Fibrodysplasia Ossificans Progressiva (FOP)

Osteopetrosis is a rare, genetic disease that causes extremely dense and brittle bones. This is because individuals affected with osteopetrosis do not have normal osteoclasts, which bones need to work correctly. Healthy bones require properly functioning osteoblasts and osteoclasts. Osteoblasts are responsible for making new bones and osteoclasts are bone cells that are responsible for bone resorption, which is the breaking down of bones and providing space for new bone marrow to grow. An individual with osteopetrosis has osteoclasts that do not function properly, therefore their bones are not healthy (Stocks, Wang, Thompson, Stocks, & Horwitz, 1998).

The FBN1 gene is responsible for providing instructions for the production of fibrillin-1, which is a protein that is secreted into the matrix of connective tissue (“FBN1,” 2015). Therefore, a mutation in this gene can cause the excessive production of fibrillin-1, and when fibrillin-1 binds to other proteins they form threads called microfibrils. Microfibrils contain a growth factor called transforming growth factor beta or TGF-β (“FBN1,” 2015), so when there is an increase of TGF-β, problems with the connective tissue throughout the body can occur (“What is Marfan Syndrome? | The Marfan Foundation,” n.d.), more of these problems will be elaborated upon further in the report. The genetic mutation in the FBN1 gene is usually hereditary, but it is possible for one to be the first in their family to have this genetic mutation. If one has this mutation

Fibrodysplasia ossificans progressiva also known as FOP is a one of the rarest, most disabling genetic bone conditions known to medicine. FOP causes muscles, tendons, ligaments, and other connective tissues to turn in to bone. Movement becomes limited in the affected areas of the body. People with FOP typically have malformed toes at birth, meaning the big toe is typically shorter than normal and abnormally turned outward in a position called a valgus deviation. Symptoms of FOP start to show up in early childhood. Most people with FOP develop painful tumor-like swellings also known as fibrous nodules. The fibrous nodules are visible on the neck, shoulders, and back.

Fibrodysplasia ossificans progressiva (FOP) is a disorder in which muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone, forming bone outside the skeleton (extra-skeletal or heterotopic bone) that constrains movement. It usually becomes evident during early childhood, always starting with the neck and shoulders and proceeding down the body into the limbs.

Crouzon syndrome is an autosomal dominant genetic disorder and is the most common craniosynostosis syndrome with an incidence of 16.5/1,000,000, representing 4.8% of craniosynostosis cases, and a prevalence of 1/60,000 in the U.S. Crouzon syndrome is caused by an activating mutation of the FGFR2 gene, an important factor in the conversion of the fibrous joint areas between sutures to bone. Specifically, the missense mutation occurs within exons IIIa and exon IIIc of the extracellular immunoglobulin domain, IgIII, in 95% of Crouzon patients. Generally, cysteine residues are replaced, preventing critical disulfide bond formation and ultimately cause spatiotemporal malformations. There are at least 32 documented unique mutations, 30-60% of which are sporadic, spontaneous mutations.

Fibrodysplasia Ossificans Progressiva is a rare disease that over activates osteogenesis, or bone formation. The disease may also be referred to as “the stone man” disease because it essentially leads to the stiffening of the body, causing restricted mobility. Overall, the predisposition for fibrodysplasia is extremely low for individuals worldwide, as it only affects 1 in 2 million people (10). There seems to be no clear correlation of demographics of people suffering from FOP; the genetic disorder occurs randomly. However, those who live with the disorder face a difficult predicament.

Fibrodysplasia Ossificans Progressiva disease also known as ‘FOP’ is a rare genetic disease of the connective tissue. FOP can be characterized by malformations of the big toe. This malformation is a characteristic feature that helps distinguish the disease from other muscle and bone issues. It is a disease that is caused by a mutation in the bodies repair mechanism. This causes muscle and connective tissue such as ligaments and tendons, to be ossified spontaneously or when they are damaged. Sometimes the bone can be permanently frozen in place in some cases. FOP is usually seen in early childhood it starts with the neck and shoulder and proceeds down the body and into the limbs. People who suffer from FOP are basically imprisoned by their own skeleton. Majority of FOP cases are sporadic and are a result from a new gene mutation (Lerardi-Curto and Lynne). This mutation is an autosomal dominant disorder; this means it affects those who are heterozygous with a homozygous recessive partner because of this it means their children will have a fifty percent chance of having FOP. Most cases of FOP are a result from new mutations in the gene. People who have FOP and have the heterozygous phenotype have less severe affects than those who have the homozygous dominant phenotype. Patients who have FOB have the ossification gene that is still working in their bodies and it is usually turned off after a

