Part 3: Bone Pathology

1. Part 3:Bone Pathology

2. Bone Topics to Look Into • Rickets and Vitamin D • Dwarfism achondroplasia • rheumatoid arthritis • arthritis • tendonitis • bone marrow • bone grafts • bone marrow transplants • fossil arthritis dinosaurs • mummy X-rays • tooth development • tooth decay • Neurofibromatosis “Elephant Man” • bone cancer • multiple myoloma • fractures and treatment • hip replacement • osteoporosis • bone mass • thalidomide • teratogens

3. Congenital Malformations: Pie Chart • albinism- autosomal recessive trait resulting in lack of pigment in skin, hair and retina. • amelogenesis imperfecta- hypocalcification leads to soft enamal on teeth. Yellow dentine is visible through the thin layer of enamal. • angiomas- vascular disorder resulting in excessive vascularisation. • dentinogenesis imperfecta-odontoblasts fail to differentiate. Enamal of teeth wears excessively. • enamal hypoplasia- environmental facors affecting ameloblast formation of enamal on teeth. • gynecomastia- stimulation by maternal sex hormones leads to excessive development of newborn male mammary glands. • ichthyosis- excessive keratinization disorder. • http://anatomy.med.unsw.edu.au/cbl/embryo/Notes/skin2.htm#abnormal

4. Rickets and Vitamin D http://georgia.ncl.ac.uk/VitaminD/vitaminD.html

5. Bone Growth and Development and Vitamin D When crystals of hydroxyapatite (a complex of calcium, hydroxyl and phosphate ions) are laid down between collagen fibres, bone calcification occurs. These ions in bone are in dynamic equilibrium with ions present in the bloodstream, an equilibrium which is regulated by Vitamin D and by two peptide hormones, Parathyroid Hormone (PTH) and calcitonin. As late as the 1930s and 1940s, when the role of dietary Vitamin D in normal bone growth and development was not recognised, rickets was an all too common feature of community life, particularly in areas with little sun exposure. The role of Vitamin D is largely played at the site of the mucosal cells of the intestine, where it stimulates calcium absorption and retrieval to the blood stream from food passing through the gut, as well as in the proximal tubules of the kidney, where it promotes re-absorption of phosphate which would otherwise be excreted in urine. The constant turnover (dynamic equilibrium) of the ions of bone crystal between those in the bloodstream and those stored in bone itself, is an important feature both in formation and in repair of bone. Three types of cells work together in this process: osteoblasts, osteocytes, osteoclasts. The osteoblasts synthesis the matrix upon which bone crystals are laid down; the osteocytes interlink this matrix with long filaments; the osteoclasts, which sit on the surface of bone crystals, are important in maintaining calcium and phosphate ion equilibrium with the blood stream. (it goes on…) http://georgia.ncl.ac.uk/VitaminD/BoneGD.html

6. NeurofibromatosisJoseph Merrick the “Elephant Man” Suffered from Either Nuerofibromatosis or Proteus Syndrome http://nfinc.org/noele.html http://www.jsitton.pwp.blueyonder.co.uk/elephantman/elephant_man.htm Proteus Syndrome: http://dermis.net/doia/diagnose.asp?zugr=d&lang=e&diagnr=9940&topic=t

7. Effects of Neurofibromatosis type 1 (NF-1) • Neurofibromatosis type 1 (NF-1) is an autosomal dominantgenetic disorder that causes tumors to grow on the coveringof the nerves anywhere in the body at any time. The disorderaffects 1 in 3,000 males and females of all races and ethnicgroups. The NF-1 gene is located on chromosome 17. • http://nfinc.org/nfbody1.html

8. Effects of Neurofibromatosis type 2 (NF-2) Neurofibromatosis type 2 (NF-2) is an autosomal dominantgenetic disorder that causes tumors to form on the nervesof the central nervous system, in the brain, and on the spine.It affects one in 33,000-40,000 males and females of allraces and ethnic groups. The NF-2 gene is located onchromosome 22.http://nfinc.org/nfbody2.html

9. Teratogen and Thalidomide • Teratogen • A teratogen, also referred to as a teratogenic agent, is an environmental agent that can cause abnormalities in a developing organism, resulting in either fetal death or congenital abnormality. The human fetus is separated from the mother by the placental barrier, but the barrier is imperfect and permits a number of chemical and infectious agents to pass to the fetus. Well-known teratogens include (but are not limited to) alcohol, vitamin A and retinoic acid in excessive doses, the rubella virus, the syphilis bacterium, and high levels of ionizing radiation. In the 1960s, it was discovered that the tranquilizer thalidomide had serious side effects when taken during pregnancy. Although thalidomide was never sold legally in the United States, it was available elsewhere in the world and prescribed freely during the 1940s and 1960s. It was later shown to induce birth defects, especially severe limb abnormalities known as phocomelia, in children whose mothers took the drug. • http://www.findarticles.com/cf_dls/g2602/0005/2602000523/p1/article.jhtml

