Fibrodysplasia Ossificans Progressiva

The congenital disease Fibrodysplasia ossificans progressiva (FOP) was discovered in the late 1600's by G. Patin. This disease is marked by the ossification of soft tissues (i.e. muscle and connective tissue). Although FOP is a topic of current research it continues to perplex medical professionals. Few treatments are availble for those diagnosed with this disease.

History

French physician Guy Patin documented the first confirmed case of fibrodysplasis ossificans progressiva (FOP) in 1692 [1]. Fibrodysplasia ossificans progressiva is such a rare disease that patients are often misdiagnosed with cancer [2]. One of the more famous cases is Harry Eastlack. Diagnosed at the age of ten, Eastlack’s condition immobilized his entire body except for his lips [2]. Although stricken with this disease, Harry lived to 39 years of age. Prior to his death Eastlack agreed to donate his body for scientific study, his skeleton is on display at the Mutter Museum in Philadelphia, Pennsylvania, Figure 1[2]. The diagnosis of this disease is very rare with only a few hundred cases being reported worldwide.

Figure 1.Harry Eastlack. [1]

Symptoms

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease in which bone develops outside of the skeleton, replacing connective and muscle tissue [3]. This is a congenital disease and the initial symptoms foreshadow near total immobility by adulthood [4]. The first symptom of FOP to appear is a malformed big toe in newborns, Figure 2, [5]. This characteristic is crucial when separating fibrodysplasia from other medical disorders during the initial stages [5]. Ossification of tissue begins in early childhood at the neck and shoulders, overtime the disease spreads down the body and to the limbs [5]. As bone continues to develop in the patient, tumor–like protrusions are commonly observed [2]. The uncontrollable growth of bone is magnified by trauma to muscle tissue, which can be caused by invasive medical procedures, falling, bruising, or viral illnesses [5]. Fibrodysplasia often leads to difficulty breathing and speaking, as well as malnutrition [5]. Although each case is unique, individuals with FOP are normally handicapped around 30 years of age [1]. However, patients may live well into their middle ages and some women have even had successful pregnancies. Pneumonia is the leading cause of death for those diagnosed with FOP [1].

Figure 2.Characteristically malformed big toe. [2]

Mechanisms of the Disease

Fibrodysplasia Ossificans Progressiva is caused by a genetic mutation which affects a gene that is crucial for bone development. It has been determined after years of study on this disease that it is most likely inherited through an autosomal dominant pattern. Following simple Mendelian genetic inheritance rules, it can be determined that this disease is caused by a single mutation in a single gene[6]. However due to the very low reproduction sucess, there are very few multigenerational families showing inheritance for the disease, making linking analysis almost an impossibility for FOP patients[7].

The main gene of focus is in the BMP pathway. BMPs are extracellular signaling proteins that regulate gene transcription by binding to kinase receptors in the cell membrane.[6] Kinases are used to phosphorylate different receptors within the cell. BMPs are part of the TGF-beta family; these cells determine the fate of cells in many different contexts. With this in mind, it has been determined that a mutation in BMPs can induce the formation of endochondral bone all over the body. FOP patients seem to have a large amount of BMP4 in their cells due to over expression. This accumulation of BMP4 hinders the cell's normal function in regulation of mRNA.

In addition to the accumulation of BMP4, FOP patients all seem to have the same amino acid mutation causing this disease. There is a recurrent mutation in amino acid 206 (changing the amino acid from an arginine to a histadine). This amino acid sequence is found on the GS domain of ACVR1, which is an evolutionarily conserved amino acid used in the alteration of protein conformation.[6]

Treatments

There is no treatment for FOP. The primary form of therapy for this disease is supportive care. Some adaptations are now available for a patient disabled by FOP; these adaptations allow them to become more independent and increase their ability to perform activites of daily living. These include specially made shoes and the use of canes and wheelchairs. There are also some methods of management and general guidelines of what a person with this condition should avoid.[8]

It is suggested idividuals with FOP avoid trauma, intramuscular injections and multiple biopsies. These procedures can cause heterotopic ossification to occur. Physical therapy is also not recommended for patiens with FOP because it often leads to a painful flare up due to stretching of the soft tissue surrounding the joints.[8]

