Introduction

Fibrodysplasia Ossificans Progressiva (FOP) is a rare condition where soft tissues slowly turn into bone, causing pain and disabling the patient’s movement. A primary sign is a congenital big toe malformation, but diagnostic criteria differ with the disease development. Appropriate care can prevent the worsening of the symptoms and improve the quality of life in patients. Hence, the early and accurate diagnosis of FOP is essential. This article focuses on the diagnosis and diagnostic criteria of FOP.

What is Fibrodysplasia ossificans progressiva (FOP)?

Fibrodysplasia Ossificans Progressiva (FOP) is also called Myositis Ossificans Progressiva or ‘Stone Man Syndrome’. As per its name, this genetic condition is characterised by the heterotopic ossification of soft tissues - skeletal muscle and other connective tissues such as ligaments and tendons slowly turning into bone. This abnormal tissue growth around joints makes them stiff, thus impeding movement. It results in partial to total patient immobilisation. One given identifying factor is the congenital malformation of the big toe, which is often identified in infancy.^1,2,3 FOP is a rare pathology, with it estimated to only affect 1 in 2 million individuals with no predilections based on biological sex, ethnicity, or geographical region.¹

Evolution of FOP

As a genetic condition, the causing factor for the development of FOP is the presence of a gene mutation: the ACVR1/ALK2 gene. Within the human DNA, this gene encodes the formation of bone during the embryonic development.² A mutation in this gene means that some tissues that should not be directed to turn into bone retain this potential after birth and are dictated to do so at several points in the lifetime of FOP patients. Note that physiologically speaking, the bone created is of standard composition. Solely it is not located where it should be.⁴

Several steps can be identified in the development of FOP:^2,4,5

• Presence of the ACVR1/ALK2 gene mutation
• Big toe (Hallux) and other foot congenital malformations –often appear symmetrical and bilateral
• Episodic flare-ups lead to ossification of the soft tissues
• Bone formation can also result in trauma as the tissue is distressed
• Resulting in cumulative joint stiffness and immobilisation 

It is worth noting that the progression of FOP matches a given pattern, with the limbs, spine and neck regions mainly affected. The disease seems to develop from the upper to lower side, starting from the joints closer to the trunk, such as the shoulder and hips, before spreading to more distal joints, such as the elbows and knees.²

Symptoms and early signs

Importance of early diagnosis

Because FOP slowly leads to joint stiffness and immobilisation in patients, to maintain a certain quality of life, early diagnosis would prevent the worsening and progression of the disease. Although some FOP patients display congenital malformations, the first symptoms, such as muscle inflammation, which would later lead to hardening of the tissues, tend to occur around five years of age.^4,5 

The muscle attacked is skeletal; those muscles notably allow movement of the limbs (arms and legs) rather than smooth muscle surrounding the heart.⁴

First signs of FOP

• Congenital great toe malformation (hallux valgus) 
• Thumb malformation, in 50% of cases
• Inflammatory muscular lumps (flare-up)
• Delayed motor skills milestones^3,4,5

Diagnostic criteria for FOP

Clinical and differential diagnosis

A thorough clinical examination is required to diagnose FOP. This consists of noting the patient's symptoms and taking their medical history. Those actions constitute the first step towards a FOP diagnosis. No generic diagnostic procedures have been recommended for FOP diagnosis in primary healthcare settings.

Differential diagnosis is required to ensure an accurate FOP diagnosis. Indeed, there are other diseases which have symptoms similar to FOP. This is the case of Progressive Osseous Heteroplasia (POH), which, despite having very similar symptoms, has different underlying processes and is not associated with tissue inflammation preceding heterotopic ossification as FOP does.⁴

Genetic testing

Discovery of the gene mutation causing FOP has allowed for genetic testing to confirm an FOP diagnosis. 90% of patients with FOP symptoms display the exact same genetic mutation.²

Clinical staging

Lead researchers in the field of FOP have been able to set clinical staging criteria, which can significantly help diagnose FOP. Those are categorised according to criteria such as the affected body parts, inflammatory flare-up history, thoracic insufficiency and the impact that the disease has on patients’ lives, thus affecting daily life activities.⁶

Clinical stages of FOP include the following:⁶

1. Early/mild stage
2. Moderate stage
3. Late/severe stage
4. Profound stage
5. End-Stage

Recent research and advancement in FOP 

FOP is a complex condition that remains partly misunderstood. Studying living tissues changing due to FOP pathology could bring further insight into the underlying ossification processes. This can be achieved via biopsy.⁴ However, trauma-induced ossification is not uncommon, so investigation of the pathology in patients is not recommended and could be considered unethical. Hence, it has been difficult for researchers to investigate treatment and preferred diagnostic approach for FOP.²

FAQs

What are the first signs of FOP?

The first sign of FOP is a malformation of the big toe, sometimes accompanied by thumb deformities. A delay in motor skill development in infants could also be an indicating factor for FOP.^3,4,5

How is a definite FOP diagnosis confirmed?

As FOP is a genetic disease, a diagnosis can only be confirmed through genetic testing. It is caused by a mutation of the ACVR1/ALK2 gene.^2,4

Is there a cure or effective treatment for FOP?

Although there are currently no licenced treatments for FOP, avoidance of trauma is primordial to limit new pathological ossification growth. New drugs are currently in development and could help reduce extraskeletal bone formation in both adults and children.⁸

Summary 

Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease. The causing factor for FOP is the presence of a gene mutation. The preliminary indicator for the disease is the congenital malformation of the big toe and sometimes the thumb. Only genetic testing can ensure an accurate FOP diagnosis following clinical and differential diagnosis. Because this disease is disabling with ossification leading to immobilisation, it must be identified early so all precautions can be taken in regard to care and appropriate treatment.⁷