10. What is Thalidomide Thalidomide is a drug that was introduced on to the market on October 1, 1957 in West Germany. Thalidomide soon became a drug prescribed to pregnant women to combat symptoms associated with morning sickness. When taken during the first trimester of pregnancy, Thalidomide prevented the proper growth of the foetus resulting in horrific birth defects in thousands of children around the world. These children were born in the late 1950's and early 1960's and became known as "Thalidomide babies". See What Is Thalidomide for more information. http://www.ogopogo.com/thalidomide/english/index.htm

11. Effects of Thalidomide • When Thalidomide was taken during pregnancy (particularly during a specific window of time in the first trimester), it caused startling birth malformations, and death to babies. Any part of the foetus that was in development at the time of ingestion could be affected. • For those babies who survived, birth defects included: deafness, blindness, disfigurement, cleft palate, many other internal disabilities, and of course the disabilities most associated with Thalidomide: phocomelia. • http://www.ogopogo.com/thalidomide/english/wit.html

12. History of Thalidomide Thalidomide was synthesized in West Germany in 1953 by Chemie Grünenthal. It was marketed (available to patients) from October 1, 1957 (West Germany) into the early 1960's. Thalidomide was present in at least 46 countries under many different brand names. (See The many faces of Thalidomide for a partial list of those names.) Thalidomide became available in "sample tablet form" in Canada in late 1959. It was licensed for prescription use on April 1, 1961. Although Thalidomide was withdrawn from the West German and United Kingdom markets by December 2, 1961, it remained legally available in Canada until March 2, 1962, a full three months later. Incredulously Thalidomide was still available in some Canadian pharmacies until mid-May 1962. http://www.ogopogo.com/thalidomide/english/wit.html

13. The pattern of thalidomide defects The pattern of thalidomide defects Thalidomide is associated in the public mind with limb defects, and these certainly account for the majority of cases. However, almost any organ of the body would be affected. The second major group of defects involves the ears, the eyes, and the nerve supplies to the face, the eye muscles, and the lacrimal (tear) glands. Internal defects commonly affected the heart, the kidneys and urinary tract, the alimentary tract, and the genital tract, and none was unique to thalidomide. The early mortality rate among ‘thalidomide babies’ was about 40%, largely as a result of serious internal malformations. Consequently, internal defects are much less common among survivors than they were among the whole group at birth. Most of the serious internal defects caused problems at or soon after birth which either required treatment or led to death. Some defects of the kidneys and female genital tract which can only be shown by special tests did not become apparent until many years after birth. It is possible that there are still undetected internal problems in people aged 30 years or more, but as time passes it becomes increasingly unlikely that any such hidden defects will cause significant problems. They will therefore play little part in the diagnosis of thalidomide damage in the future. A small but important group of thalidomide related problems includes conditions which are not present at birth but develop later. Abnormalities of the spine were recognized early, and of the knees rather later. Other bones/joints may also be affected. It is to be expected that the thalidomide damaged people will be prone to the same ills as beset the rest of the population. A causal connection with thalidomide would be suggested if a particular disease was more common among the thalidomide population than among the general population from which they came, or if the disease presented at an unusual age or in an unusual way. http://www.ogopogo.com/thalidomide/english/smithell.htm

14. THALIDOMIDE SURVIVORS TODAY Giselle Cole now champions the cause for thalidomade victims. http://www.tv.cbc.ca/witness/thalidomide/extratoday.htm

15. Thalidomide Children The most common deformity suffered by children whose mothers took thalidomide was stunted or missing arms and legs (DPA/Archive Photos) http://more.abcnews.go.com/sections/living/thalidbkgd/

16. X-Rays of Shortened Limbs Fig. 1. Photographic reproduction of a tracing of the upper extremity roentgenograms of four patients with Thalidomide related anomalies of the upper extremities (see Table I). http://www.jacpoc.oandp.com/library/1994_02_051.asp

17. Rheumatoid Arthritis A joint is where two bones meet to allow movement of body parts. Arthritis means joint inflammation. The joint inflammation of rheumatoid arthritis causes swelling, pain, stiffness, and redness in the joints. The inflammation of rheumatoid disease can also occur in tissues around the joints, such as the tendons, ligaments, and muscles. In some patients with rheumatoid arthritis, chronic inflammation leads to the destruction of the cartilage, bone and ligaments causing deformity of the joints. http://www.medicinenet.com/Rheumatoid_Arthritis/page1.htm