There have been several suggested methods of management, some with positive results and others without. Steroids and non-steroidal anti-inflammatory drugs (NSAIDs) have shown some proven benefit for halting the disease progression. Surgery has proven to be a catalyst for the progression of the disease. Removal of heterotopic bone is ineffective and causes exacerbation of the disease; surgery is almost always contraindicated. A few drugs have shown some positive results; isotretinoin, a medication often used to treat acne, is questionably beneficial because of its ability to inhibit mesenchymal tissue from differentiating into bone and cartilage. [9] Etidronate is an FDA approved drug that appears to slow the rate of bone metabolism however, this benefit is most effective in short term treatment and is not effective in long term treatment.[8]

Prognosis

Due to the unfortunate lack of a treatment or cure of FOP, individuals with this disease will eventually totally ossify if they live a long enough life. [10]

A sketch comparing the exterior body to the ossified internal skeletal structures. (See the original image [here http://www.theatlantic.com/issues/98feb/images/backsm.jpg])

A new experimental treatment is currently being tested in patients suffering from FOP. Squalamine, an antiangiogenic found in sharks, is being tested to see if it helps with the progression of FOP. [10]

Unfortunately this disease is incurable and fatal and there is currently little hope for patients suffering from FOP. Surgical release of ossified joints is generally not an option due to the chance of trauma-induced ossification. Only treatment of the symptoms, pain, and discomfort can be managed with treatments and medications. [11]

One of the only things that patients with FOP can do to help prevent the progression of their aliment is to avoid damaging their muscle and connective tissue. By avoiding bumps and falls, these tissues will not be damaged and the progression of the bony growths can be slowed, but unfortunately not avoided. [10]

Current Research

A study completed in 2006 was done on a 10 year old boy with FOP. The boy had several lumps growing on his back and shoulders. Although there was no associated pain, the stiffness caused the boy to be hunched over. Using magnetic resonance imaging (MRI) the use of oral prednisolone was tested. After 3 months the MRI showed almost complete resolution of the lumps. [12]

Another study done in 2007 explored the role of hematopoietic stem cells on the bone morphogenetic protein (BMP). It was thought that these stems cells could be used a cure. This study was conducted on rats and found no conclusive evidence that hematopoietic stem cells prevent or slow any osteogenesis. [13]

References

[1] Beighton, P. McKusick's Heritable Disorders of Connective Tissue (5th ed., pp. 501-518).

[2] Fibrodysplasia ossificans progressiva. (n.d.). Wikipedia. Retrieved November 1, 2009, from [3]

[3] Gau-Tyan, L., Hsueh-Wei, C., Chih-Shan, L., Peng-Ju, H., Hsien-Chung, W., & Yuh-Min, C. (2006). De novo 617G–A nucleotide mutation in the ACVR1 gene in a Taiwanese patient with fibrodysplasia ossificans progressiva. Journal of Human Genetics,12: 1083-1086.

[4] Meier, R., & Bolliger, K. (1996). [Anesthesiologic problems in patients with fibrodysplasia ossificans progressiva]. Der Anaesthesist, 7:631-634.

[5] Fibrodysplasia ossificans progressiva. (2009, October 30). Retrieved November 1, 2009, from [4]

[6]Kaplan, E. M. (2008). Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva ( FOP). Bone , 427-433.

[7] KAPLAN, F., FIORI, J., DE LA PEÑA, L., AHN, J., BILLINGS, P., & SHORE, E. (2006). Dysregulation of the BMP-4 Signaling Pathway in Fibrodysplasia Ossificans Progressiva. Annals of the New York Academy of Sciences, 1068(1), 54-65.

[8]Chen, H. 2006. Atlas of genetic diagnosis and counseling. Fibrodysplasia ossifcans progressiva, 410-413. Humana Press Inc., New Jersey.

[9]Wikipedia-Isotretinoin

[10] Wikipedia - Fibrodysplasia ossificans progressiva

[11] Kaplan, S., Shen, Q., Lounev, V., Seemann, P., Groppe, J., Katagiri, T., Pingnolo, R., and E. Smith. 2008. Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP). The Japanese Society for Bone and Mineral Research 26:521-530.

[12] Merchant, R., Sainani, N., Lawande, M., Pungavkarm, S., Patkar, D., and Walawalkar, A. 2006. Pre- and post-therapy MR imaging in fibrodysplasia ossificans progressiva. Pediatric Radiology. 36:1108-1111.

[13] Kaplan F., Glaser D., Shore E., Pignolo R., Xu M., Zhang Y., Senitzer D., Forman SJ., and Emerson S. 2007. Hematopoietic stem-cell contribution to ectopic skeletogenesis. The Journal Of Bone And Joint Surgery. 89:347-357