Overview

Genetic diseases are generally characterized by changes in people’s genes. These diseases can have chromosomal, multifactorial or monogenic origin and can cause a variety of symptoms. These symptoms can range from physical changes to more severe complications with or without multisystem involvement. However, there is a deleterious condition where patients gradually develop a second skeleton and makes them feel like they are “trapped” in their own bodies and unable to move their limbs. 

This devastating genetic disorder called Fibrodysplasia Ossificans Progressiva (FOP) does not only render movement impossible, but is also difficult to predict when or how the disease will progress. Terrifyingly, this disorder can cause extra bones to grow around the heart or lungs resulting in death. 

This article reveals the clinical presentation and symptoms of FOP as well as treatment options.  

What is fibrodysplasia ossificans progressiva?

Fibrodysplasia Ossificans Progressiva (FOP) is an uncommon genetic condition characterized by the abnormal growth of bones in parts of the body where bone is not normally present such as the skeletal muscles, tendons and ligaments.¹ The phenomenon of bone growth in unusual areas is called heterotopic ossification. This condition causes the skeletal muscles and soft connective tissues of an individual to gradually change into bones. This results in restricted movements in affected areas which can lead to patients being confined to a wheelchair by their third decade of life.² 

The unusual episodic development of bone at multiple soft tissue sites leads to stiffness in those areas, limited movement and ankylosis of affected joints (neck, back, shoulders, elbows, hips, knees, wrists, ankles, jaw – usually in this order).

This condition affects people assigned male at birth (AMAB) and people assigned female at birth (AFAB) equally. However, being an ultra rare condition, the world prevalence of FOP is approximately 1 case in 2 million people.² The average lifespan of people with FOP is approximately 40 years. Death is usually caused by respiratory infections or complications with thoracic insufficiency syndrome.³  Most individuals with FOP require lifelong assistance with performing daily living activities and more than 50% experience lifelong disabilities with lifetime management.³

Why does FOP occur? 

FOP is a disabling condition that occurs due to mutation in one of the copies of the gene that codes for bone morphogenetic proteins (BMPs) called Activin type 1 receptor or ACVR1.⁴ BMPs are regulatory proteins that are essential in embryonic skeletal formation and in repairs of postnatal (after birth) skeleton. The ACVR1 encodes a BMP receptor (i.e activin type 1 receptor) which is found on the cell surface. BMP receptors regulate cell growth, differentiation and apoptosis. In other words, BMP controls how bones grow and develop.

These receptors are able to induce formation of bones in non-bony sites by influencing the fate of the stem cells along the cartilage lineage pathway.⁵ Thus, a mutation in the ACVR1 gene results from a specific substitution of a particular amino acid (arginine) from position 206 in the ACVR1 protein for another amino acid (histidine). This causes the endothelial cells in non-bony sites to transform into mesenchymal stem cells and then into bones. FOP can also be inherited in an autosomal dominant pattern, which means just one copy of the altered gene in each cell is sufficient to cause the disorder.⁵

The two defining features of FOP are congenital malformations of the great toes (i.e. the largest toes in both feet) and heterotopic ossification which progresses throughout life.²  These unusual bone-forming phenomena start in the upper back and neck, and then gradually progress through the trunk of the body including the arms and legs. Over time, this extra-skeletal bone fuses with the skeleton and together with the joints, form a tight-knit network of extra-skeletal bone that causes a nearly complete immobilization of the entire body.⁶

Other malformations of the toes and fingers can include hallux valgus, macrodactyly and/or clinodactyly. Other congenital signs of FOP include proximal medial tibial osteochondromas, malformation of the upper part of the spinal cord and a short broad neck of the femur that extends from the knee to the pelvis. 

Clinical presentation of FOP

There is no formal diagnostic criteria for FOP. Therefore, FOP should be suspected in the following clinical presentation:

• Congenital deformities: These include hallux valgus and macrodactyly⁸
• General pattern of flare-ups: The appearance of firm tender swellings often called flare-ups, are the first sign of heterotopic ossification. The advancement of flare-ups from the axial regions (i.e. the head, neck, thorax, abdomen and pelvis) to the extremities is a distinguishing factor between early/mild and moderate severity FOP. There could also be severe weight loss accompanied by ankylosis of the jaw⁹
• Thoracic Insufficiency Syndrome (TIS): This is a complex condition which occurs due to the inability of the chest wall (thorax) to support breathing and development of the lungs. End-stage FOP usually presents with symptomatic TIS alongside features associated with pulmonary hypertension and right-sided heart failure.⁹ TIS occurs due to severe scoliosis or when chest expansion is restricted by congenital or early fusions of the costovertebral joints⁹
• Hereditary multiple osteochondromas (HMO), progressive osseous heteroplasia (POH), metachondromatosis (METCDS), and brachydactyly type B1 (BDB1) are differential presentations of FOP that lack hallux malformations or heterotopic ossification (HMO, POH and METCDS and BDB1)¹⁰
• Kyphoscoliosis and lordosis