18. Rheumatoid Arthritis in the Hand The attack on a joint by the disease usually begins with the synovium. Early in the disease, edema begins to be seen in cells in the synovium and multiplication of synovial lining cells occur. As the disease progresses, the synovium may grow considerably larger eventually forming tissue called pannus. Pannus can be considered the most destructive element affecting joints in the patient with rheumatoid arthritis. Pannus can attack articular cartilage and destroy it. Further, pannus can destroy the soft subchondral bone once the protective articular cartilage is gone. The synovial fluid secreted by the synovium is thought to serve two main purposes, lubrication of the joint and provision of nutrients to the avascular articular cartilage. In this disease process, an interaction between antibodies and antigens occurs, and causes alterations in the composition of the synovial fluid. Ultimately, digestants are formed in the fluid which attack the surrounding tissue. Once the composition of this fluid is altered, it is less able to perform the normal functions noted above, and more likely to become destructive. http://www.duq.edu/PT/RA/EffectsOnJoints.html#Effects

19. Rheumatoid arthritis is an autoimmune disease Rheumatoid arthritis is an autoimmune disease which causes chronic inflammation of the joints. Rheumatoid arthritis can also cause inflammation of the tissue around the joints, as well as other organs in the body. Autoimmune diseases are illnesses which occur when the body tissues are mistakenly attacked by its own immune system. The immune system is a complex organization of cells and antibodies designed normally to "seek and destroy" invaders of the body, particularly infections. Patients with these diseases have antibodies in their blood which target their own body tissues, where they can be associated with inflammation. Because it can affect multiple other organs of the body, rheumatoid arthritis is referred to as a systemic illness and is sometimes called rheumatoid disease. http://www.medicinenet.com/Rheumatoid_Arthritis/page1.htm

20. Severe Rheumatoid Arthritis of the Hand http://www.duq.edu/PT/RA/EffectsOnJoints.html#Effects

21. Severe Hand Deformity fromRheumatoid Arthritis This deformity of the hand is due to rheumatoid arthritis (RA). This autoimmune disease leads to synovial proliferation and joint destruction, typically in a symmetrical pattern involving small joints of hands and feet, followed by wrists, ankles, elbows, and knees. Rheumatoid factor can be identified serologically in most, but not all, RA patients. http://www-medlib.med.utah.edu/WebPath/BONEHTML/BONE043.html

22. Dwarism and Achondroplasia Achondroplasia is the most common form of disproportionate short stature.[1] The diagnosis is based on very specific features on the radiographs, which include a contracted base of the skull, a square shape to the pelvis with a small sacrosciatic notch, short pedicles of the vertebrae, rhizomelic (proximal) shortening of the long bones, trident hands, a normal length trunk, proximal femoral radiolucency, and, by mid-childhood, a characteristic chevron shape of the distal femoral epiphysis. Hypochondroplasia and thanatophoric dysplasia are part of the differential diagnosis, but achondroplasia can be distinguished from these because the changes in hypochondroplasia are milder and the changes in thanatophoric dysplasia are much more severe and invariably lethal. Achondroplasia is an autosomal dominant disorder, but approximately 75% of cases represent new dominant mutations. The gene for achondroplasia has recently been found. Achondroplasia is due to a change in the genetic information for fibroblast growth factor receptor 3.[2,3] Almost all of the mutations have been found to occur in exactly the same spot. Now that the gene has been found and the mutation known, potential therapies and diagnostic methodologies are likely to be developed. A great deal is known about the natural history of the disorder that can be shared with the family. The average adult height in achondroplasia is about 4 ft for both men and women ( Fig 1, Fig 2, Fig 3, Fig 4, Fig 5, and Fig 6).[4] Other features include disproportionate short stature, with shortening of the proximal segment of the limbs, a prominent forehead, a flattened midface, and an average-sized trunk. The head usually appears relatively large compared with the body. The most common complication, occurring in adulthood, is related to lumbosacral spinal stenosis with compression of the spinal cord or nerve roots.[5,6] This complication is usually treatable by surgical decompression, if diagnosed at an early stage.        Children affected with achondroplasia frequently have delayed motor milestones, otitis media, and bowing of the knees ( Fig 7).[7] Occasionally in infancy or early childhood there is symptomatic airway obstruction, development of thoracolumbar kyphosis, symptomatic hydrocephalus, or symptomatic upper cord compression. Most individuals with achondroplasia are of normal intelligence and are able to lead independent and productive lives.[8] Because of their disproportionate short stature, however, a number of psychosocial problems can arise. Families can benefit from anticipatory guidance and the opportunity to learn from other families with children of disproportionate short stature.http://www.aap.org/policy/00696.html

