Introduction

Fibrodysplasia ossificans progressiva, also called Münchmeyer disease or formerly myositis ossificans progressiva, is an extremely rare connective tissue disease in which fibrous connective tissue, such as muscle, tendons, and ligaments, turns into bone tissue (ossification).¹ 

This condition causes the skeletal muscles and connective tissues of the body to transform into bone over a period of time. As a result, joints gradually become locked in place, restricting movements and making movement extremely difficult or even impossible. 

Common complications associated with Fibrodysplasia ossificans progressiva include

• System infection
• Joint disabilities 
• Cardiopulmonary complications (thoracic insufficiency syndrome and right-sided congestive heart failure)
• Submandibular swelling
• Temporomandibular joint ankylosis
• Conductive loss of hearing²

Pathophysiology of FOP

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder caused by a mutation in the ACVR1/ALK2 gene, located on chromosome 2.² This gene makes a protein, ALK2, which helps control bone growth. In FOP, a specific mutation in this gene makes ALK2 overactive. Under normal conditions, ALK2 assist in regulating bone formation by responding to signals received from Bone Morphogenetic Proteins (BMPs) that are part of the bone matrix. In people with FOP, ALK2 becomes hyperactive due to the mutation, leading to abnormal bone growth in muscles and other tissues where bone shouldn't form. 

Respiratory Complications in FOP

Thoracic insufficiency syndrome

Patients suffering from Fibrodysplasia ossificans progressiva tend to develop thoracic insufficiency syndrome (TIS). This dangerous cardiopulmonary complication causes pneumonia and right-sided heart failure.³  

Fibrodysplasia ossificans progressiva is characterised by heterotopic ossification. This heterotopic ossification first appears in the thoracic region compared to any other peripheral sites. Due to this reason, the movements of the thoracic cage are restricted and weaken the ability of the thoracic cavity to facilitate normal respiratory mechanics. As a result, individuals may face difficulties such as impaired ventilation and increased susceptibility to respiratory infections.

Thoracic insufficiency syndrome (TIS) is defined as the inability of the thorax to support normal respiration or lung growth.⁴

In children with normal development, lung growth is aligned with chest and spine growth; however, in children with thoracic insufficiency syndrome, rib deformities and spinal curves restrict lung growth. 

Primary TIS arises from anatomical variations in the spine or thorax that directly affect lung development and function. Secondary TIS indicates failure of the spine and thorax to support lung function secondary to global neuromuscular differences, causing weakness or contracture. Eventually, restrictive lung disease is found with both primary and secondary TIS.⁵

Restrictive lung disease

Restrictive lung diseases are a diverse set of pulmonary disorders showing restrictive patterns on spirometry. These disorders are characterised by a reduced distensibility of the lungs, compromising lung expansion, and, in turn, reduced lung volumes, particularly with reduced total lung capacity (TLC).⁶

Examples of restrictive lung diseases include 

• Asbestosis
• Sarcoidosis
• Pulmonary fibrosis

Asbestosis is a lung disease in which inflammation and scarring of lung tissue occur due to inhalation of asbestos fibres.

Sarcoidosis is the formation of clusters of inflammatory cells, called granulomas.

Pulmonary fibrosis is a condition where the lungs become increasingly scarred due to fibrosis of lung tissue, causing progressive difficulty with breathing.

Symptoms of restrictive lung disease include 

• Cough
• Shortness of breath
• Wheezing
• Chest pain

Other pulmonary complications

Airway obstruction, sleep apnea and hypovenilation are possible complications of Fibrodysplasia ossificans progressiva. 

Formation of heterotopic bone restricts the flexibility of tissues, limiting the expansion of the thoracic cavity. This can exacerbate breathing difficulties and lead to significant airway obstruction. 

As abnormal bone growth envelopes the chest and neck, anatomical structures in the airway can get compressed, leading to partial or complete obstruction during sleep. As a result, this interference results in obstructive sleep apnea, in which breathing repeatedly pauses and resumes due to blocked airways.

Hypoventilation is caused by the progressive formation of abnormal bone that restricts chest expansion. Hence, lung capacity is reduced, leading to inadequate ventilation and raised levels of carbon dioxide in the blood.

Clinical Manifestations

Common respiratory symptoms in FOP patients

• Reduced Lung Capacity: The ossification around the rib cage and spine can restrict chest expansion, leading to decreased lung capacity
• Shortness of Breath: Breathing difficulty may occur, particularly during physical exertion, due to limited movement of the chest wall
• Recurrent Respiratory Infections: The inability to clear respiratory secretions effectively can lead to frequent infections
• Sleep Apnea: Obstruction of the airway can potentially cause sleep apnea
• Hypoxemia: Low levels of oxygen in the blood can occur due to restricted breathing

Diagnosis of respiratory complications:

Imaging and pulmonary function tests

The chest x-ray is the most frequently conducted diagnostic x-ray test. It helps in imaging of the heart, lungs, airways, blood vessels, and the bones in the spine and chest.

A chest CT (computed tomography) scan uses special X-ray equipment to take detailed images of the lungs, heart, blood vessels, airways, ribs and lymph nodes. Chest CT scans can help your doctor determine the causes of chest symptoms such as cough, shortness of breath and chest pain.

Pulmonary function tests are a set of assessments that evaluate breathing and the efficiency of lung function.

Management Strategies

Preventive (prophylactic) antibiotic treatment might be suitable to avoid infections in individuals who are more susceptible to respiratory infections. Certain types of drugs have been used to relieve pain and swelling associated with FOP during acute flare-ups (most notably corticosteroids) and non-steroidal anti-inflammatory medication between flare-ups.⁷

The U.S. Food and Drug Administration (FDA) has approved Sohonos (palovarotene) capsules for a reduction in the volume of new heterotopic ossification (extra-skeletal bone formation) in adults and children aged 8 years and older for females, and 10 years and older for males with fibrodysplasia ossificans progressiva.⁸ 

Use of respiratory support - BiPAP and CPAP can be used for managing sleep apnea caused by FOB. BiPAP and CPAP devices mainly differ in how they deliver air pressure. BiPAPs offer separate pressure levels for inhaling and exhaling, while CPAPs maintain a constant pressure throughout the breathing cycle.

Although surgery is relatively contraindicated in FOP patients, as it almost always results in the development of additional heterotopic bone,33 there are some exceptions. Potentially life-saving surgery should not be avoided and has been done with positive outcomes.⁹

Conclusion

Fibrodysplasia ossificans progressiva (FOP) leads to severe complications due to abnormal bone growth in muscles and connective tissues. Respiratory complications include thoracic insufficiency syndrome, which restricts chest wall movement and impedes breathing, leading to an increased risk of infection, such as pneumonia and right-sided heart failure.

Restrictive lung disease further compromises lung capacity, causing shortness of breath and recurrent respiratory infections.Additional complications include airway obstruction, sleep apnea, and hypoventilation due to encasement of the chest and neck in bone. Management strategies primarily focus on alleviating these complications and improving the quality of life for those affected.