull (large fontanelle). Affected infants may also have thin, fragile skin and low muscle tone (hypotonia).Osteogenesis Type III (COL1A1 or COL1A2)Extremely fragile malformed bones and multiple fractures characterize OI type III. Fractures are often present at birth and x-rays may show signs of healing fractures that occurred prenatally. Progressive malformations of various bones commonly result in short stature, spinal deformity (scoliosis, thoracic kyphosis and lumbar lordosis) and malformation of the junction where the bone in the back of the skull (occipital bone) and the top of the spine meet (basilar invagination). Approximately 70 percent of children with type III OI develop scoliosis. These curves have a high risk of progression during skeletal growth. Chest wall deformities are common, resulting in a barrel shaped rib cage. Frequent fractures and bone deformities of the upper and lower extremities may require multiple surgeries for stabilization as the child grows. Adult height is severely reduced. Individuals with type III OI may become more dependent on the use wheelchairs and other mobility aids by young adulthood. Infants with OI type III may have a slight blue discoloration to the whites of the eyes at birth. In most patients, the bluish tinge fades during the first year of life. Affected infants often have a triangular facial appearance due to an abnormally prominent forehead (frontal bossing) and a small jaw (micrognathia). Hearing loss may develop during the first decade. Dentinogenesis imperfecta may also be present. Type III patients may develop pulmonary problems secondary to abnormal lung tissue and chest wall abnormalities.Osteogenesis Type IV (COL1A1 or COL1A2)The clinical severity of type IV OI (the moderate type) may resemble type I or type III. Fractures are more common before puberty. Affected individuals experience mild to moderate bone malformation and are usually shorter than average. Patients with type IV OI may also develop scoliosis.Individuals with OI type IV may have a triangular facial appearance. In most patients, the sclera are normal or pale blue during infancy. As an infant ages, the pale blue discoloration of the sclera fades. Affected individuals may also experience hearing impairment and dentinogenesis imperfecta.Osteogenesis Type V (IFITM5)OI type V is moderate in severity, with a clinical picture similar to type IV. Individuals may develop an abundance of healing bone (hypertrophic callus) at fracture sites or where bones have been cut surgically. They may also have an abnormal bony connection between the two long bones of the forearm resulting in limitations of motion at the wrist and elbow. Osteogenesis Type VI (SERPINF1)Type VI OI is moderate in severity and affected individuals have a clinical picture similar to type IV. Children who have type OI type VI do not have fractures at birth, but develop them later. Vertebral compression fractures and scoliosis are common, as is progressive bowing of the bones in the arms and legs. Height is moderate to severely affected. The sclera of the eyes are white, teeth are normal and hearing loss has not been observed. Osteogenesis Imperfecta Type VII (CRTAP)Type VII OI is severe and affected individuals have clinical cases similar to type II. Osteogenesis Imperfecta Type VIII (LEPREI)Affected individuals have white sclera, severe growth deficiency and a clinical course similar to types either II or III.Osteogenesis Imperfecta Type IX (PPIB)Type IX OI is very rare and affected individuals have white sclera, proportionate limbs and moderate to severe clinical cases.Osteogenesis Imperfecta Type X (SERPINH1)Type X OI is extraordinarily rare and the bones are severely affected. Individuals with type X OI have a head that appears large for body size and blue sclera. Pulmonary complications, renal stones and muscle weakness have been reported.Osteogenesis Imperfecta Type XI (FKBP10)Type XI OI encompasses a spectrum of disorders that include variable severities of both brittle bones and abnormalities in joint mobility. Progressive scoliosis and kyphosis, abnormal hips and normal hearing are common features. Bruck syndrome type I is also caused by mutations in the FKBP10 gene and is characterized by severe OI and joint contractures (limited mobility). Osteogenesis Imperfecta Type XII (BMP1)Type XII OI includes several disorders that are characterized by recurrent fractures, poor bone density, muscle weakness, delayed tooth eruption, progressive hearing loss and white sclera. Bone density may be above normal.Osteogenesis Imperfecta Type XIII (SP7)Affected individuals have bone density just at or below normal and develop mild to moderate bone deformities. They have a small lower jaw, normal teeth, faint blue sclera and growth deficiency. Osteogenesis Imperfecta Type XIV (TMEM38B)The severity of symptoms in affected individuals varies widely. Some individuals have bowing of the bones in the legs and recurrent fractures, whereas others are asymptomatic. Muscle weakness and heart abnormalities have been reported in patients with type XIV OI. Osteogenesis Imperfecta Type XV (WNT1)Affected individuals have moderate to severe bowing of the long bones, scoliosis, vertebral fractures and muscle weakness. Some have blueish sclera and neurological problems have been reported.Osteogenesis Imperfecta Type XVI (CREB3L1)OI type XVI is severe. Fractures are present at the time of birth and the long bones of the upper arms and legs develop bowing. Osteogenesis Imperfecta Type XVII (SPARC)Type XVII is severe. Affected individuals have white sclera, no dental involvement, joint hypermobility and may develop scoliosisOsteogenesis Imperfecta Type XVIII (FAM46A)OI Type XVIII causes severe bony abnormalities, scoliosis, chest wall deformity and the sclera may be blue or white. OI Type XIX (MBTPS2)Type XIX OI is a severe type caused by a mutation on the X chromosome. It is characterized by prenatal fractures, growth deficiency, scoliosis and severe angulation of the lower leg bone (tibia).OI Type XX (MESD)OI type XX is severe. Features include fractures, severe bowing deformities of the long bones, and possible respiratory failure.OI Type XXI (KDELR2)Type XXI OI is moderate to severe and results in progressive bone deformities and multiple fractures. Growth deficiency and scoliosis are also reported.
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Osteogenesis Imperfecta
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Causes of Osteogenesis Imperfecta
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Osteogenesis Imperfecta types I through IV are caused by mutations in the COL1A1 or COL1A2 genes. These genes carry instructions for the production of type 1 collagen. Collagen is the major protein of bone and connective tissue including the skin, tendons and sclera. The collagen protein is made up of three strands of proteins (two alpha 1 strands and one alpha 2 strand) that wind together in a helical fashion. These helical molecules then pack side by side to form characteristic bands that are linked together. This structure gives collagen enormous tensile strength. When a mutation occurs, the collagen that the mutated gene produces may be faulty or insufficient. In type I, the gene mutation results in a normal collagen protein, but only one-half of the normal amount is produced. Types II through IV are the result of mutations that affect the structure of the collagen protein. The precise location and type of mutation determines the severity of the resulting disease. The non-collagen types of OI (types V-XXI) are caused by mutations in genes that code for other proteins that play a pivotal role in the production of normal collagen. Over 80 percent of the mutations that cause osteogenesis imperfecta are inherited in an autosomal dominant pattern. That means that an affected individual has only one copy of the mutated gene. The mutated gene dominates the normal gene such that the affected individual forms only abnormal collagen (as in types II-V) or only makes half the normal amount of collagen (as in type I). Autosomal dominant mutations can be passed down from parent to child. This autosomal dominant transmission accounts for about 60 percent of new diagnoses of OI cases each year. In another 20-30 percent of new cases annually, OI is caused by a spontaneous autosomal dominant mutation in the affected individual. This new dominant mutation can then be passed down to future generations. The risk of transmitting the autosomal dominant disorder from affected parent to offspring is 50 percent for each pregnancy and the risk is the same for males and females. The rarer types of OI (except for type V and some type XVI) are recessive types that only occur when an individual has two copies of the mutated gene, one from each parent. If an individual receives one normal gene and one mutated 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 mutated 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 normal genes from both parents is 25%. The risk is the same for males and females.
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Causes of Osteogenesis Imperfecta. Osteogenesis Imperfecta types I through IV are caused by mutations in the COL1A1 or COL1A2 genes. These genes carry instructions for the production of type 1 collagen. Collagen is the major protein of bone and connective tissue including the skin, tendons and sclera. The collagen protein is made up of three strands of proteins (two alpha 1 strands and one alpha 2 strand) that wind together in a helical fashion. These helical molecules then pack side by side to form characteristic bands that are linked together. This structure gives collagen enormous tensile strength. When a mutation occurs, the collagen that the mutated gene produces may be faulty or insufficient. In type I, the gene mutation results in a normal collagen protein, but only one-half of the normal amount is produced. Types II through IV are the result of mutations that affect the structure of the collagen protein. The precise location and type of mutation determines the severity of the resulting disease. The non-collagen types of OI (types V-XXI) are caused by mutations in genes that code for other proteins that play a pivotal role in the production of normal collagen. Over 80 percent of the mutations that cause osteogenesis imperfecta are inherited in an autosomal dominant pattern. That means that an affected individual has only one copy of the mutated gene. The mutated gene dominates the normal gene such that the affected individual forms only abnormal collagen (as in types II-V) or only makes half the normal amount of collagen (as in type I). Autosomal dominant mutations can be passed down from parent to child. This autosomal dominant transmission accounts for about 60 percent of new diagnoses of OI cases each year. In another 20-30 percent of new cases annually, OI is caused by a spontaneous autosomal dominant mutation in the affected individual. This new dominant mutation can then be passed down to future generations. The risk of transmitting the autosomal dominant disorder from affected parent to offspring is 50 percent for each pregnancy and the risk is the same for males and females. The rarer types of OI (except for type V and some type XVI) are recessive types that only occur when an individual has two copies of the mutated gene, one from each parent. If an individual receives one normal gene and one mutated 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 mutated 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 normal genes from both parents is 25%. The risk is the same for males and females.
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Affects of Osteogenesis Imperfecta
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Osteogenesis imperfecta affects males and females in equal numbers. The incidence of cases recognizable at birth is 1:10-20,000. More mild types that are only recognized later in life occur at about the same incidence. It is estimated that 20,000 to 50,000 individuals in the United States have OI.
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Affects of Osteogenesis Imperfecta. Osteogenesis imperfecta affects males and females in equal numbers. The incidence of cases recognizable at birth is 1:10-20,000. More mild types that are only recognized later in life occur at about the same incidence. It is estimated that 20,000 to 50,000 individuals in the United States have OI.
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Related disorders of Osteogenesis Imperfecta
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Symptoms of the following disorders can be similar to those of osteogenesis imperfecta. Comparisons may be useful for a differential diagnosis:Achondroplasia is a skeletal dysplasia characterized by short stature, abnormally short arms and legs (short-limbed dwarfism), abnormal facial features and skeletal malformations. Characteristic facial features may include an abnormally large head (macrocephaly), unusual prominence of the forehead (frontal bossing), a low nasal bridge and underdevelopment of the middle portion of the face (midface hypoplasia). Skeletal malformations may include unusually short fingers and toes (brachydactyly), an increased concave curvature of the lower spine (lordosis), legs that bow outward (genu varum) and/or narrowing (stenosis) of the spine. Additional abnormalities may include limited extension of the elbows and hips, diminished muscle tone (hypotonia) and/or frequent infections of the middle ear (otitis media). Achondroplasia is caused by a mutation in the FGFR3 gene. Eighty percent of cases are sporadic, and it is inherited in an autosomal dominant manner. (For more information on this disorder, choose “achondroplasia” as your search term in the Rare Disease Database.)Hypophosphatasia is a rare disorder characterized by defective bone hardening (mineralization) resulting in weakened bones. Symptoms vary widely across the six major clinical forms. Repeated fractures, bowing of the long bones of the arms and legs, and rib and chest wall deformities are some symptoms and features that may present. Hypophosphatasia is caused by mutations in the ALPL gene and can be inherited in an autosomal recessive or an autosomal dominant manner. (For more information on this disorder, choose “hypophosphatasia” as your search term in the Rare Disease Database.)Pyknodysostosis is a rare disorder characterized by increased density of bones (osteosclerosis) and fractures. Affected individuals may have short stature, an abnormally prominent forehead, underdeveloped lower jaw, dental abnormalities and fragile bones that are prone to stress fractures. Pyknodysostosis is caused by a mutation in the CTSK gene and is inherited in an autosomal recessive manner. (For more information on this disorder, choose “pyknodysostosis” as your search term in the Rare Disease Database.)Osteopetrosis is a rare disorder marked by increased bone density, brittle bones and, in some patients, skeletal abnormalities. There are three types, with the adult type (the milder type) and the intermediate type presenting with abnormalities of bone and frequent fractures. Osteopetrosis is caused by an abnormality in bone resorption. (For more information on this disorder, choose “osteopetrosis” as your search term in the Rare Disease Database.)
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Related disorders of Osteogenesis Imperfecta. Symptoms of the following disorders can be similar to those of osteogenesis imperfecta. Comparisons may be useful for a differential diagnosis:Achondroplasia is a skeletal dysplasia characterized by short stature, abnormally short arms and legs (short-limbed dwarfism), abnormal facial features and skeletal malformations. Characteristic facial features may include an abnormally large head (macrocephaly), unusual prominence of the forehead (frontal bossing), a low nasal bridge and underdevelopment of the middle portion of the face (midface hypoplasia). Skeletal malformations may include unusually short fingers and toes (brachydactyly), an increased concave curvature of the lower spine (lordosis), legs that bow outward (genu varum) and/or narrowing (stenosis) of the spine. Additional abnormalities may include limited extension of the elbows and hips, diminished muscle tone (hypotonia) and/or frequent infections of the middle ear (otitis media). Achondroplasia is caused by a mutation in the FGFR3 gene. Eighty percent of cases are sporadic, and it is inherited in an autosomal dominant manner. (For more information on this disorder, choose “achondroplasia” as your search term in the Rare Disease Database.)Hypophosphatasia is a rare disorder characterized by defective bone hardening (mineralization) resulting in weakened bones. Symptoms vary widely across the six major clinical forms. Repeated fractures, bowing of the long bones of the arms and legs, and rib and chest wall deformities are some symptoms and features that may present. Hypophosphatasia is caused by mutations in the ALPL gene and can be inherited in an autosomal recessive or an autosomal dominant manner. (For more information on this disorder, choose “hypophosphatasia” as your search term in the Rare Disease Database.)Pyknodysostosis is a rare disorder characterized by increased density of bones (osteosclerosis) and fractures. Affected individuals may have short stature, an abnormally prominent forehead, underdeveloped lower jaw, dental abnormalities and fragile bones that are prone to stress fractures. Pyknodysostosis is caused by a mutation in the CTSK gene and is inherited in an autosomal recessive manner. (For more information on this disorder, choose “pyknodysostosis” as your search term in the Rare Disease Database.)Osteopetrosis is a rare disorder marked by increased bone density, brittle bones and, in some patients, skeletal abnormalities. There are three types, with the adult type (the milder type) and the intermediate type presenting with abnormalities of bone and frequent fractures. Osteopetrosis is caused by an abnormality in bone resorption. (For more information on this disorder, choose “osteopetrosis” as your search term in the Rare Disease Database.)
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Diagnosis of Osteogenesis Imperfecta
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A diagnosis of osteogenesis imperfecta is made based upon a detailed patient and family history and a thorough clinical evaluation to identify characteristic signs and symptoms. Genetic testing is performed to detect the known genetic mutations that cause OI. In some patients, the diagnosis of OI is made before birth (prenatally), based upon specialized tests such as ultrasound, amniocentesis and/or chorionic villus sampling (CVS). Ultrasound studies may reveal characteristic findings such as fractures and/or bowing of the long bones in the moderate to severe cases. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. Genetic testing performed on this fluid or tissue sample may reveal a genetic mutation that causes OI.
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Diagnosis of Osteogenesis Imperfecta. A diagnosis of osteogenesis imperfecta is made based upon a detailed patient and family history and a thorough clinical evaluation to identify characteristic signs and symptoms. Genetic testing is performed to detect the known genetic mutations that cause OI. In some patients, the diagnosis of OI is made before birth (prenatally), based upon specialized tests such as ultrasound, amniocentesis and/or chorionic villus sampling (CVS). Ultrasound studies may reveal characteristic findings such as fractures and/or bowing of the long bones in the moderate to severe cases. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and studied. During chorionic villus sampling, a tissue sample is removed from a portion of the placenta. Genetic testing performed on this fluid or tissue sample may reveal a genetic mutation that causes OI.
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Therapies of Osteogenesis Imperfecta
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TreatmentThe treatment of OI is directed toward the specific symptoms that are apparent in each individual. Treatment is aimed at preventing symptoms, maintaining individual mobility, and strengthening bone and muscle. Attention to nutrition and overall physical and psychological well-being is also very important. Exercise and physical therapy programs have proven beneficial in strengthening muscles, increasing weight-bearing capacity and reducing the tendency to fracture. Physical therapy in the water (hydrotherapy) has proven helpful since moving around in water lessens the chance of fracture. Individuals with OI should consult with their physicians and physical therapists to determine a safe and appropriate exercise program.Bisphosphonate therapy (intravenous infusions with either pamidronate or zolendronate) is commonly used to treat children with OI who have frequent fractures, spinal compression fractures, bone pain and decreased bone density measured by DEXA scan. Bisphosphonates work by slowing down the resorption of existing bone while new bone is being formed. This allows bone mass and strength to increase. It does not, however, make the new bone normal. Adults with OI may be treated with oral or intravenous bisphosphonates. Other drugs used to treat osteoporosis may be used in adult patients with OI to prevent loss of bone mass. Denosumab decreases bone resorption and teriparatide has been shown to increase bone strength. The decision to initiate or alter drug therapy is dependent on multiple clinical factors and should be pursued under the direction of an experienced physician. A surgical procedure in which metal rods are placed into the long bones of the upper and lower extremities (rodding) is used to treat some individuals with OI. This surgery may be necessary in patients where there is progressive deformity of a bone or if a bone fractures repeatedly. Rodding of the forearms is typically reserved for patients where deformities significantly impair function. The timing of surgery, type of rod used (expandable or non-expandable) and the aftercare is very individual and should be discussed thoroughly between the surgeon and parents or adult with OI.Surgery to relieve compression between the base of the skull and the top of the spine (basilar invagination) may prove necessary in severe symptomatic patients. Specialized dental and orthodontic procedures may be necessary to correct abnormalities of the teeth and jaw. MonitoringIndividuals with OI should undergo routine screenings to detect hearing loss. Regular dental care is also important. A consultation with an orthodontist should be obtained before age seven to assess jaw development and alignment. Pulmonary function should be measured using pulmonary function tests (PFTs) at approximately age 5 and then between ages 20 and 25. If normal, it should be repeated bi-annually. A baseline echocardiogram should be obtained in the late teens or early adulthood. Clinical evaluations for basilar invagination should be performed regularly and at least one lateral radiograph of the junction of the skull and the cervical spine obtained as a baseline. Serial screening for scoliosis should also be performed. If it is detected, regular x-rays may be necessary to monitor for curve progression.
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Therapies of Osteogenesis Imperfecta. TreatmentThe treatment of OI is directed toward the specific symptoms that are apparent in each individual. Treatment is aimed at preventing symptoms, maintaining individual mobility, and strengthening bone and muscle. Attention to nutrition and overall physical and psychological well-being is also very important. Exercise and physical therapy programs have proven beneficial in strengthening muscles, increasing weight-bearing capacity and reducing the tendency to fracture. Physical therapy in the water (hydrotherapy) has proven helpful since moving around in water lessens the chance of fracture. Individuals with OI should consult with their physicians and physical therapists to determine a safe and appropriate exercise program.Bisphosphonate therapy (intravenous infusions with either pamidronate or zolendronate) is commonly used to treat children with OI who have frequent fractures, spinal compression fractures, bone pain and decreased bone density measured by DEXA scan. Bisphosphonates work by slowing down the resorption of existing bone while new bone is being formed. This allows bone mass and strength to increase. It does not, however, make the new bone normal. Adults with OI may be treated with oral or intravenous bisphosphonates. Other drugs used to treat osteoporosis may be used in adult patients with OI to prevent loss of bone mass. Denosumab decreases bone resorption and teriparatide has been shown to increase bone strength. The decision to initiate or alter drug therapy is dependent on multiple clinical factors and should be pursued under the direction of an experienced physician. A surgical procedure in which metal rods are placed into the long bones of the upper and lower extremities (rodding) is used to treat some individuals with OI. This surgery may be necessary in patients where there is progressive deformity of a bone or if a bone fractures repeatedly. Rodding of the forearms is typically reserved for patients where deformities significantly impair function. The timing of surgery, type of rod used (expandable or non-expandable) and the aftercare is very individual and should be discussed thoroughly between the surgeon and parents or adult with OI.Surgery to relieve compression between the base of the skull and the top of the spine (basilar invagination) may prove necessary in severe symptomatic patients. Specialized dental and orthodontic procedures may be necessary to correct abnormalities of the teeth and jaw. MonitoringIndividuals with OI should undergo routine screenings to detect hearing loss. Regular dental care is also important. A consultation with an orthodontist should be obtained before age seven to assess jaw development and alignment. Pulmonary function should be measured using pulmonary function tests (PFTs) at approximately age 5 and then between ages 20 and 25. If normal, it should be repeated bi-annually. A baseline echocardiogram should be obtained in the late teens or early adulthood. Clinical evaluations for basilar invagination should be performed regularly and at least one lateral radiograph of the junction of the skull and the cervical spine obtained as a baseline. Serial screening for scoliosis should also be performed. If it is detected, regular x-rays may be necessary to monitor for curve progression.
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Overview of Osteomyelitis
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SummaryOsteomyelitis can be broken down into “osteo” meaning bone, and “myelitis”, meaning inflammation of the fatty tissues within the bone. Osteomyelitis is caused by an infection of the bone or joint, and can be both acute and chronic. It can occur at any age and involve any bone. These infections can be due to one, or many types of bacteria and/or fungi. In order of frequency, osteomyelitis can be the result of a trauma, surgery, or joint insertion or any type of prosthetic material; it can be due to lack of blood flow in diabetes associated foot infections, or it can be the result of an infection that has spread via the blood and has reached the bone (seen mostly in prepubescent children or the elderly). Among children and teens, the long bones of the legs and arms are most frequently affected. In adults, osteomyelitis most often affects the vertebrae of the spine and/or the hips. However, extremities are frequently involved due to skin wounds, trauma and surgeries. The prevalence of this disease depends on the age group and disease category in question. With respect to the blood-related spread of infection to the bone, which is the most common type in children, the United States estimates 2-5 cases per 10,000 people, with an estimated higher incidence in developing countries. Older adults are more prone to osteomyelitis because they experience more disorders that can lead to infection, namely orthopedic surgeries and diabetes mellitus. The overall observed trend in osteomyelitis is that it has been increasing over the last few decades. This could be because we have gotten better at diagnosing osteomyelitis, but also because the prevalence of certain risk factors is increasing, namely diabetes. Osteomyelitis patients may present with many symptoms, ranging from an open wound that exposes fractured bone, to no obvious skin lesion but with associated swelling, bone pain, lower extremity warmth, and tenderness when examined. With the appropriate diagnostics, antibiotics can make up the effective treatment regimen, but may include the surgical removal of dead bone in chronic osteomyelitis.IntroductionOsteomyelitis is one of the oldest diseases ever recorded. Evidence of the disease has been found in the fractured spine of a Permian reptile, close to 250 million years ago. This evidence consisted of bone inflammation based on the roughened swollen area above the fracture, hinting that the injury was in fact infected. Hippocrates (460-370 BC) also recognized infection after bone fracture, but it was only in 1773 that an Englishman named William Bromfield published on the observed “abcessus in medulla”, referring to the infected fatty tissues within the inner cavity of the bone. In 1844, French physician and renowned surgeon Auguste Nélaton coined the term “osteomyelitis”, which described an infectious condition of the entire bone, but included “itis” in the word so as to make reference to the inflammatory damage. Bone is usually good at fighting infection, but trauma, bacteremia, surgery, or foreign body insertion may disrupt blood flow and lead to the development of osteomyelitis. Early diagnosis is very important because fast antibiotic delivery may prevent permanent bone loss.
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Overview of Osteomyelitis. SummaryOsteomyelitis can be broken down into “osteo” meaning bone, and “myelitis”, meaning inflammation of the fatty tissues within the bone. Osteomyelitis is caused by an infection of the bone or joint, and can be both acute and chronic. It can occur at any age and involve any bone. These infections can be due to one, or many types of bacteria and/or fungi. In order of frequency, osteomyelitis can be the result of a trauma, surgery, or joint insertion or any type of prosthetic material; it can be due to lack of blood flow in diabetes associated foot infections, or it can be the result of an infection that has spread via the blood and has reached the bone (seen mostly in prepubescent children or the elderly). Among children and teens, the long bones of the legs and arms are most frequently affected. In adults, osteomyelitis most often affects the vertebrae of the spine and/or the hips. However, extremities are frequently involved due to skin wounds, trauma and surgeries. The prevalence of this disease depends on the age group and disease category in question. With respect to the blood-related spread of infection to the bone, which is the most common type in children, the United States estimates 2-5 cases per 10,000 people, with an estimated higher incidence in developing countries. Older adults are more prone to osteomyelitis because they experience more disorders that can lead to infection, namely orthopedic surgeries and diabetes mellitus. The overall observed trend in osteomyelitis is that it has been increasing over the last few decades. This could be because we have gotten better at diagnosing osteomyelitis, but also because the prevalence of certain risk factors is increasing, namely diabetes. Osteomyelitis patients may present with many symptoms, ranging from an open wound that exposes fractured bone, to no obvious skin lesion but with associated swelling, bone pain, lower extremity warmth, and tenderness when examined. With the appropriate diagnostics, antibiotics can make up the effective treatment regimen, but may include the surgical removal of dead bone in chronic osteomyelitis.IntroductionOsteomyelitis is one of the oldest diseases ever recorded. Evidence of the disease has been found in the fractured spine of a Permian reptile, close to 250 million years ago. This evidence consisted of bone inflammation based on the roughened swollen area above the fracture, hinting that the injury was in fact infected. Hippocrates (460-370 BC) also recognized infection after bone fracture, but it was only in 1773 that an Englishman named William Bromfield published on the observed “abcessus in medulla”, referring to the infected fatty tissues within the inner cavity of the bone. In 1844, French physician and renowned surgeon Auguste Nélaton coined the term “osteomyelitis”, which described an infectious condition of the entire bone, but included “itis” in the word so as to make reference to the inflammatory damage. Bone is usually good at fighting infection, but trauma, bacteremia, surgery, or foreign body insertion may disrupt blood flow and lead to the development of osteomyelitis. Early diagnosis is very important because fast antibiotic delivery may prevent permanent bone loss.
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Symptoms of Osteomyelitis
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Acute osteomyelitis is a serious bone inflammation that can result from a previous trauma, puncture wound, surgery, bone fracture, abscessed tooth, or infection of soft tissue, the ear or sinus. Osteomyelitis can be the result of a spreading infection in the blood (hematogenous) and occurs more often in children than adults. In prepubescent children, it usually affects the long bones: the tibia and the femur. The most common site of infection is the metaphysis, which is the narrow portion of the long bone). In adults, the bones of the spinal column (vertebra) are often affected.Initially there may be several days of fever, pain at the site of infection, and a generalized feeling of ill health (malaise). This may be followed by an increase in fever (104-105 degrees Fahrenheit), deep localized bone pain, chills, sweating, swelling and painful or limited movement of the nearby joints. The skin near the affected bone may be red (erythema) and there may be a purulent buildup (pus), loss of calcium, destruction of the surrounding tissue (necrosis) and bone deterioration or deformity. However, patients with osteomyelitis involving the hip, vertebrae, and/or pelvis are less likely to present with many signs other than pain. In long bone infections, if the infection spreads from the metaphysis through the bone cortex and within the joint capsular reflection of knee, any discharge of pus into the joint can present as septic arthritis secondary to osteomyelitis. These joints include the knees, wrists hip, ankles, symphysis pubis, and shoulders.Chronic osteomyelitis usually occurs after an acute episode of osteomyelitis when the infection has not been totally cured, and is sometimes associated with a draining sinus tract. There may be bone pain, swelling, redness and tenderness of the affected area. A discharge of pus from an opening to the infected bone is often the first symptom. There may also be destruction of the bone with pieces of the infected bone separating from the healthy bone. When this occurs, surgery to remove the bone fragments may be necessary.Spinal infections, referring to vertebral osteomyelitis, are most commonly distributed or spread by way of the bloodstream, or present as post-surgical complications. These spinal infections are often characterized by chronic back pain not relieved by ordinary treatment, including bed rest, heat or pain relievers. There may be fever, localized tenderness, pain, muscle spasms and limited movement. Any patients with known fever, weight loss, bacteremia and/or endocarditis should be sent for spinal imaging if they are experiencing new or worsening back pain. This form of osteomyelitis usually affects people over 50 years of age, and is usually caused by a previous injury, urinary tract infection, inflammation of the lining of the heart (endocarditis) or drug addiction. (For more information on this disorder, choose “Endocarditis” as your search term in the Rare Disease Database.)Anaerobic osteomyelitis often affects the lower jawbone (mandible), skull or feet. It is characterized by ulceration and swelling, foul smelling drainage and redness of the affected area.Diabetic foot infections can progress into osteomyelitis as a result blood vessel insufficiency. These infections usually occur following skin ulcerations in patients with nerve damage (neuropathy). This phenomenon is more common in people with diabetes mellitus or vascular diseases affecting the extremities, especially the toes and small bones of the feet. It is usually seen in people over 50 years old and is characterized by pain and redness of the affected area (erythema), swelling, ulcerations, and drainage of pus. This type of osteomyelitis is difficult to treat because of the underlying vascular disorder that can impair the therapeutic effect of antibiotic treatment.
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Symptoms of Osteomyelitis. Acute osteomyelitis is a serious bone inflammation that can result from a previous trauma, puncture wound, surgery, bone fracture, abscessed tooth, or infection of soft tissue, the ear or sinus. Osteomyelitis can be the result of a spreading infection in the blood (hematogenous) and occurs more often in children than adults. In prepubescent children, it usually affects the long bones: the tibia and the femur. The most common site of infection is the metaphysis, which is the narrow portion of the long bone). In adults, the bones of the spinal column (vertebra) are often affected.Initially there may be several days of fever, pain at the site of infection, and a generalized feeling of ill health (malaise). This may be followed by an increase in fever (104-105 degrees Fahrenheit), deep localized bone pain, chills, sweating, swelling and painful or limited movement of the nearby joints. The skin near the affected bone may be red (erythema) and there may be a purulent buildup (pus), loss of calcium, destruction of the surrounding tissue (necrosis) and bone deterioration or deformity. However, patients with osteomyelitis involving the hip, vertebrae, and/or pelvis are less likely to present with many signs other than pain. In long bone infections, if the infection spreads from the metaphysis through the bone cortex and within the joint capsular reflection of knee, any discharge of pus into the joint can present as septic arthritis secondary to osteomyelitis. These joints include the knees, wrists hip, ankles, symphysis pubis, and shoulders.Chronic osteomyelitis usually occurs after an acute episode of osteomyelitis when the infection has not been totally cured, and is sometimes associated with a draining sinus tract. There may be bone pain, swelling, redness and tenderness of the affected area. A discharge of pus from an opening to the infected bone is often the first symptom. There may also be destruction of the bone with pieces of the infected bone separating from the healthy bone. When this occurs, surgery to remove the bone fragments may be necessary.Spinal infections, referring to vertebral osteomyelitis, are most commonly distributed or spread by way of the bloodstream, or present as post-surgical complications. These spinal infections are often characterized by chronic back pain not relieved by ordinary treatment, including bed rest, heat or pain relievers. There may be fever, localized tenderness, pain, muscle spasms and limited movement. Any patients with known fever, weight loss, bacteremia and/or endocarditis should be sent for spinal imaging if they are experiencing new or worsening back pain. This form of osteomyelitis usually affects people over 50 years of age, and is usually caused by a previous injury, urinary tract infection, inflammation of the lining of the heart (endocarditis) or drug addiction. (For more information on this disorder, choose “Endocarditis” as your search term in the Rare Disease Database.)Anaerobic osteomyelitis often affects the lower jawbone (mandible), skull or feet. It is characterized by ulceration and swelling, foul smelling drainage and redness of the affected area.Diabetic foot infections can progress into osteomyelitis as a result blood vessel insufficiency. These infections usually occur following skin ulcerations in patients with nerve damage (neuropathy). This phenomenon is more common in people with diabetes mellitus or vascular diseases affecting the extremities, especially the toes and small bones of the feet. It is usually seen in people over 50 years old and is characterized by pain and redness of the affected area (erythema), swelling, ulcerations, and drainage of pus. This type of osteomyelitis is difficult to treat because of the underlying vascular disorder that can impair the therapeutic effect of antibiotic treatment.
