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Fibrodysplasia ossificans progressiva (; abbr. FOP), also called Münchmeyer disease or formerly myositis ossificans progressiva, is an extremely rare connective tissue disease in which fibrous connective tissue such as muscle, tendons, and ligaments turn into bone tissue. It is the only known medical condition where one organ system changes into another. It is a severe, disabling disorder with no cure. FOP is caused by a mutation of the gene ACVR1. The mutation affects the body's repair mechanism, causing fibrous tissue including muscle, tendons, and ligaments to become ossified, either spontaneously or when damaged as the result of trauma. In many cases, otherwise minor injuries can cause joints to become permanently fused as new bone forms, replacing the damaged muscle tissue. This new bone formation (known as "heterotopic ossification") eventually forms a secondary skeleton and progressively restricts the patient's ability to move. Bone formed as a result of this process is identical to "normal" bone, simply in improper locations. Circumstantial evidence suggests that the disease can cause joint degradation separate from its characteristic bone growth. Surgical removal of the extra bone growth has been shown to cause the body to "repair" the affected area with additional bone. Although the rate of bone growth may differ depending on the patient, the condition ultimately leaves sufferers immobilized as new bone replaces musculature and fuses with the existing skeleton. This has earned FOP the nickname "stone man disease". Signs and symptoms For unknown reasons, children born with FOP often have malformed big toes, sometimes missing a joint or, in other cases, simply presenting with a notable lump at the minor joint. The first "flare-up" that leads to the formation of FOP bone usually occurs before the age of 10. The bone growth generally progresses from the top of the body downward, just as bones grow in fetuses. A child with FOP will typically develop additional bones starting at the neck, then at the shoulders, arms, chest area, and finally at the feet. Specifically, ossification is typically first seen in the dorsal, axial, cranial and proximal regions of the body. Later the disease progresses in the ventral, appendicular, caudal and distal regions. However, it does not necessarily occur in this order due to injury-caused flare-ups. Often, the tumor-like lumps that characterize a flare-up of the disease appear suddenly. Bone growth occurring during flare-ups may result in the loss of mobility to affected joints, including, if the jaw/mandible is involved, the inability to fully open the mouth, limiting speech and eating. A specific occurrence of a flare-up of this condition in the foot/ankle joints can result in the limited ability to put a foot flat on the ground. Bone growth can also result in the immobilization of the hip or knee, affecting the individual's ability to walk. Extra bone formation around the rib cage restricts the expansion of lungs and diaphragm causing respiratory complications. Since the disorder is so rare, the condition may be misdiagnosed as cancer or fibrosis. This leads physicians to order biopsies which can exacerbate the growth of FOP bone. The presence of malformed toes or thumbs in those born with FOP help distinguish this disorder from other skeletal problems. With proper medical management the median age of survival is 40 years. However, delayed diagnosis, trauma, and infections can decrease life expectancy. Causes FOP is caused by an autosomal dominant allele on chromosome 2q23-24. The allele has variable expressivity, but complete penetrance. Most cases are caused by spontaneous mutation in the gametes; most people with FOP cannot or choose not to have children. A similar but less catastrophic disease is fibrous dysplasia, which is caused by a post-zygotic mutation. A mutation in the gene ACVR1 (also known as activin-like kinase 2 (ALK2)) is responsible for the disease. ACVR1 encodes activin receptor type-1, a BMP type-1 receptor. The mutation causes substitution of codon 206 from arginine to histidine in the ACVR1 protein. This substitution causes abnormal activation of ACVR1, leading to the transformation of connective tissue and muscle tissue into a secondary skeleton. This causes endothelial cells to transform to mesenchymal stem cells and then to bone. Normally, the ACVR1 gene encodes the activin receptor type-1 transmembrane kinase that bind BMP receptors (Type I BMPR and Type II BMPR) for chondrogenesis signaling. BMPs belong to a superfamily of proteins known as Transforming growth factor-beta (TGF-β) proteins. The binding of ACVR1 protein to BMP receptors start a signaling cascade that is crucial for inducing endochondral bone formation during development, as well as, skeletal and tissue homeostasis. Genetics FOP is an autosomal dominant disorder. Thus, a child of an affected heterozygous parent and an unaffected parent has a 50% probability of being affected. Two affected individuals can produce unaffected children. Two unaffected individuals can produce an affected offspring as a result of the mutation of the gene. The homozygous dominant form is more severe than the heterozygous form. The protein that causes ossification is normally deactivated by an inhibitory protein after a fetus's bones are formed in the womb, but in patients with FOP, the protein keeps working. Aberrant bone formation in patients with FOP occurs when injured connective tissue or muscle cells at the sites of injury or growth incorrectly express an enzyme for bone repair during apoptosis (self-regulated cell death), resulting in lymphocytes containing excess bone morphogenetic protein 4 (BMP4) provided during the immune system response. The bone that results occurs independently of the normal skeleton, forming its own discrete skeletal elements. These elements, however, can fuse with normal skeletal bone. The diaphragm, tongue, and extra-ocular muscles are spared in this process, as well as cardiac and smooth muscle. Since the incorrect enzyme remains unresolved within the immune response, the body continues providing the incorrect BMP4-containing lymphocytes. BMP4 is a product that contributes to the development of the skeleton in the normal embryo. The ACVR1 gene encodes a bone morphogenic protein (BMP) receptor; this gene is mutated in FOP. It is responsible for growth and development of bone and muscles. The typical mutation, R202H, makes the inhibitor FKBP1A bind less tightly to the activation GS-loop. The result is that ACVR1 is not effectively turned off, and an overgrowth of bone and cartilage and fusion of joints occurs. Atypical mutations involving other residues work similarly. In some cases, the receptor can end up signalling that it's active without being bound to its activating ligand. Most of the cases of FOP were results of a new gene mutation: these people had no history of this particular disorder in their family. The.... Discover the Christopher J Feeley popular books. Find the top 100 most popular Christopher J Feeley books.