Fibrodysplasia ossificans progressiva

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Fibrodysplasia ossificans progressiva
SynonymsStoneman Disease
Fibrodysplasia ossificans progressiva.jpg
The effects of fibrodysplasia ossificans progressiva, a disease which causes damaged soft tissue to regrow as bone.
Specialty Medical genetics

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare connective tissue disease. It is a severe, disabling disease with no cure or treatment and is the only known medical condition where one organ system changes into another.

A connective tissue disease is any disease that has the connective tissues of the body as a target of pathology. Connective tissue is any type of biological tissue with an extensive extracellular matrix that supports, binds together, and protects organs. These tissues form a framework, or matrix, for the body, and are composed of two major structural protein molecules: collagen and elastin. There are many different types of collagen protein in each of the body's tissues. Elastin has the capability of stretching and returning to its original length—like a spring or rubber band. Elastin is the major component of ligaments and skin. In patients with connective tissue disease, it is common for collagen and elastin to become injured by inflammation (ICT). Many connective tissue diseases feature abnormal immune system activity with inflammation in tissues as a result of an immune system that is directed against one's own body tissues (autoimmunity).

Contents

The disease is caused by a mutation of the body's repair mechanism, which causes fibrous tissue (including muscle, tendon, and ligament) to be ossified spontaneously or when damaged. In many cases, otherwise minor injuries can cause joints to become permanently frozen in place, as new bone forms and replaces the damaged muscle tissue. This new bone eventually forms a secondary skeleton and progressively restricts the patient’s ability to move. Circumstantial evidence suggests that the disease can cause joint degradation separate from its characteristic bone growth. [1]

Mutation A permanent change of the nucleotide sequence of the genome of an organism

In biology, a mutation is the permanent alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA or other genetic elements.

Muscle contractile soft tissue of animals

Muscle is a soft tissue found in most animals. Muscle cells contain protein filaments of actin and myosin that slide past one another, producing a contraction that changes both the length and the shape of the cell. Muscles function to produce force and motion. They are primarily responsible for maintaining and changing posture, locomotion, as well as movement of internal organs, such as the contraction of the heart and the movement of food through the digestive system via peristalsis.

Tendon type of tissue that connects muscle to bone

A tendon or sinew is a tough band of fibrous connective tissue that usually connects muscle to bone and is capable of withstanding tension.

Surgical removal of the extra bone growths has been shown to cause the body to "repair" the affected area with even more bone. Although the rate of bone growth develops differently depending on the patient, the condition ultimately leaves those affected in a “frozen” position as new bone replaces musculature and fuses with the skeleton. Adult patients eventually have to decide on what position they wish to predominantly take for the rest of their lives.

Signs and symptoms

For unknown reasons, children born with FOP have deformed 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 bones usually occurs before the age of 10. The bone growth 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 of the body. [2] 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. This condition causes loss of mobility to affected joints, including the inability to fully open the mouth, limiting speech and eating; a specific occurrence of this condition to the foot joints can result in limited ability of the FOP patient to put their foot flat on the ground. Bone growth can also result in the immobilization of the hip or knee, also limiting 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 disease is so rare, the condition may be misdiagnosed as cancer or fibrosis. This leads physicians to order biopsies, which can exacerbate the growth of the FOP bone. [3] The presence of malformed toes or thumbs in those born with FOP help distinguish this disorder from other skeletal problems. [4]

Cancer disease of uncontrolled, unregulated and abnormal cell growth

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss and a change in bowel movements. While these symptoms may indicate cancer, they may have other causes. Over 100 types of cancers affect humans.

Fibrosis

Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This can be a reactive, benign, or pathological state. In response to injury, this is called scarring, and if fibrosis arises from a single cell line, this is called a fibroma. Physiologically, fibrosis acts to deposit connective tissue, which can interfere with or totally inhibit the normal architecture and function of the underlying organ or tissue. Fibrosis can be used to describe the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing. Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis results in scarring and thickening of the affected tissue, it is in essence an exaggerated wound healing response which interferes with normal organ function.

Physician professional who practices medicine

A physician, medical practitioner, medical doctor, or simply doctor is a professional who practises medicine, which is concerned with promoting, maintaining, or restoring health through the study, diagnosis, prognosis and treatment of disease, injury, and other physical and mental impairments. Physicians may focus their practice on certain disease categories, types of patients and methods of treatment—known as specialities—or they may assume responsibility for the provision of continuing and comprehensive medical care to individuals, families, and communities—known as general practice. Medical practice properly requires both a detailed knowledge of the academic disciplines underlying diseases and their treatment—the science of medicine—and also a decent competence in its applied practice—the art or craft of medicine.