Acute flare-ups can occur due to minor traumas such as intramuscular immunization, muscle fatigue, bumps, bruises and falls. Also, influenza-like illnesses can trigger painful and debilitating episodes of heterotopic ossification, indicating that inflammation plays a critical role in FOP progression.¹¹

Progressive symptoms of FOP

The characteristic symptom of FOP is malformation of the great toes. Other progressive symptoms include: 

• Chronic inflammatory swellings in various parts of the body
• Hearing problems
• Joint stiffness
• Kidney stones
• Mild cognitive impairment
• Sparse/thin scalp hair
• Severe growth retardation
• Mobility issues
• Difficulty speaking and eating

In end-stage FOP, secondary complications that can occur include pneumonia and pressure ulcers due to TIS and immobility. Recurrent respiratory infections are also common.⁹

Diagnosis of FOP

FOP is commonly misdiagnosed as tumour, soft tissue sarcoma or lymphedema. This misdiagnosis occurs in approximately 90% of all cases nationwide. This leads to harmful biopsies that exacerbates the condition.¹² Lesion biopsies can be dangerous at the neck, back or jaw and can cause progressive deformity of the spine, ankylosis of the temporomandibular joints and worsened TIS.¹²

The correct diagnosis of FOP can be done by clinically associating episodes of flare-ups or soft tissues lesions with symmetrical malformations of the great toes. However, the most definitive diagnosis of FOP is by detection of the mutated ACVR1 gene. This detection can prevent triggering the onset of flare-ups episodes and avoid biopsies that could cause further ossification. 

Treatment options and management of FOP

FOP cannot be cured. However, the management of this condition is aimed at controlling inflammation and flare-ups as these trigger the chain of events that lead to heterotopic ossification.⁷ Corticosteroids are the first choice recommended at the beginning of flare-up episodes. This is followed by Non-steroidal anti-inflammatory drugs (NSAIDs) when the corticosteroids are discontinued for the duration of the flare-up. Short-term use of muscle relaxants can be used under strict supervision and can help to decrease muscle spasms and improve mobility.⁷ Extremely painful flare-ups may require the use of narcotic analgesics in addition to the use of NSAIDs and intravenous glucocorticoids.⁷ 

In 2023, palovarotene, a retinoic acid receptor γ agonist, was approved by the U.S. Food and Drug Administration (FDA) as the first treatment option for FOP to reduce bone formation in soft connective tissues and muscles in adults and children aged 8 years and above for AFAB, and 10 years above for AMAB.¹³ Prophylactic antibiotic therapy may be appropriate to prevent infection in patients with an increased susceptibility to developing respiratory infections due to progressive dysfunctional mobility.

The use of physical rehabilitation and therapy should be implemented to improve the quality of life of FOP patients, especially those confined in wheelchairs. Safety precautions such as improvement in household safety, use of protective headgears can also be incorporated to reduce injury when fall occurs which can lead to flare-ups. Intramuscular injections and dental procedures that involve stretching the jaws should also be avoided.⁷ 

FAQs

Is there a cure for FOP? 

There is currently no permanent cure for FOP. The treatment option available serves to reduce the extra-skeletal bone formation in adults and children. Management strategies are aimed at controlling inflammation and subsequent flare-up episodes as well as prevent complications in patients with FOP. 

Is there a difference between normal bone formation and extra bones formed in FOP?

The extra bone formed in FOP occurs by a progressive transformation of soft tissue into cartilage and then into bone. This is the same process by which bone regenerates after a fracture occurs. The abnormality in FOP is not due to normal bone formation but where the bone develops, the frequency and timing. 

Can the extra bone formed in FOP be removed?

Surgical removal of the extra bones formed in FOP triggers ossification in soft tissues which further exacerbates the condition.  

Summary

FOP is an ultra rare disabling disease that presents with bone formation in non-bony sites such as soft tissues, tendons and muscles. It occurs as a result of genetic mutation in the ACVR1 gene which codes for bone morphogenetic protein (BMP). BMP coordinates the growth and occurrence of bones in various parts of the body. This condition is mainly characterized by heterotopic ossification and malformed great toes. Early detection of this disease is paramount to the control of the symptoms and episodic flare-ups which can be debilitating and excruciatingly painful. The use of NSAIDs and corticosteroids is focused on the management of FOP and in reducing the severity of the flare-ups in patients.