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Causes of Osteomyelitis
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Traditionally, osteomyelitis is a bone infection that has been classified into three categories: (1) a bone infection that has spread through the blood stream (Hematogenous osteomyelitis) (2) osteomyelitis caused by bacteria that gain access to bone directly from an adjacent focus of infection (seen with trauma or surgery) and (3) osteomyelitis that is the result of diabetic foot infection or any other reason for diminished blood supply to the bones. Therefore, risk factors of bone vulnerability to osteomelitis include recent trauma, having diabetes, being on hemodialysis, intravenous drug abuse, and having had one’s spleen removed. Osteomyelitis is an infection frequently caused by Staphylococcus bacteria. While some cases of osteomyelitis are of unknown causes, the infection is usually transmitted through the bloodstream from one area of the body to another (Hematogenous osteomyelitis). These blood infections are commonly due to Staphylococcus aureus, Streptococcus species, and aerobic Gram-negative bacilli. If the patient has a compromised immune system, M tuberculosis, Brucella species and fungi should be included as possible causing agents in the disease work-up.Polyarticular septic arthritis can be associated with osteomyelitis, and is the result of pus discharge into the joints. The deposition of pus therefore leads to septic arthritis, and so the patient can experience chills, fatigue, fever, inability to move the limb with the infected joint because of severe pain, swelling, and warmth to the touch. Septic arthritis is more common in patients with inflammatory joint disease or those experiencing an overwhelming systemic bacterial infection (sepsis). Injection drug use is also a risk factor for septic arthritis, and is often also associated with endocarditis.
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Causes of Osteomyelitis. Traditionally, osteomyelitis is a bone infection that has been classified into three categories: (1) a bone infection that has spread through the blood stream (Hematogenous osteomyelitis) (2) osteomyelitis caused by bacteria that gain access to bone directly from an adjacent focus of infection (seen with trauma or surgery) and (3) osteomyelitis that is the result of diabetic foot infection or any other reason for diminished blood supply to the bones. Therefore, risk factors of bone vulnerability to osteomelitis include recent trauma, having diabetes, being on hemodialysis, intravenous drug abuse, and having had one’s spleen removed. Osteomyelitis is an infection frequently caused by Staphylococcus bacteria. While some cases of osteomyelitis are of unknown causes, the infection is usually transmitted through the bloodstream from one area of the body to another (Hematogenous osteomyelitis). These blood infections are commonly due to Staphylococcus aureus, Streptococcus species, and aerobic Gram-negative bacilli. If the patient has a compromised immune system, M tuberculosis, Brucella species and fungi should be included as possible causing agents in the disease work-up.Polyarticular septic arthritis can be associated with osteomyelitis, and is the result of pus discharge into the joints. The deposition of pus therefore leads to septic arthritis, and so the patient can experience chills, fatigue, fever, inability to move the limb with the infected joint because of severe pain, swelling, and warmth to the touch. Septic arthritis is more common in patients with inflammatory joint disease or those experiencing an overwhelming systemic bacterial infection (sepsis). Injection drug use is also a risk factor for septic arthritis, and is often also associated with endocarditis.
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Affects of Osteomyelitis
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Osteomyelitis is a prevalent condition that affects males and females in equal numbers. Osteomyelitis more commonly affects people younger than 20, or adults older than 50 years of age. While there is a higher incidence of bone infections in adults that live in developing countries, hemodialysis patients, injection drug users, and patients with diabetes are also more susceptible to this infection. Osteomyelitis that is the result of an infection that has spread through the blood occurs more commonly in children than adults. Inoculation or direct osteomyelitis tends to happen more in younger individuals in the setting of trauma and related surgery. When direct osteomyelitis does occur in adults, it is usually secondary to an infected ulcer from diabetes or an infection from a total joint replacement.
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Affects of Osteomyelitis. Osteomyelitis is a prevalent condition that affects males and females in equal numbers. Osteomyelitis more commonly affects people younger than 20, or adults older than 50 years of age. While there is a higher incidence of bone infections in adults that live in developing countries, hemodialysis patients, injection drug users, and patients with diabetes are also more susceptible to this infection. Osteomyelitis that is the result of an infection that has spread through the blood occurs more commonly in children than adults. Inoculation or direct osteomyelitis tends to happen more in younger individuals in the setting of trauma and related surgery. When direct osteomyelitis does occur in adults, it is usually secondary to an infected ulcer from diabetes or an infection from a total joint replacement.
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Related disorders of Osteomyelitis
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Symptoms of the following disorders can be similar to those of osteomyelitis. Comparisons may be useful for a differential diagnosis:Soft tissue infections– Soft tissues infections, affecting muscles, tendons, ligaments, fascia, nerves, fat, blood vessels, and joint capsules, may occur with or without osteomyelitis. Any chronic soft tissue infection that does not improve with appropriate antibiotic medication should be imaged for the evaluation of bone involvement. This is more likely to occur in the setting of diabetic patients.Charcot arthropathy – Also referred to as Charcot joint or neuropathic joint, Charcot arthropathy is a gradually progressing musculoskeletal condition that is characterized by onset of joint dislocations, associated fractures, and pathologic deformations. Acute Charcot arthropathy may present with localized redness and warmth. In such cases, patients may have osteomyelitis, Charcot Joint, or both. Secondary osteomyelitis can develop from Charcot arthropathies because of associated skin ulcerations. In the past, syphilis was thought to be linked to Charcot arthropathy. However, it is now more commonly associated to diabetes. Bone biopsy may therefore be needed when acute Charcot arthropathy is presumed, especially in patients in whom rest, immobility, and elevation do not result in improvement.Osteonecrosis – also referred to as avascular necrosis of bone, osteonecrosis is more easily distinguished from osteomyeltits because it is usually associated with prolonged use of steroids, radiation, or bisphosphonate treatment.Gout – While gout can also present with joint inflammation, it is distinguished from osteomyelitis when uric acid crystals are present in joint fluid. Gout attacks are more likely to present acutely, while osteomyelitis presentation is likely to manifest in a chronic manner. Pseudogout is a similar disease process due to calcium pyrophosphate crystals.Fracture – Osteomyelitis may present similarly to a fracture on radiologic imaging. While a fracture is usually associated with a preceding trauma, a lack of one may be more telling of osteomyelitis. A bone biopsy may be required to distinguish between the two, especially if a suspected fracture is not healing as planned.Malignancy – Bone pain may be present with both osteomyelitis and malignancy. A bone biopsy and radiographic imaging will help with the differentiation.Bursitis – Inflammation of the bursa, which is a fluid-filled sac meant to protect various joints, can be present with both osteomyelitis and bursitis. While bursitis involves an infection localized to the fluid of the bursa, osteomyelitis is characterized by the infection of the underlying bone. With adequate physical examination, radiographic imaging, and fluid analysis, one can be differentiated from the other.Rheumatoid arthritis is an inflammatory autoimmune disease in which the body’s natural defenses against foreign agents (antibodies & lymphocytes) attack healthy bones and joints. This disorder is characterized by a lack of appetite (anorexia), fatigue, painful and deformed joints, and early morning stiffness chiefly in the hands, knees, feet, jaw, and spine. Once affected, a patient’s joints remain painful or uncomfortable for weeks, months, or years. Rheumatic fever is an inflammatory infectious disease that can occur following streptococcal infections of the throat (strep throat). Patients initially experience moderate fever, a general feeling of ill health (malaise), a sore throat and fatigue. A toe or finger may become swollen and red, mimicking a local infection. Major complications can include heart disease, joint pain and arthritis, involuntary abrupt limb movements with characteristic grimaces (chorea), and possible skin symptoms. Treatment with antibiotics should begin as soon as possible. Rheumatic fever can be avoided if strep throat is vigorously treated and cured with antibiotics. (For more information on this disorder, choose “Rheumatic Fever” as your search term in the Rare Disease Database.)Infectious arthritis occurs as a result of an infection in the tissues of a joint by bacteria, viruses or fungi. It is characterized by fever, chills, general weakness and headaches, followed by inflammation of one or more joints. The affected joint or joints often become very painful, swollen, slightly red and stiff within a few hours or days. (For more information on this disorder, choose “Arthritis, Infectious” as your search term in the Rare Disease Database.)Cellulitis is a bacterial infection of the skin usually caused by Staphylococcus or Streptococcus bacteria. The infection commonly results from an existing wound of the nose, ears, face or hands or anywhere on the surface of the body including the lower extremities. It is characterized by localized pain, swelling and redness of the skin, fever, chills, enlarged lymph nodes (lymphadenitis) and a general feeling of ill health.Giant cell tumors can be a recurring condition characterized by tumors of the growth areas (epiphysis) of the long bones. These tumors can cause erosion of the bone and may infiltrate into the surrounding tissue. They are usually treated by surgical removal.Sickle cell disease is an inherited blood disease. Symptomatic of this disease are the painful “crisis periods” which can occur in conjunction with other infections. It is characterized by joint pain (arthralgia), fever, severe abdominal pain, and vomiting. (For more information on this disorder, choose “sickle cell” as your search term in the Rare Disease Database.)Secondary amyloidosis is a metabolic disorder resulting from the extracellular accumulation of amyloid (a glycoprotein) in almost any organ system, in quantities sufficient to cause dysfunction. It can be a secondary disorder associated with osteomyelitis. (For more information on this disorder, choose “Amyloidosis” as your search term in the Rare Disease Database.)
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Related disorders of Osteomyelitis. Symptoms of the following disorders can be similar to those of osteomyelitis. Comparisons may be useful for a differential diagnosis:Soft tissue infections– Soft tissues infections, affecting muscles, tendons, ligaments, fascia, nerves, fat, blood vessels, and joint capsules, may occur with or without osteomyelitis. Any chronic soft tissue infection that does not improve with appropriate antibiotic medication should be imaged for the evaluation of bone involvement. This is more likely to occur in the setting of diabetic patients.Charcot arthropathy – Also referred to as Charcot joint or neuropathic joint, Charcot arthropathy is a gradually progressing musculoskeletal condition that is characterized by onset of joint dislocations, associated fractures, and pathologic deformations. Acute Charcot arthropathy may present with localized redness and warmth. In such cases, patients may have osteomyelitis, Charcot Joint, or both. Secondary osteomyelitis can develop from Charcot arthropathies because of associated skin ulcerations. In the past, syphilis was thought to be linked to Charcot arthropathy. However, it is now more commonly associated to diabetes. Bone biopsy may therefore be needed when acute Charcot arthropathy is presumed, especially in patients in whom rest, immobility, and elevation do not result in improvement.Osteonecrosis – also referred to as avascular necrosis of bone, osteonecrosis is more easily distinguished from osteomyeltits because it is usually associated with prolonged use of steroids, radiation, or bisphosphonate treatment.Gout – While gout can also present with joint inflammation, it is distinguished from osteomyelitis when uric acid crystals are present in joint fluid. Gout attacks are more likely to present acutely, while osteomyelitis presentation is likely to manifest in a chronic manner. Pseudogout is a similar disease process due to calcium pyrophosphate crystals.Fracture – Osteomyelitis may present similarly to a fracture on radiologic imaging. While a fracture is usually associated with a preceding trauma, a lack of one may be more telling of osteomyelitis. A bone biopsy may be required to distinguish between the two, especially if a suspected fracture is not healing as planned.Malignancy – Bone pain may be present with both osteomyelitis and malignancy. A bone biopsy and radiographic imaging will help with the differentiation.Bursitis – Inflammation of the bursa, which is a fluid-filled sac meant to protect various joints, can be present with both osteomyelitis and bursitis. While bursitis involves an infection localized to the fluid of the bursa, osteomyelitis is characterized by the infection of the underlying bone. With adequate physical examination, radiographic imaging, and fluid analysis, one can be differentiated from the other.Rheumatoid arthritis is an inflammatory autoimmune disease in which the body’s natural defenses against foreign agents (antibodies & lymphocytes) attack healthy bones and joints. This disorder is characterized by a lack of appetite (anorexia), fatigue, painful and deformed joints, and early morning stiffness chiefly in the hands, knees, feet, jaw, and spine. Once affected, a patient’s joints remain painful or uncomfortable for weeks, months, or years. Rheumatic fever is an inflammatory infectious disease that can occur following streptococcal infections of the throat (strep throat). Patients initially experience moderate fever, a general feeling of ill health (malaise), a sore throat and fatigue. A toe or finger may become swollen and red, mimicking a local infection. Major complications can include heart disease, joint pain and arthritis, involuntary abrupt limb movements with characteristic grimaces (chorea), and possible skin symptoms. Treatment with antibiotics should begin as soon as possible. Rheumatic fever can be avoided if strep throat is vigorously treated and cured with antibiotics. (For more information on this disorder, choose “Rheumatic Fever” as your search term in the Rare Disease Database.)Infectious arthritis occurs as a result of an infection in the tissues of a joint by bacteria, viruses or fungi. It is characterized by fever, chills, general weakness and headaches, followed by inflammation of one or more joints. The affected joint or joints often become very painful, swollen, slightly red and stiff within a few hours or days. (For more information on this disorder, choose “Arthritis, Infectious” as your search term in the Rare Disease Database.)Cellulitis is a bacterial infection of the skin usually caused by Staphylococcus or Streptococcus bacteria. The infection commonly results from an existing wound of the nose, ears, face or hands or anywhere on the surface of the body including the lower extremities. It is characterized by localized pain, swelling and redness of the skin, fever, chills, enlarged lymph nodes (lymphadenitis) and a general feeling of ill health.Giant cell tumors can be a recurring condition characterized by tumors of the growth areas (epiphysis) of the long bones. These tumors can cause erosion of the bone and may infiltrate into the surrounding tissue. They are usually treated by surgical removal.Sickle cell disease is an inherited blood disease. Symptomatic of this disease are the painful “crisis periods” which can occur in conjunction with other infections. It is characterized by joint pain (arthralgia), fever, severe abdominal pain, and vomiting. (For more information on this disorder, choose “sickle cell” as your search term in the Rare Disease Database.)Secondary amyloidosis is a metabolic disorder resulting from the extracellular accumulation of amyloid (a glycoprotein) in almost any organ system, in quantities sufficient to cause dysfunction. It can be a secondary disorder associated with osteomyelitis. (For more information on this disorder, choose “Amyloidosis” as your search term in the Rare Disease Database.)
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Diagnosis of Osteomyelitis
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Making the appropriate osteomyelitis diagnosis is critical to providing fast and adequate treatment. Different imaging techniques play a key role in early diagnosis and follow-up. Symptoms of osteomyelitis can resemble those of many other bone disorders. Bone scans and bone biopsies are tests that help diagnose this disorder so that treatment can be started immediately.The diagnosis of osteomyelitis is usually established using a bacterial culture from a bone biopsy, in combination with markers from the histology report, and findings of inflammations and/or osteonecrosis. In the setting of a positive bacterial culture and radiographic findings indicative of osteomyelitis, a bone biopsy may not be required.Diagnosing chronic osteomyelitis can prove to be challenging when prosthetic material, skin or soft tissue ulceration, or vascular insufficiency is present. However, a draining sinus tract is almost always diagnostic of chronic osteomyelitis. Additional presentations of chronic osteomyelitis include fractures that do not heal, and Brodie’s abscess (a particular form of chronic osteomyelitis that follows an acute attack of an organism whose virulence is evenly matched by the patients’ resistance). Brodie’s abscess is also referred to as a distinct form of subacute osteomyelitis.Clinical Testing and Work-Up
The clinical approach of patients presenting with suspected osteomyelitis including obtaining a proper history and physical exam, and assessing for any predisposing factors, including diabetes, vascular pathologies, any history of recent procedures, injection drug use, and any associated trauma. If osteomyelitis is suspected based on clinical history and other physical findings, plain radiographs of the involved bones, laboratory evaluation for inflammation, and blood cultures can be ordered. If the patient is diabetic and has symptoms referable to the foot, or if the patient has symptoms referable to the spine, then magnetic resonance imaging (MRI) is the test of choice.In diabetic patients, the probe-to-bone test can also be used as a screening tool for suspected osteomyelitis. The basis of this test is if a probe can reach the bone, so might bacteria. The probe-to-bone test has been shown to help rule in diabetic foot osteomyelitis in high-risk patients, and help rule it out in low-risk patients. It is however not a diagnostic tool.Radiographic findings do not indicate the need for a bone biopsy unless the blood cultures are positive for bacteria such as Staphylococcus aureus or Pseudomonas aeruginosa. Bacterial culture from a bone biopsy can then be used to direct antimicrobial therapy. In the absence of any evidence found on the MRI or CT scan, osteomyelitis is unlikely.
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Diagnosis of Osteomyelitis. Making the appropriate osteomyelitis diagnosis is critical to providing fast and adequate treatment. Different imaging techniques play a key role in early diagnosis and follow-up. Symptoms of osteomyelitis can resemble those of many other bone disorders. Bone scans and bone biopsies are tests that help diagnose this disorder so that treatment can be started immediately.The diagnosis of osteomyelitis is usually established using a bacterial culture from a bone biopsy, in combination with markers from the histology report, and findings of inflammations and/or osteonecrosis. In the setting of a positive bacterial culture and radiographic findings indicative of osteomyelitis, a bone biopsy may not be required.Diagnosing chronic osteomyelitis can prove to be challenging when prosthetic material, skin or soft tissue ulceration, or vascular insufficiency is present. However, a draining sinus tract is almost always diagnostic of chronic osteomyelitis. Additional presentations of chronic osteomyelitis include fractures that do not heal, and Brodie’s abscess (a particular form of chronic osteomyelitis that follows an acute attack of an organism whose virulence is evenly matched by the patients’ resistance). Brodie’s abscess is also referred to as a distinct form of subacute osteomyelitis.Clinical Testing and Work-Up
The clinical approach of patients presenting with suspected osteomyelitis including obtaining a proper history and physical exam, and assessing for any predisposing factors, including diabetes, vascular pathologies, any history of recent procedures, injection drug use, and any associated trauma. If osteomyelitis is suspected based on clinical history and other physical findings, plain radiographs of the involved bones, laboratory evaluation for inflammation, and blood cultures can be ordered. If the patient is diabetic and has symptoms referable to the foot, or if the patient has symptoms referable to the spine, then magnetic resonance imaging (MRI) is the test of choice.In diabetic patients, the probe-to-bone test can also be used as a screening tool for suspected osteomyelitis. The basis of this test is if a probe can reach the bone, so might bacteria. The probe-to-bone test has been shown to help rule in diabetic foot osteomyelitis in high-risk patients, and help rule it out in low-risk patients. It is however not a diagnostic tool.Radiographic findings do not indicate the need for a bone biopsy unless the blood cultures are positive for bacteria such as Staphylococcus aureus or Pseudomonas aeruginosa. Bacterial culture from a bone biopsy can then be used to direct antimicrobial therapy. In the absence of any evidence found on the MRI or CT scan, osteomyelitis is unlikely.
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Therapies of Osteomyelitis
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Treatment
The treatment of osteomyelitis depends on the extent of the infection. It might be necessary to drain and clean the infected area surgically and then continue treatment with antibiotic therapy. In some cases, a bone graft may be necessary.In order to prevent osteomyelitis in adults following open trauma, prophylactic antibiotics should be given intravenously (via IV) to reduce the risk of soft tissue infection. If possible, antibiotic therapy should be tailored to the findings of the tissue culture. However, if the patient is not stable, and the culture results are not obtainable, then broad-spectrum antibiotics should be given. If and after the infectious organism has been identified, osteomyelitis is usually treated with massive doses of the appropriate antibiotic regiment. Treatment with intravenous delivery of antibiotics is not uncommon, even though some of the newer antibiotics are effective when administered orally.The antibiotic treatment may last from several days to a few weeks, but the therapy duration is not certain and is usually individualized based on a given patient's progress. Antibiotic therapy of osteomyelitis usually requires prolonged regimen of medication, typically in the form of outpatient IV antibiotics. Many experts favor IV antimicrobial therapy for up to 6 weeks from when the site of infection was drained and cleaned surgically. This is especially true in patients with vascular diseases, because the antibiotics have more trouble reaching the bone, and so a prolonged regime is favored.It is most important that diabetics and those with vascular disorders be treated as quickly as possible for suspected osteomyelitis. If left untreated, this disorder can result in destruction of the bone and surrounding tissue and may lead to amputation of the affected toes or foot. Other treatment is symptomatic and supportive. Any prosthetic joint infection must be treated with immediate prosthesis removal and re-implantation.Additional therapies include hyperbaric oxygen and negative pressure wound therapy (vacuum-assisted closure). This is because the oxygen may help the immune cells to function, since osteomyelitis is associated with reduced blood flow and limited oxygen access in the infected bone tissue.
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Therapies of Osteomyelitis. Treatment
The treatment of osteomyelitis depends on the extent of the infection. It might be necessary to drain and clean the infected area surgically and then continue treatment with antibiotic therapy. In some cases, a bone graft may be necessary.In order to prevent osteomyelitis in adults following open trauma, prophylactic antibiotics should be given intravenously (via IV) to reduce the risk of soft tissue infection. If possible, antibiotic therapy should be tailored to the findings of the tissue culture. However, if the patient is not stable, and the culture results are not obtainable, then broad-spectrum antibiotics should be given. If and after the infectious organism has been identified, osteomyelitis is usually treated with massive doses of the appropriate antibiotic regiment. Treatment with intravenous delivery of antibiotics is not uncommon, even though some of the newer antibiotics are effective when administered orally.The antibiotic treatment may last from several days to a few weeks, but the therapy duration is not certain and is usually individualized based on a given patient's progress. Antibiotic therapy of osteomyelitis usually requires prolonged regimen of medication, typically in the form of outpatient IV antibiotics. Many experts favor IV antimicrobial therapy for up to 6 weeks from when the site of infection was drained and cleaned surgically. This is especially true in patients with vascular diseases, because the antibiotics have more trouble reaching the bone, and so a prolonged regime is favored.It is most important that diabetics and those with vascular disorders be treated as quickly as possible for suspected osteomyelitis. If left untreated, this disorder can result in destruction of the bone and surrounding tissue and may lead to amputation of the affected toes or foot. Other treatment is symptomatic and supportive. Any prosthetic joint infection must be treated with immediate prosthesis removal and re-implantation.Additional therapies include hyperbaric oxygen and negative pressure wound therapy (vacuum-assisted closure). This is because the oxygen may help the immune cells to function, since osteomyelitis is associated with reduced blood flow and limited oxygen access in the infected bone tissue.
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Overview of Osteonecrosis
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Osteonecrosis, also known as avascular necrosis (AVN), aseptic necrosis or ischemic bone necrosis, is a disease resulting in the death of bone cells. If the process involves the bones near a joint, it often leads to collapse of the joint surface and subsequent arthritis due to an irregular joint surface. The exact cause is unknown.Although it can happen in any bone, osteonecrosis most commonly affects the ends (epiphysis) of long bones such as the femur (thigh bone). Commonly involved bones are the upper femur (ball part of the hip socket) the lower femur (a part of the knee joint), the upper humerus (upper arm bone involving the shoulder joint), and the bones of ankle joint. The disease may affect just one bone, more than one bone at the same time, or more than one bone at different times. Orthopedic surgeons most often diagnose the disease using either an X-ray of magnetic resonance scan (MRI).The amount of disability that results from osteonecrosis depends on what part of the bone is affected, how large an area is involved, how far the disease has progressed, and how effectively the bone rebuilds itself. The process of bone rebuilding takes place after an injury as well as during normal growth. Normally, bone continuously breaks down and rebuilds – old bone is reabsorbed and replaced with new bone. The process keeps the skeleton strong and helps it to maintain a balance of minerals. With osteonecrosis, the healing process is usually ineffective and the bone tissues break down faster than the body can repair them. If left untreated, the disease progresses, and the bone may develop a crack whereby the bone can get compressed (collapse) together (similar to compressing a snowball). If this occurs at the end of the bone, it leads to an irregular joint surface, arthritic pain and loss of function of the affected areas.
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Overview of Osteonecrosis. Osteonecrosis, also known as avascular necrosis (AVN), aseptic necrosis or ischemic bone necrosis, is a disease resulting in the death of bone cells. If the process involves the bones near a joint, it often leads to collapse of the joint surface and subsequent arthritis due to an irregular joint surface. The exact cause is unknown.Although it can happen in any bone, osteonecrosis most commonly affects the ends (epiphysis) of long bones such as the femur (thigh bone). Commonly involved bones are the upper femur (ball part of the hip socket) the lower femur (a part of the knee joint), the upper humerus (upper arm bone involving the shoulder joint), and the bones of ankle joint. The disease may affect just one bone, more than one bone at the same time, or more than one bone at different times. Orthopedic surgeons most often diagnose the disease using either an X-ray of magnetic resonance scan (MRI).The amount of disability that results from osteonecrosis depends on what part of the bone is affected, how large an area is involved, how far the disease has progressed, and how effectively the bone rebuilds itself. The process of bone rebuilding takes place after an injury as well as during normal growth. Normally, bone continuously breaks down and rebuilds – old bone is reabsorbed and replaced with new bone. The process keeps the skeleton strong and helps it to maintain a balance of minerals. With osteonecrosis, the healing process is usually ineffective and the bone tissues break down faster than the body can repair them. If left untreated, the disease progresses, and the bone may develop a crack whereby the bone can get compressed (collapse) together (similar to compressing a snowball). If this occurs at the end of the bone, it leads to an irregular joint surface, arthritic pain and loss of function of the affected areas.
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Symptoms of Osteonecrosis
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In the early stages of osteonecrosis, patients may not have any symptoms. As the disease progresses, however, most patients experience joint pain – at first, only when putting weight on the affected joint, and then even when resting. Pain usually develops gradually and may be mild or severe. If osteonecrosis progresses and the bone and surrounding joint surface collapse, pain may develop or increase dramatically. Pain may be severe enough to cause joint stiffness by limiting the range of motion in the affected joint. Disabling osteoarthritis may develop in the affected joint. The period of time between the first symptoms and loss of joint function is different for each patient, ranging from several months to more than a year.
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Symptoms of Osteonecrosis. In the early stages of osteonecrosis, patients may not have any symptoms. As the disease progresses, however, most patients experience joint pain – at first, only when putting weight on the affected joint, and then even when resting. Pain usually develops gradually and may be mild or severe. If osteonecrosis progresses and the bone and surrounding joint surface collapse, pain may develop or increase dramatically. Pain may be severe enough to cause joint stiffness by limiting the range of motion in the affected joint. Disabling osteoarthritis may develop in the affected joint. The period of time between the first symptoms and loss of joint function is different for each patient, ranging from several months to more than a year.
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Causes of Osteonecrosis
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Osteonecrosis has many different causes. Loss of blood supply to the bone may lead to bone cell death and can be caused by an injury (bone fracture or joint dislocation; called traumatic osteonecrosis). At times, there may be no history of injury (non-traumatic osteonecrosis); however, other risk factors are associated with the disease such as some medications (steroids, also known as corticosteroids), alcohol usage or blood coagulation disorders. Increased pressure within the bone also is associated with osteonecrosis. One theory is that the pressure within the bone causes the blood vessels to narrow, making it difficult for blood to circulate through the bone. Osteonecrosis can also be associated with other disorders. The exact reason osteonecrosis develops is not fully understood for some risk factors. Sometimes, osteonecrosis occurs in people with no risk factors (idiopathic). Some people have multiple risk factors. Osteonecrosis most likely develops because of the combination of factors, possibly including genetic, metabolic, self-imposed (alcohol, smoking), and other diseases that you may have and their treatment. Injury:
When a joint is injured, as in a fracture or dislocation, the blood vessels may be damaged. This can interfere with the blood circulation to the bone and lead to trauma-related osteonecrosis. Studies suggest that this type of osteonecrosis may develop in more than 20% of people who dislocate their hip joint.Corticosteroid Medications:
Corticosteroids, such as prednisone, are commonly used to treat diseases in which there is inflammation, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and vasculitis. Studies suggest that long-term, high dose systemic (oral or intravenous) corticosteroid use is a major risk factor for non-traumatic osteonecrosis with reports of up to 35 percent of all people with non-traumatic osteonecrosis. However, there is little risk of osteonecrosis associated with the infrequent use of corticosteroids, inhaled corticosteroids, or most steroid injections into joints. Patients should discuss concerns about corticosteroid use with their doctor.Doctors aren’t sure exactly why the use of corticosteroids sometimes is associated with osteonecrosis. They may have negative effects on different organs and tissues within the body. For example, they may interfere with the body’s ability to build new bones and to break down fatty substances. These substances would then build up in and clog the blood vessels, causing them to narrow. This then would reduce the ability of blood to flow inside a bone.Alcohol Use:
Excessive alcohol use is another major risk factor for non-traumatic osteonecrosis. Studies have reported that alcohol accounts for about 30% of all people with non-traumatic osteonecrosis. While alcohol can slow down bone remodeling (the balance between forming new bone and removing bone), it is not known why or how alcohol can trigger osteonecrosis.Other Risk Factors:
Other risk factors or conditions associated with non-traumatic osteonecrosis include Gaucher disease, pancreatitis, autoimmune disease, cancer, HIV infection, decompression disease (Caisson disease), and blood disorders such as sickle cell disease. Certain medical treatments including radiation treatments and chemotherapy can cause osteonecrosis. People who have received a kidney or other organ transplant may also have an increased risk.
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Causes of Osteonecrosis. Osteonecrosis has many different causes. Loss of blood supply to the bone may lead to bone cell death and can be caused by an injury (bone fracture or joint dislocation; called traumatic osteonecrosis). At times, there may be no history of injury (non-traumatic osteonecrosis); however, other risk factors are associated with the disease such as some medications (steroids, also known as corticosteroids), alcohol usage or blood coagulation disorders. Increased pressure within the bone also is associated with osteonecrosis. One theory is that the pressure within the bone causes the blood vessels to narrow, making it difficult for blood to circulate through the bone. Osteonecrosis can also be associated with other disorders. The exact reason osteonecrosis develops is not fully understood for some risk factors. Sometimes, osteonecrosis occurs in people with no risk factors (idiopathic). Some people have multiple risk factors. Osteonecrosis most likely develops because of the combination of factors, possibly including genetic, metabolic, self-imposed (alcohol, smoking), and other diseases that you may have and their treatment. Injury:
When a joint is injured, as in a fracture or dislocation, the blood vessels may be damaged. This can interfere with the blood circulation to the bone and lead to trauma-related osteonecrosis. Studies suggest that this type of osteonecrosis may develop in more than 20% of people who dislocate their hip joint.Corticosteroid Medications:
Corticosteroids, such as prednisone, are commonly used to treat diseases in which there is inflammation, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, and vasculitis. Studies suggest that long-term, high dose systemic (oral or intravenous) corticosteroid use is a major risk factor for non-traumatic osteonecrosis with reports of up to 35 percent of all people with non-traumatic osteonecrosis. However, there is little risk of osteonecrosis associated with the infrequent use of corticosteroids, inhaled corticosteroids, or most steroid injections into joints. Patients should discuss concerns about corticosteroid use with their doctor.Doctors aren’t sure exactly why the use of corticosteroids sometimes is associated with osteonecrosis. They may have negative effects on different organs and tissues within the body. For example, they may interfere with the body’s ability to build new bones and to break down fatty substances. These substances would then build up in and clog the blood vessels, causing them to narrow. This then would reduce the ability of blood to flow inside a bone.Alcohol Use:
Excessive alcohol use is another major risk factor for non-traumatic osteonecrosis. Studies have reported that alcohol accounts for about 30% of all people with non-traumatic osteonecrosis. While alcohol can slow down bone remodeling (the balance between forming new bone and removing bone), it is not known why or how alcohol can trigger osteonecrosis.Other Risk Factors:
Other risk factors or conditions associated with non-traumatic osteonecrosis include Gaucher disease, pancreatitis, autoimmune disease, cancer, HIV infection, decompression disease (Caisson disease), and blood disorders such as sickle cell disease. Certain medical treatments including radiation treatments and chemotherapy can cause osteonecrosis. People who have received a kidney or other organ transplant may also have an increased risk.
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Affects of Osteonecrosis
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Osteonecrosis usually affects people between 30 and 50 years of age; about 10,000 to 20,000 people develop osteonecrosis each year in the United States. Osteonecrosis affects both men and women and affects people of all ages. It is most common among people in their thirties and forties. Depending on a person’s risk factors and whether the underlying cause is trauma, it also can affect younger or older people.
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Affects of Osteonecrosis. Osteonecrosis usually affects people between 30 and 50 years of age; about 10,000 to 20,000 people develop osteonecrosis each year in the United States. Osteonecrosis affects both men and women and affects people of all ages. It is most common among people in their thirties and forties. Depending on a person’s risk factors and whether the underlying cause is trauma, it also can affect younger or older people.
