Fibrodysplasia Ossificans Progressiva

Fibrodysplasia Ossificans Progressiva

Fibrodysplasia Ossificans Progressiva (FOP), also known as Stone Man Syndrome,  is a very rare inherited disorder in which muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone, forming bone outside the skeleton that constrains movement. This process generally becomes noticeable in early childhood, starting with the neck and shoulders and proceeding down the body and into the limbs. FOP is characterized by malformed big toes that are present at birth. Other skeletal malformations of the cervical spine and ribs and the abnormal development of bone at multiple soft tissue sites may lead episodically to stiffness in affected areas, limited movement, and eventual ankylosis of affected joints.  In many cases, injuries can cause joints to become permanently frozen in place. Surgical removal of the extra bone growths has been shown to cause the body to “repair” the affected area with more bone.

Causes

FOP is caused by an autosomal dominant allele on chromosome 2q23-24. The allele has variable expressivity, but complete penetrance. Most cases are caused by spontaneous mutation in the gametes; most people with FOP cannot have children. A study has determined that it affects approximately 1 in every 2 million people. A similar but less catastrophic disease is fibrous dysplasia, which is caused by a post-zygotic mutation.

A mutation in the gene ACVR1 (also known as activin-like kinase 2 [ALK-2]) is responsible for the disease. ACVR1 encodes activin receptor type-1, a BMP type-1 receptor. The mutation causes substitution of codon 206 from arginine to histidine in the ACVR1 protein. This substitution causes abnormal activation of ACVR1 leading to the transformation of connective tissue and musccle tissue into a secondary skeleton. This causes endothelial cells to transform to mesenchymal stem cells and then to bone.

Symptoms

The hallmark symptom of fibrodysplasia ossificans progressiva (FOP) is a malformation of a newborn’s big toe. This malformation, which is apparent at birth, consists of a short big toe with an abnormal turning of the toe called a valgus deviation.

During early childhood, most of those with FOP form painful fibrous nodules, or tumor-like swellings, over the neck, back and shoulders. These nodules often develop after a child experiences some sort of trauma to the body, such as a bump or fall. Episodes also can occur without any warning or may not occur at all. In most cases, the nodules transform into bone during a process known as heterotopic ossification.

When the body starts to generate new bone, the patient usually experiences a painful flare-up. Tissue swelling, joint stiffness and serious discomfort can occur. Some may have a low-grade fever. Flare-ups can last as long as six to eight weeks. The disease then progresses along the trunk and limbs of the body. These lesions slowly replace the body’s muscles with normal-looking bone.

Diagnosis

The diagnosis of FOP is made by clinical evaluation. Plain radiographs can substantiate more subtle great toe abnormalities and the presence of heterotopic ossification. Confirmatory genetic testing is available.

Differential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors, aggressive juvenile fibromatosis, and non-hereditary heterotopic ossification.

Due to a lack of knowledge of FOP among doctors, the rate of misdiagnosis of the disease is estimated at 80 percent or higher. These errors in diagnosing FOP have caused pain and suffering for FOP patients and their families worldwide. For instance, misdiagnosis has led to unnecessary invasive procedures, such as biopsies, as well as permanent complications from medical interventions, including loss of mobility. 

Three of the most common misdiagnoses for FOP are cancer, aggressive juvenile fibromatosis, also called desmoid tumors, and progressive osseous heteroplasia, another rare disease characterized by the abnormal growth of bone. 

Treatment

At present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Attempts to surgically remove the bone result in more robust bone growth. While under anesthesia, patients with FOP may face problems, which include difficulties with intubation, restrictive pulmonary disease, and changes in the electrical conduction system of the heart.  

Preventative management is based on prophylactic measures against falls (e.g. improvement in household safety, use of protective headgear), respiratory decline (e.g., incentive spirometry), and viral infections.

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