Fibrodysplasia Ossificans Progressiva
Fibrodysplasia Ossificans Progressiva
One of the more difficult aspects of practicing medicine may be determining the proper course of treatment for a patient. A physician has to be part scientist and part detective, following clues based on a patient’s presentation and clinical tests. Even routine questions into a patient’s history can require a fair amount of intuition. What happens when the very tests essential in making a diagnosis actually exacerbate the condition? That is precisely what can happen to patients with fibrodysplasia ossificans progressiva (FOP), or the colloquial “stone man syndrome.” Taking tissue samples, poorly drawn blood, and even a physical exam can lead to a flare-up, which may intensify the pathology of the disease.
FOP was once known as myositis ossificans progressiva, which means “muscle turns progressively to bone.” Myositis ossificans progressiva was a misnomer because this condition affects connective tissues as well (ligaments, tendons, fasciae, and aponeuroses), turning them into sheets, ribbons, and plates of bone. In the 1970s, Dr. Victor McKusick, who many consider the father of medical genetics, was influential in changing the name to fibrodysplasia ossificans progressiva, which means “soft connective tissue that progressively turns to bone.”
Approximately 1 person out of 2 million is afflicted with FOP. The disease is characterized by congenital skeletal malformations and heterotopic ossification (HO; bone growth outside of skeletal tissue). It is considered the most catastrophic form of HO, with episodic flare-ups leading to cumulative immobility. FOP is an autosomal dominant condition, with a 50% chance of a child developing the disease if 1 parent is positive. There are no differences in prevalence rates across racial or ethnic groups and geographical regions. The severe disability associated with FOP often results in poor reproductive fitness. To date there are fewer than 10 multigenerational families afflicted worldwide. A curious aspect of this condition is that the majority of diagnosed cases are spontaneous mutations with no apparent hereditary link.
FOP is linked to a mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. The ACVR1 gene is found in many tissues, including bone, muscle, and cartilage. Under normal circumstances it provides instructions for producing BMP receptors and helps control bone and muscle growth. It is influential in the gradual replacement of cartilage with bone that occurs over the course of normal human development. It has been suggested that the mutation may change the shape of BMP receptors and disrupt mechanisms that control the receptors’ activity, essentially leaving receptors in a constant “on” state.
Patients with FOP are born with characteristic malformations of the great toes (short and bent, sometimes turning inward), but otherwise these children appear normal. Within the first decade of life, inflammation and a swelling of soft tissue can be seen (flare-ups); these swellings can be painful, as they transform soft tissue into bone. Typically, the first indications of HO appear in the back, head, neck, and shoulders, and later can be seen in the chest, hips, knees, and lower extremities. Oddly, the disease spares some tissue, including the diaphragm, tongue, extra-ocular muscle, cardiac muscle, and smooth muscle. Further complications from FOP can be seen as the disease progresses to include thoracic insufficiency syndrome (TIS). As TIS progresses, the intercostal and paravertebral muscles ossify, as do the aponeuroses. At this point, spinal deformities may become visually apparent, including kyphoscoliosis or thoracic lordosis. People in the late stages of TIS are chronically hypercarbic, and they lose an important component of respiratory drive. Common comorbidities of TIS are pneumonia and right-sided heart failure. Patients in advanced stages of TIS may need oxygen therapy. Therapy should be monitored due to a high risk of sudden death associated with oxygen therapy and late-stage TIS.
Rates of HO differ in individuals with FOP. In the early stages, new growths can appear rapidly, sometimes overnight. Some triggers have been identified. Trauma to muscle or connective tissue can cause flare-ups, eg, intramuscular vaccinations, dental work, bumps, bruises, or falls can lead to new bone formations. Fever has also been reported prior to HO. Individuals with FOP have a high risk (50%) of degenerative hearing loss and it is usually conductive in nature. Submandibular swelling can be a life-threating factor for individuals with FOP; it can lead to difficulty swallowing and breathing. Glucocorticoids may be necessary to reduce inflammation in such cases.
One of the more well-known cases of FOP is that of Harry Eastlack, who donated his skeleton for scientific research. Today it is on display at the Mutter Museum of the College of Physicians of Philadelphia. At the age of 5, Harry broke his leg while playing with his sister. The fracture never healed properly and shortly thereafter his hip and knee began to stiffen. During an examination, his doctor observed bony growths on the muscles of his thigh. Within a few years the growths spread throughout his body, along his back, neck, chest, and buttocks. He underwent surgery to excise the bony growths, only to have them reappear again, thicker and more predominant than before. In his mid-20s, his vertebrae fused together and the muscles in his back ossified, contorting his torso, pushing his frame forward into a fixed position. Later, his jaw locked up, a common occurrence with FOP, and he subsequently died of pneumonia in 1973, just before his 40th birthday.
Harry Eastlack is not so much the exception to the rule but the rule itself. The median age of survival for individuals with FOP is approximately 40 years. The most common cause of death for individuals with FOP is from TIS complications, which results in cardiorespiratory failure. Pneumonia and influenza can be very serious conditions in these individuals, and prophylactic measures are recommended to decrease mortality rates. Individuals afflicted with this condition eventually are confined to a wheelchair, typically by their mid-20s. Some individuals with FOP may be lucky enough to choose the orientation or direction in which a limb/joint will become frozen and fixed into position. For unlucky individuals, the disease chooses the position, which may leave the individual in an unnatural and uncomfortable posture.
FOP is one of the rarest diseases in the world. Students in medical school generally do not learn about FOP, and because of that it is often misdiagnosed. Common misdiagnoses are juvenile fibromatosis, lymphedema, and soft tissue sarcomas. In one such case, a young child around 3 years old had her right arm amputated because doctors feared that the growth was a cancerous tumor. Children often undergo harmful tests and biopsies that result in swelling, inflammation, and flare-ups. There is some literature describing successful surgical removal of bony growths, but in the overwhelming majority of cases, surgery only exacerbates the condition. Children should exercise caution when playing in order to minimize typical childhood accidents that can result in even minor trauma to muscles or soft tissue. In essence, children shouldn’t behave like children.
With the exception of glucocorticoids that may help reduce inflammation, there is currently no treatment or cure for FOP. For the afflicted, it disfigures, distorts, and renders the person immobile, frozen into fixed positions. Often FOP forces individuals to become reliant on others for basic needs, eg, eating, drinking, and hygiene. The worst part of this disease is that not only does it entomb individuals in a shell of bony growths but their dignity and independence get slowly stripped away.
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