“Marfan syndrome is a genetic disorder that affects the body’s connective tissue.” (Marfan Foundation, 2014) Connective tissue serves a crucial role in the functions of the human body. More specifically, connective tissue is what holds together the cells, organs, and tissue in the human body. Due to its structural significance, it also helps the body to develop and grow properly. “Connective tissue is made up of proteins. The protein that plays a role in Marfan syndrome is called fibrillin-1.” (Marfan Foundation, 2014) Marfan syndrome stems from a mutation within the gene that codes for fibrillin-1. This mutation increases the production of a protein called “…transforming growth factor beta…” In response to the increase of this protein, problems in connective tissues result, therefore causing Marfan syndrome. (Marfan Foundation, 2014)

The condition is caused by a mutation in the gene that controls the structure of fibrillin-1, a protein that is a vital part of connective tissue. The main purpose of connective tissue is to hold the body together

Fibrodysplasia Ossificans Progressiva, FOP, is a rare and disabling bone disease. It is caused by a genetic mutation of the gene that controls the growth and development of the bones and muscles. The man who discovered this game-changing information is Dr. Kaplan. “The discovery of the mutation immediately suggests an approach to treatment: either to block the renegade proteins or to destroy the message coming from the mutant copy of the gene that creates the renegade proteins, says Kaplan” (Cause of: FOP). Muscle and connective tissues, as well as tendons and ligaments, are gradually ossified, meaning they are replaced by bone. This limits and eventually permanently prohibits movement. FOP usually starts

The FBN1 gene located on chromosome 15q21.1 codes for fibrillin-1 and contains 65 coding and 3 spliced exons. Fibrillin-1 has 6 conserved cysteine residues and 7 TGF-B binding domains and its role is to form sheaths around elastic fibres thus controlling the elasticity and flexibility of connective tissue [6]. Sixty six percent of genetic mutations causing Marfan’s syndrome are missense mutations. This can cause an amino acid to be changed for another, resulting in changes in the protein’s

Crouzon Syndrome is an autosomal dominant disorder of the first branchial arch, which acts as a precursor to the maxilla and mandible. The disease was originally known as craniofacial dysostosis, referring to the malformation of bone around the face. The malformation of bone is due to early fusing of an infant’s skull and facial bones, or the bones’ inability to expand correctly. Common symptoms that arise from the disease include low-set ears, bulging eyes, relatively large distance between the eyes, and a beak-like nose. The major genetic cause of Crouzon Syndrome is a mutation occurring in a gene known as the fibroblast growth factor receptor 2 (FGFR2) gene that resides on chromosome 10, which encodes for the FGFR2 protein. This protein is involved in many bodily processes such as wound healing and embryonic development. Due to the widespread importance of the FGFR2 gene, mutations can have morbid and fatal consequences.

A concomitant mechanism involving the overproduction of bone morphogenic protein-4 by muscle cells or the muscle fascia is also present. Myositis ossificans commonly referred to as ‘heterotopic ossification’, is an extraosseous, non-neoplastic formation of new bone within a muscle and most frequently follows a blunt trauma or persistent inflammation. However, 25% of cases may have no known etiology. The exact mechanism for pathogenesis is ill-defined, but trauma is universally made-out as trigger involved.33 Four main theories of this phenomenon are listed

Achondroplasia is caused by an abnormal gene located on one of the chromosome 4 pair (humans have 23 pairs of chromosomes). It is a result of an autosomal dominant mutation in the fibroblast growth factor receptor gene 3 (FGFR3), which causes an abnormality of cartilage formation. FGFR3 normally has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones.

Achondroplasia is caused by a mutation in the FGFR3 gene which is located on the fourth chromosome. It is an autosomal gene that is dominant that can be passed down by the parents. Most parents of people who suffer from achondroplasia have parents without the disorder, but new mutations constantly arise with the FGFR3 gene. Normally cartilage converts to bone during human development, but people who suffer from achondroplasia are unable to do so with most cartilage in the body. This is mostly due to the FGFR3 gene producing too many proteins that interfere with human development.