23. Autosomal Dominant Inheritancein Acondroplasia • As discussed above, conditions due to autosomal dominant conditions result from an individual carrying one changed gene. Examples of autosomal dominant forms of dwarfism include achondroplasia and hypochondroplasia. A person with achondroplasia for example, has a 50% or 1 in 2 chance of passing the gene on to his/her offspring. • Clues that geneticists use when looking at pedigrees to determine autosomal dominant inheritance include the following facts: • Autosomal dominant conditions are seen in every generation (vertical pattern). • Males and females have the condition with equal frequency and severity. • Unaffected individuals do not have children with the condition. • Each child of an affected individual has a 50% chance of being affected, regardless of sex or birth order. • Homozygotes for autosomal dominant conditions (individuals with two changed genes) have a more severe form of the disease. An example of this is the "double-dominant" form of achondroplasia that can occur when two people with achondroplasia have children (see below). • Autosomal Dominant Pedigree • http://www.hopkinsmedicine.org/greenberg.center/tutorial.htm#autodom

24. Autosomal Dominant Pedigree http://www.hopkinsmedicine.org/greenberg.center/tutorial.htm#autodom

25. Key to Pedigree Symbols Greenberg Center for Skeletal Dysplasias http://www.hopkinsmedicine.org/greenberg.center/key.htm

26. Type II Collagen Conditions • Hypochondrogenesis, SED, SEMD, Kniest Syndrome • I. Introduction • Collagen is a protein that is a component of bone, cartilage, and connective tissue. Several skeletal dysplasias (dwarfing conditions) are due to changes in a protein called type II collagen. These include: • hypochondrogenesis • spondyloepiphyseal dysplasia congenita (SEDc) • spondyloepimetaphyseal dysplasia, Strudwick (SEMD) • Kniest dysplasia • Type 2 collagen is the major collagen of the nucleus pulposa (a component of the spine), cartilage, and vitreous (a component of the eye), All of these conditions therefore have common clinical and radiographic findings including spinal changes resulting in a short-trunked form of dwarfism, myopia, and retinal degeneration. • http://www.hopkinsmedicine.org/greenberg.center/SED.htm

27. Scoliosis http://members.tripod.com/my_back/scoliosis/index.html

28. Gout: Xray of Foot Chronic gout leads to deposion of urates into a chalky mass known as a "tophus". Such tophi can destroy the joint and adjacent bone as seen here radiographically in sequential radiographs of the same foot (the patient did not have two right feet). In most, but not all, cases there is hyperuricemia. http://www-medlib.med.utah.edu/WebPath/BONEHTML/BONE062.html

29. Sickle Cell Anemia Sickle cells are red blood cells that have become crescent shaped. When a person with sickle cell anemia is exposed to dehydration, infection, or low oxygen supply, their fragile red blood cells form liquid crystals and assume a crescent shape causing red cell destruction and thickening of the blood. Since the life span of the red blood cell is shortened, there is a temporary depression of red cell production in the bone marrow, and a subsequent fall in hemoglobin (and therefore the resultant anemia). http://www.wadsworth.org/chemheme/heme/microscope/sicklecell.htm

30. Sickle Cells - Another Picture Severe cickling in sickle cell anemia http://www.mcl.tulane.edu/classware/pathology/Krause/AbnormalRBC/AbnormalRBC.html

31. Plasma Cell Leukemia A plasma cell is a mature B lymphocyte that is specialized for antibody (immunoglobulin) production. Plasma cells are rarely found in the peripheral blood. They comprise from 0.2% to 2.8% of the bone marrow white cell count. Mature plasma cells are often oval or fan shaped, measuring 8-15 µm. The nucleus is eccentric and oval in shape. The nucleus to cytoplasm ratio is typically 2:1 to 1:1. The nucleus may be bilobed or multilobed, especially in patients with lymphoid blood dyscrasias. The perinuclear zone is very distinct, appearing white in the deeply basophilic cytoplasm. Nuclear chromatin is condensed and very patchy, appearing as dark blocks on a reddish-purple background. The cytoplasm stains deep blue to gray blue, depending on the stain and the ribosomal content of the individual cell. Plasma cells are seen in multiple myeloma, plasma cell leukemia, Waldenström's macroglobulinemia, and MGUS (monoclonal gammopathy of uncertain significance. The cells depicted in this image are from a patient with plasma cell leukemia. http://www.wadsworth.org/chemheme/heme/microscope/plasmacell.htm

32. Osteomyelitis This is chronic osteomyelitis. Note the fibrosis of the marrow space accompanied by chronic inflammatory cells. There can be bone destruction with remodelling. Osteomyelitis is very difficult to treat. http://www-medlib.med.utah.edu/WebPath/BONEHTML/BONE016.html