Fibrodysplasia Ossificans Progressiva
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling, progressive, chronic disease in which soft tissue transforms into threads, ribbons and sheets of extraskeletal bone. This development of bone in abnormal places is known as heterotopic ossification, or HO. FOP has an estimated prevalence of just 1.3 cases per 1 million individuals — less than 1,000 people worldwide have a confirmed clinical diagnosis.
Affected individuals live with frequent, painful and recurrent episodes of soft tissue swelling, called flare-ups, that often precede bone growth. These flare-ups typically begin in infancy or early childhood, continuing over the course of a person’s life. Flare-ups may occur spontaneously or after some type of trauma. Most affected individuals are confined to a wheelchair by the third decade of life and at risk of early mortality in their fourth decade due to thoracic insufficiency syndrome that results from HO in and around the ribcage.
Causes and Symptoms
FOP is caused by a mutation in the ACVR1 gene that encodes for the ACVR1/ALK2 receptor located on the surface of cells. This receptor is part of the bone morphogenetic protein, or BMP, signaling pathway within cells and is critical in the regulation of cartilage and bone development and growth. The mutation leads to increased activity of the ACVR1/ALK2 receptor, resulting in excessive BMP signaling, which causes bone growth in abnormal areas of the body.
At birth, all individuals with FOP have a hallmark, bilateral toe malformation, in which the big toes are shortened and bent inwards resembling a bunion (hallux valgus). Over half of affected individuals also have shortened thumbs (brachydactyly). Genetic testing for FOP can confirm or rule out clinical suspicion of FOP, which is extremely important as misdiagnosis or a delay in diagnosis may have serious consequences.
Painful and recurrent episodes of soft tissue swelling called flare-ups often precede heterotopic bone formation. These flare-ups typically begin in infancy or early childhood and may occur spontaneously or after trauma, muscular stretching, overexertion, fatigue, intramuscular immunizations, mandibular blocks (nerve block injection) for dental work, or flu-like infections. Flare-ups may involve a combination of swelling (from mild to severe, or “tumor-like”), redness, warmth, pain and weakness, or limited use of muscles/joints.
Bone formation in the jaw area can cause difficulty with speech and eating, potentially leading to severe malnutrition. Additionally, bone formation around the rib cage restricts the expansion of the lungs and diaphragm, which can lead to potentially fatal breathing issues.
Steroids and non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve the swelling and pain associated with flare-ups. However, they don’t prevent further development of bone in abnormal place. Surgery to remove extra bone is contraindicated in FOP patients, and results in explosive bone growth, further limiting mobility.
Since FOP flare-ups are frequently misdiagnosed as tumors, recognizing these tell-tale signs is important as it may help prevent the use of chemotherapy or other inappropriate medical interventions, like biopsies, that exacerbate new bone formation.
Other features associated with FOP include
- Curvature of a digit (clinodactyly)
- Shortened thumbs (brachydactyly)
- Short, broad femoral necks (part of the thigh bone)
- Osteochondromas (benign bone tumor) – commonly of the proximal or upper part of the tibia (large bone in lower front portion of leg)
- Dental anomalies
- Hearing loss
A small percentage of people with FOP have severe or very mild toe/thumb malformations, neurological manifestations, eye conditions, or sparse hair.
Multiple osteochondromas (MO), also called multiple hereditary exostoses, or HME, is an ultra-rare, severely disabling, progressive, chronic disease in which multiple benign bone tumors, also known as osteochondromas (OCs) or osteocartilaginous exostoses, develop on bones. MO is estimated to affect approximately 20 out of 1 million lives.
Causes and Symptoms
MO is caused by loss-of-function mutations in exostosin 1 (EXT1) and exostosin 2 (EXT2) genes. The EXT genes encode for enzymes (glycosyltransferases) that synthesize heparan sulphate molecular chains on bonded proteins called proteoglycans (HSPGs). Decreases in, or absence of, HSPGs cause local increases in specific types of signaling proteins—primarily bone morphogenetic proteins (BMP) and Smads. Increases in these proteins ultimately lead to the abnormal budding of osteochondromas at bone growth plates.
MO is typically diagnosed in early childhood due to symptomatic OCs, with a median age at diagnosis of three years. These OCs consist of a growth plate-like cartilage cap overlying a bony base. They originate as an outgrowth from bone growth plates, but frequently detach from the growth plate as a child grows. OCs form at the end of most long bones (such as the forearm or femur) and on flat bones (such as the hip, shoulder blade, or ribs). They can often be seen as lumps during a clinical exam. The image below illustrates the appearance of OCs on a long bone.
The symptoms of MO vary across individuals. Symptoms include various skeletal abnormalities such as short stature, joint deformity, bowed bones, limb length discrepancies, and early-onset osteoarthritis. Functional problems and morbidity occur due to pain, reduced mobility and joint range of motion, pinching of blood vessels, nerves, tendons, and spinal cord compression. Of patients with MO, 70 percent often undergo surgeries, sometimes in excess of 20, to remove OCs or correct deformities. In 2 to 5 percent of patients with MO, OCs become cancerous during adulthood.
Of patients with MO, 70 percent often undergo surgeries, sometimes in excess of 20, to remove OCs or address deformities. In 2-5 percent of patients with MO, OCs become neoplastic during adulthood.
Once bone growth is complete in late adolescence and early adulthood, new OCs do not form; however, existing OCs can cause substantial morbidity. The severity of MO has been classified according to the number of OCs detected at a certain age, as well as the number of sites with deformities or functional limitations. However, it is difficult to determine beforehand who is likely to have more severe disease.
Dry Eye Disease
Dry eye disease is a condition in which the eye does not adequately produce tears. Dry eye disease is one of the most common ocular diseases. General estimates for the prevalence of dry eye disease are 14.5 percent. The disorder is most prevalent in elderly patients and women, in particular menopausal or post-menopausal women.
Dry eye disease is characterized by ocular discomfort (including redness, gritty or burning eyes, and foreign body sensation), mucous discharge, disturbed vision and tear film instability. Advanced dry eye disease can lead to pain, ulcers, or scars on the cornea, and some loss of vision.
There are both primary and secondary causes for dry eye disease, which result in disruptions to the precorneal tear film. The primary causes include systemic disorders, while the secondary causes can be from hormonal imbalances, environmental conditions (extreme temperatures, low humidity) and inflammatory disease. Other risk factors for dry eye disease include extensive use of display screens, refractive surgery, contact lens wear and certain medications.
Data suggest that previously observed beneficial effects of retinoids on ocular health may be mediated via RARγ receptors. Agonists such as palovarotene, which are selective for RARγ receptors, were able to completely reproduce the effects of ATRA in an ex vivo model of corneal fibrosis, whereas agonists which preferentially bind RARα or RARβ receptors had minimal or no effect.