The median age of survival is 40 years with proper management. However, delayed diagnosis, trauma, and infections can decrease life expectancy. [5]

Causes

FOP is caused by an autosomal dominant allele on chromosome 2q23-24. [6] 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. [7] 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. [8] [9] 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. [10]

Genetics

DNA sequencing electropherograms of a typical FOP patient being compared to other 2 patients "DNA sequencing electropherograms of a typical FOP patient".png
DNA sequencing electropherograms of a typical FOP patient being compared to other 2 patients

FOP is an autosomal dominant disorder. Thus, children of an affected heterozygous parent and an unaffected parent have a 50% probability of being affected. Two affected individuals can produce unaffected children. The homozygous dominant form is more severe than the heterozygous form. [11]

The gene that causes ossification is normally deactivated after a fetus's 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 (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. [12] The diaphragm, tongue, and extra-ocular muscles are spared in this process, as well as cardiac and smooth muscle. [2] 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. [13]

DNA sequencing electropherograms of a typical FOP patient can differ when being compared to two other patients. The ACVR1 gene encodes a bone morphogenic protein (BMP) receptor; this gene is mutated in FOP. This protein is responsible for growth and development of bone and muscles. Scientists theorize that a mutation in the ACVR1 changes the shape of the receptor and disrupts certain mechanisms that control the receptor's activity. There is a certain molecule, otherwise known as a ligand, that binds at the site to cause this reaction to activate with which it forms a complex. Due to the mutation, however, the bind site is modified and no longer stops the reaction. [14] The end result is an overgrowth of bone and cartilage and fusion of joints. [15]

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. There are some cases which have shown people inheriting the mutation from one affected parent. [15]

Diagnosis

Outbreaks may be measurable clinically by elevated levels of alkaline phosphatase and bone-specific alkaline phosphatase. [16]

Treatment

There is no cure or approved treatment for FOP. [17] Attempts to surgically remove the bone may result in explosive bone growth. [18] While under anesthesia, people with FOP may encounter difficulties with intubation, restrictive pulmonary disease, and changes in the electrical conduction system of the heart. [19] Activities that increase the risk of falling or soft tissue injury should be avoided, as even minor trauma may provoke heterotopic bone formation. [20]

Epidemiology

As of 2017, approximately 800 cases of FOP have been confirmed worldwide making FOP one of the rarest diseases known. [17] The estimated incidence of FOP is 0.5 cases per million people and affects all ethnicities. [17]

History

Medical reports describing individuals affected by FOP date back as far as the seventeenth century. [17] FOP was originally called myositis ossificans progressiva and was thought to be caused by muscular inflammation (myositis) that caused bone formation. [17] The disease was renamed by Victor A. McKusick in 1970 following the discovery that soft tissue other than muscles (e.g. ligaments) were also affected by the disease process. [17]

The best known FOP case is that of Harry Eastlack (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. Eastlack only lived to meet one other person with his same disease.

Eastlack donated his body to science. His skeleton is now at the Mütter Museum in Philadelphia, and has proven to be an invaluable source of information in the study of FOP. Another FOP sufferer, Carol Orzel (c.1960-2018), also donated her body to the museum and her skeleton was placed on exhibit there, adjacent to Eastlack's, in February 2019. [21]

Research

Clinical trials of isotretinoin, etidronate with oral corticosteroids, and perhexiline maleate have failed to demonstrate effectiveness, though the variable course of the disease and small prevalence induces uncertainty. [16]

A handful of pharmaceutical companies focused on rare disease are currently in varying stages of investigation into different therapeutic approaches for FOP.

In August 2015, U.S. Food and Drug Administration (FDA) Office of Orphan Products Development granted La Jolla Pharmaceuticals orphan drug designation for two novel compounds for FOP. The compounds are small-molecule protein kinase inhibitors designed to selectively block ACVR1 (ALK2). [22]

In August 2015, Clementia Pharmaceuticals also began the enrollment of children (ages 6 and above) into its Phase II clinical trial investigating palovarotene for the treatment of FOP. [23] Preclinical studies demonstrated that palovarotene, a retinoic acid receptor gamma agonist, blocked abnormal bone formation in animal models via inhibition of secondary messenger systems in the BMP pathway. [24] Clementia licensed palovarotene from Roche Pharmaceuticals, which previously evaluated the compound in more than 800 individuals including healthy volunteers and patients with chronic obstructive pulmonary disease. Palovarotene received Fast Track designation from the U.S. Food and Drug Administration (FDA) and orphan designations for the treatment of FOP from both the FDA and the European Medicines Agency (EMA). [23]

In September 2015, Regeneron announced new insight into the mechanism of disease involving the activation of the ACVR1 receptor by activin A. In 2016, the company initiated a phase 1 study of its activin antibody, REGN 2477, in healthy volunteers; a phase 2 trial in FOP patients was conducted in 2017. [25]

Another potential therapeutic approach involves allele-specific RNA interference that targets mutated mRNA for degradation while preserving normal ACVR1 gene expression. [26]

Further investigation into the mechanisms of heterotopic bone formation in FOP could aid in the development of treatments for other disorders involving extra-skeletal bone formation.