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Related disorders of Osteonecrosis
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Symptoms of the disorders listed below may be similar to those of osteonecrosis. Comparisons may be useful for a differential diagnosis:Osteopetrosis is a combination of several rare genetically caused symptoms grouped together as one disorder. It can be inherited and is marked by increased bone density, brittle bones, and, in some people, skeletal abnormalities. Although symptoms may not initially be apparent to people with mild forms of this disorder, trivial injuries may cause bone fractures due to abnormalities of the bone. The dominantly transmitted form is milder than the recessive form and may not be diagnosed until adolescence or adulthood when symptoms first appear. More serious complications occur in the recessive form which may be diagnosed from examination of skeletal x-rays during infancy or childhood. (For more information on this disorder, choose “Osteopetrosis” as your search term in the Rare Disease Database.)Reflex sympathetic dystrophy syndrome (RSDS), also known as complex regional pain syndrome, is a rare disorder of the sympathetic nervous system that is characterized by chronic and severe pain. The sympathetic nervous system is that part of the autonomic nervous system that regulates involuntary functions of the body such as increasing heart rate, constricting blood vessels, and increasing blood pressure. Excessive or abnormal responses of portions of the sympathetic nervous system are thought to be responsible for the pain associated with reflex sympathetic dystrophy syndrome. The symptoms of RSDS typically begin with burning pain, especially in an arm, finger(s), palm of the hand(s), and/or shoulder(s). In some individuals, RSDS may occur in one or both legs or it may be localized to one knee or hip. Frequently, RSDS may be misdiagnosed as a painful nerve injury. The skin over the affected area(s) may become swollen (edema) and inflamed. Affected skin may be extremely sensitive to touch and to hot or cold temperatures (cutaneous hypersensitivity). The affected limb(s) may perspire excessively and be warm to the touch (vasomotor instability). The exact cause of RSDS is not fully understood, although it may be associated with injury to the nerves, trauma, surgery, atherosclerotic cardiovascular disease, infection, or radiation therapy. (For more information on this disorder, choose “reflex sympathetic dystrophy” as your search term in the Rare Disease Database.)Legg-Calvé-Perthes disease (LCPD) is one of a group of disorders known as the osteochondroses. The osteochondroses typically are characterized by degeneration and subsequent regeneration of the growing end of a bone (epiphyses). In LCPD, the growing end of the upper portion of the thigh bone (femur) is affected. The upper section of the thigh bone is known as the head or “the ball” and connects to the hip in a depression or “socket”. This is the hip joint, which is a ball and socket joint. The disorder results from an unexplained interruption of the blood supply (ischemia) to the head of the femur, which causes degeneration and deformity of the femoral head. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; and/or limited or restricted movement of the affected hip. The disease process seems to be self-limiting as new blood supplies are established (revascularization) and new healthy bone forms (re-ossifies) in the affected area. The exact cause for the temporary interruption of blood flow to the femoral epiphysis is not fully understood. Most times the disorder appears to occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose “Legg Calvé Perthes” as your search term in the Rare Disease Database.)
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Related disorders of Osteonecrosis. Symptoms of the disorders listed below may be similar to those of osteonecrosis. Comparisons may be useful for a differential diagnosis:Osteopetrosis is a combination of several rare genetically caused symptoms grouped together as one disorder. It can be inherited and is marked by increased bone density, brittle bones, and, in some people, skeletal abnormalities. Although symptoms may not initially be apparent to people with mild forms of this disorder, trivial injuries may cause bone fractures due to abnormalities of the bone. The dominantly transmitted form is milder than the recessive form and may not be diagnosed until adolescence or adulthood when symptoms first appear. More serious complications occur in the recessive form which may be diagnosed from examination of skeletal x-rays during infancy or childhood. (For more information on this disorder, choose “Osteopetrosis” as your search term in the Rare Disease Database.)Reflex sympathetic dystrophy syndrome (RSDS), also known as complex regional pain syndrome, is a rare disorder of the sympathetic nervous system that is characterized by chronic and severe pain. The sympathetic nervous system is that part of the autonomic nervous system that regulates involuntary functions of the body such as increasing heart rate, constricting blood vessels, and increasing blood pressure. Excessive or abnormal responses of portions of the sympathetic nervous system are thought to be responsible for the pain associated with reflex sympathetic dystrophy syndrome. The symptoms of RSDS typically begin with burning pain, especially in an arm, finger(s), palm of the hand(s), and/or shoulder(s). In some individuals, RSDS may occur in one or both legs or it may be localized to one knee or hip. Frequently, RSDS may be misdiagnosed as a painful nerve injury. The skin over the affected area(s) may become swollen (edema) and inflamed. Affected skin may be extremely sensitive to touch and to hot or cold temperatures (cutaneous hypersensitivity). The affected limb(s) may perspire excessively and be warm to the touch (vasomotor instability). The exact cause of RSDS is not fully understood, although it may be associated with injury to the nerves, trauma, surgery, atherosclerotic cardiovascular disease, infection, or radiation therapy. (For more information on this disorder, choose “reflex sympathetic dystrophy” as your search term in the Rare Disease Database.)Legg-Calvé-Perthes disease (LCPD) is one of a group of disorders known as the osteochondroses. The osteochondroses typically are characterized by degeneration and subsequent regeneration of the growing end of a bone (epiphyses). In LCPD, the growing end of the upper portion of the thigh bone (femur) is affected. The upper section of the thigh bone is known as the head or “the ball” and connects to the hip in a depression or “socket”. This is the hip joint, which is a ball and socket joint. The disorder results from an unexplained interruption of the blood supply (ischemia) to the head of the femur, which causes degeneration and deformity of the femoral head. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; and/or limited or restricted movement of the affected hip. The disease process seems to be self-limiting as new blood supplies are established (revascularization) and new healthy bone forms (re-ossifies) in the affected area. The exact cause for the temporary interruption of blood flow to the femoral epiphysis is not fully understood. Most times the disorder appears to occur randomly for no apparent reason (sporadically). (For more information on this disorder, choose “Legg Calvé Perthes” as your search term in the Rare Disease Database.)
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Osteonecrosis
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Diagnosis of Osteonecrosis
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After performing a complete physical examination and asking about the patient’s medical history (for example, what health problems the patient has had and for how long), the doctor may use one or more imaging techniques to diagnose osteonecrosis. As with many other diseases, early diagnosis increases the chances of treatment success.It is likely that the doctor first will recommend an x-ray. X-rays can help identify many causes of joint pain, such as a fracture or arthritis. If the x-ray is normal, the patient may need to have more tests.Research studies have shown that magnetic resonance imaging (MRI) is currently the most sensitive method for diagnosing osteonecrosis in the early stages. The tests described below may be used to determine the amount of bone affected and how far the disease has progressed.X-Ray
An x-ray is a common tool that the doctor may use to help diagnose the cause of joint pain. It is a simple way to produce pictures of bones. The x-ray of a person with early osteonecrosis is likely to be normal because x-rays are not sensitive enough to detect the bone changes in the early stages of the disease. X-rays can show bone damage in the later stages, and once the diagnosis is made, they are often used to monitor the course of the condition.Magnetic Resonance Imaging (MRI)
MRI is a common method for diagnosing osteonecrosis. Unlike x-rays, bone scans, and CT (computed/computerized tomography) scans, MRI detects chemical changes in the bone marrow and can show osteonecrosis in its earliest stages before it is seen on an x-ray. MRI provides the doctor with a picture of the area affected and the bone rebuilding process. In addition, MRI may show diseased areas that are not yet causing any symptoms. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues.Bone Scan
Also known as bone scintigraphy, bone scans should not be used for the diagnosis of osteonecrosis because they may miss 20 to 40% of the bone locations affected.Computed/Computerized Tomography (CT)
A CT scan is an imaging technique that provides the doctor with a three-dimensional picture of the bone. It also shows “slices” of the bone, making the picture much clearer than x-rays and bone scans. CT scans usually do not detect early osteonecrosis as early as MRI scans but are the best way to show a crack in the bone. Occasionally it may be useful in determining the extent of bone or joint surface collapse.Biopsy
A biopsy is a surgical procedure in which tissue from the affected bone is removed and studied. It is rarely used for diagnosis, as the other imaging studies are usually sufficiently distinct to make the diagnosis with a high level of confidence.
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Diagnosis of Osteonecrosis. After performing a complete physical examination and asking about the patient’s medical history (for example, what health problems the patient has had and for how long), the doctor may use one or more imaging techniques to diagnose osteonecrosis. As with many other diseases, early diagnosis increases the chances of treatment success.It is likely that the doctor first will recommend an x-ray. X-rays can help identify many causes of joint pain, such as a fracture or arthritis. If the x-ray is normal, the patient may need to have more tests.Research studies have shown that magnetic resonance imaging (MRI) is currently the most sensitive method for diagnosing osteonecrosis in the early stages. The tests described below may be used to determine the amount of bone affected and how far the disease has progressed.X-Ray
An x-ray is a common tool that the doctor may use to help diagnose the cause of joint pain. It is a simple way to produce pictures of bones. The x-ray of a person with early osteonecrosis is likely to be normal because x-rays are not sensitive enough to detect the bone changes in the early stages of the disease. X-rays can show bone damage in the later stages, and once the diagnosis is made, they are often used to monitor the course of the condition.Magnetic Resonance Imaging (MRI)
MRI is a common method for diagnosing osteonecrosis. Unlike x-rays, bone scans, and CT (computed/computerized tomography) scans, MRI detects chemical changes in the bone marrow and can show osteonecrosis in its earliest stages before it is seen on an x-ray. MRI provides the doctor with a picture of the area affected and the bone rebuilding process. In addition, MRI may show diseased areas that are not yet causing any symptoms. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues.Bone Scan
Also known as bone scintigraphy, bone scans should not be used for the diagnosis of osteonecrosis because they may miss 20 to 40% of the bone locations affected.Computed/Computerized Tomography (CT)
A CT scan is an imaging technique that provides the doctor with a three-dimensional picture of the bone. It also shows “slices” of the bone, making the picture much clearer than x-rays and bone scans. CT scans usually do not detect early osteonecrosis as early as MRI scans but are the best way to show a crack in the bone. Occasionally it may be useful in determining the extent of bone or joint surface collapse.Biopsy
A biopsy is a surgical procedure in which tissue from the affected bone is removed and studied. It is rarely used for diagnosis, as the other imaging studies are usually sufficiently distinct to make the diagnosis with a high level of confidence.
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Osteonecrosis
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Therapies of Osteonecrosis
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Treatment
Appropriate treatment for osteonecrosis is necessary to keep joints from collapsing. If untreated, most patients will experience severe pain and limitation in movement within two years. There is no agreed upon optimal treatment for individuals with osteonecrosis. Early intervention is essential to preserve the joints, but most people are diagnosed late in the disease process.Several treatments are available that can help prevent further bone and joint damage and reduce pain. To determine the most appropriate treatment, the doctor considers the following aspects of a patient's disease: the age of the patient; the stage of the disease–early or late; the location and amount of bone affected–a small or large area. The underlying cause has not been shown to influence outcomes of treatment.The goal in treating osteonecrosis is to improve the patient’s use of the affected joint, stop further damage to the bone, and ensure bone and joint survival. If osteonecrosis is diagnosed early enough, collapse and joint replacement can be prevented. To reach these goals, the doctor may use one or more of the following treatments.Non-operative TreatmentThere is no known pharmaceutical cure for osteonecrosis. Several non-operative treatments have been studied including hyperbaric oxygen therapy, shock wave therapy, electrical stimulation, pharmaceuticals (anticoagulants, bisphosphonates, vasodilators, lipid lowering agents), physiotherapy and muscle strengthening exercises, and combinations thereof. There are conflicting results for some of these treatments, therefore, rigorous, randomized controlled trials with large numbers of patients are still needed to determine the effectiveness of these treatments. Non-operative treatment may be part of a wait-and-see approach based on the size of the area of dead bone. Non-operative treatments cannot be labeled as conservative, since many of them do not slow the progression of the disease or lead to avoidance of a total hip arthroplasty. Most are simply pain-relieving at best.Reduced weight bearing does not alter the course of the disease and is not a treatment. It may be used to simply permit the patient to better cope with pain until appropriate treatment is instituted.Surgical TreatmentCore decompression – This surgical procedure removes or drills a tunnel into the area of the affected bone, which reduces pressure within the bone. Core decompression works best in people who are in the earliest stages of osteonecrosis, before the collapse of the dead bone. This procedure sometimes can reduce pain and slow the progression of bone and joint destruction in these patients.Osteotomy – This surgical procedure reshapes the bone to reduce stress on the affected area. There is a lengthy recovery period, and the patient's activities are very limited for 3 to 12 months after an osteotomy. This procedure is most effective for patients with advanced osteonecrosis and those with a small area of affected bone.Bone graft – Bone grafts can be used as part of the surgical treatment for osteonecrosis. Bone grafts can use bone from the same patient or donor bone. Bone graft or synthetic bone graft can be inserted into the hole created by the core decompression procedure. A specialized procedure, called vascularized bone grafting, involves moving a piece of bone from another site (often the fibula, one of the bones of the calf, or the iliac crest, a portion of the pelvic bone) with a vascular attachment. This allows for support of the diseased area as well as a new source of blood supply. This is a complex procedure and is performed by surgeons that are specially trained. Another type of bone grafting, involves scraping out all of the dead bone and replacing it with healthier bone graft, often from other portions of the patient’s skeleton.A unique type of bone graft involves the use of a patient’s own cells that are capable of making new bone. Often these cells are a type of stem cell from the bone marrow or other bodily tissues. There has been increasing interest in the potential of stem cell therapy. This is also being studied for the treatment of osteonecrosis. Mesenchymal stem cells, which are a type of ‘adult’ stem cell, can grow and develop into many different cell types in the body. Physicians take the patient’s own mesenchymal stem cells (autologous transplant) and place them into the affected bone to stimulate bone repair and regeneration.Arthroplasty/total joint replacement – Total joint replacement is the treatment of choice in late-stage osteonecrosis when the joint is destroyed. In this surgery, the diseased joint is replaced with artificial parts. It may be recommended for people who are not good candidates for other treatments, such as patients who do not do well with repeated attempts to preserve the joint. Various types of replacements are available, and people should discuss specific needs with their doctor.In 2021, the U.S. Food and Drug Administration (FDA) approved the Patient Specific Talus Spacer 3D-printed talus implant for humanitarian use. The Patient Specific Talus Spacer is the first-of-its-kind implant to replace the talus—the bone in the ankle joint that connects the leg and foot—for the treatment of AVN of the ankle joint.For most people with osteonecrosis, treatment is an ongoing process. Doctors may first recommend the least complex and invasive procedure, such as protecting the joint by limiting high impact activities, and watch the effect on the patient’s condition.Other treatments then may be used to prevent further bone destruction and reduce pain such as core decompression with bone graft/stem cell therapy. Eventually patients may need joint replacement if the disease has progressed to collapse of the bone. It is important that patients carefully follow instructions about activity limitations and work closely with their doctor to ensure that appropriate treatments are used.
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Therapies of Osteonecrosis. Treatment
Appropriate treatment for osteonecrosis is necessary to keep joints from collapsing. If untreated, most patients will experience severe pain and limitation in movement within two years. There is no agreed upon optimal treatment for individuals with osteonecrosis. Early intervention is essential to preserve the joints, but most people are diagnosed late in the disease process.Several treatments are available that can help prevent further bone and joint damage and reduce pain. To determine the most appropriate treatment, the doctor considers the following aspects of a patient's disease: the age of the patient; the stage of the disease–early or late; the location and amount of bone affected–a small or large area. The underlying cause has not been shown to influence outcomes of treatment.The goal in treating osteonecrosis is to improve the patient’s use of the affected joint, stop further damage to the bone, and ensure bone and joint survival. If osteonecrosis is diagnosed early enough, collapse and joint replacement can be prevented. To reach these goals, the doctor may use one or more of the following treatments.Non-operative TreatmentThere is no known pharmaceutical cure for osteonecrosis. Several non-operative treatments have been studied including hyperbaric oxygen therapy, shock wave therapy, electrical stimulation, pharmaceuticals (anticoagulants, bisphosphonates, vasodilators, lipid lowering agents), physiotherapy and muscle strengthening exercises, and combinations thereof. There are conflicting results for some of these treatments, therefore, rigorous, randomized controlled trials with large numbers of patients are still needed to determine the effectiveness of these treatments. Non-operative treatment may be part of a wait-and-see approach based on the size of the area of dead bone. Non-operative treatments cannot be labeled as conservative, since many of them do not slow the progression of the disease or lead to avoidance of a total hip arthroplasty. Most are simply pain-relieving at best.Reduced weight bearing does not alter the course of the disease and is not a treatment. It may be used to simply permit the patient to better cope with pain until appropriate treatment is instituted.Surgical TreatmentCore decompression – This surgical procedure removes or drills a tunnel into the area of the affected bone, which reduces pressure within the bone. Core decompression works best in people who are in the earliest stages of osteonecrosis, before the collapse of the dead bone. This procedure sometimes can reduce pain and slow the progression of bone and joint destruction in these patients.Osteotomy – This surgical procedure reshapes the bone to reduce stress on the affected area. There is a lengthy recovery period, and the patient's activities are very limited for 3 to 12 months after an osteotomy. This procedure is most effective for patients with advanced osteonecrosis and those with a small area of affected bone.Bone graft – Bone grafts can be used as part of the surgical treatment for osteonecrosis. Bone grafts can use bone from the same patient or donor bone. Bone graft or synthetic bone graft can be inserted into the hole created by the core decompression procedure. A specialized procedure, called vascularized bone grafting, involves moving a piece of bone from another site (often the fibula, one of the bones of the calf, or the iliac crest, a portion of the pelvic bone) with a vascular attachment. This allows for support of the diseased area as well as a new source of blood supply. This is a complex procedure and is performed by surgeons that are specially trained. Another type of bone grafting, involves scraping out all of the dead bone and replacing it with healthier bone graft, often from other portions of the patient’s skeleton.A unique type of bone graft involves the use of a patient’s own cells that are capable of making new bone. Often these cells are a type of stem cell from the bone marrow or other bodily tissues. There has been increasing interest in the potential of stem cell therapy. This is also being studied for the treatment of osteonecrosis. Mesenchymal stem cells, which are a type of ‘adult’ stem cell, can grow and develop into many different cell types in the body. Physicians take the patient’s own mesenchymal stem cells (autologous transplant) and place them into the affected bone to stimulate bone repair and regeneration.Arthroplasty/total joint replacement – Total joint replacement is the treatment of choice in late-stage osteonecrosis when the joint is destroyed. In this surgery, the diseased joint is replaced with artificial parts. It may be recommended for people who are not good candidates for other treatments, such as patients who do not do well with repeated attempts to preserve the joint. Various types of replacements are available, and people should discuss specific needs with their doctor.In 2021, the U.S. Food and Drug Administration (FDA) approved the Patient Specific Talus Spacer 3D-printed talus implant for humanitarian use. The Patient Specific Talus Spacer is the first-of-its-kind implant to replace the talus—the bone in the ankle joint that connects the leg and foot—for the treatment of AVN of the ankle joint.For most people with osteonecrosis, treatment is an ongoing process. Doctors may first recommend the least complex and invasive procedure, such as protecting the joint by limiting high impact activities, and watch the effect on the patient’s condition.Other treatments then may be used to prevent further bone destruction and reduce pain such as core decompression with bone graft/stem cell therapy. Eventually patients may need joint replacement if the disease has progressed to collapse of the bone. It is important that patients carefully follow instructions about activity limitations and work closely with their doctor to ensure that appropriate treatments are used.
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Osteonecrosis
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nord_919_0
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Overview of Osteopetrosis
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SummaryOsteopetrosis is marked by increased bone density due to a defect in bone reabsorption by cells called osteoclasts. This leads to accumulation of bone with defective architecture, making them brittle and susceptible to fracture. In some cases, this is also accompanied by skeletal abnormalities. Although symptoms may not initially be apparent in people with mild forms of this disorder, trivial injuries may cause bone fractures due to bone fragility. Early diagnosis is important in the most severe forms of these disorders, as they cause irreversible complications, and may be treated with hematopoietic stem cell transplant.There are three types of osteopetrosis, classified by their mode of inheritance: autosomal dominant, autosomal recessive, and X-linked recessive. The autosomal dominant form is the most common: usually, patients have mild symptoms that present in late childhood to adulthood. The autosomal recessive form, also called the malignant infantile type, is apparent soon after birth and frequently shortens life expectancy. Finally, the X-linked form of osteopetrosis is extremely rare, with only a few cases reported. There is also an intermediate type of osteopetrosis, comprising both milder autosomal recessive forms and dominant ones with early and severe presentation.IntroductionOsteopetrosis was first identified by radiologist Albers-Schonberg in 1904.
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Overview of Osteopetrosis. SummaryOsteopetrosis is marked by increased bone density due to a defect in bone reabsorption by cells called osteoclasts. This leads to accumulation of bone with defective architecture, making them brittle and susceptible to fracture. In some cases, this is also accompanied by skeletal abnormalities. Although symptoms may not initially be apparent in people with mild forms of this disorder, trivial injuries may cause bone fractures due to bone fragility. Early diagnosis is important in the most severe forms of these disorders, as they cause irreversible complications, and may be treated with hematopoietic stem cell transplant.There are three types of osteopetrosis, classified by their mode of inheritance: autosomal dominant, autosomal recessive, and X-linked recessive. The autosomal dominant form is the most common: usually, patients have mild symptoms that present in late childhood to adulthood. The autosomal recessive form, also called the malignant infantile type, is apparent soon after birth and frequently shortens life expectancy. Finally, the X-linked form of osteopetrosis is extremely rare, with only a few cases reported. There is also an intermediate type of osteopetrosis, comprising both milder autosomal recessive forms and dominant ones with early and severe presentation.IntroductionOsteopetrosis was first identified by radiologist Albers-Schonberg in 1904.
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Osteopetrosis
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nord_919_1
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Symptoms of Osteopetrosis
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Osteopetrosis is characterized by overly dense bones throughout the body. Symptoms include fractures, low blood cell production, and loss of cranial nerve function causing blindness, deafness, and/or facial nerve paralysis. Affected individuals may experience frequent infections of teeth and the bone in the jaw.Osteopetrosis, Autosomal Recessive; Malignant Infantile Type
The most severe type of osteopetrosis, malignant infantile type, is apparent from birth, and if left untreated, can lead to death in the first decade of life. Symptoms vary depending on the exact gene change (mutation). Affected individuals may have an abnormally large head (macrocephaly). They may also have hydrocephalus, characterized by inhibition of the normal flow of cerebrospinal fluid (CSF) within and abnormal widening (dilatation) of the cerebral spaces of the brain (ventricles), causing accumulation of CSF in the skull and potentially increased pressure on brain tissue. Symptoms that affect the eyes may include wasting away (atrophy) of the retina, eyes that appear widely spaced (hypertelorism), eyes that protrude from their orbits (exophthalmos), cross-eyes (strabismus), involuntary rhythmic movements of the eyes (nystagmus), and blindness.Other symptoms associated with malignant infantile type of osteopetrosis include hearing loss, abnormally small jaw (micrognathia), chronic inflammation of the mucous membranes in the nose (rhinitis), eating difficulties and/or growth retardation. Some affected individuals experience delays in acquiring skills that require the coordination of muscles and voluntary movements (delayed psychomotor development). Some affected individuals may experience delayed tooth development or severe dental caries. In addition, abnormal enlargement of the liver and spleen (hepatosplenomegaly); abnormal hardening of some bones (osteosclerosis); fractures, usually of the ribs and long bones; inflammation of the lumbar vertebrae (osteomyelitis); increased density of the cranial bones (cranial hyperostosis) leading to nerve compression; and/or increased pressure inside the skull may also occur. Patients can also present with seizures due to low levels of calcium in the blood. Symptoms of severe neurodegeneration can manifest in rare variants of malignant infantile osteopetrosis. Some affected individuals with the malignant infantile type of osteopetrosis may also experience consequences of reduced bone marrow space: marked deficiency of all types of blood cells (pancytopenia), the formation and development of blood cells outside the bone marrow, as in the spleen and liver (extramedullary hematopoiesis), and the occurrence of myeloid tissue in extramedullary sites (myeloid metaplasia). This may lead to frequent infections such as pneumonia and urinary tract infections. Affected individuals may also experience low levels of iron in red blood cells (anemia), due to both reduced bone marrow space and increased destruction of red blood cells due to an enlarged spleen. Of note, hematological defects usually present before neurological ones. Osteopetrosis, Autosomal Dominant; Adult Type
A milder form of osteopetrosis, the adult type, is usually diagnosed in late childhood or adulthood. There is predominance of bone symptoms, including osteosclerosis, fractures after minimal trauma (usually of the ribs and long bones), osteomyelitis (especially of the jaw) and cranial hyperostosis. In some cases, affected individuals may have pus-filled sacs in the tissue around the teeth (dental abscess). In many cases, individuals may exhibit no symptoms (asymptomatic). Affected individuals may also experience rhinitis, hepatosplenomegaly, anemia and extramedullary hematopoiesis.Osteopetrosis, Intermediate Autosomal Recessive
The intermediate type is usually found in children and can be inherited as a autosomal recessive or autosomal dominant trait. The severity of the disease is variable. Symptoms may include abnormal hardening of some bones; fractures; osteomyelitis especially of the mandible, knees that are abnormally close together and ankles that are abnormally wide apart (genu valgum) and cranial hyperostosis.Symptoms of the intermediate type of osteopetrosis may also include gradual deterioration of the nerves of the eyes (optic atrophy), loss of vision, muscular weakness, and rhinitis. Some affected individuals may experience abnormal protrusion of the lower jaw (mandibular prognathism), dental anomalies, baby teeth that do not fall out (deciduous retention), tooth crown malformation, dental caries, and facial paralysis. Other symptoms include hepatosplenomegaly, anemia, decreased levels of circulating blood platelets (thrombocytopenia), pancytopenia, and extramedullary hematopoiesis. Osteopetrosis: X-linked Recessive
X-linked osteopetrosis is extremely rare but severe, with only a few cases reported worldwide. In addition to classical symptoms linked with osteopetrosis, it is associated with immunodeficiency, localized fluid retention and tissue swelling (lymphedema) as well as abnormalities of the hair, skin, nails and sweat glands (ectodermal dysplasia).
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Symptoms of Osteopetrosis. Osteopetrosis is characterized by overly dense bones throughout the body. Symptoms include fractures, low blood cell production, and loss of cranial nerve function causing blindness, deafness, and/or facial nerve paralysis. Affected individuals may experience frequent infections of teeth and the bone in the jaw.Osteopetrosis, Autosomal Recessive; Malignant Infantile Type
The most severe type of osteopetrosis, malignant infantile type, is apparent from birth, and if left untreated, can lead to death in the first decade of life. Symptoms vary depending on the exact gene change (mutation). Affected individuals may have an abnormally large head (macrocephaly). They may also have hydrocephalus, characterized by inhibition of the normal flow of cerebrospinal fluid (CSF) within and abnormal widening (dilatation) of the cerebral spaces of the brain (ventricles), causing accumulation of CSF in the skull and potentially increased pressure on brain tissue. Symptoms that affect the eyes may include wasting away (atrophy) of the retina, eyes that appear widely spaced (hypertelorism), eyes that protrude from their orbits (exophthalmos), cross-eyes (strabismus), involuntary rhythmic movements of the eyes (nystagmus), and blindness.Other symptoms associated with malignant infantile type of osteopetrosis include hearing loss, abnormally small jaw (micrognathia), chronic inflammation of the mucous membranes in the nose (rhinitis), eating difficulties and/or growth retardation. Some affected individuals experience delays in acquiring skills that require the coordination of muscles and voluntary movements (delayed psychomotor development). Some affected individuals may experience delayed tooth development or severe dental caries. In addition, abnormal enlargement of the liver and spleen (hepatosplenomegaly); abnormal hardening of some bones (osteosclerosis); fractures, usually of the ribs and long bones; inflammation of the lumbar vertebrae (osteomyelitis); increased density of the cranial bones (cranial hyperostosis) leading to nerve compression; and/or increased pressure inside the skull may also occur. Patients can also present with seizures due to low levels of calcium in the blood. Symptoms of severe neurodegeneration can manifest in rare variants of malignant infantile osteopetrosis. Some affected individuals with the malignant infantile type of osteopetrosis may also experience consequences of reduced bone marrow space: marked deficiency of all types of blood cells (pancytopenia), the formation and development of blood cells outside the bone marrow, as in the spleen and liver (extramedullary hematopoiesis), and the occurrence of myeloid tissue in extramedullary sites (myeloid metaplasia). This may lead to frequent infections such as pneumonia and urinary tract infections. Affected individuals may also experience low levels of iron in red blood cells (anemia), due to both reduced bone marrow space and increased destruction of red blood cells due to an enlarged spleen. Of note, hematological defects usually present before neurological ones. Osteopetrosis, Autosomal Dominant; Adult Type
A milder form of osteopetrosis, the adult type, is usually diagnosed in late childhood or adulthood. There is predominance of bone symptoms, including osteosclerosis, fractures after minimal trauma (usually of the ribs and long bones), osteomyelitis (especially of the jaw) and cranial hyperostosis. In some cases, affected individuals may have pus-filled sacs in the tissue around the teeth (dental abscess). In many cases, individuals may exhibit no symptoms (asymptomatic). Affected individuals may also experience rhinitis, hepatosplenomegaly, anemia and extramedullary hematopoiesis.Osteopetrosis, Intermediate Autosomal Recessive
The intermediate type is usually found in children and can be inherited as a autosomal recessive or autosomal dominant trait. The severity of the disease is variable. Symptoms may include abnormal hardening of some bones; fractures; osteomyelitis especially of the mandible, knees that are abnormally close together and ankles that are abnormally wide apart (genu valgum) and cranial hyperostosis.Symptoms of the intermediate type of osteopetrosis may also include gradual deterioration of the nerves of the eyes (optic atrophy), loss of vision, muscular weakness, and rhinitis. Some affected individuals may experience abnormal protrusion of the lower jaw (mandibular prognathism), dental anomalies, baby teeth that do not fall out (deciduous retention), tooth crown malformation, dental caries, and facial paralysis. Other symptoms include hepatosplenomegaly, anemia, decreased levels of circulating blood platelets (thrombocytopenia), pancytopenia, and extramedullary hematopoiesis. Osteopetrosis: X-linked Recessive
X-linked osteopetrosis is extremely rare but severe, with only a few cases reported worldwide. In addition to classical symptoms linked with osteopetrosis, it is associated with immunodeficiency, localized fluid retention and tissue swelling (lymphedema) as well as abnormalities of the hair, skin, nails and sweat glands (ectodermal dysplasia).
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Osteopetrosis
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nord_919_2
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Causes of Osteopetrosis
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Osteopetrosis can be inherited in either an autosomal dominant or recessive pattern, and extremely rarely, in a X-linked recessive pattern. The basic defect in bone reabsorption is an insufficient production or defective function of cells called osteoclasts. These cells are responsible for bone resorption and aid in the maintenance of healthy bone, which relies on a balance between bone resorption (by osteoclasts) and bone formation (by other specialized cells called osteoblasts). The human skeleton is completely regenerated every 10 years. In this context, osteoclasts are essential for the bone turnover (replacement of old bone by new bone), bone remodeling, as well as micro-fracture repair. Human traits including the classic genetic diseases are the product of the interaction of two alleles for that condition, one received from the father and one from the mother.
The adult type of osteopetrosis is inherited as an autosomal dominant genetic trait. Dominant genetic disorders occur when only a single mutated copy of a gene is sufficient to cause a particular disease. The mutated copy of the gene can be inherited from either parent or can be the result of a mutational event occurred directly in the affected individual. The risk of passing the abnormal copy of the gene from an affected parent to an offspring is 50% at each pregnancy. The risk is the same for males and females.The malignant infantile type of osteopetrosis is inherited as an autosomal recessive genetic trait. Recessive genetic disorders occur when an individual inherits two abnormal copies of a gene, one from each parent. If an individual receives one normal and one abnormal copy of a 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 abnormal copy of the same gene and, therefore, have an affected child is 25% at each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% at each pregnancy. The chance for a child to receive the normal copy of the gene from both parents is 25%. The risk is the same for males and females. The X-linked form of osteopetrosis is recessive and extremely rare. X-linked recessive disorders are caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal copy of a gene present on one of their X chromosomes are carriers for that disorder: they usually do not display symptoms because females have two X chromosomes. Males have a single X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease. Female carriers of an X-linked recessive disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. The intermediate type of osteopetrosis can be inherited as an autosomal recessive or autosomal dominant genetic trait.
