Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic disorder of HO in humans. Episodic disease flare-ups are precipitated by soft tissue injury, and immobility is cumulative. Recently, a recurrent mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved target for drug development in the transforming growth factor (TGF)-beta/BMP signalling pathway, and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for ACVR1/ALK2. Present management involves early diagnosis, assiduous avoidance of iatrogenic harm, and symptomatic amelioration of painful flare-ups. Effective therapies for FOP, and possibly for other common conditions of HO, may potentially be based on future interventions that block ACVR1/ALK2 signalling.

Tracheal occlusion did not improve survival or morbidity rates in this cohort of fetuses with congenital diaphragmatic hernia.

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ABSTRACT. Background. Little is known about diagnostic errors for a disease worldwide. Such errors could alter the disease's natural history, especially if unwarranted interventions cause irreversible harm. Fibrodysplasia ossificans progressiva (FOP), a rare, autosomal dominant genetic disease characterized by episodes of permanent heterotopic ossification of soft tissues, occurs worldwide without racial, ethnic, or geographic predilection. There is no effective treatment, and soft-tissue trauma (eg, biopsies, surgical procedures, intramuscular injections, or mandibular blocks for dental procedures) and viral illnesses are likely to induce episodes of rapidly progressive heterotopic ossification, with resultant permanent loss of motion in the affected area. Accurate diagnoses can be made on the basis of the clinical findings of tumor-like swellings on the head, neck, back, or shoulders and characteristic short great toes with hallux valgus-like malformations and missing interphalangeal joints. On the basis of conversations with numerous individuals with FOP, we suspected that diagnostic errors with FOP are common and often associated with inappropriate and harmful diagnostic and therapeutic procedures.Objective. To document the frequency of diagnostic errors with FOP and complications resulting from misdiagnoses.Design. A questionnaire requesting detailed demographic, diagnostic, and treatment information was sent to all 269 patient-members of the International FOP Association; the sampling frame included >90% of all known FOP patients worldwide. We received 138 replies (51% response) from 25 countries. The age range was 2 to 71 years; there were 78 female subjects and 60 male subjects. In addition, to assess the availability and adequacy of information about FOP, we reviewed 184 English-language textbooks in relevant specialties published in the past 20 years.Results. Incorrect diagnoses were given initially to 87% of individuals with FOP. This astonishing rate of diagnostic errors occurred worldwide, regardless of ethnicity, geographic background, or misdiagnosing physician's specialty. The most common incorrect diagnosis was cancer (32%). The mean period from the onset of symptoms to correct diagnosis was 4.1 years, and the median number of physicians consulted before the correct diagnosis of FOP was 6. For 67% of patients, unnecessary invasive procedures (biopsies) were performed; 68% received inappropriate therapies. Forty-nine percent of all patients reported permanent loss of mobility resulting from invasive medical interventions that caused posttraumatic ossification. Notably, only 8% of the 184 textbooks that were reviewed contained adequate descriptions of FOP, including the caution that trauma can accelerate the process of heterotopic ossification.Conclusions. T he accurate diagnosis of disease has been a basic principle of medical care since antiquity. Mistaken or delayed diagnosis can lead to morbidity or death through use of inappropriate procedures or through withholding of necessary treatments. R...

Fibrodysplasia ossificans progressiva is not only an extremely disabling disease but also a condition of considerably shortened lifespan. The most common cause of death in patients with fibrodysplasia ossificans progressiva is cardiorespiratory failure from thoracic insufficiency syndrome.