Fibro/adipogenic progenitors (FAPs) may be the disease causing cell type responsible for activin A dependent ectopic bone formation in both the muscles and tendons of mice bearing the FOP causing ACVR1(R206H) mutation. [27]

Clinical trials of several potential treatments are in progress as of 2019. [28]

See also

Related Research Articles

Paracrine signaling

Paracrine signaling is a form of cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behavior of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to endocrine factors, juxtacrine interactions, and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

Myostatin protein-coding gene in the species Homo sapiens

Myostatin is a myokine, a protein produced and released by myocytes that acts on muscle cells' autocrine function to inhibit myogenesis: muscle cell growth and differentiation. In humans it is encoded by the MSTN gene. Myostatin is a secreted growth differentiation factor that is a member of the TGF beta protein family.

Fibrodysplasia may refer to:

Myositis ossificans myositis that is accompanied by ossification of muscle tissue or bony deposits in the muscles

Myositis ossificans comprises two syndromes characterized by heterotopic ossification (calcification) of muscle.

Heterotopic ossification

Heterotopic ossification (HO) is the process by which bone tissue forms outside of the skeleton.

Noggin (protein) protein-coding gene in the species Homo sapiens

Noggin, also known as NOG, is a protein that is involved in the development of many body tissues, including nerve tissue, muscles, and bones. In humans, noggin is encoded by the NOG gene. The amino acid sequence of human noggin is highly homologous to that of rat, mouse, and Xenopus.

Bone morphogenetic protein 4 gene of the species Homo sapiens

Bone morphogenetic protein 4 is a protein that in humans is encoded by BMP4 gene. BMP4 is found on chromosome 14q22-q23

The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.

ACVR1B protein-coding gene in the species Homo sapiens

Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.

ACVR1 protein-coding gene in the species Homo sapiens

Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; also known as ALK-2. ACVR1 has been linked to the 2q23-24 region of the genome. This protein is important in the bone morphogenic protein (BMP) pathway which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to Fibrodysplasia Ossificans Progressiva, a disease characterized by the formation of heterotopic bone throughout the body.

ACVR2A protein-coding gene in the species Homo sapiens

Activin receptor type-2A is a protein that in humans is encoded by the ACVR2A gene. ACVR2A is an activin type 2 receptor.

The activin type 2 receptors belong to a larger TGF-beta receptor family and modulate signals for transforming growth factor beta ligands. These receptors are involved in a host of physiological processes including, growth, cell differentiation, homeostasis, osteogenesis, apoptosis and many other functions. There are two activin type two receptors: ACVR2A and ACVR2B.

ACVR2B protein-coding gene in the species Homo sapiens

Activin receptor type-2B is a protein that in humans is encoded by the ACVR2B gene. ACVR2B is an activin type 2 receptor.

Activin and inhibin

Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle. Many other functions have been found to be exerted by activin, including roles in cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine function. Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion. The existence of inhibin was hypothesized as early as 1916; however, it was not demonstrated to exist until Neena Schwartz and Cornelia Channing's work in the mid 1970s, after which both proteins were molecularly characterized ten years later.

Harry Raymond Eastlack Eastlack had fibrodysplasia ossificans progressiva. He willed his skeleton to medical science.

Harry Raymond Eastlack, Jr. was the subject of the most recognized case of FOP from the 1900s. His case is also particularly acknowledged, by scientists and researchers, for his contribution to medical advancement. After suffering from a rare, disabling, and currently incurable genetic disease, Eastlack decided to have his skeleton and medical history donated to the Mütter Museum of the College of Physicians of Philadelphia in support of FOP research. His skeleton is one of the few FOP-presenting, fully articulated ones in existence, and it has proved valuable to the study of the disease.

The International Fibrodysplasia Ossificans Progressiva Association (IFOPA) is a US-based 501(c)(3) non-profit organization supporting medical research, education and communication for those afflicted by the rare genetic condition Fibrodysplasia Ossificans Progressiva (FOP). IFOPA's mission is to fund research to find a cure for FOP while supporting, connecting, and advocating for individuals with FOP and their families, and raising awareness worldwide. IFOPA is governed by a volunteer board of directors which may range in number from 9 to 15, at least one of whom must have FOP. The association's location is 1520 Clay St., Suite H2, North Kansas City, MO, 64116, part of the Kansas City, Missouri metropolitan area.

Palovarotene chemical compound

Palovarotene is a highly selective retinoic acid receptor gamma (RAR-γ) agonist that is under investigation as a potential treatment for fibrodysplasia ossificans progressiva (FOP), an ultra-rare and severely disabling genetic disease characterized by extra-skeletal bone formation in muscle and soft tissues.

FOP Friends

FOP Friends, formerly Friends of Oliver, is a registered charity in the United Kingdom established on 1 March 2012. It aims to raise funds that are needed to find effective treatments for the rare genetic condition Fibrodysplasia Ossificans Progressiva (FOP). The charity also works to raise awareness and understanding of FOP amongst medical communities and the general public.

Frederick Kaplan

Frederick S. Kaplan is an American medical doctor specializing in research of muscoskeletal disorders such as fibrodysplasia ossificans progressiva (FOP).

Eileen Shore

Eileen Shore is an American medical researcher and geneticist specializing in research of muscoskeletal disorders such as fibrodysplasia ossificans progressiva.

References

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Further reading

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