Fibrodysplasia Ossificans Progressiva

This disease presents at birth typically with infants having deformed big toes and/or thumbs, or lumps on their toes or fingers. Sometimes a joint may simple be missing. Overgrowths of the rib cage result in decreased expansion and growth of lungs resulting in respiratory compromise. The disease progresses from above downwards (proximal-to-distal fashion) and the child suffering from FOP may have difficulty in opening the mouth and eating due to involvement of the facial and neck muscles and maxillofacial bones. Painful, rubbery indurations in the soft tissues occur sporadically, usually as a result of, and at the site of trauma.

Because FOP is such a rare disease, it can be confused with cancer. Some characteristic features of this disease include deformity of the big toes and/or thumbs; the characteristic hallux valgus deformity, torticollis and a thorax deformity.

Fibrodysplasia ossificans progressiva is sometime associated with alopecia and deafness [7]. Neurologic symptoms are also common in these patients.

Workup consists of a detailed history and physical examination.

Laboratory tests

• Complete blood count
• Serum alkaline phosphatase levels 
• Parathyroid hormone (PTH) levels 

Biopsies should not be performed as they may exacerbate the condition.

Imaging 

• CT scan is the best imaging modality. It may show heterotopic ossification of pterygoid muscles and retrognathia in older patients [8]. 
• MRI may be conduced to see the extent of soft tissue involvement
• Bone scintigraphy

Test results 

Diagnosis is mainly through physical findings such as the hallux valgus, big toe or thumb deformity, torticollis, etc. A high serum alkaline phosphatase may also indicate FOP.

Currently, there is no cure or treatment for FOP. Effective therapies for FOP and possibly other common conditions of HO (heterotopic ossification), may potentially be based on future interventions that block ACVR1/ALK2 signalling [9]. Rituximab has been used [10].

Prognosis for fibrodysplasia ossificans progressiva is poor because of the involvement of thoracic muscles and restrictive lung disease [5]. The median lifespan is approximately 40 years of age [1]. Most patients remain severely debilitated in the course of their life and ultimately die of complications caused by this disease.

Complications

Patients should be protected from surgical procedures, including biopsies if possible, to avoid harming them [6]. FOP, for reasons unknown, occurs in sites where trauma has occurred. So patients suffering from this condition need to take special care in avoiding unnecessary surgical procedures and/or tests. Common complications of this disease include restrictive lung disease, respiratory compromise, cardiac failure, and one or more of these complications are usually the cause in death in FOP.

FOP is a rare, disabling genetic disease of progressive heterotopic endochondral ossification enabled by missense mutations that promiscuously and provisionally activate ACVR1/ALK2, a bone morphogenetic protein type 1 receptor, in all affected individuals [2]. The FOP gene has recently been mapped to human chromosome 4q 27-31 [3]. It is an idiopathic condition as the cause or precipitating factor(s) of these mutation are heretofore unknown.

Incidence

It is an extremely rare disease with an estimated prevalence of only 1 case per 1.64 million in the United Kingdom. The exact incidence of FOP in the United States is unknown.

Age

It starts in infancy and persists for life. It is also known to have in utero involvement.

Sex

It occurs equally in both sexes, however some studies show that it is slightly more common in females.

Race

There is no ethnic, racial, gender or geographic predilection to FOP [1].

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by symmetrical congenital malformations of the blastemal anlage of hands and feet and by progressive heterotopic chondrogenesis and ossification of the soft connective tissues [4].

The recent discovery of overproduction of bone morphogenetic protein-4 in lesional cells and lymphocytic cells of affected patients provides a clue to both the underlying pathophysiology and potential therapy [3].

This overactivation of the gene encoding the bone forming receptor leads to deposition of extracellular matrix in different nonskeletal sites of the body. This results in ossification of ligaments, tendons and muscles and ultimately the patient's body starts "turning into stone".

Fibrodysplasia ossificans progressiva, unfortunately, has no prevention. It is a heritable genetic disorder which can only be diagnosed during the intrauterine period or after birth.

Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites [1]. It results in conversion of soft tissues into hard bone and slow but complete destruction of the normal musculature and structure of the body.

Definition

Fibrodysplasia ossificans progressiva is an extremely rare disease of the connective tissue in which bone starts to form in all parts of the body including muscles, ligaments, tendons, etc.

Cause

It occurs due to a genetic mutation in the bone forming receptor gene which results in abnormal overproduction of bone.

Symptoms

Initial symptoms include deformities or lumps in the big toes and/or thumbs leading to a characteristic 'hallux valgus' deformity. Slowly the muscles of the chest become involved which affects the respiratory and cardiac musculature. The patients become physically debilitated and often survive up to only 35 to 45 years of age.

Treatment

This disease has no known cure. It can be managed with some medications but no known drug is known to suitably treat this disease.

1. Pignolo RJ, Shore EM, Kaplan FS. Fibrodysplasia Ossificans Progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011 Dec 1;6:80. 
2. Kaplan FS, Lounev VY, Wang H, Pignolo RJ, Shore EM. Fibrodysplasia Ossificans Progressiva: a blueprint for metamorphosis. Ann N Y Acad Sci. 2011 Nov;1237:5-10 
3. Mahboubi S, Glaser DL, Shore EM, Kaplan FS. Fibrodysplasia Ossificans Progressiva. Paediatr Radiol. 2001 May;31(5):307-14. 
4. Kaplan FS, Tabas JA, Zasloff MA. Fibrodysplasia Ossificans Progressiva: a clue from the fly? Calcif Tissue Int. 1990 Aug;47(2):117-25. 
5. Kaplan FS, Zasloff MA, Kitterman JA, Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with Fibrodysplasia Ossificans Progressiva. J Bone Joint Surg Am. Mar 2010;92(3):686-91
6. Muthu V, Khaire NS, Varma S. Fibrodysplasia Ossificans Progressiva-primum non nocere. Clin Rheumatol. Apr 2014;33(4):591-2
7. Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with Fibrodysplasia Ossificans Progressiva. Am J Audiol. June 1999;8(1):29-33.
8. Carvalho DR, Farage L, Martins BJ, Speck-Martins CE. Craniofacial findings in Fibrodysplasia Ossificans Progressiva: Computerized tomography evaluation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Apr 2011;111(4):499-502.
9. Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby RE, Kitterman JA, Groppe J, Shore EM. Fibrodysplasia Ossificans Progressiva. Best Prac Res Clin Rheumatol. 2008 Mar;22(1):191-205
10. Altschuler EL. Consideration of Rituximab for Fibrodysplasia Ossificans Progressiva. Med Hypotheses. 2004;63(3):407-8