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Causes of Osteopetrosis. Osteopetrosis can be inherited in either an autosomal dominant or recessive pattern, and extremely rarely, in a X-linked recessive pattern. The basic defect in bone reabsorption is an insufficient production or defective function of cells called osteoclasts. These cells are responsible for bone resorption and aid in the maintenance of healthy bone, which relies on a balance between bone resorption (by osteoclasts) and bone formation (by other specialized cells called osteoblasts). The human skeleton is completely regenerated every 10 years. In this context, osteoclasts are essential for the bone turnover (replacement of old bone by new bone), bone remodeling, as well as micro-fracture repair. Human traits including the classic genetic diseases are the product of the interaction of two alleles for that condition, one received from the father and one from the mother.
The adult type of osteopetrosis is inherited as an autosomal dominant genetic trait. Dominant genetic disorders occur when only a single mutated copy of a gene is sufficient to cause a particular disease. The mutated copy of the gene can be inherited from either parent or can be the result of a mutational event occurred directly in the affected individual. The risk of passing the abnormal copy of the gene from an affected parent to an offspring is 50% at each pregnancy. The risk is the same for males and females.The malignant infantile type of osteopetrosis is inherited as an autosomal recessive genetic trait. Recessive genetic disorders occur when an individual inherits two abnormal copies of a gene, one from each parent. If an individual receives one normal and one abnormal copy of a 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 abnormal copy of the same gene and, therefore, have an affected child is 25% at each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% at each pregnancy. The chance for a child to receive the normal copy of the gene from both parents is 25%. The risk is the same for males and females. The X-linked form of osteopetrosis is recessive and extremely rare. X-linked recessive disorders are caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal copy of a gene present on one of their X chromosomes are carriers for that disorder: they usually do not display symptoms because females have two X chromosomes. Males have a single X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease. Female carriers of an X-linked recessive disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. The intermediate type of osteopetrosis can be inherited as an autosomal recessive or autosomal dominant genetic trait.
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Affects of Osteopetrosis
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Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. In the general population, one in every 250,000 individuals is born with this form of osteopetrosis. Higher rates have been found in specific regions of Costa Rica, the Middle East, Sweden and Russia. Males and females are affected in equal numbers.The adult type of osteopetrosis affects about 1,250 individuals in the United States. The incidence is about one in every 20,000 individuals. Males and females are affected in equal numbers.The X-linked form of osteopetrosis affects predominantly males due to the mode of inheritance of the mutation. Due to the rarity of cases, there are no population-wide studies.
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Affects of Osteopetrosis. Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. In the general population, one in every 250,000 individuals is born with this form of osteopetrosis. Higher rates have been found in specific regions of Costa Rica, the Middle East, Sweden and Russia. Males and females are affected in equal numbers.The adult type of osteopetrosis affects about 1,250 individuals in the United States. The incidence is about one in every 20,000 individuals. Males and females are affected in equal numbers.The X-linked form of osteopetrosis affects predominantly males due to the mode of inheritance of the mutation. Due to the rarity of cases, there are no population-wide studies.
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Related disorders of Osteopetrosis
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Symptoms of the following disorders may be similar to those of osteopetrosis. Comparisons may be useful for a differential diagnosis:Melorheostosis is a rare disorder resulting from abnormal development of the outer layer of the bone (cortex) which becomes hyperdense and widened. It also affects the surrounding soft tissues. It is characterized by deformity of one or more limbs, with pain and restriction of movement of the affected limb. It usually occurs sporadically. (For more information on this disorder, choose “melorheostosis” as your search term in the Rare Disease Database.)Osteopoikilosis, also known as “spotted bones”, is a rare disorder which may occur in conjunction with melorheostosis. Usually without apparent symptoms, osteopoikilosis may be discovered during x-ray examination. The diagnosis usually is made between the ages of 15 and 60. Spotty shadows appear on x-rays of wrist and ankle bones, finger or toe bones, long bones, pelvis, skull, and/or ribs (spinal bones are spared). These spots are less than one centimeter in diameter and usually of uniform density. Bone growth nodules can grow larger or diminish and disappear. Osteopoikilosis may be inherited in an autosomal dominant genetic pattern; sporadic forms exist too.Osteogenesis imperfecta, or “brittle bone disease”, is a group of hereditary connective tissue disorders characterized by unusual bone fragility and tendency to fracture. Traditionally, the disease has been recognized in two forms: osteogenesis imperfecta congenita, which is apparent at birth, and osteogenesis imperfecta tarda, which manifests itself usually in early childhood with milder symptoms. However, it is important to note that nowadays, 17 forms of osteogenesis imperfecta are distinguished by different genetic and clinical findings. (For more information on this disorder, choose “osteogenesis imperfecta” as your search term in the Rare Disease Database.)Osteopetrosis with renal tubular acidosis, also known as carbonic anhydrase II deficiency and Guibaud-Vainsel syndrome, is a rare inherited disorder characterized by multiple fractures within the first years of life. Affected infants demonstrate abnormal accumulation of acid in the body (metabolic acidosis), including within the tubes of the kidneys (renal tubular acidosis). Physical findings associated with the disorder include short stature, osteosclerosis, hepatosplenomegaly, upper and lower teeth that do not meet properly (malocclusion), cranial hyperostosis, and/or anemia. Some affected children may have intellectual disability and cerebral calcifications. Osteopetrosis with renal tubular acidosis is inherited as an autosomal recessive trait.
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Related disorders of Osteopetrosis. Symptoms of the following disorders may be similar to those of osteopetrosis. Comparisons may be useful for a differential diagnosis:Melorheostosis is a rare disorder resulting from abnormal development of the outer layer of the bone (cortex) which becomes hyperdense and widened. It also affects the surrounding soft tissues. It is characterized by deformity of one or more limbs, with pain and restriction of movement of the affected limb. It usually occurs sporadically. (For more information on this disorder, choose “melorheostosis” as your search term in the Rare Disease Database.)Osteopoikilosis, also known as “spotted bones”, is a rare disorder which may occur in conjunction with melorheostosis. Usually without apparent symptoms, osteopoikilosis may be discovered during x-ray examination. The diagnosis usually is made between the ages of 15 and 60. Spotty shadows appear on x-rays of wrist and ankle bones, finger or toe bones, long bones, pelvis, skull, and/or ribs (spinal bones are spared). These spots are less than one centimeter in diameter and usually of uniform density. Bone growth nodules can grow larger or diminish and disappear. Osteopoikilosis may be inherited in an autosomal dominant genetic pattern; sporadic forms exist too.Osteogenesis imperfecta, or “brittle bone disease”, is a group of hereditary connective tissue disorders characterized by unusual bone fragility and tendency to fracture. Traditionally, the disease has been recognized in two forms: osteogenesis imperfecta congenita, which is apparent at birth, and osteogenesis imperfecta tarda, which manifests itself usually in early childhood with milder symptoms. However, it is important to note that nowadays, 17 forms of osteogenesis imperfecta are distinguished by different genetic and clinical findings. (For more information on this disorder, choose “osteogenesis imperfecta” as your search term in the Rare Disease Database.)Osteopetrosis with renal tubular acidosis, also known as carbonic anhydrase II deficiency and Guibaud-Vainsel syndrome, is a rare inherited disorder characterized by multiple fractures within the first years of life. Affected infants demonstrate abnormal accumulation of acid in the body (metabolic acidosis), including within the tubes of the kidneys (renal tubular acidosis). Physical findings associated with the disorder include short stature, osteosclerosis, hepatosplenomegaly, upper and lower teeth that do not meet properly (malocclusion), cranial hyperostosis, and/or anemia. Some affected children may have intellectual disability and cerebral calcifications. Osteopetrosis with renal tubular acidosis is inherited as an autosomal recessive trait.
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Diagnosis of Osteopetrosis
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A diagnosis of osteopetrosis is based on a thorough clinical evaluation, detailed patient history, and a variety of specialized tests such as x-ray imaging and measurement of bone mass density (BMD) which is increased. Skeletal X-ray findings are very specific and are considered sufficient to make a diagnosis. Biochemical findings like increased concentration of creatinine kinase BB isoenzyme and tartrate-resistant acid phosphatase (TRAP) can also help making the diagnosis. Clinical Testing and Work-Up
Genetic testing can pinpoint the mutation in over 90% of cases: this can identify forms of osteopetrosis with unique clinical associations or complications and direct the management plan. A bone biopsy is sometimes performed to confirm the diagnosis, but not routinely done as it is an invasive procedure with non-negligible risks. Once the diagnosis is made, the following blood tests should be done: serum calcium, parathyroid hormone, phosphorus, creatinine, 25-hydroxyvitamin D, complete blood count with differential, creatine kinase isoenzymes (specifically the BB isozyme of creatine kinase), and lactate dehydrogenase. These measurements will determine the need for supplementation and for referral to specialists. Baseline magnetic resonance imaging of the brain should be arranged to evaluate cranial nerve involvement, hydrocephalus and vascular abnormalities. Affected individuals should be evaluated regularly by an ophthalmologist for optic nerve involvement, and benefit from a multidisciplinary approach including endocrinology, ophthalmology, genetics, and dentistry, with input from orthopedics, otorhinolaryngology, neurology, neurosurgery, nephrology, infectious disease and hematology specialists as needed.Prenatal diagnosis is theoretically possible in families in whom the genetic mutation has been identified.
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Diagnosis of Osteopetrosis. A diagnosis of osteopetrosis is based on a thorough clinical evaluation, detailed patient history, and a variety of specialized tests such as x-ray imaging and measurement of bone mass density (BMD) which is increased. Skeletal X-ray findings are very specific and are considered sufficient to make a diagnosis. Biochemical findings like increased concentration of creatinine kinase BB isoenzyme and tartrate-resistant acid phosphatase (TRAP) can also help making the diagnosis. Clinical Testing and Work-Up
Genetic testing can pinpoint the mutation in over 90% of cases: this can identify forms of osteopetrosis with unique clinical associations or complications and direct the management plan. A bone biopsy is sometimes performed to confirm the diagnosis, but not routinely done as it is an invasive procedure with non-negligible risks. Once the diagnosis is made, the following blood tests should be done: serum calcium, parathyroid hormone, phosphorus, creatinine, 25-hydroxyvitamin D, complete blood count with differential, creatine kinase isoenzymes (specifically the BB isozyme of creatine kinase), and lactate dehydrogenase. These measurements will determine the need for supplementation and for referral to specialists. Baseline magnetic resonance imaging of the brain should be arranged to evaluate cranial nerve involvement, hydrocephalus and vascular abnormalities. Affected individuals should be evaluated regularly by an ophthalmologist for optic nerve involvement, and benefit from a multidisciplinary approach including endocrinology, ophthalmology, genetics, and dentistry, with input from orthopedics, otorhinolaryngology, neurology, neurosurgery, nephrology, infectious disease and hematology specialists as needed.Prenatal diagnosis is theoretically possible in families in whom the genetic mutation has been identified.
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Therapies of Osteopetrosis
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TreatmentAt present, the only established cure for autosomal recessive malignant infantile osteopetrosis is hematopoietic stem cell transplantation (HSCT) for specific cases. This allows the restoration of bone resorption by donor-derived osteoclasts. Genetic studies are important to determine whether HSCT is appropriate, as certain specific mutations will not benefit from the transplant (those in the RANKL gene); moreover, some patients (all those with mutations in the OSTM1 gene and some of those with two mutations in the CLCN7 gene) develop progressive neurodegeneration, which is not cured by HSCT. In mild forms of osteopetrosis it is important to weight the risks and benefits as they may not warrant the dangerous risks associated with HSCT like rejection, severe infections and very high levels of calcium in the blood leading to a significant mortality rate in the first year. For patients in whom HSCT has been deemed not appropriate, corticosteroids may be considered, but there is not enough evidence to support their routine use. Gamma-1b (Actimmune) was approved by the U.S. Food and Drug Administration to delay disease progression in individuals with severe malignant infantile osteopetrosis. Actimmune is manufactured by Horizon Pharma. Inc.Good nutrition is very important for patients with osteopetrosis, including the use of calcium and vitamin D supplements if there are low levels of calcium in the blood. Other treatments are symptomatic and supportive. Genetic counseling is recommended for families in which this disorder occurs.
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Therapies of Osteopetrosis. TreatmentAt present, the only established cure for autosomal recessive malignant infantile osteopetrosis is hematopoietic stem cell transplantation (HSCT) for specific cases. This allows the restoration of bone resorption by donor-derived osteoclasts. Genetic studies are important to determine whether HSCT is appropriate, as certain specific mutations will not benefit from the transplant (those in the RANKL gene); moreover, some patients (all those with mutations in the OSTM1 gene and some of those with two mutations in the CLCN7 gene) develop progressive neurodegeneration, which is not cured by HSCT. In mild forms of osteopetrosis it is important to weight the risks and benefits as they may not warrant the dangerous risks associated with HSCT like rejection, severe infections and very high levels of calcium in the blood leading to a significant mortality rate in the first year. For patients in whom HSCT has been deemed not appropriate, corticosteroids may be considered, but there is not enough evidence to support their routine use. Gamma-1b (Actimmune) was approved by the U.S. Food and Drug Administration to delay disease progression in individuals with severe malignant infantile osteopetrosis. Actimmune is manufactured by Horizon Pharma. Inc.Good nutrition is very important for patients with osteopetrosis, including the use of calcium and vitamin D supplements if there are low levels of calcium in the blood. Other treatments are symptomatic and supportive. Genetic counseling is recommended for families in which this disorder occurs.
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Overview of Osteosarcoma
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Osteosarcoma is a form of cancer. It is a type of tumor that affects the bones. Osteosarcoma can affect people of any age but is most common during the teen-aged years and is the most common bone cancer affecting children and adolescents under the age of 20. The long bones of the legs, usually near where they connect to the knees, and the upper long bone of the arms, near where this bone meets the shoulders are the most common sites for osteosarcoma formation. Symptoms will vary depending upon the exact location and extent of disease. Pain is the most common symptom of osteosarcoma and there is often a mass or bump that can be felt (palpable). Eighty percent of individuals present with localized disease, which means the cancer remains in the area it first developed. Osteosarcoma can spread (metastasize) to other areas of the body, most likely the lungs. The exact cause is unknown in most individuals, but osteosarcoma can be induced by radiation. Most individuals are treated with a combination of chemotherapy and surgery. Sometimes, radiation therapy may be used.
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Overview of Osteosarcoma. Osteosarcoma is a form of cancer. It is a type of tumor that affects the bones. Osteosarcoma can affect people of any age but is most common during the teen-aged years and is the most common bone cancer affecting children and adolescents under the age of 20. The long bones of the legs, usually near where they connect to the knees, and the upper long bone of the arms, near where this bone meets the shoulders are the most common sites for osteosarcoma formation. Symptoms will vary depending upon the exact location and extent of disease. Pain is the most common symptom of osteosarcoma and there is often a mass or bump that can be felt (palpable). Eighty percent of individuals present with localized disease, which means the cancer remains in the area it first developed. Osteosarcoma can spread (metastasize) to other areas of the body, most likely the lungs. The exact cause is unknown in most individuals, but osteosarcoma can be induced by radiation. Most individuals are treated with a combination of chemotherapy and surgery. Sometimes, radiation therapy may be used.
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Symptoms of Osteosarcoma
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The most commonly affected bones are the long bones of the legs. These are the femur and the tibia. The femur, also called the thighbone, runs from the hip to the knee, and the tibia, or shinbone, runs from the knee to the ankle. The femur and the tibia meet at the knee where they help to form the knee joint. Osteosarcomas can form where these bones are growing the fastest in children and adolescents, which is called the growth plate. About 50% of individuals develop an osteosarcoma around the knee. For the legs this is near the knees and includes the bottom of the femur and the tops of the tibia. Osteosarcomas can also affect the upper part of the long bone of the arms called the humerus. The humerus runs from the elbow to the shoulder. The area near where the humerus connects to the shoulder accounts for about 15% of osteosarcomas.Less often, the middle portions of the femurs or tibia can be affected. Osteosarcomas can potentially be found in any bone of the body, although this is far less common. Other areas that can be affected include the spine, shoulder, pelvis, skull, or jaw.Pain is common in the area where the tumor is located. Pain may increase or decrease (wax and wane) over time. Pain may increase when a person does something that requires effort, such as lifting or another activity. A tumor may appear as a mass that can be seen or can be felt (palpable) and may be tender to the touch. Swelling near the tumor is also common. Sometimes, a tumor causes decreased movement in the affected arm or leg or nearby joint. Some people may limp because of a tumor in the leg or near the knee. Bones affected by osteosarcoma are weakened, and they may be more likely to fracture or break, although this is not a common occurrence.Osteosarcomas can spread (metastasize) to other areas of the body, most often the lungs. Generally, if the cancer has spread to other areas, then the prognosis is worse. Researchers are currently working on ways to prevent or treat metastatic osteosarcoma.
Osteosarcomas can be classified as high-grade, intermediate-grade or low-grade. This refers to how the cancer looks like under a microscope and determines how likely an osteosarcoma is to grow and spread. High-grade osteosarcomas are the most common form in children and adolescents and are the fastest growing form. They also have the greatest tendency to spread (metastasize).
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Symptoms of Osteosarcoma. The most commonly affected bones are the long bones of the legs. These are the femur and the tibia. The femur, also called the thighbone, runs from the hip to the knee, and the tibia, or shinbone, runs from the knee to the ankle. The femur and the tibia meet at the knee where they help to form the knee joint. Osteosarcomas can form where these bones are growing the fastest in children and adolescents, which is called the growth plate. About 50% of individuals develop an osteosarcoma around the knee. For the legs this is near the knees and includes the bottom of the femur and the tops of the tibia. Osteosarcomas can also affect the upper part of the long bone of the arms called the humerus. The humerus runs from the elbow to the shoulder. The area near where the humerus connects to the shoulder accounts for about 15% of osteosarcomas.Less often, the middle portions of the femurs or tibia can be affected. Osteosarcomas can potentially be found in any bone of the body, although this is far less common. Other areas that can be affected include the spine, shoulder, pelvis, skull, or jaw.Pain is common in the area where the tumor is located. Pain may increase or decrease (wax and wane) over time. Pain may increase when a person does something that requires effort, such as lifting or another activity. A tumor may appear as a mass that can be seen or can be felt (palpable) and may be tender to the touch. Swelling near the tumor is also common. Sometimes, a tumor causes decreased movement in the affected arm or leg or nearby joint. Some people may limp because of a tumor in the leg or near the knee. Bones affected by osteosarcoma are weakened, and they may be more likely to fracture or break, although this is not a common occurrence.Osteosarcomas can spread (metastasize) to other areas of the body, most often the lungs. Generally, if the cancer has spread to other areas, then the prognosis is worse. Researchers are currently working on ways to prevent or treat metastatic osteosarcoma.
Osteosarcomas can be classified as high-grade, intermediate-grade or low-grade. This refers to how the cancer looks like under a microscope and determines how likely an osteosarcoma is to grow and spread. High-grade osteosarcomas are the most common form in children and adolescents and are the fastest growing form. They also have the greatest tendency to spread (metastasize).
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Causes of Osteosarcoma
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As with many forms of cancer, the exact, underlying cause of osteosarcoma is unknown in most individuals. In most children and adolescents, this cancer is thought to occur randomly, for no specific reason (sporadically). Sporadic occurrence of cancer is thought to occur because of multiple factors acting together. This can include genetic and environmental factors. The cancerous cells in osteosarcomas are usually mesenchymal stem cells or osteoblasts. Mesenchymal stem cells are “adult” stem cells that can grow and change (differentiate) into different types of cells including bone, cartilage, muscle, fat, or connective tissue. Osteoblasts are cells that work to develop new bone. When they become cancerous, they may produce an immature form of bone called an osteoid, which is how the pathologist makes the diagnosis.Changes (variants or mutations) in certain genes have been noted to occur in greater frequency in individuals with osteosarcoma than in people without this form of cancer. These genes include the retinoblastoma 1 (RB1) gene, which is associated with a rare childhood eye cancer called retinoblastoma, or the TP53 gene, which is also associated with cancer. A variant in the WWOX gene is also seen in increased frequency in individuals with osteosarcoma. The genetic factors that contribute to the development of osteosarcomas are heterogeneous; this means that there are different genetic abnormalities or mechanisms that result in susceptibility to disease. Although mutations in genes like RB1 or p53 lead to a higher risk of osteosarcoma, most affected individuals do not have changes in these genes. The underlying genetic factors associated with osteosarcoma are very complex and more research is necessary for doctors to figure out all the genetic and environmental interactions that contribute to the development of osteosarcoma.Because osteosarcomas tend to affect adolescents in their teen years and disproportionately affects the growing portions (growth plates), many researchers believe that there may be problems with bone growth contributing to the development of this form of bone cancer.Although the causes and genetic aspects of osteosarcoma are not fully understood, several risk factors have been identified. Risk factors are anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will definitely develop that condition, and people who do not have any risk factors can still develop a condition.Individuals who have been treated by radiation therapy or certain anticancer medications called alkylating agents have a greater risk of developing osteosarcoma. Male gender, being tall, and people of African American or Hispanic/Latino descent are aspects that make people more likely to develop an osteosarcoma. Osteosarcomas also occur with greater frequency in people or families that have rare genetic disorders such as hereditary retinoblastoma (RB1), Li-Fraumeni syndrome (p53), Rothmund-Thompson syndrome, Blackfan-Diamond anemia, Bloom syndrome or Werner syndrome.Some individuals, including many adults, develop osteosarcoma when they have another, noncancerous bone disorder including Paget disease of bone or fibrous dysplasia, which result in increased bone turnover. Bone turnover is a normal process in which bone gradually breaks down and then reforms.
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Causes of Osteosarcoma. As with many forms of cancer, the exact, underlying cause of osteosarcoma is unknown in most individuals. In most children and adolescents, this cancer is thought to occur randomly, for no specific reason (sporadically). Sporadic occurrence of cancer is thought to occur because of multiple factors acting together. This can include genetic and environmental factors. The cancerous cells in osteosarcomas are usually mesenchymal stem cells or osteoblasts. Mesenchymal stem cells are “adult” stem cells that can grow and change (differentiate) into different types of cells including bone, cartilage, muscle, fat, or connective tissue. Osteoblasts are cells that work to develop new bone. When they become cancerous, they may produce an immature form of bone called an osteoid, which is how the pathologist makes the diagnosis.Changes (variants or mutations) in certain genes have been noted to occur in greater frequency in individuals with osteosarcoma than in people without this form of cancer. These genes include the retinoblastoma 1 (RB1) gene, which is associated with a rare childhood eye cancer called retinoblastoma, or the TP53 gene, which is also associated with cancer. A variant in the WWOX gene is also seen in increased frequency in individuals with osteosarcoma. The genetic factors that contribute to the development of osteosarcomas are heterogeneous; this means that there are different genetic abnormalities or mechanisms that result in susceptibility to disease. Although mutations in genes like RB1 or p53 lead to a higher risk of osteosarcoma, most affected individuals do not have changes in these genes. The underlying genetic factors associated with osteosarcoma are very complex and more research is necessary for doctors to figure out all the genetic and environmental interactions that contribute to the development of osteosarcoma.Because osteosarcomas tend to affect adolescents in their teen years and disproportionately affects the growing portions (growth plates), many researchers believe that there may be problems with bone growth contributing to the development of this form of bone cancer.Although the causes and genetic aspects of osteosarcoma are not fully understood, several risk factors have been identified. Risk factors are anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will definitely develop that condition, and people who do not have any risk factors can still develop a condition.Individuals who have been treated by radiation therapy or certain anticancer medications called alkylating agents have a greater risk of developing osteosarcoma. Male gender, being tall, and people of African American or Hispanic/Latino descent are aspects that make people more likely to develop an osteosarcoma. Osteosarcomas also occur with greater frequency in people or families that have rare genetic disorders such as hereditary retinoblastoma (RB1), Li-Fraumeni syndrome (p53), Rothmund-Thompson syndrome, Blackfan-Diamond anemia, Bloom syndrome or Werner syndrome.Some individuals, including many adults, develop osteosarcoma when they have another, noncancerous bone disorder including Paget disease of bone or fibrous dysplasia, which result in increased bone turnover. Bone turnover is a normal process in which bone gradually breaks down and then reforms.
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Affects of Osteosarcoma
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There are estimated to be about 750-1,000 people diagnosed with osteosarcoma each year in the United States. About 450 of those are children or adolescents under the age of 20. Osteosarcoma is a rare disorder, but it is the most common cause of bone cancer in children and adolescents. These tumors usually affect individuals in their second decade of life (10-19 years of age), most often between 13 and 16 years of age, which most likely coincides with adolescent growth spurts. There is a second increase in the number of people with osteosarcoma in people over the age of 60. Overall, osteosarcoma accounts for about 1% of all cancers diagnosed each year in the United States. Osteosarcoma affect slightly more males than females and is slightly more common in African Americans and Hispanics/Latinos than in Caucasians.
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Affects of Osteosarcoma. There are estimated to be about 750-1,000 people diagnosed with osteosarcoma each year in the United States. About 450 of those are children or adolescents under the age of 20. Osteosarcoma is a rare disorder, but it is the most common cause of bone cancer in children and adolescents. These tumors usually affect individuals in their second decade of life (10-19 years of age), most often between 13 and 16 years of age, which most likely coincides with adolescent growth spurts. There is a second increase in the number of people with osteosarcoma in people over the age of 60. Overall, osteosarcoma accounts for about 1% of all cancers diagnosed each year in the United States. Osteosarcoma affect slightly more males than females and is slightly more common in African Americans and Hispanics/Latinos than in Caucasians.
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Related disorders of Osteosarcoma
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Symptoms of the following disorders can be similar to those of osteosarcoma. Comparisons may be useful for a differential diagnosis.The main disorders that need to be differentiated from osteosarcoma are others forms of cancer or tumors that affect the bone. These include chondrosarcoma, malignant fibrous histiocytoma, Ewing sarcoma, fibrosarcoma, chordoma, malignant giant cell tumor of bone and lymphoma that affects bone. There are noncancerous (benign) tumors that need to be differentiated as well including chondroblastoma and osteoblastoma. The most common illness that produces similar symptoms is osteomyelitis, which is a bone infection. Other conditions include Langerhans cell histiocytosis and certain types of bone cysts. Traumatic growing pains can also cause similar symptoms. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Osteosarcoma. Symptoms of the following disorders can be similar to those of osteosarcoma. Comparisons may be useful for a differential diagnosis.The main disorders that need to be differentiated from osteosarcoma are others forms of cancer or tumors that affect the bone. These include chondrosarcoma, malignant fibrous histiocytoma, Ewing sarcoma, fibrosarcoma, chordoma, malignant giant cell tumor of bone and lymphoma that affects bone. There are noncancerous (benign) tumors that need to be differentiated as well including chondroblastoma and osteoblastoma. The most common illness that produces similar symptoms is osteomyelitis, which is a bone infection. Other conditions include Langerhans cell histiocytosis and certain types of bone cysts. Traumatic growing pains can also cause similar symptoms. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Osteosarcoma
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A diagnosis of osteosarcoma is suspected upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A physical examination may reveal swelling or a mass that is tender to the touch, and limited mobility of a nearby joint.Clinical Testing and Workup
X-rays should be taken if there is a suspicion of osteosarcoma. Plain x-rays are used to obtain images of the tumor or the affected area. An osteosarcoma typically will have a distinct appearance on an x-ray.More specialized imaging techniques may be used to help evaluate the size, placement and extension of the tumor (e.g., into the soft tissue or surrounding areas), to determine whether the tumor has spread (metastasized) to the lungs or other areas of the body, and to serve as an aid for future surgical procedures. Such imaging techniques may include magnetic resonance imaging (MRI), computerized tomography (CT scan), or bone scans. Plain films are most effective in helping to diagnose osteosarcoma. CT scans and MRIs give different information. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues including bone marrow and soft tissue. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. During a bone scan, a relatively harmless radioactive dye is injected into the affected bone. A special camera that can track the dye as it travels through the bone is used to create a picture of the skeleton and determine all affected areas and can help determine whether an osteosarcoma has spread to other areas of the body.Another advanced imaging technique known as positron emission tomography or PET scan may also be used, although it is not a standard diagnostic tool for osteosarcoma. During a PET scan, radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading and will soak up the radioactive sugar. When the x-ray (scan) is taken areas that soak up the radioactive sugar including an osteosarcoma show up as bright spots on the film.A diagnosis of osteosarcoma is confirmed through the surgical removal (biopsy) and microscopic study of a portion of affected tissue. A biopsy can reveal characteristic changes in the tumor tissue that are diagnostic of osteosarcomas. A malignant cell produces osteoid, which typically leads to the diagnosis of osteosarcoma.Some individuals may have their blood tested to detect elevated levels of chemicals called alkaline phosphatase and lactate dehydrogenase. These chemicals are sometimes high in people with an osteosarcoma. Although they may be indicative of osteosarcoma, there are other conditions that can cause these chemicals to be high. Therefore, these blood tests cannot diagnose osteosarcoma. However, if people with an osteosarcoma have high levels of these chemicals, it may help to reveal how advanced the cancer is. However, this does not supplant imaging, which is used to stage the cancer.
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Diagnosis of Osteosarcoma. A diagnosis of osteosarcoma is suspected upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A physical examination may reveal swelling or a mass that is tender to the touch, and limited mobility of a nearby joint.Clinical Testing and Workup
X-rays should be taken if there is a suspicion of osteosarcoma. Plain x-rays are used to obtain images of the tumor or the affected area. An osteosarcoma typically will have a distinct appearance on an x-ray.More specialized imaging techniques may be used to help evaluate the size, placement and extension of the tumor (e.g., into the soft tissue or surrounding areas), to determine whether the tumor has spread (metastasized) to the lungs or other areas of the body, and to serve as an aid for future surgical procedures. Such imaging techniques may include magnetic resonance imaging (MRI), computerized tomography (CT scan), or bone scans. Plain films are most effective in helping to diagnose osteosarcoma. CT scans and MRIs give different information. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues including bone marrow and soft tissue. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. During a bone scan, a relatively harmless radioactive dye is injected into the affected bone. A special camera that can track the dye as it travels through the bone is used to create a picture of the skeleton and determine all affected areas and can help determine whether an osteosarcoma has spread to other areas of the body.Another advanced imaging technique known as positron emission tomography or PET scan may also be used, although it is not a standard diagnostic tool for osteosarcoma. During a PET scan, radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading and will soak up the radioactive sugar. When the x-ray (scan) is taken areas that soak up the radioactive sugar including an osteosarcoma show up as bright spots on the film.A diagnosis of osteosarcoma is confirmed through the surgical removal (biopsy) and microscopic study of a portion of affected tissue. A biopsy can reveal characteristic changes in the tumor tissue that are diagnostic of osteosarcomas. A malignant cell produces osteoid, which typically leads to the diagnosis of osteosarcoma.Some individuals may have their blood tested to detect elevated levels of chemicals called alkaline phosphatase and lactate dehydrogenase. These chemicals are sometimes high in people with an osteosarcoma. Although they may be indicative of osteosarcoma, there are other conditions that can cause these chemicals to be high. Therefore, these blood tests cannot diagnose osteosarcoma. However, if people with an osteosarcoma have high levels of these chemicals, it may help to reveal how advanced the cancer is. However, this does not supplant imaging, which is used to stage the cancer.
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Osteosarcoma
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Therapies of Osteosarcoma
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Treatment
The therapeutic management of individuals with osteosarcoma may require the coordinated efforts of a team of medical professionals, such as specialists in the diagnosis and treatment of disorders of the skeletal system (orthopedists), orthopedic surgeons, orthopedic surgeons who specialize in treating cancer (orthopedic oncologists), physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), physicians who specialize in the diagnosis and treatment of cancer (oncologists), physicians who specialize in the use of radiation therapy for treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists and other healthcare specialists. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific tumor subtype; whether the cancer has spread; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.The main treatment option for individuals with osteosarcoma is a combination of chemotherapy and surgery. Chemotherapy is the use of certain medications to stop the growth or kill cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. In osteosarcoma, chemotherapy may be given before surgery to shrink a tumor or following surgery to eliminate any remaining cancer cells and lessen the risk of a recurrence. Usually, chemotherapy is given before and after surgery. Different combinations of medications may be used; this is called a chemotherapy regimen. When chemotherapy is given, the specific chemotherapy regimen used can vary. Different medical centers may have their own preferences as to the best way to approach treatment and what chemotherapeutic regimen is best for each individual.Surgical removal (resection) of a tumor is a mainstay for the treatment of osteosarcoma. Ideally, doctors will perform limb-sparing surgery. This surgery is designed to remove the tumor but preserve the function of the limb as well as the physical appearance of the limb. Sometimes, this surgery can leave a limb fragile and affected individuals may need to avoid high-stress, physical activities. If doctors cannot remove the entire tumor or can only do so without preserving the function of the affected limb, amputation may be recommended. This eliminates the tumor and will prevent the cancer from spreading further.Sometimes, doctors may recommend radiation therapy for individuals in whom a tumor could not be completely removed by surgery. There is a risk for side effects following radiation therapy.Late Effects of Osteosarcoma Therapy
Late effects of cancer therapy refer to the risk that survivors of childhood cancer may develop problems later in life because of treatment they received during childhood. Children treated with chemotherapy or radiation therapy have a risk of developing various issues later in life including heart problems, toxicity to the kidneys or central nervous system, infertility and an increased risk of developing a second, different cancer later in life.
