Fibrodysplasia Ossificans Progressiva (FOP) Or Stone Man Syndrome

Fibrodysplasia Ossificans Progressiva (FOP) Or Stone Man Syndrome


FOP is a disorder in which muscle tissue and connective tissue (tendons and ligaments) are gradually replaced by bone (ossified), forming bone outside the skeleton (extra-skeletal or heterotopic bone) that constrains movement.

It is a rare idiopathic or autosomal dominant condition of irregular penetration and pre-pubertal onset, in which connective/interstitial tissues undergo extensive fibrosis and heterotopic ossification of ligaments, tendons, muscle, fascia, aponeuroses and skin, first seen in late childhood as firm masses. The abnormal development of bone may lead to stiffness in affected areas and may also limit movement in affected joints, e.g., knees, wrists, shoulders, spine, and/or neck. It can also be called Myositis ossificans progressiva.

 Fibrodysplasia Ossificans Progressiva (Pictures Credit; reddit)

First described in 1736 by John Freke (1688–1756), an English surgeon who was instrumental in separating the profession of Surgeons from that of Barbers.

It affects about 1 in 2 million people, has no gender, ethnic, racial or geographic predilection. About 800 confirmed cases have been documented across the globe.

In Stone Man Syndrome, there is mutation of a gene in the bone morphogenetic protein (BMP) pathway, which is important during the formation of the skeleton in the embryo and the repair of the skeleton following birth.
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.
It is believed that this mutation in ACVR1 gene may change the shape of the receptor under certain conditions and disrupt mechanisms that control the receptor's activity.

As a result, the receptor may be constantly turned on (constitutive activation). Constitutive activation of the receptor causes overgrowth of bone and cartilage and fusion of joints, resulting in the signs and symptoms of fibrodysplasia ossificans progressiva.


Risk Factors
Often precipitated by soft tissue injury or Minor trauma e.g;
  intramuscular injections,
  mandibular blocks for dental work,
  muscular stretching,
  muscle fatigue,
  blunt muscle trauma from bumps,
  bruises,
  falls
  influenza-like viral illnesses

Signs and Symptoms
    The hallmark symptom of fibrodysplasia ossificans progressiva (FOP) is a congenital malformation of a newborn's big toe. This malformations of the great toe, which is apparent at birth, presents as hallux valgus, malformed first metatarsal, and/or monophalangism.
   During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur. Though some exacerbations spontaneously regress, Episodic soft tissue injuries may lead to stiffness in affected areas, limited movement, and eventual ankylosis of affected joints (neck, shoulders, elbows, hips knees, wrists, ankles, jaw, often in that order).

    Heterotopic ossification is typically seen first in the dorsal, axial, cranial, and proximal regions of the body and later in the ventral, appendicular, caudal, and distal regions. Although the cervical spine often becomes ankylosed early in life, any minimal residual movement may eventually result in painful arthritic symptoms.

    Other skeletal anomalies commonly associated with fibrodysplasia ossificans progressiva include; short malformed thumbs, clinodactyly, short broad femoral necks, and proximal medial tibial osteochondromas. Several skeletal muscles, including the diaphragm, tongue, and extraocular muscles, are spared from fibrodysplasia ossificans progressiva. Cardiac muscle and smooth muscle are also spared from heterotopic ossification.

   The Classic Defining features of  Typical stone man syndrome are;
 Characteristic malformations of the great toe & progressive heterotopic ossification.

    Atypical fibrodysplasia ossificans progressiva patients are categorized as fibrodysplasia ossificans progressiva–plus;
  Here the Patients either present with the classic features of FOP plus one or more atypical features (e.g. intercurrent aplastic anemia, craniopharyngioma, childhood glaucoma or growth retardation) (FOP plus), or present major variations in one or both of the two classic defining features of FOP (e.g., normal great toes or severe reduction deficits of digits) (FOP variants).

Diagnosis  The diagnosis of FOP is made by clinical evaluation. Confirmatory genetic testing is available.
      serum alkaline phosphatase activity and the erythrocyte sedimentation rate may be increased, especially during disease flare-ups.
      Urinary basic fibroblast growth factor levels may be elevated during disease flare-ups.
      Plain radiographs can substantiate more subtle great toe abnormalities and the presence of heterotopic ossification   

Outbreaks may be measurable clinically by elevated levels of alkaline phosphatase and bone-specific alkaline phosphatase

Differential Diagnosis; Osseous metaplasia,
                                      myositis ossificans,
                                      extraskeletal osteosarcoma.

Treatment
Unfortunately, there is no effective treatment for fibrodysplasia ossificans progressiva. Surgery is not an option for removing the excess bones because surgery often results in more bone formation. And these new bones don't disappear on their own.

• 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)
        - Viral infections
        - Avoid Deep Tissue Trauma: including intramuscular (IM) injections, if possible but venipuncture, subcutaneous & intravenous meds are OK
        - Take Intubation precautions: protect jaw and get expert anesthesia assistance since the jaw & neck may be completely or partially locked
        - Consulting of expert doctors is strongly recommended regarding potential risks of any surgical or medical interventions being considered.

• 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.

• Medications also are available to help relieve symptoms of FOP, such as Narcotic analgesia & Muscle relaxants

The good news is that researchers are investigating FOP and new treatments. For example, a drug is being developed that may help to control bone growth.


Complications

•  Most patients with fibrodysplasia ossificans progressiva are confined to a wheelchair by the third decade of life and require lifelong assistance in performing activities of daily living.

•     Severe weight loss may result following ankylosis of the jaw.

•     Pneumonia and right-sided heart failure are complications of rigid fixation of the chest wall.

•     The severe disability of fibrodysplasia ossificans progressiva results in low reproductive fitness.

•     Death due to complications of thoracic insufficiency syndrome.

 Fibrodysplasia Ossificans Progressiva (Pictures Credit; reddit.)

 


NOTES;


1.  Connor JM, Evans DA (1982). "Genetic aspects of fibrodysplasia ossificans progressiva". J. Med. Genet. 19 (1): 35–39. doi:10.1136/jmg.19.1.35. PMC 1048816. PMID 7069743.

2.  Fibrodysplasia ossificans profressiva","Genetics Home Reference", February 18, 2014

3.  International Fibrodysplasia Ossificans Progressiva | www.ifopa.org

4.  Medscape| http://emedicine.medscape.com/article/1007104

5.  Philosophical Transactions of the Royal Society 41 (January, 1753): pp. 369 – 370.

6.  Pignolo RJ, Foley, KL. Non-hereditary heterotopic ossification. Implications for injury, arthropathy, and aging. Clin Rev Bone Miner Metabol. 2005;3:261-266.

7.  Segen's Medical Dictionary. © 2012 Farlex, Inc.

8.  Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. May 2006;38(5):525-7.

9.  The Chirurgeons Apprentice | disturbing-disorders-fop-stone-man-syndrome

10. Wikipedia| Fibrodysplasia ossificans progressiva