Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP), a rare and catastrophic genetic disorder of progressive heterotopic ossification, is the most disabling condition of extraskeletal ossification known in humans. FOP causes immobility through progressive metamorphosis of skeletal muscle and soft connective tissue into a second skeleton of heterotopic bone. ⁽¹⁾

According to the International Fibrodysplasia Ossificans Progressiva Association (IFOPA), FOP is one of the rarest, most disabling genetic conditions known to medicine; it causes bone formation in muscles, tendons, ligaments and other connective tissues. Bridges of extra bone develop across joints, progressively restricting movement and forming a second skeleton that imprisons the body in bone. There are no other known examples in medicine of one normal organ system turning into another. ⁽²⁾

During the first decade of life, children with FOP develop painful and highly inflammatory soft tissue swellings (or flare-ups) that transform soft connective tissues, including aponeuroses, fascia, ligaments, tendons and skeletal muscles, into an armament-like encasement of bone. ^{(3, 4)} Spontaneous flare-ups of the disease arise in defined temporal and spatial patterns, resulting in ribbons and sheets of bone that fuse the joints of the axial and appendicular skeleton, entombing a patient in a skeleton of heterotopic bone. A flare-up occurs when the body starts to generate new bone, although not every flare-up results in a completion of the process. No one knows what initiates this process, but once it begins, inflammation, tissue swelling, and discomfort follow. While flare-ups are usually painful, the degree of pain can vary. In addition, sometimes the individual will not feel well and may develop a low-grade fever. ⁽¹⁰⁾

Minor trauma such as intramuscular immunizations, mandibular blocks for dental work, muscle fatigue and blunt muscle trauma from bumps, bruises, falls or influenza-like illnesses can trigger painful new flare-ups of FOP leading to progressive heterotrophic ossification. ^{(5, 6, 7, 8)} Surgical attempts to remove heterotopic bone commonly lead to episodes of explosive and painful new bone growth. ⁽¹⁾

FOP involvement is typically seen first in the dorsal, axial, cranial and proximal regions of the body and later in the ventral, appendicular, caudal and distal regions. Several skeletal muscles including the diaphragm, tongue and extra-ocular muscles are enigmatically spared from FOP. Cardiac muscle and smooth muscle are not involved in the FOP process.⁽¹⁾

FOP is extremely rare with a worldwide prevalence of approximately one in two million.  It is found that genetic transmission is autosomal dominant and can be inherited from either mothers or fathers. However, most cases arise as a result of a spontaneous new mutation. ⁽¹¹⁾ FOP gene is ACVR1, a gene that is located within chromosome 2. ACVR1 stands for Activin Receptor Type 1A. The ACVR1 receptor is present in skeletal muscle and connective tissues, although exactly what its normal function in these cells and tissues is not currently understood. ⁽¹⁰⁾

Symptoms:

The skeletal malformation consists of:

• abnormal big toes. These are mostly short, monophalangeal with valgus deviation;
• short thumbs, due to short metacarpals;
• short broad femoral necks;
• abnormal cervical vertebrae with small bodies, large pedicles and large spinous processes.

Two clinical features define classic FOP: malformation of the great toes; and progressive heterotopic ossification (HO) in specific spatial patterns. Individuals with FOP appear normal at birth except for the characteristic malformations of the great toes which are present in all classically affected individuals. ⁽¹⁾

FOP is commonly misdiagnosed as aggressive juvenile fibromatosis (extra-abdominal desmoid tumours), lymphoedema or soft tissue sarcomas. Children often undergo unnecessary and harmful diagnostic biopsies that exacerbate progression of the condition. This can be particularly dangerous at any anatomical site, but especially so in the neck or back where asymmetric HO can lead to rapidly progressive spinal deformity and exacerbation of  Thoracic Insufficiency Syndrome TIS. The correct diagnosis of FOP can be made clinically even before radiographic evidence of heterotopic ossification is seen, if soft tissues lesions are associated with symmetrical malformations of the great toes. ⁽¹²⁾

Bone formation in FOP is episodic, but disability is cumulative. Most patients with FOP are confined to a wheelchair by the third decade of life, and require lifelong assistance in performing activities of daily living. The median age of survival is approximately 45 years, and death often results from complications of thoracic insufficiency syndrome (TIS). ⁽⁹⁾

References

1.      Frederick S. Kaplan, Martine Le Merrer, David L. Glaser, Robert J. Pignolo, Robert Goldsby, Joseph A. Kitterman, Jay Groppe, Eileen M. Shore. Fibrodysplasia ossificans progressive. Best Pract Res Clin Rheumatol. 2008 March; 22(1): 191–205.

2.      FOP factsheet [Internet]. 2011 [cited 2011 July 01]. Available from: http://www.ifopa.org/en/what-is-fop/overview.html

3.      Cohen RB, Hahn GV, Tabas J, et al. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. 1993;75:215–219. 

4.      Rocke DM, Zasloff M, Peeper J, Cohen RB, Kaplan FS. Age and joint-specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res. 1994; 301: 243–248.

5.      Janoff HB, Zasloff MA, Kaplan FS. Submandibular swelling in patients with fibrodysplasia ossificans progressiva. Otolaryngol Head Neck Surg. 1996; 114: 599–604. 

6.      Luchetti W, Cohen RB, Hahn GV. Severe restriction in jaw movement after routine injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:21–25. 

7.      Glaser DL, Rocke DM, Kaplan FS. Catastrophic falls in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res. 1998;346:110–116.

8.      Scarlett RF, Rocke DM, Kantanie S, Patel JB, Shore EM, Kaplan FS. Influenza-like viral illnesses and flare-ups of fibrodysplasia ossificans progressiva (FOP) Clin Orthop Rel Res. 2004; 423:275–279.

9.      Kaplan FS, Glaser DL. Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab. 2005; 3:213–216.

10.  FOP guidebook for families. International FOP Association. 3^rd ed. Winter Springs, Florida; 2009.