Fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva (FOP), sometimes referred to as Stone Man Syndrome, is an extremely rare disease of the connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...

. A mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

 of the body's repair mechanism causes fibrous tissue (including muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

, tendon
A tendon is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension. Tendons are similar to ligaments and fasciae as they are all made of collagen except that ligaments join one bone to another bone, and fasciae connect muscles to other...

, and ligament
In anatomy, the term ligament is used to denote any of three types of structures. Most commonly, it refers to fibrous tissue that connects bones to other bones and is also known as articular ligament, articular larua, fibrous ligament, or true ligament.Ligament can also refer to:* Peritoneal...

) to be ossified
Ossification is the process of laying down new bone material by cells called osteoblasts. It is synonymous with bone tissue formation...

 when damaged. In many cases, injuries can cause joints to become permanently frozen in place. Surgical removal of the extra bone growths has been shown to cause the body to "repair" the affected area with more bone.


Children born with FOP have deformed great toes
In tetrapods, the hallux is the innermost toe of the foot. Despite its name it may not be the longest toe on the foot of some individuals...

, possibly missing a joint or simply presenting with a notable lump at the minor joint. The first "flare-up" that leads to the formation of FOP bones usually occurs before the age of 10. FOP is a genetic disease. The bone growth progresses from the top downward, just as bones grow in fetuses. A child with FOP will typically develop bones starting at the neck, then on the shoulders, arms, chest area and finally on the feet. Specifically, FOP involvement is typically seen first in the dorsal, axial, cranial and proximal regions of the body. Later the disease progresses in the in the ventral, appendicular, caudal and distal regions of the body. However it does not necessarily occur in this order due to injury-caused flare-ups. Often, the tumor-like lumps that characterize the disease appear suddenly.

The gene that causes ossification is normally deactivated after a fetus' bones are formed in the womb, but in patients with FOP, the gene 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
Bone morphogenetic protein 4
Bone morphogenetic protein 4 is a protein that in humans is encoded by` BMP4 gene.BMP4 is a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfamily...

 (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. Interestingly, 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.

Because the disease is so rare, the symptoms are often misdiagnosed as cancer or fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...

. This leads doctors to order biopsies
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...

, which can actually exacerbate the growth of these lumps.


Since the 1800s there have been references in medicine describing people who apparently "turned to stone"; some of these cases may be attributable to FOP.

The best known FOP case is that of Harry Eastlack
Harry Raymond Eastlack
-External links:* The skeleton of Harry Eastlack at the International Fibrodysplasia Ossificans Progressiva Association website...

 (1933–1973). His condition began to develop at the age of ten and, by the time of his death from pneumonia in November 1973, six days before his 40th birthday, his body had completely ossified, leaving him able to move only his lips.

Shortly before Eastlack's death he made it known that he wanted to donate his body to science, in the hope that in death he would be able to help find a cure for this little-understood and particularly cruel disease. Pursuant to his wishes, his preserved skeleton is now kept at the Mütter Museum
Mütter Museum
The Mütter Museum is a medical museum located in the Center City area of Philadelphia, Pennsylvania. It contains a collection of medical oddities, anatomical and pathological specimens, wax models, and antique medical equipment. The museum is part of The College of Physicians of Philadelphia. The...

 in Philadelphia, and has proven to be an invaluable source of information in the study of FOP.

Currently, there are approximately 450 confirmed cases of FOP in the world.


There is no known cure for FOP. Attempts to surgically remove the bone result in more robust bone growth. While under anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...

, patients with FOP may face problems, which include difficulties with intubation
Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic or rubber tube into the trachea to maintain an open airway or to serve as a conduit through which to administer certain drugs...

, restrictive pulmonary disease and changes in the electrical conduction system of the heart
Electrical conduction system of the heart
The normal intrinsic electrical conduction of the heart allows electrical propagation to be transmitted from the Sinoatrial Node through both atria and forward to the Atrioventricular Node. Normal/baseline physiology allows further propagation from the AV node to the ventricle or Purkinje Fibers...

Activities that increase the risk of falling should be avoided, as injuries from falling can provoke the growth of bone.

In 1999 scientists discovered that squalamine
Squalamine is a strong naturally derived broad-spectrum antibiotic that is predominantly derived from the livers of dogfish and other shark species...

 in sharks might be useful in treating those suffering from FOP. Squalamine is antiangiogenic and can prevent the growth of blood vessels in cartilaginous tissue, thus preventing creation of bone in sharks. A trial of squalamine started in 2002 but terminated about 2007. (Note that squalene
Squalene is a natural organic compound originally obtained for commercial purposes primarily from shark liver oil, though plant sources are used as well, including amaranth seed, rice bran, wheat germ, and olives. All plants and animals produce squalene, including humans...

 is a different compound, also found in sharks, that has no such properties.)

there are no registered clinical trials for FOP.


FOP is caused by an autosomal
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...

 dominant allele on chromosome 2q23-24. The allele has variable expressivity
Expressivity is a term used in genetics to refer to variations in a phenotype among individuals carrying a particular genotype. The term can be used to characterize qualitatively or quantitatively the extent of phenotypic variation given a particular genotype. The term is analogous to the...

, but complete penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...

. Most cases are caused by spontaneous mutation in the gamete
A gamete is a cell that fuses with another cell during fertilization in organisms that reproduce sexually...

s; most people with FOP cannot have children. A study has determined that it affects approximately 1 in every 2 million people ("1.8 (SE ± 1.04) × 10-6 mutations per gene per generation"). A similar but less catastrophic disease is fibrous dysplasia
Fibrous dysplasia
Fibrous dysplasia is a disease that causes bone thinning and growths or lesions in one or more bones, and leads to bone weakness and scar formation within the bones.-Presentation:...

, which is caused by a post-zygotic mutation
Post-zygotic mutation
A post-zygotic mutation is a mutation that an organism acquires during its lifespan, rather than inheriting from its parent by the fusion of the haploid pronuclei in the sperm and egg....


A mutation in the gene ACVR1
Activin A receptor, type I also known as ALK-2 is a protein which in humans is encoded by the ACVR1 gene.- Function :...

 (= ALK2) is responsible for the disease. ACVR1 encodes activin receptor type-1, a BMP
Bone morphogenetic protein
Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...

 type-1 receptor. The mutation causes the ACVR1 protein to have the amino acid histidine substituted for the amino acid arginine at position 206. This causes endothelial cells to transform to mesenchymal stem cell
Mesenchymal stem cell
Mesenchymal stem cells, or MSCs, are multipotent stem cells that can differentiate into a variety of cell types, including: osteoblasts , chondrocytes and adipocytes...

s and then to bone.

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.