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Therapies of Osteosarcoma. Treatment
The therapeutic management of individuals with osteosarcoma may require the coordinated efforts of a team of medical professionals, such as specialists in the diagnosis and treatment of disorders of the skeletal system (orthopedists), orthopedic surgeons, orthopedic surgeons who specialize in treating cancer (orthopedic oncologists), physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), physicians who specialize in the diagnosis and treatment of cancer (oncologists), physicians who specialize in the use of radiation therapy for treatment of cancer (radiation oncologists), oncology nurses, psychiatrists, nutritionists and other healthcare specialists. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific tumor subtype; whether the cancer has spread; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.The main treatment option for individuals with osteosarcoma is a combination of chemotherapy and surgery. Chemotherapy is the use of certain medications to stop the growth or kill cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. In osteosarcoma, chemotherapy may be given before surgery to shrink a tumor or following surgery to eliminate any remaining cancer cells and lessen the risk of a recurrence. Usually, chemotherapy is given before and after surgery. Different combinations of medications may be used; this is called a chemotherapy regimen. When chemotherapy is given, the specific chemotherapy regimen used can vary. Different medical centers may have their own preferences as to the best way to approach treatment and what chemotherapeutic regimen is best for each individual.Surgical removal (resection) of a tumor is a mainstay for the treatment of osteosarcoma. Ideally, doctors will perform limb-sparing surgery. This surgery is designed to remove the tumor but preserve the function of the limb as well as the physical appearance of the limb. Sometimes, this surgery can leave a limb fragile and affected individuals may need to avoid high-stress, physical activities. If doctors cannot remove the entire tumor or can only do so without preserving the function of the affected limb, amputation may be recommended. This eliminates the tumor and will prevent the cancer from spreading further.Sometimes, doctors may recommend radiation therapy for individuals in whom a tumor could not be completely removed by surgery. There is a risk for side effects following radiation therapy.Late Effects of Osteosarcoma Therapy
Late effects of cancer therapy refer to the risk that survivors of childhood cancer may develop problems later in life because of treatment they received during childhood. Children treated with chemotherapy or radiation therapy have a risk of developing various issues later in life including heart problems, toxicity to the kidneys or central nervous system, infertility and an increased risk of developing a second, different cancer later in life.
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Osteosarcoma
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Overview of Otopalatodigital Syndrome Type I and II
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Otopalatodigital syndromes type I and II are rare X-linked genetic disorders in which complete expression of the disease occurs only in males. Females may be affected with some of the symptoms. OPD type I is the milder form of the disease and is characterized by cleft palate, hearing loss and skeletal abnormalities in the skull and limbs. OPD type II includes these abnormalities as well as growth deficiency and, in a minority, abnormalities of the brain and is frequently not compatible with life.
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Overview of Otopalatodigital Syndrome Type I and II. Otopalatodigital syndromes type I and II are rare X-linked genetic disorders in which complete expression of the disease occurs only in males. Females may be affected with some of the symptoms. OPD type I is the milder form of the disease and is characterized by cleft palate, hearing loss and skeletal abnormalities in the skull and limbs. OPD type II includes these abnormalities as well as growth deficiency and, in a minority, abnormalities of the brain and is frequently not compatible with life.
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Otopalatodigital Syndrome Type I and II
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Symptoms of Otopalatodigital Syndrome Type I and II
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Individuals with OPD type I typically have short stature, an incomplete closure of the roof of the mouth (cleft palate), a downward slant of the opening between the upper and lower eyelids, hearing loss due to a defect of the middle ear (conductive hearing loss), and abnormal shortness of the fingers and toes. Symptoms that are sometimes seen in OPD type I are: short, broad thumbs and great toes; wide spaces between the toes; one or more fingers bent to the side; two or more digits united (syndactyly); short fingernails; dislocation of the head of the radius (one of the bones of the forearm); a broad bridge of the nose; underdeveloped bones of the face; and/or slow speech development. Females with the disorder may have an overhanging brow, a depressed nasal bridge, a wide space between the eyes, and a flat midface. The symptoms expressed in females vary and are fewer. Females do not have the full expression of this disorder. Individuals with OPD type II are more severely affected. Major characteristics in males with this disorder may be a small head, broad forehead, flat bridge of the nose, wide space between the eyes, small mouth, cleft palate, downward slant of the opening between the upper and lower eyelids, small mouth, small jaw, fingers that are bent and overlap, short fingers and toes, curved long bones of the forearms and legs, and small chest, heart defects and occasionally intellectual disability. Less common symptoms may include split tongue-tip, clouded eyes, and Dandy-Walker malformation (a brain malformation). OPD type II typically results in stillbirth or early infant death in males. Females do not have the full expression of OPD type II and may have mild symptoms such as an arched palate in the mouth, broad face, low-set ears, split uvula (the fleshy lobe in the middle of the back border of the soft palate), hearing loss, fingers bent to the side, short stature, and a downward slant of the opening between the upper and lower eyelids.
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Symptoms of Otopalatodigital Syndrome Type I and II. Individuals with OPD type I typically have short stature, an incomplete closure of the roof of the mouth (cleft palate), a downward slant of the opening between the upper and lower eyelids, hearing loss due to a defect of the middle ear (conductive hearing loss), and abnormal shortness of the fingers and toes. Symptoms that are sometimes seen in OPD type I are: short, broad thumbs and great toes; wide spaces between the toes; one or more fingers bent to the side; two or more digits united (syndactyly); short fingernails; dislocation of the head of the radius (one of the bones of the forearm); a broad bridge of the nose; underdeveloped bones of the face; and/or slow speech development. Females with the disorder may have an overhanging brow, a depressed nasal bridge, a wide space between the eyes, and a flat midface. The symptoms expressed in females vary and are fewer. Females do not have the full expression of this disorder. Individuals with OPD type II are more severely affected. Major characteristics in males with this disorder may be a small head, broad forehead, flat bridge of the nose, wide space between the eyes, small mouth, cleft palate, downward slant of the opening between the upper and lower eyelids, small mouth, small jaw, fingers that are bent and overlap, short fingers and toes, curved long bones of the forearms and legs, and small chest, heart defects and occasionally intellectual disability. Less common symptoms may include split tongue-tip, clouded eyes, and Dandy-Walker malformation (a brain malformation). OPD type II typically results in stillbirth or early infant death in males. Females do not have the full expression of OPD type II and may have mild symptoms such as an arched palate in the mouth, broad face, low-set ears, split uvula (the fleshy lobe in the middle of the back border of the soft palate), hearing loss, fingers bent to the side, short stature, and a downward slant of the opening between the upper and lower eyelids.
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Otopalatodigital Syndrome Type I and II
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Causes of Otopalatodigital Syndrome Type I and II
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OPD type I and II are caused by mutations in the FLNA gene on the X chromosome which is responsible for production of the filamin (FLNA) protein. Different mutations in the FLNA gene are responsible for the two syndromes. The filamin protein is normally responsible for helping with the formation and function of the cell’s cytoskeleton, and the mutations appear to give filamin a new function (referred to as a “gain-of-function” mutation) that leads to OPD type I and II. OPD type I and II are inherited in an X-linked pattern with variable expression in carrier females. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display prominent symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Otopalatodigital Syndrome Type I and II. OPD type I and II are caused by mutations in the FLNA gene on the X chromosome which is responsible for production of the filamin (FLNA) protein. Different mutations in the FLNA gene are responsible for the two syndromes. The filamin protein is normally responsible for helping with the formation and function of the cell’s cytoskeleton, and the mutations appear to give filamin a new function (referred to as a “gain-of-function” mutation) that leads to OPD type I and II. OPD type I and II are inherited in an X-linked pattern with variable expression in carrier females. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an altered gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display prominent symptoms because females have two X chromosomes and only one carries the altered gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an altered gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the altered gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Otopalatodigital Syndrome Type I and II
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Affects of Otopalatodigital Syndrome Type I and II
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OPD type 1 and II are rare disorders affecting less than 1 in every 100,000 individuals. The specific incidence for these conditions is unknown.
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Affects of Otopalatodigital Syndrome Type I and II. OPD type 1 and II are rare disorders affecting less than 1 in every 100,000 individuals. The specific incidence for these conditions is unknown.
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Otopalatodigital Syndrome Type I and II
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Related disorders of Otopalatodigital Syndrome Type I and II
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Symptoms of the following disorders can be similar to those of otopalatodigital syndrome type I and II. Comparisons may be useful for a differential diagnosis: Craniometaphyseal dysplasia is a rare genetic disorder that is characterized by head and facial abnormalities, hearing loss and bone deformities of the legs. The nose is abnormally small with narrow nasal passages and the eyes are widely spaced and bulging. The limbs may be affected by a hardening or broadening of the shaft of the long bones close to the growth center. Craniometaphyseal dysplasia is usually inherited as an autosomal dominant trait, but may also be inherited as a recessive genetic trait. (For more information on this disorder, choose “craniometaphyseal” as your search term in the Rare Disease Database.) Frontometaphyseal dysplasia is a rare genetic disorder characterized by coarse facial features that include a wide nasal bridge, widely spaced eyes, overgrowth of the bone over the eyes, a small jawbone and incomplete development of the sinuses. Multiple deformities of the teeth and bones may also be present. Occasionally intellectual disability may occur. This condition is very similar to OPD type 1 and since some individuals also have mutations in FLNA it can be difficult to differentiate the two. Larsen syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple bone dislocations and abnormalities, an extremely high arch of the foot, non-tapering cylindrically shaped fingers, and an unusual facial appearance. In some cases short stature, heart problems, cleft palate or lips and deafness may occur. This disorder is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Larsen” as your search term in the Rare Disease Database.) Oral-facial-digital syndrome is a rare genetic disorder in which there have been ten types identified. Symptoms common to all types include episodes of neuromuscular disturbances, split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oral-facial-digital syndrome” as your search term in the Rare Disease Database). Osteopetrosis is a rare genetic bone disorder inherited through an autosomal dominant or autosomal recessive trait. Initial symptoms of the dominant form may include bone fragility leading to easy fractures and unusual dental problems. Bone pain may occur in the spine, and cranial nerves may be affected. Some vision defects or facial palsy may also be symptomatic of the dominant form of osteopetrosis. (For more information on this disorder choose “osteopetrosis” as your search term in the Rare Disease Database.) Melnick-Needles syndrome is a rare genetic disorder of bone characterized by skeletal abnormalities and a specific facial appearance. The skeletal abnormalities include bowing of long bones, s-curved leg bones, ribbon-like ribs and a hardening of the skull base. The typical facial features include prominent, protruding eyes, full cheeks, an extremely small lower jaw and a hairy forehead. The condition may affect many bones of the body causing deformity and in some cases short stature. MNS is inherited as an X-linked dominant genetic disorder and is also caused by mutations in the FLNA gene. (For more information on this disorder choose “Melnick-Needles” as your search term in the Rare Disease Database).
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Related disorders of Otopalatodigital Syndrome Type I and II. Symptoms of the following disorders can be similar to those of otopalatodigital syndrome type I and II. Comparisons may be useful for a differential diagnosis: Craniometaphyseal dysplasia is a rare genetic disorder that is characterized by head and facial abnormalities, hearing loss and bone deformities of the legs. The nose is abnormally small with narrow nasal passages and the eyes are widely spaced and bulging. The limbs may be affected by a hardening or broadening of the shaft of the long bones close to the growth center. Craniometaphyseal dysplasia is usually inherited as an autosomal dominant trait, but may also be inherited as a recessive genetic trait. (For more information on this disorder, choose “craniometaphyseal” as your search term in the Rare Disease Database.) Frontometaphyseal dysplasia is a rare genetic disorder characterized by coarse facial features that include a wide nasal bridge, widely spaced eyes, overgrowth of the bone over the eyes, a small jawbone and incomplete development of the sinuses. Multiple deformities of the teeth and bones may also be present. Occasionally intellectual disability may occur. This condition is very similar to OPD type 1 and since some individuals also have mutations in FLNA it can be difficult to differentiate the two. Larsen syndrome is a multi-system genetic disorder that is present at birth. It is characterized by multiple bone dislocations and abnormalities, an extremely high arch of the foot, non-tapering cylindrically shaped fingers, and an unusual facial appearance. In some cases short stature, heart problems, cleft palate or lips and deafness may occur. This disorder is inherited as an autosomal dominant trait. (For more information on this disorder, choose “Larsen” as your search term in the Rare Disease Database.) Oral-facial-digital syndrome is a rare genetic disorder in which there have been ten types identified. Symptoms common to all types include episodes of neuromuscular disturbances, split tongue, splits in the jaw, midline cleft lip, overgrowth of the membrane that supports the tongue, a broad based nose, vertical folds of the skin covering the inner angle where the eyelids meet (epicanthic folds), more than the normal number of fingers and/or toes, shorter than normal fingers and/or toes, and more than the normal number of divisions between skull sections. (For more information on this disorder, choose “Oral-facial-digital syndrome” as your search term in the Rare Disease Database). Osteopetrosis is a rare genetic bone disorder inherited through an autosomal dominant or autosomal recessive trait. Initial symptoms of the dominant form may include bone fragility leading to easy fractures and unusual dental problems. Bone pain may occur in the spine, and cranial nerves may be affected. Some vision defects or facial palsy may also be symptomatic of the dominant form of osteopetrosis. (For more information on this disorder choose “osteopetrosis” as your search term in the Rare Disease Database.) Melnick-Needles syndrome is a rare genetic disorder of bone characterized by skeletal abnormalities and a specific facial appearance. The skeletal abnormalities include bowing of long bones, s-curved leg bones, ribbon-like ribs and a hardening of the skull base. The typical facial features include prominent, protruding eyes, full cheeks, an extremely small lower jaw and a hairy forehead. The condition may affect many bones of the body causing deformity and in some cases short stature. MNS is inherited as an X-linked dominant genetic disorder and is also caused by mutations in the FLNA gene. (For more information on this disorder choose “Melnick-Needles” as your search term in the Rare Disease Database).
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Otopalatodigital Syndrome Type I and II
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Diagnosis of Otopalatodigital Syndrome Type I and II
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The diagnosis of OPD type I or II is based on physical features and X-ray findings. Clinical molecular genetic testing for mutations in the FLNA gene is available to confirm the diagnosis. Skeletal abnormalities associated with these conditions can sometimes be seen on a prenatal ultrasound exam.
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Diagnosis of Otopalatodigital Syndrome Type I and II. The diagnosis of OPD type I or II is based on physical features and X-ray findings. Clinical molecular genetic testing for mutations in the FLNA gene is available to confirm the diagnosis. Skeletal abnormalities associated with these conditions can sometimes be seen on a prenatal ultrasound exam.
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Otopalatodigital Syndrome Type I and II
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Therapies of Otopalatodigital Syndrome Type I and II
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Treatment
Treatment for OPD type I and II is symptomatic. Infants may have difficulty breathing and require long-term respiratory care. Orthopedic and surgical procedures may be used to correct skeletal deformities. Treatment of hearing loss may be limited due to the severity of deformities within the ear. Genetic counseling is recommended for patients and their family members.
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Therapies of Otopalatodigital Syndrome Type I and II. Treatment
Treatment for OPD type I and II is symptomatic. Infants may have difficulty breathing and require long-term respiratory care. Orthopedic and surgical procedures may be used to correct skeletal deformities. Treatment of hearing loss may be limited due to the severity of deformities within the ear. Genetic counseling is recommended for patients and their family members.
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Otopalatodigital Syndrome Type I and II
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nord_922_0
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Overview of Ovarian Cancer
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Ovarian cancer refers to cancer that arises in the almond-shaped reproductive organs in women in which eggs, or ova, are produced (ovaries), in either of the two tubes through which eggs travel from the ovaries to the uterus (fallopian tubes), or in the membrane that lines the pelvis and the abdominal cavity and covers all of the abdominal organs (peritoneum). There are usually no symptoms (asymptomatic) during the early stages. As a result, ovarian cancer is usually not diagnosed until an advanced stage. Common symptoms that can develop include abdominal swelling or bloating, unintended weight loss, or changes in the bowel habits including constipation. The cause of ovarian cancer is multifactorial, which means that multiple factors that occur together are necessary for the cancer to develop. These factors include genetic, immunologic and environmental factors. About 20% of all women with ovarian cancer have a variation in one of two genes called BRCA1 or BRCA2. BRCA-associated ovarian cancer is not specifically discussed in this report. NORD has a separate report on ovarian cancer caused by variations in these two genes that is titled Hereditary Breast and Ovarian Cancer (HBOC) Syndrome. Ovarian cancer is a nonspecific term for a group of tumors. However, more than 90% of ovarian cancer arises from epithelial cells; these cells cover most internal and external surfaces of the body and its organs. Epithelial cancer of the ovaries, fallopian tubes, and peritoneum share similar behavior and characteristics. These closely related cancers are often grouped together and can be referred to as epithelial ovarian cancer or EOC. This report primarily deals with epithelial ovarian cancer (carcinoma). Most instances of EOC are high grade serous carcinoma. Most high grade serous carcinomas are now believed to originate in the very tips of the fallopian tubes. Additional subtypes of EOC are low-grade serous carcinoma, mucinous, clear cell, endometroid, and undifferentiated, in which the cancer cells are very immature and do not look like the cells in the tissue in which the cancer begins. Other types of ovarian cancer include stromal tumors, in which cancer arises in the ovarian tissue that contains hormone-producing cells, and germ cell tumors, in which cancer arises in the egg-producing cells. Stromal tumors are also called sex cord-stromal tumors and make up about 7% of women with ovarian cancer. Types of stromal tumor include granulosa, granulosa-theca, and Sertoli-Leydig cell. Germ cell tumors are extremely rare and occur in younger women (about 80% in women under 30 years of age). Types of germ cell tumors include teratoma, dysgerminoma, endodermal sinus tumor, and choriocarcinoma.
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Overview of Ovarian Cancer. Ovarian cancer refers to cancer that arises in the almond-shaped reproductive organs in women in which eggs, or ova, are produced (ovaries), in either of the two tubes through which eggs travel from the ovaries to the uterus (fallopian tubes), or in the membrane that lines the pelvis and the abdominal cavity and covers all of the abdominal organs (peritoneum). There are usually no symptoms (asymptomatic) during the early stages. As a result, ovarian cancer is usually not diagnosed until an advanced stage. Common symptoms that can develop include abdominal swelling or bloating, unintended weight loss, or changes in the bowel habits including constipation. The cause of ovarian cancer is multifactorial, which means that multiple factors that occur together are necessary for the cancer to develop. These factors include genetic, immunologic and environmental factors. About 20% of all women with ovarian cancer have a variation in one of two genes called BRCA1 or BRCA2. BRCA-associated ovarian cancer is not specifically discussed in this report. NORD has a separate report on ovarian cancer caused by variations in these two genes that is titled Hereditary Breast and Ovarian Cancer (HBOC) Syndrome. Ovarian cancer is a nonspecific term for a group of tumors. However, more than 90% of ovarian cancer arises from epithelial cells; these cells cover most internal and external surfaces of the body and its organs. Epithelial cancer of the ovaries, fallopian tubes, and peritoneum share similar behavior and characteristics. These closely related cancers are often grouped together and can be referred to as epithelial ovarian cancer or EOC. This report primarily deals with epithelial ovarian cancer (carcinoma). Most instances of EOC are high grade serous carcinoma. Most high grade serous carcinomas are now believed to originate in the very tips of the fallopian tubes. Additional subtypes of EOC are low-grade serous carcinoma, mucinous, clear cell, endometroid, and undifferentiated, in which the cancer cells are very immature and do not look like the cells in the tissue in which the cancer begins. Other types of ovarian cancer include stromal tumors, in which cancer arises in the ovarian tissue that contains hormone-producing cells, and germ cell tumors, in which cancer arises in the egg-producing cells. Stromal tumors are also called sex cord-stromal tumors and make up about 7% of women with ovarian cancer. Types of stromal tumor include granulosa, granulosa-theca, and Sertoli-Leydig cell. Germ cell tumors are extremely rare and occur in younger women (about 80% in women under 30 years of age). Types of germ cell tumors include teratoma, dysgerminoma, endodermal sinus tumor, and choriocarcinoma.
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Ovarian Cancer
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Symptoms of Ovarian Cancer
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The specific symptoms and physical findings of ovarian cancer can vary from one person to another, depending upon the extent and region(s) of involvement and other factors. Ovarian cancer usually does not cause any symptoms in the early stages. Symptoms may be described as acute (developing rapidly and severely) or subacute (having a slower onset and slower progression). Affected individuals can develop abdominal bloating, the need to urinate quickly and frequently, changes in bowel habits including constipation, difficulty eating and a sense of feeling full quickly, unintended weight loss, and pelvic or abdominal pain or discomfort. Some women may have ascites, a condition characterized by the buildup of fluid in the abdomen. Additional symptoms that can develop including fatigue, back pain, an upset stomach, pain during sex, and changes to the menstrual cycle. Some women have an adnexal mass. An adnexal mass of the uterus is found in any area nearby the uterus that is related structurally or functionally. This includes the ovaries, fallopian tubes, and other nearby tissue. An adnexal mass can sometimes be the first sign of ovarian cancer and can cause a sense of pressure or pain in the pelvic region. Some women develop more severe symptoms of ovarian cancer. This usually occurs when the cancer is at an advanced stage. Such symptoms include fluid buildup around the lungs (pleural effusion) and obstruction or blockage of the digestive tract (bowel obstruction). The pleura are thin membranes that line the lungs. A small amount of fluid allows the lungs to move within the chest cavity. When excess fluid builds up in this space, the lungs cannot move easily or properly. Pleural effusion can cause shortness of breath, a cough, or chest pain. Bowel obstruction refers to the inability of the body to propel waste through the intestines. This can cause crampy abdominal pain, loss of appetite, swelling of the abdomen, and constipation. Severe nausea and vomiting can also occur.
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Symptoms of Ovarian Cancer. The specific symptoms and physical findings of ovarian cancer can vary from one person to another, depending upon the extent and region(s) of involvement and other factors. Ovarian cancer usually does not cause any symptoms in the early stages. Symptoms may be described as acute (developing rapidly and severely) or subacute (having a slower onset and slower progression). Affected individuals can develop abdominal bloating, the need to urinate quickly and frequently, changes in bowel habits including constipation, difficulty eating and a sense of feeling full quickly, unintended weight loss, and pelvic or abdominal pain or discomfort. Some women may have ascites, a condition characterized by the buildup of fluid in the abdomen. Additional symptoms that can develop including fatigue, back pain, an upset stomach, pain during sex, and changes to the menstrual cycle. Some women have an adnexal mass. An adnexal mass of the uterus is found in any area nearby the uterus that is related structurally or functionally. This includes the ovaries, fallopian tubes, and other nearby tissue. An adnexal mass can sometimes be the first sign of ovarian cancer and can cause a sense of pressure or pain in the pelvic region. Some women develop more severe symptoms of ovarian cancer. This usually occurs when the cancer is at an advanced stage. Such symptoms include fluid buildup around the lungs (pleural effusion) and obstruction or blockage of the digestive tract (bowel obstruction). The pleura are thin membranes that line the lungs. A small amount of fluid allows the lungs to move within the chest cavity. When excess fluid builds up in this space, the lungs cannot move easily or properly. Pleural effusion can cause shortness of breath, a cough, or chest pain. Bowel obstruction refers to the inability of the body to propel waste through the intestines. This can cause crampy abdominal pain, loss of appetite, swelling of the abdomen, and constipation. Severe nausea and vomiting can also occur.
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Causes of Ovarian Cancer
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The exact, underlying cause of ovarian cancer is not fully understood. The reason why cancer develops is a complex question and researchers speculate that multiple factors are involved in the development of ovarian cancer. These factors can include genetic, environmental and immunologic factors. People with certain genetic disorders are more likely to develop ovarian cancer. The most common underlying cause of ovarian cancer is variations in either the BRCA1 or BRCA2 genes. This is part of the hereditary breast and ovarian cancer (HBOC) syndrome, which is an inherited cancer-predisposition syndrome. Affected individuals have a significantly greater risk of developing certain cancers, particularly breast cancer, in both men and women, and ovarian cancer in women. Affected individuals tend to develop cancer earlier in life as well, usually before the age of 50. BRCA-associated ovarian cancer is a specific, genetic condition that differs from ovarian cancer due to other causes, although the cancer may appear similar when viewed under a microscope. Several other genes have been identified that may play a role in the development of ovarian cancer. These genes include the BRIP1, RAD51C, and RAD51D genes as well as the mismatch repair (MMR) genes. 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, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. Variations (mutations) in genes associated with ovarian cancer have been shown to increase a person’s risk of developing cancer (genetic predisposition). A genetic predisposition means that a person has a gene or genes for a disease, but the disease will not develop unless additional genetic or environmental factors are also present. Other subtypes of ovarian cancer may be associated with other gene variations. For example, low-grade serous carcinoma is associated with variations in the BRAF and RAS genes. Certain genes, such as a variation in the FABP4 gene, may play a role in whether ovarian cancer is more likely to spread (metastasize) to other areas of the body. Understanding the underlying genetic factors in cancer can lead to better, more targeted therapies. Lynch syndrome is another hereditary cancer syndrome in which affected women are more likely to develop ovarian cancer. Variations in several genes are known to cause Lynch syndrome including MLH1, MSH2, MSH6, PMS2, and EPCAM. Lynch syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC). Additional risk factors for ovarian cancer include infertility, long-term postmenopausal hormone therapy (estrogen replacement therapy), the use of an intrauterine device, increasing age, having never given birth to a child (nulliparity), endometriosis, and polycystic ovarian syndrome (PCOS). Endometriosis is a common condition in which the tissue that lines the uterus (endometrium) grows outside of the uterus, most often affecting the ovaries, fallopian tubes or the tissue lining the pelvis. Pain is the most common symptom of endometriosis. Endometriosis is specifically associated with an increased risk of endometrioid and clear cell ovarian cancer, but not high-grade serous carcinoma or mucinous tumors. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin. PCOS may occur as a symptom of insulin resistance. Some women enter puberty early (before the age of 8), a condition called precocious puberty. Cigarette smoking is modifiable risk factor that is associated with an increased risk of a mucinous carcinoma of the ovary. There is a theory that continuous (incessant) ovulation is a risk factor for ovarian cancer. Many things can impact ovulation, which is when a woman releases an egg during menstruation. When a woman first begins having a period and when she reaches menopause, including early onset of a woman’s period (early menarche) or late menopause, are both related to the frequency of ovulation. Prolonged use of oral contraceptives (i.e. 5 or more years) may decrease a woman’s risk of developing ovarian cancer.
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Causes of Ovarian Cancer. The exact, underlying cause of ovarian cancer is not fully understood. The reason why cancer develops is a complex question and researchers speculate that multiple factors are involved in the development of ovarian cancer. These factors can include genetic, environmental and immunologic factors. People with certain genetic disorders are more likely to develop ovarian cancer. The most common underlying cause of ovarian cancer is variations in either the BRCA1 or BRCA2 genes. This is part of the hereditary breast and ovarian cancer (HBOC) syndrome, which is an inherited cancer-predisposition syndrome. Affected individuals have a significantly greater risk of developing certain cancers, particularly breast cancer, in both men and women, and ovarian cancer in women. Affected individuals tend to develop cancer earlier in life as well, usually before the age of 50. BRCA-associated ovarian cancer is a specific, genetic condition that differs from ovarian cancer due to other causes, although the cancer may appear similar when viewed under a microscope. Several other genes have been identified that may play a role in the development of ovarian cancer. These genes include the BRIP1, RAD51C, and RAD51D genes as well as the mismatch repair (MMR) genes. 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, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. Variations (mutations) in genes associated with ovarian cancer have been shown to increase a person’s risk of developing cancer (genetic predisposition). A genetic predisposition means that a person has a gene or genes for a disease, but the disease will not develop unless additional genetic or environmental factors are also present. Other subtypes of ovarian cancer may be associated with other gene variations. For example, low-grade serous carcinoma is associated with variations in the BRAF and RAS genes. Certain genes, such as a variation in the FABP4 gene, may play a role in whether ovarian cancer is more likely to spread (metastasize) to other areas of the body. Understanding the underlying genetic factors in cancer can lead to better, more targeted therapies. Lynch syndrome is another hereditary cancer syndrome in which affected women are more likely to develop ovarian cancer. Variations in several genes are known to cause Lynch syndrome including MLH1, MSH2, MSH6, PMS2, and EPCAM. Lynch syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC). Additional risk factors for ovarian cancer include infertility, long-term postmenopausal hormone therapy (estrogen replacement therapy), the use of an intrauterine device, increasing age, having never given birth to a child (nulliparity), endometriosis, and polycystic ovarian syndrome (PCOS). Endometriosis is a common condition in which the tissue that lines the uterus (endometrium) grows outside of the uterus, most often affecting the ovaries, fallopian tubes or the tissue lining the pelvis. Pain is the most common symptom of endometriosis. Endometriosis is specifically associated with an increased risk of endometrioid and clear cell ovarian cancer, but not high-grade serous carcinoma or mucinous tumors. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip and chin. PCOS may occur as a symptom of insulin resistance. Some women enter puberty early (before the age of 8), a condition called precocious puberty. Cigarette smoking is modifiable risk factor that is associated with an increased risk of a mucinous carcinoma of the ovary. There is a theory that continuous (incessant) ovulation is a risk factor for ovarian cancer. Many things can impact ovulation, which is when a woman releases an egg during menstruation. When a woman first begins having a period and when she reaches menopause, including early onset of a woman’s period (early menarche) or late menopause, are both related to the frequency of ovulation. Prolonged use of oral contraceptives (i.e. 5 or more years) may decrease a woman’s risk of developing ovarian cancer.
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Affects of Ovarian Cancer
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In 2017, more than 22,400 women were diagnosed with ovarian cancer in the United States. It affects about 1 in 70 women in the U.S and is the second most common gynecological cancer behind only endometrial cancer. The average age at diagnosis is 63. Worldwide about 240,000 women are diagnosed each year with ovarian cancer. The incidence, which is the number of people with a disease over a given period of time such as one year, is greater in developed countries.
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Affects of Ovarian Cancer. In 2017, more than 22,400 women were diagnosed with ovarian cancer in the United States. It affects about 1 in 70 women in the U.S and is the second most common gynecological cancer behind only endometrial cancer. The average age at diagnosis is 63. Worldwide about 240,000 women are diagnosed each year with ovarian cancer. The incidence, which is the number of people with a disease over a given period of time such as one year, is greater in developed countries.
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Related disorders of Ovarian Cancer
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Symptoms of the following disorders can be similar to those of ovarian cancer. Comparisons may be useful for a differential diagnosis.There are many different conditions and disorders that must be differentiated from ovarian cancer. This includes other forms of cancer including cancer of the appendix, tumors of the bowels, retroperitoneal sarcoma, and cancers that began in another area of the body and spread to the ovaries, fallopian tubes, or peritoneum. Noncancerous (benign) tumors can include various types of cysts, endometrioma, cystadenoma, uterine leiomyosarcoma, and nerve sheath tumors. Other conditions include constipation, abscesses in the appendix or pelvic area, blockage and swelling of the fallopian tubes (hydrosalpinx), and ectopic pregnancy, in which the fertilized egg attaches itself somewhere other than the uterus (most often within the fallopian tubes).
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Related disorders of Ovarian Cancer. Symptoms of the following disorders can be similar to those of ovarian cancer. Comparisons may be useful for a differential diagnosis.There are many different conditions and disorders that must be differentiated from ovarian cancer. This includes other forms of cancer including cancer of the appendix, tumors of the bowels, retroperitoneal sarcoma, and cancers that began in another area of the body and spread to the ovaries, fallopian tubes, or peritoneum. Noncancerous (benign) tumors can include various types of cysts, endometrioma, cystadenoma, uterine leiomyosarcoma, and nerve sheath tumors. Other conditions include constipation, abscesses in the appendix or pelvic area, blockage and swelling of the fallopian tubes (hydrosalpinx), and ectopic pregnancy, in which the fertilized egg attaches itself somewhere other than the uterus (most often within the fallopian tubes).
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Diagnosis of Ovarian Cancer
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A diagnosis of ovarian cancer is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There is no screening test that can be run that detects ovarian cancer in all women. Ovarian cancer does not cause many symptoms during the early stages of development, and symptoms tend to be nonspecific (common to many diseases). Consequently, ovarian cancer is often undiagnosed until it has spread to the abdomen and pelvis. Clinical Testing and Workup
A pelvic exam is an examination where a physician evaluates a woman’s reproductive organs. A physician will insert gloved fingers into the vagina while pressing down on the abdomen. This allows a physician to feel the pelvic organs. A physician will also visually inspect a woman’s external reproductive organs. Most times, a pelvic exam does not diagnose ovarian cancer. When it does, it is usually because a physician noted an abnormally enlarged ovary. Blood tests may be ordered to test for markers of ovarian cancer. A marker is a substance that when present is indicative of a disease. If there are increased levels of cancer antigen 125 (CA-125), then this is indicative of ovarian cancer. CA-125 is a protein that is produced by ovarian cancer cells. However, other disorders, including non-cancerous conditions, can also lead to increased levels of CA-125 so this test does not conclusively diagnose ovarian cancer because other conditions must still be ruled out. HE4 (human epididymis protein 4) is another biomarker that is elevated in the blood serum of some women with ovarian cancer. HE4 can be elevated in the blood because of other types of cancer and is not diagnostic of ovarian cancer on its own. HE4 is more specific than CA-125, and some studies suggest that testing for both markers is more accurate. Specialized imaging techniques may be used to aid in a diagnosis. Such tests include transvaginal sonography, computerized tomography (CT) scanning and magnetic resonance imaging (MRI). A transvaginal sonography is a special type of ultrasound examination. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off of internal structures within the body and the echoes are recorded to create a sonogram. A transvaginal sonography is a type of ultrasound that is used to look at the vagina, uterus, ovaries and fallopian tubes. During this exam, an ultrasound wand is inserted into the vagina to allow the physician to create pictures of the organs of the pelvic region. A CT scan or MRI is more likely to be used when advanced stage ovarian cancer is present. During CT scanning, a computer and a low-dose of x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. A CT scan or MRI may be used to determine the exact location, define the boundaries of a tumor, or determine the extent or spread of cancer. They are usually recommended after initial tests indicate ovarian cancer. They can be used to help a physician plan treatment and assess the success of treatment. The main diagnostic procedure for ovarian cancer is the surgical removal of a small amount of tissue from the ovaries, fallopian tubes or peritoneal tissue, which is then studied under a microscope (biopsy). The tissue sample is studied by a doctor who specializes in examining tissue and cells and determining what disease is present (pathologist). Some physicians caution that women with suspected ovarian cancer, but with no signs of the disease (i.e. early stage disease), will benefit from the complete removal of an adnexal mass rather than taking a small sample. Any cutting or rupturing of a cancerous tumor runs a risk of spreading cancer cells and leading to more advanced disease. In addition, in some instances, such as when involvement appears to include the abdominal or pelvic region, laparoscopy or laparotomy may be necessary to obtain biopsy samples. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. Sometimes, fluid samples are taken and studied. This can include fluid from the abdomen when ascites is present or fluid from the lungs when pleural effusion is present.Staging
When an individual is diagnosed with ovarian cancer, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging ovarian cancer (e.g., blood tests, CT scanning, laparoscopic biopsy). Epithelial ovarian carcinoma is staged based on one of two staging systems – the 2017 International Federation of Gynecology and Obstetrics (FIGO) classification system, and the Tumor, Node, Metastasis (TNM) classification system. These staging systems are available at: https://emedicine.medscape.com/article/2007140-overview
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Diagnosis of Ovarian Cancer. A diagnosis of ovarian cancer is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There is no screening test that can be run that detects ovarian cancer in all women. Ovarian cancer does not cause many symptoms during the early stages of development, and symptoms tend to be nonspecific (common to many diseases). Consequently, ovarian cancer is often undiagnosed until it has spread to the abdomen and pelvis. Clinical Testing and Workup
A pelvic exam is an examination where a physician evaluates a woman’s reproductive organs. A physician will insert gloved fingers into the vagina while pressing down on the abdomen. This allows a physician to feel the pelvic organs. A physician will also visually inspect a woman’s external reproductive organs. Most times, a pelvic exam does not diagnose ovarian cancer. When it does, it is usually because a physician noted an abnormally enlarged ovary. Blood tests may be ordered to test for markers of ovarian cancer. A marker is a substance that when present is indicative of a disease. If there are increased levels of cancer antigen 125 (CA-125), then this is indicative of ovarian cancer. CA-125 is a protein that is produced by ovarian cancer cells. However, other disorders, including non-cancerous conditions, can also lead to increased levels of CA-125 so this test does not conclusively diagnose ovarian cancer because other conditions must still be ruled out. HE4 (human epididymis protein 4) is another biomarker that is elevated in the blood serum of some women with ovarian cancer. HE4 can be elevated in the blood because of other types of cancer and is not diagnostic of ovarian cancer on its own. HE4 is more specific than CA-125, and some studies suggest that testing for both markers is more accurate. Specialized imaging techniques may be used to aid in a diagnosis. Such tests include transvaginal sonography, computerized tomography (CT) scanning and magnetic resonance imaging (MRI). A transvaginal sonography is a special type of ultrasound examination. Ultrasounds use high-frequency radio waves to create a picture or image (sonogram) of specific structures like internal organs. The radio waves bounce off of internal structures within the body and the echoes are recorded to create a sonogram. A transvaginal sonography is a type of ultrasound that is used to look at the vagina, uterus, ovaries and fallopian tubes. During this exam, an ultrasound wand is inserted into the vagina to allow the physician to create pictures of the organs of the pelvic region. A CT scan or MRI is more likely to be used when advanced stage ovarian cancer is present. During CT scanning, a computer and a low-dose of x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. A CT scan or MRI may be used to determine the exact location, define the boundaries of a tumor, or determine the extent or spread of cancer. They are usually recommended after initial tests indicate ovarian cancer. They can be used to help a physician plan treatment and assess the success of treatment. The main diagnostic procedure for ovarian cancer is the surgical removal of a small amount of tissue from the ovaries, fallopian tubes or peritoneal tissue, which is then studied under a microscope (biopsy). The tissue sample is studied by a doctor who specializes in examining tissue and cells and determining what disease is present (pathologist). Some physicians caution that women with suspected ovarian cancer, but with no signs of the disease (i.e. early stage disease), will benefit from the complete removal of an adnexal mass rather than taking a small sample. Any cutting or rupturing of a cancerous tumor runs a risk of spreading cancer cells and leading to more advanced disease. In addition, in some instances, such as when involvement appears to include the abdominal or pelvic region, laparoscopy or laparotomy may be necessary to obtain biopsy samples. Laparoscopy involves examination of the abdominal cavity with an illuminated viewing tube (laparoscope) inserted through incisions in the abdominal wall. Laparotomy is a surgical procedure in which the abdomen is opened, organs are carefully examined to detect signs of disease, and samples of tissue are removed for microscopic examination. Sometimes, fluid samples are taken and studied. This can include fluid from the abdomen when ascites is present or fluid from the lungs when pleural effusion is present.Staging
When an individual is diagnosed with ovarian cancer, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging ovarian cancer (e.g., blood tests, CT scanning, laparoscopic biopsy). Epithelial ovarian carcinoma is staged based on one of two staging systems – the 2017 International Federation of Gynecology and Obstetrics (FIGO) classification system, and the Tumor, Node, Metastasis (TNM) classification system. These staging systems are available at: https://emedicine.medscape.com/article/2007140-overview
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Therapies of Ovarian Cancer
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Treatment
The therapeutic management may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), physicians who specialize in diagnosing and treating disorders of women, especially of the reproductive tract (gynecologists), a physician who specializes in diagnosing and treating cancer that involves a woman’s reproductive organs (gynecological oncologists), pathologist, oncology nurses, clinical nurse specialist, psychiatrists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on cancer.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific ovarian cancer subtype; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case. A thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors should also be had with the patient.Surgery and chemotherapy are the two most common treatment options. Surgery is usually the initial therapy and the exact surgical procedure depends on the location and extent of the cancer as well as the stage of the cancer. If ovarian cancer is contained to one ovary, then a surgeon can remove the affected ovary. This will preserve fertility in women of child-bearing age. Preserving fertility is attempted most often with young women with tumors of low malignant potential, or non-epithelial ovarian cancers. If cancer present in both ovaries, a surgeon will remove both ovaries and fallopian tubes. Doctors may recommend removing the uterus (hysterectomy) along with the ovaries and the fallopian tubes (salpino-oophorectomy). Sometimes, a thin fold of tissue in the abdomen called the omentum is also removed. In younger patients, surgeons may perform a unilateral salpino-oophorectomy to preserve fertility. These surgeries may be recommended in women after counseling on reproductive issues, degree of protection, and hormonal and menopausal issues. Surgery may be necessary to remove other areas potentially affected by ovarian cancer such as the spleen and segments of the bowels. If the cancer has spread to other areas, surgery will be performed to remove as much of the cancer as possible. This is called debulking surgery, or cytoreduction. Following this surgery, a patient will receive chemotherapy. Many different chemotherapy drugs and regimens can be used. Occasionally, chemotherapy can also be given before surgery. This treatment, called neo-adjuvant chemotherapy, helps shrink the tumor and make it easier to remove. The chemotherapy regimen for ovarian cancer is fairly standard. Treating physicians combine a DNA-damaging agent like Cisplatin or Carboplatin with another drug, called Paclitaxel that prevents cells from dividing properly. Like all medications, platinum-based chemotherapy is associated with side effects. This combination is effective in many women but resistance to these drugs can emerge.PARP inhibitors are an exciting new class of therapy for ovarian cancer. PARP is an enzyme that helps the body to repair DNA when it becomes damaged, especially in cells that have a mutation in the BRCA genes. Researchers believe that medications that stop or hinder (inhibit) the activity of PARP will prevent cancer cells from repairing themselves, and continuing to grow and spread. This is a targeted therapy, which means that it is targeting a specific molecule or substance (e.g. PARP) that contributes to cancer growth. Targeted therapies act by blocking the growth and spread of cancer rather than destroying cancer cells (cytotoxic treatments) like chemotherapy or radiation therapy and are less likely to damage healthy cells. There are currently three PARP inhibitors that are approved by the U.S. Food and Drug Administration (FDA) to treat ovarian cancer. Olaparib (Lynparza®) is approved for maintenance therapy in women with ovarian cancer, or women who have ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have responded to treatment with a platinum-based chemotherapy medication, but in whom the cancer has returned. Lynparza is also approved for advanced ovarian cancer in women who have received treatment with three or more prior chemotherapy medications. Lynparza is an inhibitor of PARP, or poly (ADP-ribose) polymerase.Rucaparib (RuBRCAa®) is a PARP inhibitor that approved for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication. Bevacizumab (Avastin) is a PARP inhibitor that is approved for use with carboplatin and paclitaxel, followed by bevacizumab alone (monotherapy) for the treatment of women with advanced ovarian cancer following initial surgical removal of cancer. Avastin is a tumor starving therapy that works by preventing the growth of new blood vessels that can feed the tumor. Bevacizumab in combination with pegylated liposomal doxorubicin, paclitaxel, or topotecan is FDA approved for women with platinum-resistance recurrent ovarian cancer. Niraparib (Zejula®) is FDA approved for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication. Gemcitabine (Gemzar®) is approved to treat women with advanced ovarian cancer that has relapsed at least six months after initial therapy. Emerging studies suggest that combining PARP inhibitor with other therapies, including immunotherapies, may be effective in patients with recurrent ovarian cancer. Radiation therapy is rarely used for ovarian cancer unless the cancer has spread to other areas of the body.
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Therapies of Ovarian Cancer. Treatment
The therapeutic management may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), physicians who use radiation to treat cancer (radiation oncologists), physicians who specialize in diagnosing and treating disorders of women, especially of the reproductive tract (gynecologists), a physician who specializes in diagnosing and treating cancer that involves a woman’s reproductive organs (gynecological oncologists), pathologist, oncology nurses, clinical nurse specialist, psychiatrists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on cancer.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; specific ovarian cancer subtype; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case. A thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors should also be had with the patient.Surgery and chemotherapy are the two most common treatment options. Surgery is usually the initial therapy and the exact surgical procedure depends on the location and extent of the cancer as well as the stage of the cancer. If ovarian cancer is contained to one ovary, then a surgeon can remove the affected ovary. This will preserve fertility in women of child-bearing age. Preserving fertility is attempted most often with young women with tumors of low malignant potential, or non-epithelial ovarian cancers. If cancer present in both ovaries, a surgeon will remove both ovaries and fallopian tubes. Doctors may recommend removing the uterus (hysterectomy) along with the ovaries and the fallopian tubes (salpino-oophorectomy). Sometimes, a thin fold of tissue in the abdomen called the omentum is also removed. In younger patients, surgeons may perform a unilateral salpino-oophorectomy to preserve fertility. These surgeries may be recommended in women after counseling on reproductive issues, degree of protection, and hormonal and menopausal issues. Surgery may be necessary to remove other areas potentially affected by ovarian cancer such as the spleen and segments of the bowels. If the cancer has spread to other areas, surgery will be performed to remove as much of the cancer as possible. This is called debulking surgery, or cytoreduction. Following this surgery, a patient will receive chemotherapy. Many different chemotherapy drugs and regimens can be used. Occasionally, chemotherapy can also be given before surgery. This treatment, called neo-adjuvant chemotherapy, helps shrink the tumor and make it easier to remove. The chemotherapy regimen for ovarian cancer is fairly standard. Treating physicians combine a DNA-damaging agent like Cisplatin or Carboplatin with another drug, called Paclitaxel that prevents cells from dividing properly. Like all medications, platinum-based chemotherapy is associated with side effects. This combination is effective in many women but resistance to these drugs can emerge.PARP inhibitors are an exciting new class of therapy for ovarian cancer. PARP is an enzyme that helps the body to repair DNA when it becomes damaged, especially in cells that have a mutation in the BRCA genes. Researchers believe that medications that stop or hinder (inhibit) the activity of PARP will prevent cancer cells from repairing themselves, and continuing to grow and spread. This is a targeted therapy, which means that it is targeting a specific molecule or substance (e.g. PARP) that contributes to cancer growth. Targeted therapies act by blocking the growth and spread of cancer rather than destroying cancer cells (cytotoxic treatments) like chemotherapy or radiation therapy and are less likely to damage healthy cells. There are currently three PARP inhibitors that are approved by the U.S. Food and Drug Administration (FDA) to treat ovarian cancer. Olaparib (Lynparza®) is approved for maintenance therapy in women with ovarian cancer, or women who have ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have responded to treatment with a platinum-based chemotherapy medication, but in whom the cancer has returned. Lynparza is also approved for advanced ovarian cancer in women who have received treatment with three or more prior chemotherapy medications. Lynparza is an inhibitor of PARP, or poly (ADP-ribose) polymerase.Rucaparib (RuBRCAa®) is a PARP inhibitor that approved for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication. Bevacizumab (Avastin) is a PARP inhibitor that is approved for use with carboplatin and paclitaxel, followed by bevacizumab alone (monotherapy) for the treatment of women with advanced ovarian cancer following initial surgical removal of cancer. Avastin is a tumor starving therapy that works by preventing the growth of new blood vessels that can feed the tumor. Bevacizumab in combination with pegylated liposomal doxorubicin, paclitaxel, or topotecan is FDA approved for women with platinum-resistance recurrent ovarian cancer. Niraparib (Zejula®) is FDA approved for the treatment of recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer in individuals who are in a complete or partial response to treatment with a platinum-based chemotherapy medication. Gemcitabine (Gemzar®) is approved to treat women with advanced ovarian cancer that has relapsed at least six months after initial therapy. Emerging studies suggest that combining PARP inhibitor with other therapies, including immunotherapies, may be effective in patients with recurrent ovarian cancer. Radiation therapy is rarely used for ovarian cancer unless the cancer has spread to other areas of the body.
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Overview of Ovotesticular Disorder of Sex Development
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Ovotesticular disorder of sex development (ovotesticular DSD) is a very rare disorder in which an infant is born with the internal reproductive organs (gonads) of both sexes (female ovaries and male testes). The gonads can be any combination of ovary, testes or combined ovary and testes (ovotestes). The external genitalia are usually ambiguous but can range from normal male to normal female.
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Overview of Ovotesticular Disorder of Sex Development. Ovotesticular disorder of sex development (ovotesticular DSD) is a very rare disorder in which an infant is born with the internal reproductive organs (gonads) of both sexes (female ovaries and male testes). The gonads can be any combination of ovary, testes or combined ovary and testes (ovotestes). The external genitalia are usually ambiguous but can range from normal male to normal female.
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Symptoms of Ovotesticular Disorder of Sex Development
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Ovotesticular DSD is characterized by the presence of both ovarian and testicular tissue in the same individual. An ovotestis is present in approximately 2/3 of affected individuals.An abnormal vagina is often present and if a uterus is present it is usually underdeveloped (hypoplastic). If a penis is present, it may show an abnormality in which the canal (urethra) that carries urine from the bladder opens on the underside (hypospadias). When testes are present, they are usually undescended (cryptorchidism).Upon reaching puberty, breast development, feminization and menstruation may occur. Most affected individuals are infertile but ovulation or spermatogenesis is possible.Tumors of the ovaries or testes have been reported but are rare.
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Symptoms of Ovotesticular Disorder of Sex Development. Ovotesticular DSD is characterized by the presence of both ovarian and testicular tissue in the same individual. An ovotestis is present in approximately 2/3 of affected individuals.An abnormal vagina is often present and if a uterus is present it is usually underdeveloped (hypoplastic). If a penis is present, it may show an abnormality in which the canal (urethra) that carries urine from the bladder opens on the underside (hypospadias). When testes are present, they are usually undescended (cryptorchidism).Upon reaching puberty, breast development, feminization and menstruation may occur. Most affected individuals are infertile but ovulation or spermatogenesis is possible.Tumors of the ovaries or testes have been reported but are rare.
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Causes of Ovotesticular Disorder of Sex Development
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The exact cause of ovotesticular DSD is known only in a small percentage of patients. Most affected individuals have a 46, XX chromosomal make-up (karyotype), which normally results in female sexual development. In about 10% of patients, testicular tissue in an individual with a 46, XX karyotype is present as a result of a translocation of the SRY gene on the Y chromosome to the X chromosome or another chromosome. In patients with 46, XX, there have been a small number of cases reported with genetic variations of other genes such as, duplication of SOX9, mutations in RSPO1, and a specific mutation in the NR5A1 gene. In the more rare individuals with ovotesticular DSD who have a Y chromosome (which normally results in male sexual development), deletions of DMRT1, mutations of SRY and mutations of MAP3K1 have been reported, as well as a karyotype that shows some cells with XY chromosomes and others with XX chromosomes (XX/XY mosaicism).Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Normally, males have one X and one Y chromosome and females have two X chromosomes.
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Causes of Ovotesticular Disorder of Sex Development. The exact cause of ovotesticular DSD is known only in a small percentage of patients. Most affected individuals have a 46, XX chromosomal make-up (karyotype), which normally results in female sexual development. In about 10% of patients, testicular tissue in an individual with a 46, XX karyotype is present as a result of a translocation of the SRY gene on the Y chromosome to the X chromosome or another chromosome. In patients with 46, XX, there have been a small number of cases reported with genetic variations of other genes such as, duplication of SOX9, mutations in RSPO1, and a specific mutation in the NR5A1 gene. In the more rare individuals with ovotesticular DSD who have a Y chromosome (which normally results in male sexual development), deletions of DMRT1, mutations of SRY and mutations of MAP3K1 have been reported, as well as a karyotype that shows some cells with XY chromosomes and others with XX chromosomes (XX/XY mosaicism).Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Normally, males have one X and one Y chromosome and females have two X chromosomes.
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Affects of Ovotesticular Disorder of Sex Development
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Ovotesticular DSD is the rarest disorder of sex development in humans and has an approximate incidence of less than 1/20,000. At least 500 affected individuals have been reported.
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Affects of Ovotesticular Disorder of Sex Development. Ovotesticular DSD is the rarest disorder of sex development in humans and has an approximate incidence of less than 1/20,000. At least 500 affected individuals have been reported.
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Related disorders of Ovotesticular Disorder of Sex Development
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Symptoms of the following disorders can be similar to those of ovotesticular DSD. Comparisons may be useful for a differential diagnosis:Klinefelter syndrome is a group of chromosomal disorders in males in which one or more extra X chromosomes are present. Males with the classic form of the disorder have one extra X chromosome. Males with variant forms of Klinefelter syndrome have additional X and/or Y chromosomes. The extra X and/or Y chromosome can effect physical and intellectual development. Common physical features may include small testes (hypogonadism), delayed pubertal development, and breast development (gynecomastia) in late puberty. These features may be associated with low testosterone level and elevated gonadotropin levels. (For more information on this disorder, choose “Klinefelter” as your search term in the Rare Disease Database.)46, XX disorder of sexual development is a disorder in which the chromosomes are 46, XX (normal female) and ovaries are present but external genitalia appear male. This usually occurs when a female embryo is exposed to excessive amounts of male hormones while in the uterus. The internal female reproductive glands are usually normal while the external genitalia are male, or a combination of male and female. The clitoris may be enlarged and there may be one common outlet for the urethra and vagina. Other symptoms may include absence of breast development, excessive growth of hair in abnormal areas (hirsutism), increased muscularity, absent or irregular menstruation (amenorrhea), obesity, a short and thick neck, protruding abdomen and thin arms and legs. 46, XX DSD can be caused by genetic disorders such as congenital adrenal hyperplasia or aromatase deficiency, the presence of a tumor in the mother that produces male hormones or male hormones taken by the mother during pregnancy.46, XY disorder of sexual development (formerly called male pseudohermaphroditism) is a disorder in which the chromosomes are 46, XY (normal male) but external genitalia are underdeveloped, ambiguous or female. This disorder can be caused by genetic abnormalities, abnormal testicular development or abnormal testosterone production.Mixed gonadal dysgenesis is the diagnosis given when individuals have a well-developed gonad (ovary or testis) on one side and an underdeveloped (streak) gonad on the other side.
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Related disorders of Ovotesticular Disorder of Sex Development. Symptoms of the following disorders can be similar to those of ovotesticular DSD. Comparisons may be useful for a differential diagnosis:Klinefelter syndrome is a group of chromosomal disorders in males in which one or more extra X chromosomes are present. Males with the classic form of the disorder have one extra X chromosome. Males with variant forms of Klinefelter syndrome have additional X and/or Y chromosomes. The extra X and/or Y chromosome can effect physical and intellectual development. Common physical features may include small testes (hypogonadism), delayed pubertal development, and breast development (gynecomastia) in late puberty. These features may be associated with low testosterone level and elevated gonadotropin levels. (For more information on this disorder, choose “Klinefelter” as your search term in the Rare Disease Database.)46, XX disorder of sexual development is a disorder in which the chromosomes are 46, XX (normal female) and ovaries are present but external genitalia appear male. This usually occurs when a female embryo is exposed to excessive amounts of male hormones while in the uterus. The internal female reproductive glands are usually normal while the external genitalia are male, or a combination of male and female. The clitoris may be enlarged and there may be one common outlet for the urethra and vagina. Other symptoms may include absence of breast development, excessive growth of hair in abnormal areas (hirsutism), increased muscularity, absent or irregular menstruation (amenorrhea), obesity, a short and thick neck, protruding abdomen and thin arms and legs. 46, XX DSD can be caused by genetic disorders such as congenital adrenal hyperplasia or aromatase deficiency, the presence of a tumor in the mother that produces male hormones or male hormones taken by the mother during pregnancy.46, XY disorder of sexual development (formerly called male pseudohermaphroditism) is a disorder in which the chromosomes are 46, XY (normal male) but external genitalia are underdeveloped, ambiguous or female. This disorder can be caused by genetic abnormalities, abnormal testicular development or abnormal testosterone production.Mixed gonadal dysgenesis is the diagnosis given when individuals have a well-developed gonad (ovary or testis) on one side and an underdeveloped (streak) gonad on the other side.
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Ovotesticular Disorder of Sex Development
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Diagnosis of Ovotesticular Disorder of Sex Development
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Ovotesticular DSD is diagnosed by a combination of tests including chromosome and genetic analysis, hormone testing, ultrasound or MRI and gonadal biopsy.
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Diagnosis of Ovotesticular Disorder of Sex Development. Ovotesticular DSD is diagnosed by a combination of tests including chromosome and genetic analysis, hormone testing, ultrasound or MRI and gonadal biopsy.
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Therapies of Ovotesticular Disorder of Sex Development
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TreatmentA team of professionals with experience in treating disorders of sex development should work together to treat a child with ovotesticular DSD.Recommendations about treatment have evolved in recent years. Gender assignment remains recommended in the neonatal period, based on the appearance of the external genitalia, the formation of the internal reproductive glands, the potential for fertility and the available medical literature. But lack of outcome data has led to challenge the practice of early genital surgery.Some experts now suggest delaying surgery and involving the child in decision-making if possible. Factors to consider include the ability to reconstruct functioning genitals as well as psychological, behavioral, chromosomal, hormonal and neural factors.
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Therapies of Ovotesticular Disorder of Sex Development. TreatmentA team of professionals with experience in treating disorders of sex development should work together to treat a child with ovotesticular DSD.Recommendations about treatment have evolved in recent years. Gender assignment remains recommended in the neonatal period, based on the appearance of the external genitalia, the formation of the internal reproductive glands, the potential for fertility and the available medical literature. But lack of outcome data has led to challenge the practice of early genital surgery.Some experts now suggest delaying surgery and involving the child in decision-making if possible. Factors to consider include the ability to reconstruct functioning genitals as well as psychological, behavioral, chromosomal, hormonal and neural factors.
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Overview of Pachydermoperiostosis
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Pachydermoperiostosis, also called primary hypertrophic osteoarthropathy (PHO) is a rare genetic condition. The three main features are large finger tips (clubbing), thickening of the skin of the face (pachydermia) and extra sweating (hyperhidrosis). It typically starts during childhood or adolescence, often around the time of puberty, and progresses slowly for about ten years.Pachydermoperiostosis is the complete form of PHO where there is also unusual thickness of the skin (pacydermia). There are also two incomplete forms, one with isolated bone problems and skin changes, and one with pachydermia and minimal or absent new bone growth (periostosis).
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Overview of Pachydermoperiostosis. Pachydermoperiostosis, also called primary hypertrophic osteoarthropathy (PHO) is a rare genetic condition. The three main features are large finger tips (clubbing), thickening of the skin of the face (pachydermia) and extra sweating (hyperhidrosis). It typically starts during childhood or adolescence, often around the time of puberty, and progresses slowly for about ten years.Pachydermoperiostosis is the complete form of PHO where there is also unusual thickness of the skin (pacydermia). There are also two incomplete forms, one with isolated bone problems and skin changes, and one with pachydermia and minimal or absent new bone growth (periostosis).
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Symptoms of Pachydermoperiostosis
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PHO is characterized by problems with the growth of skin and bones. People with PHO usually have coarse facial features with oily, thick, grooved skin on the face, joint pain, large tips of the fingers and toes (clubbing) and extra sweating of the hands and feet (hyperhidrosis).New bone growth (periostosis), often at the ends of the long bones, causes joint pain. Extra skin on the scalp can be seen that causes deep grooves or ridges (cutis verticis gyrate).These grooves or ridges usually occur during the teen years.Other symptoms can include swelling or pain of the large joints; drooping eyelids (ptosis); a long-term skin condition that causes dry or moist scales and a yellowish crust (seborrheic dermatitis); ulcers; long eyelashes; occasional diarrhea; swelling of hair follicles related to large open pores of the skin; heart disease present at birth and/or delayed closure of the space between the bones of the skull (fontanelles).The symptoms vary between individuals, but overall, males tend to have more serious symptoms than females. X-rays can help look at features that are not as noticeable to the naked eye.
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Symptoms of Pachydermoperiostosis. PHO is characterized by problems with the growth of skin and bones. People with PHO usually have coarse facial features with oily, thick, grooved skin on the face, joint pain, large tips of the fingers and toes (clubbing) and extra sweating of the hands and feet (hyperhidrosis).New bone growth (periostosis), often at the ends of the long bones, causes joint pain. Extra skin on the scalp can be seen that causes deep grooves or ridges (cutis verticis gyrate).These grooves or ridges usually occur during the teen years.Other symptoms can include swelling or pain of the large joints; drooping eyelids (ptosis); a long-term skin condition that causes dry or moist scales and a yellowish crust (seborrheic dermatitis); ulcers; long eyelashes; occasional diarrhea; swelling of hair follicles related to large open pores of the skin; heart disease present at birth and/or delayed closure of the space between the bones of the skull (fontanelles).The symptoms vary between individuals, but overall, males tend to have more serious symptoms than females. X-rays can help look at features that are not as noticeable to the naked eye.
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Causes of Pachydermoperiostosis
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For most individuals, the diagnosis of PHO is based on the clinical features. It is recognized more often in males than females, as males have more noticeable and severe features. PHO can be inherited, but a non-genetic form has also been described.Genetic conditions can be inherited in different ways. Individuals typically inherit one copy of a gene pair from their mother, and the other from their father. Genes provide instructions to tell the body how to function. When there is a harmful change (mutation) in a gene it may not function normally leading to unusual features and/or conditions. Autosomal dominant and autosomal recessive inheritance patterns have been reported for PHO.There are two genes that have been associated with PHO: HPGD and SLCO2A1. Mutations in HPGD are associated with autosomal recessive inheritance and this condition is sometimes abbreviated PHOAR1 or Touraine-Solente-Gole syndrome.Recessive genetic conditions occur when an individual inherits one non-working gene for the same condition from each parent. If an individual receives one normal gene and one gene with a mutation, the person will be a carrier for the condition and will usually not show symptoms. The chance for two carrier parents to both pass the non-working gene and, therefore, have a child with that condition is 25% with each pregnancy. The chance to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal working genes from both parents is 25%. The chance is the same for males and females.Parents who are closely related by blood (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, which increases the chance to have children with a recessive genetic disorder.PHO caused by mutations in SLCO2A1 can be dominant or recessive. The recessive form is called PHOAR2. The dominant form is called PHOAD. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to see symptoms of the condition. The non-working gene can be inherited from either parent or can be the result of a new mutation (gene change) in the individual with the condition. The chance of passing the non-working gene from an affected parent to child is 50% for each pregnancy. The risk is the same for males and females. However, with PHOAD, males are more commonly and often more severely affected.
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Causes of Pachydermoperiostosis. For most individuals, the diagnosis of PHO is based on the clinical features. It is recognized more often in males than females, as males have more noticeable and severe features. PHO can be inherited, but a non-genetic form has also been described.Genetic conditions can be inherited in different ways. Individuals typically inherit one copy of a gene pair from their mother, and the other from their father. Genes provide instructions to tell the body how to function. When there is a harmful change (mutation) in a gene it may not function normally leading to unusual features and/or conditions. Autosomal dominant and autosomal recessive inheritance patterns have been reported for PHO.There are two genes that have been associated with PHO: HPGD and SLCO2A1. Mutations in HPGD are associated with autosomal recessive inheritance and this condition is sometimes abbreviated PHOAR1 or Touraine-Solente-Gole syndrome.Recessive genetic conditions occur when an individual inherits one non-working gene for the same condition from each parent. If an individual receives one normal gene and one gene with a mutation, the person will be a carrier for the condition and will usually not show symptoms. The chance for two carrier parents to both pass the non-working gene and, therefore, have a child with that condition is 25% with each pregnancy. The chance to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal working genes from both parents is 25%. The chance is the same for males and females.Parents who are closely related by blood (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, which increases the chance to have children with a recessive genetic disorder.PHO caused by mutations in SLCO2A1 can be dominant or recessive. The recessive form is called PHOAR2. The dominant form is called PHOAD. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to see symptoms of the condition. The non-working gene can be inherited from either parent or can be the result of a new mutation (gene change) in the individual with the condition. The chance of passing the non-working gene from an affected parent to child is 50% for each pregnancy. The risk is the same for males and females. However, with PHOAD, males are more commonly and often more severely affected.
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Affects of Pachydermoperiostosis
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PHO is a rare disorder that affects males more than females with a ratio of 7:1. This means that for about every 7 males that are diagnosed with this condition, 1 female is diagnosed. However, since females tend to have milder symptoms than males, females may go undiagnosed.
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Affects of Pachydermoperiostosis. PHO is a rare disorder that affects males more than females with a ratio of 7:1. This means that for about every 7 males that are diagnosed with this condition, 1 female is diagnosed. However, since females tend to have milder symptoms than males, females may go undiagnosed.
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Related disorders of Pachydermoperiostosis
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Symptoms of the following disorders can be similar to those of pachydermoperiostosis. Comparing features can be useful to make the correct diagnosis:Acromegaly is a rare, slowly progressive, acquired disorder that affects adults. It is a condition where extra growth hormone causes different tissues to be become larger than normal and the individual to be taller. The arms, legs, jaws and face are most often affected. Enlargement of soft tissues, especially within the heart, is a serious feature of this condition. (For more information on this disorder choose “acromegaly” as your search term in the Rare Disease Database.)Hypertrophic pulmonary osteoarthropathy (Bamberger-Marie disease) is a rare condition where there is extra growth at the ends of the long bones and often unusually large fingers and toes (clubbing). This disorder occurs in people with long-term lung disease, heart disease and occasionally in other disorders.Features of PHO can be mistaken for osteoarthropathy (any condition affecting bones and joints), psoriatic arthritis (arthritis in combination with psoriasis – red and white patches on the skin), rheumatoid arthritis (condition that can cause joint damage) and thyroid acropachy (thickening and swelling of the hands and feet).
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Related disorders of Pachydermoperiostosis. Symptoms of the following disorders can be similar to those of pachydermoperiostosis. Comparing features can be useful to make the correct diagnosis:Acromegaly is a rare, slowly progressive, acquired disorder that affects adults. It is a condition where extra growth hormone causes different tissues to be become larger than normal and the individual to be taller. The arms, legs, jaws and face are most often affected. Enlargement of soft tissues, especially within the heart, is a serious feature of this condition. (For more information on this disorder choose “acromegaly” as your search term in the Rare Disease Database.)Hypertrophic pulmonary osteoarthropathy (Bamberger-Marie disease) is a rare condition where there is extra growth at the ends of the long bones and often unusually large fingers and toes (clubbing). This disorder occurs in people with long-term lung disease, heart disease and occasionally in other disorders.Features of PHO can be mistaken for osteoarthropathy (any condition affecting bones and joints), psoriatic arthritis (arthritis in combination with psoriasis – red and white patches on the skin), rheumatoid arthritis (condition that can cause joint damage) and thyroid acropachy (thickening and swelling of the hands and feet).
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Diagnosis of Pachydermoperiostosis
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The diagnosis of PHO is made based on clinical features, though genetic testing can confirm the diagnosis. Major diagnostic criteria include clubbing of the fingers (digital clubbing) and new bone growth (periostosis).
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Diagnosis of Pachydermoperiostosis. The diagnosis of PHO is made based on clinical features, though genetic testing can confirm the diagnosis. Major diagnostic criteria include clubbing of the fingers (digital clubbing) and new bone growth (periostosis).
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Therapies of Pachydermoperiostosis
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TreatmentTreatment is mostly aimed at specific symptoms and is supportive. Nonsteroidal anti-inflammatory drugs (NSAIDs, such as Advil), colchicine, or corticosteroids can be taken to decrease bone and joint pain.Vagotomy, a surgical procedure in which certain branches of the vagus nerve are cut, may improve joint pain and swelling. Retinoids can be used to treat symptoms that involve the skin. Plastic surgery may be performed to improve facial appearance. Surgery can treat clubbing of the fingers.Genetic counseling may be helpful for patients and their families.
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Therapies of Pachydermoperiostosis. TreatmentTreatment is mostly aimed at specific symptoms and is supportive. Nonsteroidal anti-inflammatory drugs (NSAIDs, such as Advil), colchicine, or corticosteroids can be taken to decrease bone and joint pain.Vagotomy, a surgical procedure in which certain branches of the vagus nerve are cut, may improve joint pain and swelling. Retinoids can be used to treat symptoms that involve the skin. Plastic surgery may be performed to improve facial appearance. Surgery can treat clubbing of the fingers.Genetic counseling may be helpful for patients and their families.
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Overview of Pachyonychia Congenita
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Summary Pachyonychia congenita (PC) is a rare keratinizing skin disorder inherited in an autosomal dominant fashion. The predominant characteristics are severe plantar pain, palmoplantar keratoderma (PPK) including calluses with underlying blisters and variable hypertrophic nail dystrophy, often accompanied by oral leukokeratosis, cysts of various types, follicular hyperkeratosis, palmoplantar hyperhidrosis and sometimes natal teeth.Introduction Historically, PC was subdivided into PC-1 (caused by mutations in the KRT6A or KRT16 genes) and PC-2 (due to mutations in the KRT6B or KRT17 genes). However, based on clinical and molecular data collected by the International Pachyonychia Congenita Research Registry (IPCRR; www.pachyonychia.org) the nomenclature was revised in 2011. Those with mutations in KRT6A are named PC-K6a, those with mutations in KRT16 are PC-K16 etc.
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Overview of Pachyonychia Congenita. Summary Pachyonychia congenita (PC) is a rare keratinizing skin disorder inherited in an autosomal dominant fashion. The predominant characteristics are severe plantar pain, palmoplantar keratoderma (PPK) including calluses with underlying blisters and variable hypertrophic nail dystrophy, often accompanied by oral leukokeratosis, cysts of various types, follicular hyperkeratosis, palmoplantar hyperhidrosis and sometimes natal teeth.Introduction Historically, PC was subdivided into PC-1 (caused by mutations in the KRT6A or KRT16 genes) and PC-2 (due to mutations in the KRT6B or KRT17 genes). However, based on clinical and molecular data collected by the International Pachyonychia Congenita Research Registry (IPCRR; www.pachyonychia.org) the nomenclature was revised in 2011. Those with mutations in KRT6A are named PC-K6a, those with mutations in KRT16 are PC-K16 etc.
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Symptoms of Pachyonychia Congenita
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The symptoms and severity of pachyonychia congenita can vary widely, even among individuals in the same family or among individuals with the same disease-causing gene mutation.The most predominant feature, palmoplantar keratoderma usually begins when a child starts weight bearing and walking. Blisters develop beneath the calluses causing extreme pain. This can lead to the use of crutches, canes or wheelchairs. Nail dystrophy (fingernails and toenails) is typically noted within the first few months/year of life. Nails tend to either (a) grow to full length with an upward slant caused by prominent distal hyperkeratosis or (b) have a nail plate that terminates prematurely to leave a gently sloping distal region of hyperkeratosis and exposed distal fingertip. Infections can occur under the nails and be painful.Cysts of various types including vellus hair cysts and steatocystomas usually develop at puberty and continue into adulthood. In some people with PC, particularly PC-K17, cysts can be the most painful and problematic characteristic. Multiple milia (particularly on the face) often occur in young children with PC-K17. Follicular keratoses occur in some patients on the trunk, elbows and knees, usually in early childhood. Oral leukokeratosis (white patches on the tongue and cheek) is more common in those with PC-K6a. It is often present at birth or within the first few months of life and can be misdiagnosed as a Candida albicans infection if no other symptoms of PC are apparent. Natal or prenatal teeth are more commonly seen in those with mutations in KRT17. Palmoplantar hyperhidrosis has been reported in about 50% of people with PC.Other less common features include angular cheilitis, laryngeal involvement resulting in a hoarse cry or hoarse voice and ‘first bite syndrome’. First bite syndrome is more common in young children and is intense pain near the jaw or ears that lasts about 15-25 seconds when beginning to eat or swallow.Variants of PC: Steatocystoma multiplex (SM) – widespread pilosebaceous cysts develop at puberty, but there is little or no nail involvement or palmoplantar keratoderma, can be due to mutations in KRT17.
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Symptoms of Pachyonychia Congenita. The symptoms and severity of pachyonychia congenita can vary widely, even among individuals in the same family or among individuals with the same disease-causing gene mutation.The most predominant feature, palmoplantar keratoderma usually begins when a child starts weight bearing and walking. Blisters develop beneath the calluses causing extreme pain. This can lead to the use of crutches, canes or wheelchairs. Nail dystrophy (fingernails and toenails) is typically noted within the first few months/year of life. Nails tend to either (a) grow to full length with an upward slant caused by prominent distal hyperkeratosis or (b) have a nail plate that terminates prematurely to leave a gently sloping distal region of hyperkeratosis and exposed distal fingertip. Infections can occur under the nails and be painful.Cysts of various types including vellus hair cysts and steatocystomas usually develop at puberty and continue into adulthood. In some people with PC, particularly PC-K17, cysts can be the most painful and problematic characteristic. Multiple milia (particularly on the face) often occur in young children with PC-K17. Follicular keratoses occur in some patients on the trunk, elbows and knees, usually in early childhood. Oral leukokeratosis (white patches on the tongue and cheek) is more common in those with PC-K6a. It is often present at birth or within the first few months of life and can be misdiagnosed as a Candida albicans infection if no other symptoms of PC are apparent. Natal or prenatal teeth are more commonly seen in those with mutations in KRT17. Palmoplantar hyperhidrosis has been reported in about 50% of people with PC.Other less common features include angular cheilitis, laryngeal involvement resulting in a hoarse cry or hoarse voice and ‘first bite syndrome’. First bite syndrome is more common in young children and is intense pain near the jaw or ears that lasts about 15-25 seconds when beginning to eat or swallow.Variants of PC: Steatocystoma multiplex (SM) – widespread pilosebaceous cysts develop at puberty, but there is little or no nail involvement or palmoplantar keratoderma, can be due to mutations in KRT17.
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Pachyonychia Congenita
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Causes of Pachyonychia Congenita
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Pachyonychia congenita is caused by a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 or KRT17. These mutations are inherited in an autosomal dominant manner, although approximately 30-40% of cases are the result of new spontaneous mutations with no previous family history. In an autosomal dominant disorder, only one copy of an abnormal gene is necessary to produce clinical symptoms. The risk of an affected individual passing the abnormal gene to offspring is 50 percent for each pregnancy. For unaffected parents of a child with PC there is a very low risk of having subsequent affected children; germline mosaicism is extremely rare, with as of Jan 2018, only one out of 792 cases reported in the IPCRR.The majority of the mutations are heterozygous single base pair changes resulting in an amino acid change (missense mutations) with a small number of deletion/insertion mutations, splice site mutations and nonsense mutations. Some mutations are found in a number of families (recurrent mutations), while other rare mutations have only been observed in single families to date. All keratins share a similar protein structure consisting of an alpha helical central rod domain (subdivided into 4 domains connected by nonhelical linker regions). The majority of mutations causing PC are within the helix boundary domains at either end of the alpha helical rod domain. These regions are highly conserved in sequence between each type of keratin and are thought to play a vital role during end to end overlap interactions during keratin filament assembly.
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Causes of Pachyonychia Congenita. Pachyonychia congenita is caused by a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 or KRT17. These mutations are inherited in an autosomal dominant manner, although approximately 30-40% of cases are the result of new spontaneous mutations with no previous family history. In an autosomal dominant disorder, only one copy of an abnormal gene is necessary to produce clinical symptoms. The risk of an affected individual passing the abnormal gene to offspring is 50 percent for each pregnancy. For unaffected parents of a child with PC there is a very low risk of having subsequent affected children; germline mosaicism is extremely rare, with as of Jan 2018, only one out of 792 cases reported in the IPCRR.The majority of the mutations are heterozygous single base pair changes resulting in an amino acid change (missense mutations) with a small number of deletion/insertion mutations, splice site mutations and nonsense mutations. Some mutations are found in a number of families (recurrent mutations), while other rare mutations have only been observed in single families to date. All keratins share a similar protein structure consisting of an alpha helical central rod domain (subdivided into 4 domains connected by nonhelical linker regions). The majority of mutations causing PC are within the helix boundary domains at either end of the alpha helical rod domain. These regions are highly conserved in sequence between each type of keratin and are thought to play a vital role during end to end overlap interactions during keratin filament assembly.
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Affects of Pachyonychia Congenita
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PC affects both males and females. No ethnic differences have been reported. Prevalence is estimated at between 5,000 and 10,000 worldwide.
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Affects of Pachyonychia Congenita. PC affects both males and females. No ethnic differences have been reported. Prevalence is estimated at between 5,000 and 10,000 worldwide.
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Related disorders of Pachyonychia Congenita
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Another autosomal dominantly inherited disorder, Clouston syndrome, can mimic PC due to the overlapping clinical characteristics; occasionally this can lead to misdiagnosis of patients. The features of Clouston sydrome are thick nails (hypertrophic nail dystrophy), partial or total hair loss (alopecia) and palmoplantar hyperkeratosis. Alopecia (partial to total) does not typically occur in PC but is relatively common in Clouson syndrome. Clouston syndrome is caused by mutations in the gap junction protein connexin 30 (GJB6) gene.Epidermolysis bullosa simplex (EBS) is another inherited keratin disorder, caused by mutations in keratins K5 or K14 that result in skin blistering. Blistering can be induced by mild mechanical trauma. There is often hyperkeratosis on the palms and soles but nail dystrophy typical of PC is not normally present. In very young children care is needed to distinguish between blistering seen in PC and that in EBS.Olmsted syndrome, normally inherited in an autosomal dominant manner is caused by gain of function mutations in the TRPV3 gene. This condition is characterized by painful palmoplantar keratoderma with periorificial keratotic plaques and sometimes constricting digital bands. Milder cases of Olmsted syndrome have been reported which can appear more similar to PC. Striate palmoplantar keratoderma is an autosomal dominant disorder, normally caused by heterozygous loss of function mutations in the desmoglein (DSG1) gene resulting in haploinsufficiency of DSG1. The distinguishing feature is a striate pattern of keratoderma on the palms; plantar keratoderma can be focal or diffuse. There is often phenotypic variability between and within families.Nonsyndromic congenital nail disorder 10 only affects the nails and is inherited as an autosomal recessive trait. Normally all 20 nails are affected by onycholysis from birth/early childhood but there is no palmoplantar keratoderma or other features of PC. It is caused by two mutations in the frizzled 6 (FZD6) gene.
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Related disorders of Pachyonychia Congenita. Another autosomal dominantly inherited disorder, Clouston syndrome, can mimic PC due to the overlapping clinical characteristics; occasionally this can lead to misdiagnosis of patients. The features of Clouston sydrome are thick nails (hypertrophic nail dystrophy), partial or total hair loss (alopecia) and palmoplantar hyperkeratosis. Alopecia (partial to total) does not typically occur in PC but is relatively common in Clouson syndrome. Clouston syndrome is caused by mutations in the gap junction protein connexin 30 (GJB6) gene.Epidermolysis bullosa simplex (EBS) is another inherited keratin disorder, caused by mutations in keratins K5 or K14 that result in skin blistering. Blistering can be induced by mild mechanical trauma. There is often hyperkeratosis on the palms and soles but nail dystrophy typical of PC is not normally present. In very young children care is needed to distinguish between blistering seen in PC and that in EBS.Olmsted syndrome, normally inherited in an autosomal dominant manner is caused by gain of function mutations in the TRPV3 gene. This condition is characterized by painful palmoplantar keratoderma with periorificial keratotic plaques and sometimes constricting digital bands. Milder cases of Olmsted syndrome have been reported which can appear more similar to PC. Striate palmoplantar keratoderma is an autosomal dominant disorder, normally caused by heterozygous loss of function mutations in the desmoglein (DSG1) gene resulting in haploinsufficiency of DSG1. The distinguishing feature is a striate pattern of keratoderma on the palms; plantar keratoderma can be focal or diffuse. There is often phenotypic variability between and within families.Nonsyndromic congenital nail disorder 10 only affects the nails and is inherited as an autosomal recessive trait. Normally all 20 nails are affected by onycholysis from birth/early childhood but there is no palmoplantar keratoderma or other features of PC. It is caused by two mutations in the frizzled 6 (FZD6) gene.
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Pachyonychia Congenita
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Diagnosis of Pachyonychia Congenita
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PC is normally diagnosed by clinical examination, which can now be confirmed at the molecular level. Molecular diagnosis (from a blood sample or saliva sample), of PC patients is available to identify the exact gene defect (mutation) in KRT6A, KRT6B, KRT6C, KRT16 or KRT17 and to confirm the clinical diagnosis. See the Pachyonychia Congenita Project website (www.pachyonychia.org) for details about genetic testing which is offered free of charge for patients that enroll in the IPCRR (http://www.pachyonychia.org/patient-registry/).
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Diagnosis of Pachyonychia Congenita. PC is normally diagnosed by clinical examination, which can now be confirmed at the molecular level. Molecular diagnosis (from a blood sample or saliva sample), of PC patients is available to identify the exact gene defect (mutation) in KRT6A, KRT6B, KRT6C, KRT16 or KRT17 and to confirm the clinical diagnosis. See the Pachyonychia Congenita Project website (www.pachyonychia.org) for details about genetic testing which is offered free of charge for patients that enroll in the IPCRR (http://www.pachyonychia.org/patient-registry/).
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Therapies of Pachyonychia Congenita
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TreatmentAt present, there is no cure or specific treatment for PC. Patients manage their symptoms in a variety of ways either at home or with professional care. The main issue of plantar hyperkeratosis is dealt with by paring/trimming/grinding/filing and, thickened nails by filing/grinding/clipping. Topical agents including keratolytics (eg. salicylic acid, urea) and moisturizers provide limited benefit in softening the skin. For some patients, retinoids can help in thinning the callus but may lead to increased pain. A small number of PC patients have been treated with plantar injections of botulinum toxin resulting in a reduction in plantar pain and blistering. A soft nipple with an enlarged opening on a feeding bottle can help young infants with oral leukokeratosis that are failing to thrive and may also have ‘first bite syndrome’. Cysts do not usually require treatment but if infected or painful can be incised and drained or surgically removed. Wicking socks and ventilated footwear can help with hyperhidrosis. For further information on patient care and tools see www.pachyonychia.org.
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Therapies of Pachyonychia Congenita. TreatmentAt present, there is no cure or specific treatment for PC. Patients manage their symptoms in a variety of ways either at home or with professional care. The main issue of plantar hyperkeratosis is dealt with by paring/trimming/grinding/filing and, thickened nails by filing/grinding/clipping. Topical agents including keratolytics (eg. salicylic acid, urea) and moisturizers provide limited benefit in softening the skin. For some patients, retinoids can help in thinning the callus but may lead to increased pain. A small number of PC patients have been treated with plantar injections of botulinum toxin resulting in a reduction in plantar pain and blistering. A soft nipple with an enlarged opening on a feeding bottle can help young infants with oral leukokeratosis that are failing to thrive and may also have ‘first bite syndrome’. Cysts do not usually require treatment but if infected or painful can be incised and drained or surgically removed. Wicking socks and ventilated footwear can help with hyperhidrosis. For further information on patient care and tools see www.pachyonychia.org.
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Overview of Paget’s Disease
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Paget's disease of bone is a chronic, slowly progressive skeletal condition of abnormally rapid bone destruction (osteolytic) and reformation (osteoblastic). The new bone may occur in one or more regions of the body and is structurally abnormal, dense and fragile. This abnormal development may cause bone pain, arthritis, deformities and fractures. The bones most frequently affected are in the spine, skull, pelvis and lower legs. The exact cause of Paget's disease is not known.
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Overview of Paget’s Disease. Paget's disease of bone is a chronic, slowly progressive skeletal condition of abnormally rapid bone destruction (osteolytic) and reformation (osteoblastic). The new bone may occur in one or more regions of the body and is structurally abnormal, dense and fragile. This abnormal development may cause bone pain, arthritis, deformities and fractures. The bones most frequently affected are in the spine, skull, pelvis and lower legs. The exact cause of Paget's disease is not known.
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Symptoms of Paget’s Disease
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Early symptoms of Paget’s disease include bone pain, joint pain (especially in the back, hips and knees), and headache. Physical signs include enlargement and bowing of the thighs (femurs) and lower legs (tibias), and enlargement of the skull in the area of the forehead. Most individuals with Paget’s disease do not have any symptoms (asymptomatic) or only develop mild symptoms.As the disease progresses, other signs and symptoms often appear. These may include further bowing of the affected limbs, a waddling manner of walking (gait), pain and inflammation of the joints (arthritis), fractures of affected bones, and muscle and sensory disturbances.Up to 50 percent of individuals with skull involvement may develop hearing loss. Additional symptoms that may occur include loss of vision and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain.Spinal stenosis, a rare complication characterized by abnormal narrowing (stenosis) of the spaces within the spinal canal, spinal nerve root canals, or the bones of the spinal column (vertebrae), may develop in some cases. Congestive heart failure (high-output) may also occur. Tumors of the bone (sarcoma) are a rare complication.
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Symptoms of Paget’s Disease. Early symptoms of Paget’s disease include bone pain, joint pain (especially in the back, hips and knees), and headache. Physical signs include enlargement and bowing of the thighs (femurs) and lower legs (tibias), and enlargement of the skull in the area of the forehead. Most individuals with Paget’s disease do not have any symptoms (asymptomatic) or only develop mild symptoms.As the disease progresses, other signs and symptoms often appear. These may include further bowing of the affected limbs, a waddling manner of walking (gait), pain and inflammation of the joints (arthritis), fractures of affected bones, and muscle and sensory disturbances.Up to 50 percent of individuals with skull involvement may develop hearing loss. Additional symptoms that may occur include loss of vision and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain.Spinal stenosis, a rare complication characterized by abnormal narrowing (stenosis) of the spaces within the spinal canal, spinal nerve root canals, or the bones of the spinal column (vertebrae), may develop in some cases. Congestive heart failure (high-output) may also occur. Tumors of the bone (sarcoma) are a rare complication.
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Causes of Paget’s Disease
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The exact cause of Paget’s disease is unknown. Researchers speculate that the cause of the disorder may be multifactorial (e.g. caused by the interaction of certain genetic and environmental factors). In most cases, no specific cause for Paget’s disease can be identified (sporadic).Research findings suggest that Paget’s disease may be related to a “slow virus” infection of bone, a condition that is present for many years before symptoms appear.In approximately 15-30 percent of cases there is a family history of the disorder. Researchers have discovered several genes that may predispose individuals to developing Paget’s disease (genetic predisposition). Genes associated with this condition are the sequestosome 1 gene, the TNFRSFIIA gene that codes for the RANK protein, and the VCP gene. The exact role that these genes play in the development of the disorder is unknown. This hereditary factor may be the reason that family members are susceptible to the suspected virus.
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Causes of Paget’s Disease. The exact cause of Paget’s disease is unknown. Researchers speculate that the cause of the disorder may be multifactorial (e.g. caused by the interaction of certain genetic and environmental factors). In most cases, no specific cause for Paget’s disease can be identified (sporadic).Research findings suggest that Paget’s disease may be related to a “slow virus” infection of bone, a condition that is present for many years before symptoms appear.In approximately 15-30 percent of cases there is a family history of the disorder. Researchers have discovered several genes that may predispose individuals to developing Paget’s disease (genetic predisposition). Genes associated with this condition are the sequestosome 1 gene, the TNFRSFIIA gene that codes for the RANK protein, and the VCP gene. The exact role that these genes play in the development of the disorder is unknown. This hereditary factor may be the reason that family members are susceptible to the suspected virus.
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Affects of Paget’s Disease
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Paget’s disease is rarely diagnosed in people under the age of 40 years but may occur in up to three percent of the population over the age of 60 years. Paget’s disease affects individuals of all ethnic and racial groups. However, it affects individuals of Asian descent less frequently. Both men and women can be affected with a slight male predominance. The prevalence of Paget’s disease in the United States is estimated to be 1-2 percent of the general population.
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Affects of Paget’s Disease. Paget’s disease is rarely diagnosed in people under the age of 40 years but may occur in up to three percent of the population over the age of 60 years. Paget’s disease affects individuals of all ethnic and racial groups. However, it affects individuals of Asian descent less frequently. Both men and women can be affected with a slight male predominance. The prevalence of Paget’s disease in the United States is estimated to be 1-2 percent of the general population.
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Related disorders of Paget’s Disease
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Symptoms of the following disorders can be similar to those of Paget’s disease. Comparisons may be useful for a differential diagnosis.Osteoporosis is a common bone condition characterized by generalized loss of bone mass that can lead to fractures. Although Paget’s disease and osteoporosis can occur in the same person, they are completely different disorders with different causes. Despite their marked differences, many treatments for Paget’s disease are also used to treat osteoporosis.The following disorders may be associated with Paget’s disease as secondary characteristics. They are not necessary for a differential diagnosis:Osteoarthritis is a prevalent form of arthritis that involves degeneration of joints in the body. Osteoarthritis is characterized by a gradual deterioration of the cartilage between bones of the joints. Later, bones may become deformed and the condition becomes painful. This is the most common form of arthritis and it commonly occurs in older people. Symptoms may include pain and joint stiffness particularly in the morning or after exercise or prolonged rest.Spinal stenosis is characterized by a constriction or compression of the space within the spinal canal, nerve root canals or vertebrae. This compression may lead to difficulties with walking, bladder control (urinary incontinence), temporary paralysis of the legs, and pain or burning sensations in the lower back and legs. Progressive loss of muscle control may also occur.
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Related disorders of Paget’s Disease. Symptoms of the following disorders can be similar to those of Paget’s disease. Comparisons may be useful for a differential diagnosis.Osteoporosis is a common bone condition characterized by generalized loss of bone mass that can lead to fractures. Although Paget’s disease and osteoporosis can occur in the same person, they are completely different disorders with different causes. Despite their marked differences, many treatments for Paget’s disease are also used to treat osteoporosis.The following disorders may be associated with Paget’s disease as secondary characteristics. They are not necessary for a differential diagnosis:Osteoarthritis is a prevalent form of arthritis that involves degeneration of joints in the body. Osteoarthritis is characterized by a gradual deterioration of the cartilage between bones of the joints. Later, bones may become deformed and the condition becomes painful. This is the most common form of arthritis and it commonly occurs in older people. Symptoms may include pain and joint stiffness particularly in the morning or after exercise or prolonged rest.Spinal stenosis is characterized by a constriction or compression of the space within the spinal canal, nerve root canals or vertebrae. This compression may lead to difficulties with walking, bladder control (urinary incontinence), temporary paralysis of the legs, and pain or burning sensations in the lower back and legs. Progressive loss of muscle control may also occur.
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Paget’s Disease
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Diagnosis of Paget’s Disease
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The diagnosis of Paget’s disease may be confirmed by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests, such as blood tests, x-rays, and urine tests. A blood test may reveal elevated levels of the enzyme alkaline phosphatase suggesting the diagnosis of Paget’s disease, usually confirmed by x-ray. A bone scan may also be used to determine the extent of the abnormalities in the bones. Urine tests, such as pyrilinks and osteomark, may also be used to assist in the diagnosis and response to therapy of Paget’s disease.
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Diagnosis of Paget’s Disease. The diagnosis of Paget’s disease may be confirmed by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests, such as blood tests, x-rays, and urine tests. A blood test may reveal elevated levels of the enzyme alkaline phosphatase suggesting the diagnosis of Paget’s disease, usually confirmed by x-ray. A bone scan may also be used to determine the extent of the abnormalities in the bones. Urine tests, such as pyrilinks and osteomark, may also be used to assist in the diagnosis and response to therapy of Paget’s disease.
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Therapies of Paget’s Disease
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TreatmentFour main methods of treatment exist for the patient with Paget’s disease: non-pharmacological therapy (focusing mainly on physical therapy as a means of improving muscle strength to help control some types of pain); pharmacological therapy using either bisphosphonates or calcitonins; pain management using analgesics; and surgical intervention.Pharmacological Treatment
Bisphosphonates
Bisphosphonates suppress or reduce bone resorption by osteoclasts. They do this both directly, by hindering the recruitment and function of osteoclasts and perhaps indirectly, by stimulating osteoblasts to produce an inhibitor of osteoclast formation. There is now a reasonable understanding of how these drugs work, and the differences between various types of bisphosphonates are better understood.Currently, six bisphosphonates are approved by the U.S. Food and Drug Administration (FDA) for the treatment of Paget’s disease. These include zoledronic acid (Reclast) and pamidronate disodium (Aredia) which are given intravenously.Zoledronic acid (Reclast) is the preferred treatment. Intravenous adminstration is in 5 mg infusion given over 15 minutes. Prior to therapy, patients should receive 1500 mg units of calcium and 1000 units of vitamin D daily for two weeks to reduce their risk of low blood calcium after infusions. Zoledronic acid (Reclast) is not indicated for individuals with low blood calcium or vitamin D deficiency and those with a compromised renal function.Zoledronic acid (Reclast) is also marketed for treating Paget’s disease with the name Aclasta in several countries outside of the United States.A mild form of Paget’s disease can be suppressed with one or two 60 mg infusions of pamidronate disodium, while a more severe manifestation of the disease may require several infusions of 60-90 mg of pamidronate on a weekly or twice-weekly basis. Serum alkaline phosphatase testing should occur approximately two to three months after the appropriate amount of infusion is administered. Several generic forms of pamidronate disodium are also available.Oral calcium and vitamin D supplementation is recommended for patients using this therapy to lessen hypocalcemia, a common side effect and patients with low blood calcium levels and or vitamin D deficiency should not be treated with paidronate disodiumPatients with either low blood calcium or vitamin D deficiency should not be treated with zoledronic acid and the drug is not indicated for patients with compromised renal functions.Etidronate (Didronel), tiludronate (Skelid), alendronate (Fosamax), and risedronate (Actonel) are taken orally. Both alendronate sodium and risedronate sodium have been shown to reduce the biochemical indices for bone turnover into the normal range in patients with a moderate-to-severe form of Paget’s disease. Alendronate is taken as a daily 40 mg tablet for six months; risedronate is taken as a 30 mg tablet for two or three months. Calcium and vitamin D supplementation is also recommended for patients using either of these drugs. Alendronate (Fosamax) 40mg tables are available in generic form at retail pharmacies with the name Alendronate sodium tablets. A prescription is required.Etidronate disodium and tiludronate disodium are less potent than alendronate and risedronate. They are both taken as daily 400 mg tablets. Etidronate, the original bisphosphonate used in treating Paget’s disease, is taken for six months while tiludronate is taken for three months. With both of these bisphosphonates, calcium supplements should not be taken for several hours following the bisphosphonate dose.Investigators have recognized that secondary resistance to individual bisphosphonates can occur. Therefore, it may be necessary for a patient to use more than one bisphosphonate in long-term management of the disease. Due to certain properties of each of these medications, it is vital that patients take bisphosphonates in their prescribed manner to avoid poor absorption of the drugs or severe gastrointestinal problems.Calcitonins
Subcutaneous injection of salmon calcitonin was the first widely used therapy for Paget’s disease. Salmon calcitonin has been shown to reduce elevated indices of bone turnover by 50 percent, decrease symptoms of bone pain, reduce warmth over affected bones, improve some neurological complications and promote healing of lytic lesions. Its use today is limited mostly to patients who do not tolerate bisphosphonates. In the case of secondary resistance to salmon calcitonin, a switch to bisphosphonate therapy is essential. Miacalcin, an injection taken daily or three times a week, is the only calcitonin approved for Paget’s disease. A nasal spray form of Miacalcin is approved for treating osteoporosis. This spray is not approved or recommended for individuals with Paget’s disease.Pain Management: Analgesics
Pain directly attributable to Paget’s disease is generally relieved through anti-osteoclast treatment as described above. Some pain may be the result of bone deformity or arthritic or neurological complications. In this case, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), or the cox-2 inhibitors may be helpful for the management of pagetic pain, in addition to the main pagetic therapy chosen.Surgery
Different orthopedic interventions may be necessary in individuals with Paget’s disease. These include:1. Fixing a complete fracture through pagetic bone 2. Realigning the knee through tibial osteotomy to decrease mechanical pain, particularly if medical therapy is unsuccessful in managing severe pain syndromes3. Replacing the hip and/or knee through total joint arthroplasty for patients unresponsive to anti-osteoclast treatment and therapy for osteoarthritisWhen repairing a pagetic fracture, total immobilization of that site should be avoided if possible. In all cases of surgical intervention, pre-treatment with a potent bisphosphonate is very important. Since hypervascularity is a symptom of Paget’s disease, this may lead to serious bleeding during an operation. Pre-treatment with a bisphosphonate will reduce the hypervascularity and reduce the risk of greater-than-normal operative blood loss.The development of specific inhibitors of osteoclast-mediated resorption, particularly the potent bisphosphonates, has brought about major changes in the treatment of Paget’s disease. Although the long-term effects of disease suppression are unknown, the capacity to restore the bone remodeling process to normal gives reason to believe that reduction in long-term complications and their related morbidity is now possible.
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Therapies of Paget’s Disease. TreatmentFour main methods of treatment exist for the patient with Paget’s disease: non-pharmacological therapy (focusing mainly on physical therapy as a means of improving muscle strength to help control some types of pain); pharmacological therapy using either bisphosphonates or calcitonins; pain management using analgesics; and surgical intervention.Pharmacological Treatment
Bisphosphonates
Bisphosphonates suppress or reduce bone resorption by osteoclasts. They do this both directly, by hindering the recruitment and function of osteoclasts and perhaps indirectly, by stimulating osteoblasts to produce an inhibitor of osteoclast formation. There is now a reasonable understanding of how these drugs work, and the differences between various types of bisphosphonates are better understood.Currently, six bisphosphonates are approved by the U.S. Food and Drug Administration (FDA) for the treatment of Paget’s disease. These include zoledronic acid (Reclast) and pamidronate disodium (Aredia) which are given intravenously.Zoledronic acid (Reclast) is the preferred treatment. Intravenous adminstration is in 5 mg infusion given over 15 minutes. Prior to therapy, patients should receive 1500 mg units of calcium and 1000 units of vitamin D daily for two weeks to reduce their risk of low blood calcium after infusions. Zoledronic acid (Reclast) is not indicated for individuals with low blood calcium or vitamin D deficiency and those with a compromised renal function.Zoledronic acid (Reclast) is also marketed for treating Paget’s disease with the name Aclasta in several countries outside of the United States.A mild form of Paget’s disease can be suppressed with one or two 60 mg infusions of pamidronate disodium, while a more severe manifestation of the disease may require several infusions of 60-90 mg of pamidronate on a weekly or twice-weekly basis. Serum alkaline phosphatase testing should occur approximately two to three months after the appropriate amount of infusion is administered. Several generic forms of pamidronate disodium are also available.Oral calcium and vitamin D supplementation is recommended for patients using this therapy to lessen hypocalcemia, a common side effect and patients with low blood calcium levels and or vitamin D deficiency should not be treated with paidronate disodiumPatients with either low blood calcium or vitamin D deficiency should not be treated with zoledronic acid and the drug is not indicated for patients with compromised renal functions.Etidronate (Didronel), tiludronate (Skelid), alendronate (Fosamax), and risedronate (Actonel) are taken orally. Both alendronate sodium and risedronate sodium have been shown to reduce the biochemical indices for bone turnover into the normal range in patients with a moderate-to-severe form of Paget’s disease. Alendronate is taken as a daily 40 mg tablet for six months; risedronate is taken as a 30 mg tablet for two or three months. Calcium and vitamin D supplementation is also recommended for patients using either of these drugs. Alendronate (Fosamax) 40mg tables are available in generic form at retail pharmacies with the name Alendronate sodium tablets. A prescription is required.Etidronate disodium and tiludronate disodium are less potent than alendronate and risedronate. They are both taken as daily 400 mg tablets. Etidronate, the original bisphosphonate used in treating Paget’s disease, is taken for six months while tiludronate is taken for three months. With both of these bisphosphonates, calcium supplements should not be taken for several hours following the bisphosphonate dose.Investigators have recognized that secondary resistance to individual bisphosphonates can occur. Therefore, it may be necessary for a patient to use more than one bisphosphonate in long-term management of the disease. Due to certain properties of each of these medications, it is vital that patients take bisphosphonates in their prescribed manner to avoid poor absorption of the drugs or severe gastrointestinal problems.Calcitonins
Subcutaneous injection of salmon calcitonin was the first widely used therapy for Paget’s disease. Salmon calcitonin has been shown to reduce elevated indices of bone turnover by 50 percent, decrease symptoms of bone pain, reduce warmth over affected bones, improve some neurological complications and promote healing of lytic lesions. Its use today is limited mostly to patients who do not tolerate bisphosphonates. In the case of secondary resistance to salmon calcitonin, a switch to bisphosphonate therapy is essential. Miacalcin, an injection taken daily or three times a week, is the only calcitonin approved for Paget’s disease. A nasal spray form of Miacalcin is approved for treating osteoporosis. This spray is not approved or recommended for individuals with Paget’s disease.Pain Management: Analgesics
Pain directly attributable to Paget’s disease is generally relieved through anti-osteoclast treatment as described above. Some pain may be the result of bone deformity or arthritic or neurological complications. In this case, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS), or the cox-2 inhibitors may be helpful for the management of pagetic pain, in addition to the main pagetic therapy chosen.Surgery
Different orthopedic interventions may be necessary in individuals with Paget’s disease. These include:1. Fixing a complete fracture through pagetic bone 2. Realigning the knee through tibial osteotomy to decrease mechanical pain, particularly if medical therapy is unsuccessful in managing severe pain syndromes3. Replacing the hip and/or knee through total joint arthroplasty for patients unresponsive to anti-osteoclast treatment and therapy for osteoarthritisWhen repairing a pagetic fracture, total immobilization of that site should be avoided if possible. In all cases of surgical intervention, pre-treatment with a potent bisphosphonate is very important. Since hypervascularity is a symptom of Paget’s disease, this may lead to serious bleeding during an operation. Pre-treatment with a bisphosphonate will reduce the hypervascularity and reduce the risk of greater-than-normal operative blood loss.The development of specific inhibitors of osteoclast-mediated resorption, particularly the potent bisphosphonates, has brought about major changes in the treatment of Paget’s disease. Although the long-term effects of disease suppression are unknown, the capacity to restore the bone remodeling process to normal gives reason to believe that reduction in long-term complications and their related morbidity is now possible.
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Overview of Paget’s Disease of the Breast
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SummaryPaget's disease of the breast is a rare form of breast cancer that almost exclusively occurs in women. However, rare cases have been reported in men. Paget's disease of the breast is characterized by inflammatory, “eczema-like” changes of the nipple that may extend to involve the areola, which is the circular, darkened (pigmented) region of skin surrounding the nipple. Initial findings often include itching (pruritus), scaling, and crusting of and/or discharge from the nipple. In individuals with Paget's disease of the breast, distinctive tumor cells (known as Paget cells) are present within the outermost layer of skin (epidermis) of the nipple, when viewed under a microscope. Most women with this disorder have an underlying cancer (malignancy) affecting the milk ducts (ductal carcinoma). The milk ducts are the channels that carry milk secreted by lobes of the breast to the nipple. The exact cause of Paget's disease of the breast is not fully understood.IntroductionPaget's disease of the breast was originally reported in 1874 by Sir James Paget, an English surgeon, who also described an unrelated skeletal condition known as Paget's disease of the bone. It is essential to note that these disorders are distinct entities that are medically unrelated.
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Overview of Paget’s Disease of the Breast. SummaryPaget's disease of the breast is a rare form of breast cancer that almost exclusively occurs in women. However, rare cases have been reported in men. Paget's disease of the breast is characterized by inflammatory, “eczema-like” changes of the nipple that may extend to involve the areola, which is the circular, darkened (pigmented) region of skin surrounding the nipple. Initial findings often include itching (pruritus), scaling, and crusting of and/or discharge from the nipple. In individuals with Paget's disease of the breast, distinctive tumor cells (known as Paget cells) are present within the outermost layer of skin (epidermis) of the nipple, when viewed under a microscope. Most women with this disorder have an underlying cancer (malignancy) affecting the milk ducts (ductal carcinoma). The milk ducts are the channels that carry milk secreted by lobes of the breast to the nipple. The exact cause of Paget's disease of the breast is not fully understood.IntroductionPaget's disease of the breast was originally reported in 1874 by Sir James Paget, an English surgeon, who also described an unrelated skeletal condition known as Paget's disease of the bone. It is essential to note that these disorders are distinct entities that are medically unrelated.
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Symptoms of Paget’s Disease of the Breast
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Paget’s disease of the breast is a malignant (cancerous) condition that initially appears as chronic, inflammatory, “eczema-like” changes of the nipple and adjacent areas.In individuals with Paget’s disease of the breast, initial characteristic skin changes may include the appearance of reddish (erythematous), scaling, crusting, and/or abnormally thickened skin patches (plaques) or lesions on the nipple that may extend to adjacent areas of the areola. Some affected individuals may also have abnormal discharge from the nipple. Additional symptoms may include itching (pruritus) or burning sensations and/or oozing or bleeding of the affected area. Eventually, pain and sensitivity of the affected area may be present. Early on, the skin symptoms of Paget’s disease of the breast may fluctuate, improving only to worsen again. Paget’s disease of the breast usually affects one breast (unilateral), but there are rare cases in which both breasts are involved (bilateral).The initial skin changes of Paget’s disease of the breast may appear relatively benign and many individuals may overlook such symptoms, mistakenly attributing them to an inflammatory skin condition or infection. As a result, diagnosis may be delayed, often up to six months or more. Most individuals with the condition eventually seek medical attention due to associated itching or burning sensations, soreness, or pain of the affected area.Most women with Paget’s disease of the breast have an underlying malignancy, which may be completely contained within the milk ducts (ductal carcinoma in situ) or may have invaded the surrounding tissue, potentially spreading to the lymph nodes under the arms (axillary lymph nodes) and other regions of the body (metastatic disease).Approximately 50 percent or more of affected individuals may have a lump or mass that may be felt (palpated) below the nipple. Some individuals with Paget’s disease of the breast may have additional symptoms or physical findings. For example, in some instances, the nipple may turn inward (retracted nipple).The overall disease course may vary greatly from one person to another, depending upon the nature and size of an underlying malignancy, whether a palpable breast tumor is present upon diagnosis, whether metastatic disease is present, specific treatment measures followed, and other possible factors.
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Symptoms of Paget’s Disease of the Breast. Paget’s disease of the breast is a malignant (cancerous) condition that initially appears as chronic, inflammatory, “eczema-like” changes of the nipple and adjacent areas.In individuals with Paget’s disease of the breast, initial characteristic skin changes may include the appearance of reddish (erythematous), scaling, crusting, and/or abnormally thickened skin patches (plaques) or lesions on the nipple that may extend to adjacent areas of the areola. Some affected individuals may also have abnormal discharge from the nipple. Additional symptoms may include itching (pruritus) or burning sensations and/or oozing or bleeding of the affected area. Eventually, pain and sensitivity of the affected area may be present. Early on, the skin symptoms of Paget’s disease of the breast may fluctuate, improving only to worsen again. Paget’s disease of the breast usually affects one breast (unilateral), but there are rare cases in which both breasts are involved (bilateral).The initial skin changes of Paget’s disease of the breast may appear relatively benign and many individuals may overlook such symptoms, mistakenly attributing them to an inflammatory skin condition or infection. As a result, diagnosis may be delayed, often up to six months or more. Most individuals with the condition eventually seek medical attention due to associated itching or burning sensations, soreness, or pain of the affected area.Most women with Paget’s disease of the breast have an underlying malignancy, which may be completely contained within the milk ducts (ductal carcinoma in situ) or may have invaded the surrounding tissue, potentially spreading to the lymph nodes under the arms (axillary lymph nodes) and other regions of the body (metastatic disease).Approximately 50 percent or more of affected individuals may have a lump or mass that may be felt (palpated) below the nipple. Some individuals with Paget’s disease of the breast may have additional symptoms or physical findings. For example, in some instances, the nipple may turn inward (retracted nipple).The overall disease course may vary greatly from one person to another, depending upon the nature and size of an underlying malignancy, whether a palpable breast tumor is present upon diagnosis, whether metastatic disease is present, specific treatment measures followed, and other possible factors.
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Causes of Paget’s Disease of the Breast
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Two main theories have been proposed to explain the development of Paget’s disease of the breast. One theory suggests that distinctive cancer cells called Paget’s cells break off from an underlying tumor or malignancy within the breast and travel through the milk ducts to the nipples. Supportive evidence includes laboratory studies demonstrating that Paget cells and the underlying breast cancer share certain characteristics, thus appearing to originate from the same cell population. In addition, malignant cells have been shown to extend along breast ductal tissue from the underlying breast tumor to the nipple. Accordingly, many researchers have concluded that Paget cells appear to be derived from the lining (epithelium) of the milk ducts, invading and multiplying (proliferating) within the surface tissue (epidermis) of the nipple and adjacent areas of the areola. This theory explains why most individuals with Paget’s disease of the breast have an underlying form of cancer.The second theory suggests that the presence and spread of Paget cells represents a distinct disease process originating in the outer skin layer of the nipple. The malignant changes occur without warning and for no known reason (spontaneously). This theory would explain the rare cases where no underlying malignancy is present or where the underlying malignancy is a different tumor type.As with other cancers, the exact underlying cause or causes of malignancy associated with Paget’s disease of the breast remain unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals and ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators at the National Cancer Institute and elsewhere are conducting ongoing basic research to learn more about the many factors that may result in cancer.In individuals with cancer, including breast malignancies, tumor development results from abnormal changes in the structure of certain cells. The specific cause of such changes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. In many patients, these abnormal changes may appear to occur spontaneously for unknown reasons (sporadically).Cells that undergo malignant transformation typically revert to a less specialized, more primitive form (anaplasia or loss of differentiation), meaning that they are no longer capable of performing their intended, specialized functions within the tissue in question. Malignant cells pass their abnormal changes on to their “daughter” cells and typically grow and divide at an unusually rapid, uncontrolled rate. This uncontrolled cellular growth may eventually result in invasion of surrounding tissues, infiltration of regional lymph nodes, and spread of the malignancy (metastasis) via the bloodstream, the lymphatic circulation, or other means.
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Causes of Paget’s Disease of the Breast. Two main theories have been proposed to explain the development of Paget’s disease of the breast. One theory suggests that distinctive cancer cells called Paget’s cells break off from an underlying tumor or malignancy within the breast and travel through the milk ducts to the nipples. Supportive evidence includes laboratory studies demonstrating that Paget cells and the underlying breast cancer share certain characteristics, thus appearing to originate from the same cell population. In addition, malignant cells have been shown to extend along breast ductal tissue from the underlying breast tumor to the nipple. Accordingly, many researchers have concluded that Paget cells appear to be derived from the lining (epithelium) of the milk ducts, invading and multiplying (proliferating) within the surface tissue (epidermis) of the nipple and adjacent areas of the areola. This theory explains why most individuals with Paget’s disease of the breast have an underlying form of cancer.The second theory suggests that the presence and spread of Paget cells represents a distinct disease process originating in the outer skin layer of the nipple. The malignant changes occur without warning and for no known reason (spontaneously). This theory would explain the rare cases where no underlying malignancy is present or where the underlying malignancy is a different tumor type.As with other cancers, the exact underlying cause or causes of malignancy associated with Paget’s disease of the breast remain unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals and ionizing radiation), diet, stress, and/or other factors may play contributing roles in causing specific types of cancer. Investigators at the National Cancer Institute and elsewhere are conducting ongoing basic research to learn more about the many factors that may result in cancer.In individuals with cancer, including breast malignancies, tumor development results from abnormal changes in the structure of certain cells. The specific cause of such changes is unknown. However, current research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. In many patients, these abnormal changes may appear to occur spontaneously for unknown reasons (sporadically).Cells that undergo malignant transformation typically revert to a less specialized, more primitive form (anaplasia or loss of differentiation), meaning that they are no longer capable of performing their intended, specialized functions within the tissue in question. Malignant cells pass their abnormal changes on to their “daughter” cells and typically grow and divide at an unusually rapid, uncontrolled rate. This uncontrolled cellular growth may eventually result in invasion of surrounding tissues, infiltration of regional lymph nodes, and spread of the malignancy (metastasis) via the bloodstream, the lymphatic circulation, or other means.
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Affects of Paget’s Disease of the Breast
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Paget’s disease of the breast is a rare form of breast cancer that almost exclusively affects women. However, there have been rare cases in which the disorder has occurred in men. Paget’s disease of the breast most commonly affects middle-aged individuals, primarily occurring between 50 to 60 years of age, although it has been reported in individuals in their 20s. It is thought to represent less than 5 percent of all breast cancer clinical presentations. The exact prevalence and incidence of Paget’s disease of the breast in the general population is unknown.
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Affects of Paget’s Disease of the Breast. Paget’s disease of the breast is a rare form of breast cancer that almost exclusively affects women. However, there have been rare cases in which the disorder has occurred in men. Paget’s disease of the breast most commonly affects middle-aged individuals, primarily occurring between 50 to 60 years of age, although it has been reported in individuals in their 20s. It is thought to represent less than 5 percent of all breast cancer clinical presentations. The exact prevalence and incidence of Paget’s disease of the breast in the general population is unknown.
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Related disorders of Paget’s Disease of the Breast
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Symptoms of the following disorders may be similar to those of Paget’s disease of the breast. Comparisons may be useful for a differential diagnosis:Extramammary Paget’s disease (EMPD) is characterized by the development of a reddish, scaling lesion that resembles that seen in Paget’s disease of the breast but does not occur on the breasts. The term extramammary refers to regions other than or outside of the breasts. In those with EMPD, additional symptoms and findings may include itching, burning, pain, and/or bleeding of the affected area. EMPD often involves the female or male external genitals (e.g., vulva, glans penis) and/or the region around the anus (perianal region). EMPD of the vulva is associated with an underlying cancer (carcinoma) in about 30 percent of patients; involvement of the perianal area is associated with a distant or underlying carcinoma in up to approximately 73 percent of individuals.Eczema is a common inflammatory condition characterized by itching (pruritus) and redness (erythema) of upper skin layers (i.e., superficial dermatitis). The condition is also often associated with blistering or scabbing, scaling, oozing, crusting, and thickening of affected skin areas. There are multiple types of eczema that may result from various internal (endogenous) and/or external (exogenous) factors, including an excessive immune response to certain, usually environmental agents.Bowen disease is a rare skin disorder. Affected individuals develop a slow-growing, reddish scaly patch or plaque on the skin. Sun exposed areas of the skin are most often affected. Bowen disease only affects the outermost layer of the skin (epidermis). Lesions are usually not painful or may not be associated with any symptoms (asymptomatic). In most cases, treatment is highly successful. Bowen disease is considered a pre-cancerous condition, although the risk of developing skin cancer is less than 10 percent. The disorder usually affects older adults. The exact cause of Bowen disease is unknown, although there are identified risk factors such as chronic sun exposure. (For more information on this disorder, choose “Bowen” as your search term in the Rare Disease Database.)Malignant melanoma is a form of skin cancer that develops from the melanin cells of the upper layer of the skin (epidermis) or from similar cells that may be found in moles (nevi). In early stages most melanomas do not produce any specific symptoms. Later, they may appear as lesions that do not heal or as existing moles that show changes in size or color. This type of skin cancer eventually spreads to the lower skin levels and adjacent tissue and may result in new tumor growths in vital organs of the body. (For more information on this disorder, choose “malignant melanoma” as your search term in the Rare Disease Database.)
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Related disorders of Paget’s Disease of the Breast. Symptoms of the following disorders may be similar to those of Paget’s disease of the breast. Comparisons may be useful for a differential diagnosis:Extramammary Paget’s disease (EMPD) is characterized by the development of a reddish, scaling lesion that resembles that seen in Paget’s disease of the breast but does not occur on the breasts. The term extramammary refers to regions other than or outside of the breasts. In those with EMPD, additional symptoms and findings may include itching, burning, pain, and/or bleeding of the affected area. EMPD often involves the female or male external genitals (e.g., vulva, glans penis) and/or the region around the anus (perianal region). EMPD of the vulva is associated with an underlying cancer (carcinoma) in about 30 percent of patients; involvement of the perianal area is associated with a distant or underlying carcinoma in up to approximately 73 percent of individuals.Eczema is a common inflammatory condition characterized by itching (pruritus) and redness (erythema) of upper skin layers (i.e., superficial dermatitis). The condition is also often associated with blistering or scabbing, scaling, oozing, crusting, and thickening of affected skin areas. There are multiple types of eczema that may result from various internal (endogenous) and/or external (exogenous) factors, including an excessive immune response to certain, usually environmental agents.Bowen disease is a rare skin disorder. Affected individuals develop a slow-growing, reddish scaly patch or plaque on the skin. Sun exposed areas of the skin are most often affected. Bowen disease only affects the outermost layer of the skin (epidermis). Lesions are usually not painful or may not be associated with any symptoms (asymptomatic). In most cases, treatment is highly successful. Bowen disease is considered a pre-cancerous condition, although the risk of developing skin cancer is less than 10 percent. The disorder usually affects older adults. The exact cause of Bowen disease is unknown, although there are identified risk factors such as chronic sun exposure. (For more information on this disorder, choose “Bowen” as your search term in the Rare Disease Database.)Malignant melanoma is a form of skin cancer that develops from the melanin cells of the upper layer of the skin (epidermis) or from similar cells that may be found in moles (nevi). In early stages most melanomas do not produce any specific symptoms. Later, they may appear as lesions that do not heal or as existing moles that show changes in size or color. This type of skin cancer eventually spreads to the lower skin levels and adjacent tissue and may result in new tumor growths in vital organs of the body. (For more information on this disorder, choose “malignant melanoma” as your search term in the Rare Disease Database.)
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Diagnosis of Paget’s Disease of the Breast
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Paget's disease of the breast is diagnosed based upon thorough clinical examination, identification of characteristic physical findings, a complete patient history, and a variety of specialized tests. The disorder can be confused with other skin conditions such as eczema potentially causing a delay in the diagnosis.Clinical Testing and Work-UpTests that may be used to help diagnose Paget's disease of the breast include blood tests, surgical removal (biopsy) and microscopic examination of affected breast tissue, mammography or other specialized imaging of the breasts, and/or microscopic evaluation of any nipple discharge for cancerous cells (cytologic smear).During a biopsy a small sample of breast tissue is taken and examined under a microscope to determine whether Paget cells are present. If a lump is found in the breast, a sample of that tissue will also be taken.A mammogram is an x-ray of the breast tissue and may be used to determine whether Paget cells are present. Mammography is also used to detect or rule out whether an underlying cancer is present. Additional specialized imaging techniques such as an ultrasound or magnetic resonance imaging (MRI) may be used to create additional images of the breast and to determine whether an underlying cancer is present.If nipple discharge is present, a sample may be taken and studied to detect the presence of Paget cells.If affected individuals have an underlying invasive cancer, then a sentinel lymph node biopsy may be performed. During this biopsy, a sample of tissue is taken from the lymph nodes under the armpits (axillary lymph nodes) to check and see whether cancer has spread to this area. A physician will locate and remove the sentinel lymph node, which refers to the first (or first few) lymph node(s) to which cancer cells are most likely to spread.
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Diagnosis of Paget’s Disease of the Breast. Paget's disease of the breast is diagnosed based upon thorough clinical examination, identification of characteristic physical findings, a complete patient history, and a variety of specialized tests. The disorder can be confused with other skin conditions such as eczema potentially causing a delay in the diagnosis.Clinical Testing and Work-UpTests that may be used to help diagnose Paget's disease of the breast include blood tests, surgical removal (biopsy) and microscopic examination of affected breast tissue, mammography or other specialized imaging of the breasts, and/or microscopic evaluation of any nipple discharge for cancerous cells (cytologic smear).During a biopsy a small sample of breast tissue is taken and examined under a microscope to determine whether Paget cells are present. If a lump is found in the breast, a sample of that tissue will also be taken.A mammogram is an x-ray of the breast tissue and may be used to determine whether Paget cells are present. Mammography is also used to detect or rule out whether an underlying cancer is present. Additional specialized imaging techniques such as an ultrasound or magnetic resonance imaging (MRI) may be used to create additional images of the breast and to determine whether an underlying cancer is present.If nipple discharge is present, a sample may be taken and studied to detect the presence of Paget cells.If affected individuals have an underlying invasive cancer, then a sentinel lymph node biopsy may be performed. During this biopsy, a sample of tissue is taken from the lymph nodes under the armpits (axillary lymph nodes) to check and see whether cancer has spread to this area. A physician will locate and remove the sentinel lymph node, which refers to the first (or first few) lymph node(s) to which cancer cells are most likely to spread.
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Therapies of Paget’s Disease of the Breast
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TreatmentThe therapeutic management of individuals with Paget's disease of the breast may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses and other healthcare professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as extent of the primary tumor (stage) and degree of malignancy (grade); the nature, size, and invasiveness of an underlying breast malignancy and the presence or absence of metastatic disease; individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference, and other appropriate factors.Treatment has traditionally included surgical removal of breast tissue, adjacent lymph nodes, and, in some cases, underlying muscles of the upper chest wall and other tissues (modified radical or radical mastectomy). Some individuals may only require a simple mastectomy, in which the breast and the lining over the chest muscles are removed.In selected cases where there is no palpable breast mass and negative mammograms, or in those with disease confined to the nipple and areola, conservative tissue-sparing surgery (lumpectomy) may be recommended. During this surgery, the nipple and areola are removed along with a small section of breast tissue. A physician will attempt to remove as little breast tissue as necessary. Individuals who received a lumpectomy will receive follow up radiation therapy.Individuals with Paget's disease of the breast will receive additional, supportive therapy called adjuvant therapy that is designed to complement surgery and prevent the cancer from recurring. Adjuvant therapy may include radiation therapy, anti-cancer drugs (chemotherapy) and hormone therapy.Paget’s disease of the breast has a prognosis that is intimately tied with the underlying ductal cancer. The underlying ductal cancers often have poor prognostic features than typical, often screen detected breast cancers including higher grade, larger size, and negative hormone receptor expression (loss of estrogen and progesterone) receptors. However, a Paget’s presentation does not make the prognosis any worse than the underlying malignancy’s prognosis.
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Therapies of Paget’s Disease of the Breast. TreatmentThe therapeutic management of individuals with Paget's disease of the breast may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses and other healthcare professionals.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as extent of the primary tumor (stage) and degree of malignancy (grade); the nature, size, and invasiveness of an underlying breast malignancy and the presence or absence of metastatic disease; individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference, and other appropriate factors.Treatment has traditionally included surgical removal of breast tissue, adjacent lymph nodes, and, in some cases, underlying muscles of the upper chest wall and other tissues (modified radical or radical mastectomy). Some individuals may only require a simple mastectomy, in which the breast and the lining over the chest muscles are removed.In selected cases where there is no palpable breast mass and negative mammograms, or in those with disease confined to the nipple and areola, conservative tissue-sparing surgery (lumpectomy) may be recommended. During this surgery, the nipple and areola are removed along with a small section of breast tissue. A physician will attempt to remove as little breast tissue as necessary. Individuals who received a lumpectomy will receive follow up radiation therapy.Individuals with Paget's disease of the breast will receive additional, supportive therapy called adjuvant therapy that is designed to complement surgery and prevent the cancer from recurring. Adjuvant therapy may include radiation therapy, anti-cancer drugs (chemotherapy) and hormone therapy.Paget’s disease of the breast has a prognosis that is intimately tied with the underlying ductal cancer. The underlying ductal cancers often have poor prognostic features than typical, often screen detected breast cancers including higher grade, larger size, and negative hormone receptor expression (loss of estrogen and progesterone) receptors. However, a Paget’s presentation does not make the prognosis any worse than the underlying malignancy’s prognosis.
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Overview of Pallister Killian Mosaic Syndrome
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SummaryPallister-Killian mosaic syndrome is a rare chromosomal disorder caused by the presence of at least four copies of the short arm of chromosome 12 instead of the normal two. Major symptoms may include a coarse face with a high forehead, sparse hair on the scalp, an abnormally wide space between the eyes, a fold of the skin over the inner corner of the eyes, and a broad nasal bridge with a highly arched palate. Intellectual disability, loss of muscle tone, and streaks of skin lacking color are often present.IntroductionIn 1977, the syndrome was reported independently by Pallister, and again in 1981 by Teschler-Nicola and Killian. However, it wasn’t until 2003 when Pallister performed chromosome an analysis on skin fibroblast that the presence of tetrasomy 12p was found.
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Overview of Pallister Killian Mosaic Syndrome. SummaryPallister-Killian mosaic syndrome is a rare chromosomal disorder caused by the presence of at least four copies of the short arm of chromosome 12 instead of the normal two. Major symptoms may include a coarse face with a high forehead, sparse hair on the scalp, an abnormally wide space between the eyes, a fold of the skin over the inner corner of the eyes, and a broad nasal bridge with a highly arched palate. Intellectual disability, loss of muscle tone, and streaks of skin lacking color are often present.IntroductionIn 1977, the syndrome was reported independently by Pallister, and again in 1981 by Teschler-Nicola and Killian. However, it wasn’t until 2003 when Pallister performed chromosome an analysis on skin fibroblast that the presence of tetrasomy 12p was found.
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Symptoms of Pallister Killian Mosaic Syndrome
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Individuals with Pallister-Killian mosaic syndrome typically have low muscle tone at birth (hypotonia), sparse scalp hair, a high forehead, a coarse face, an abnormally wide space between the eyes, a broad nasal bridge, a highly arched palate, a fold of the skin over the inner corner of the eyes, and large ears with lobes that are thick and protrude outward.Infants that are born with significant hypotonia can experience problems with feeding, breathing, walking and standing. About seventy percent of affected individuals are unable to walk without assistance. Additional features frequently found in affected individuals may include streaks of skin in which there is no color (hypopigmentation); extra nipples; seizures; droopy upper eyelids, crossed eyes (strabismus); joints that will not move (contractures); and delays in perceiving, recognizing, judging, sensing, reasoning or imagining (cognitive delays). Intellectual disability and difficulties with speech development often occur as well. In rare cases, affected children may experience hearing loss.Congenital heart defects, hernias of the diaphragm, a narrowing of the external auditory canal (stenosis) and an abnormal opening in the anus have also been associated with Pallister-Killian Mosaic Syndrome. Some affected individuals may have an underdeveloped (hypoplastic) lung, abnormalities of the genitourinary system, and skeletal malformations. Symptoms may vary according to which tissue has the additional chromosomal material, and may also affect each side of the body unevenly.
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Symptoms of Pallister Killian Mosaic Syndrome. Individuals with Pallister-Killian mosaic syndrome typically have low muscle tone at birth (hypotonia), sparse scalp hair, a high forehead, a coarse face, an abnormally wide space between the eyes, a broad nasal bridge, a highly arched palate, a fold of the skin over the inner corner of the eyes, and large ears with lobes that are thick and protrude outward.Infants that are born with significant hypotonia can experience problems with feeding, breathing, walking and standing. About seventy percent of affected individuals are unable to walk without assistance. Additional features frequently found in affected individuals may include streaks of skin in which there is no color (hypopigmentation); extra nipples; seizures; droopy upper eyelids, crossed eyes (strabismus); joints that will not move (contractures); and delays in perceiving, recognizing, judging, sensing, reasoning or imagining (cognitive delays). Intellectual disability and difficulties with speech development often occur as well. In rare cases, affected children may experience hearing loss.Congenital heart defects, hernias of the diaphragm, a narrowing of the external auditory canal (stenosis) and an abnormal opening in the anus have also been associated with Pallister-Killian Mosaic Syndrome. Some affected individuals may have an underdeveloped (hypoplastic) lung, abnormalities of the genitourinary system, and skeletal malformations. Symptoms may vary according to which tissue has the additional chromosomal material, and may also affect each side of the body unevenly.
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Causes of Pallister Killian Mosaic Syndrome
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Pallister-Killian mosaic syndrome is caused by the presence of four copies of the short arm of chromosome 12 instead of the normal two. The extra two copies of the short arm of chromosome 12 (12p) usually appear as a single chromosome (isochromosome) and are sometimes present in some but not all cells examined (mosaicism). The chromosome abnormality in Pallister-Killian mosaic syndrome is limited to specific cell types. The mechanism and parental origin of the isochromosome 12p can usually not be determined. The extra genetic material disrupts the normal course of development and results in the signs and symptoms of this disorder.Pallister-Killian mosaic syndrome is not inherited; the disorder is the result of a random event during the formation of reproductive cells, it usually occurs in the mother. Typically, an error in cell division (nondisjunction) causes a reproductive cell to contain an isochromosome 12p.
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Causes of Pallister Killian Mosaic Syndrome. Pallister-Killian mosaic syndrome is caused by the presence of four copies of the short arm of chromosome 12 instead of the normal two. The extra two copies of the short arm of chromosome 12 (12p) usually appear as a single chromosome (isochromosome) and are sometimes present in some but not all cells examined (mosaicism). The chromosome abnormality in Pallister-Killian mosaic syndrome is limited to specific cell types. The mechanism and parental origin of the isochromosome 12p can usually not be determined. The extra genetic material disrupts the normal course of development and results in the signs and symptoms of this disorder.Pallister-Killian mosaic syndrome is not inherited; the disorder is the result of a random event during the formation of reproductive cells, it usually occurs in the mother. Typically, an error in cell division (nondisjunction) causes a reproductive cell to contain an isochromosome 12p.
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Affects of Pallister Killian Mosaic Syndrome
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Pallister-Killian mosaic syndrome is a very rare disorder that affects males and females in equal numbers. The exact prevalence is unknown; this disorder may be underdiagnosed because it is difficult to detect in patients with mild symptoms. Currently, more than 150 people with this disorder have been reported in the medical literature.
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Affects of Pallister Killian Mosaic Syndrome. Pallister-Killian mosaic syndrome is a very rare disorder that affects males and females in equal numbers. The exact prevalence is unknown; this disorder may be underdiagnosed because it is difficult to detect in patients with mild symptoms. Currently, more than 150 people with this disorder have been reported in the medical literature.
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Pallister Killian Mosaic Syndrome
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