Evaluation of 20?years experience of fibrodysplasia ossificans progressiva in Iran: lessons for early diagnosis and prevention

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic inflammatory disorder characterized by progressive heterotopic ossification presenting as recurrent soft tissue masses and swelling which may cause disabling, restricted joint mobility. Congenital malformations of the hallux are characteristic features of classic FOP, predating the appearance of disabling features. As no definite treatment is available, the early diagnosis and prevention of exacerbating factors may lead to significant benefits in terms of the life quality of patients. A retrospective study of 12 consecutive FOP patients referred to and admitted in the rheumatology unit at an urban tertiary care academic center between 1991 and 2011. Data, such as age, gender, and past medical history, were collected from the medical history, physical examination, and skeletal survey in order to characterize the clinical presentations. All 12 children (six boys and six girls; ages 2.0-13.5 years) had congenital malformations of the great toes (microdactyly and hallux valgus deformity), in addition to heterotopic ossification presenting as multiple soft tissue tumor-like swellings. Spinal involvement, most notably in the cervical region, suggestive of an early FOP, was present in 83.3 %. Eleven patients (91.6 %) had a prior history of direct physical trauma, while 7 of 11 (63.6 %) had undergone invasive diagnostic procedures, both correlating with the exacerbations of their condition. Clinical awareness of fibrodysplasia ossificans progressiva and its early diagnostic features, particularly congenital malformations of the hallux, during a thorough neonatal examination may lead to an early diagnosis preventing the development of disabling, practically irreversible lesions of heterotopic ossification. Genetic and molecular studies can play a considerable role in the diagnosis of FOP in suspected cases. Early institution of prophylactic and precautionary measures, such as categorical avoidance of trauma and invasive procedures, can significantly reduce the debilitating acute exacerbations of the condition.     

Fibrodysplasia ossificans progressiva

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.     

Early fibrodysplasia ossificans progressiva-like lesion formation in nude mice following implantation of lymphoblastoid cells from FOP patients

Fibrodysplasia ossificans progessiva (FOP) is a genetic disease of progressive, heterotopic ossification, resulting in profound decreased mobility. To investigate the pathophysiology of this condition, lymphoblastoid cells (LCLs) derived from patients with FOP or unaffected family members were implanted subcutaneously into athymic (nude) mice. Cells from unaffected individuals persisted as small masses with little evidence of a fibrotic or angiogenic response. In contrast, cells from patients with FOP gave rise to palpable, solid, fibrotic cellular masses in the animals. Histological and immunohistochemical evaluation revealed that FOP cells proliferated in the host and induced a fibrotic and angiogeneic response similar to the early-stage FOP lesions in patients, but did not progress to form ettopic cartilage or bone. These results de monstrate that lymphoblastoid cells from patients with FOP induce early preosseous FOP-like lesions in mice, but are not sufficient to induce heterotopic ossification in immunocompromised host animals. Implantation of FOP-derived cells in nude mice provides a useful model system for examining the earliest stages of the disease.     

The neuron-specific enolase-bone morphogenic protein 4 transgenic mouse

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and by progressive, postnatal beterotopic bone formation. Although the genetic defect in FOP is not known, several lines of evidence suggest that dysregulation of bone morphogenetic protein (BMP) 4 may be involved in the pathophysiology of the condition. Transgenic mice that overex press BMP4 under the control of the neuron-specific enolase (Nse) promoter is the first mouse model to develop progressive, postnatal heterotopic endochondral ossification. The Nse-BMP4 transgenic mouse provides a unique opportunity to study the pathophysiology and treatment of progressive heterotopic ossification in an animal model relevant to the study of FOP.     

Fibrodysplasia ossificans progressiva in a young adult with genetic mutation: Case report

Rationale:Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital skeletal deformities and soft tissue masses that progress into heterotopic ossification. Deformities of the great toes are distinctive and heterotrophic ossification usually begins in the first decade of the patient''s life. Any invasive procedure could potentially trigger a flare and heterotopic calcification. The diagnosis is difficult and there is no effective treatment for FOP and the approximate life expectancy is 4 decades.Patient concerns:A 22-year-old male patient who had suffered from pain and movement limitations for 14 years. At the early stage of disease, the child underwent an operation on both thighs with a diagnosis of myophagism. He had serious stiffness and multiple bony masses with the characteristic bilateral hallux valgus deformity and microdactyly.Diagnoses:The patient was diagnosed with FOP by the help of characteristic great toe malformations and widespread heterotopic ossification throughout the body. Deoxyribonucleic acid sequencing demonstrated that the patient had a de novo heterozygous mutation (c.617G>A; p.R206H) in activin A receptor/activin-like kinase 2.Interventions:We administered a co-therapy of glucocorticoids, NSAIDs to relieve pain, and montelukast for 2 months. Bisphosphonate (5 mg, intravenous) was used once.Outcomes:At the follow-up 12 months later, the patient still felt low back pain sometimes and need take NSAIDs three times a week.Lessons:Clinicians and radiologists should realize the characteristic features of FOP and early diagnosis can prevent additional invasive harm to the patient.     

Fibrodysplasia ossificans progressiva in a Malian boy of Bamako

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare hereditary connective tissue disorder characterized by congenital malformation of the great toes and by progressive heterotopic ossification of striated muscles and soft tissues. We report a case of FOP in a Malian boy and review the clinical and radiographic manifestations of this disorder. The body TDM showed ossifications and calcifications in the muscles of the large rhomboid, the erector muscles of the rachis and the trapezius muscles.Radiography of the dorsolumbar rachis showed paravertebral soft tissue calcification adjacent to intact lumbar vertebrae. The diagnosis is based on clinical and radiological findings and demonstration of skeletal malformations. The differential diagnosis of this rare condition from other muscle and joint disease is discussed. There is no effective prevention or treatment. There is a need for a wider knowledge of this condition.     

Rehabilitation for individuals with fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification of soft tissue. As heterotopic bone accumulates, range of motion is progressively lost and leads, eventually, to near-complete immobility. Proper rehabilitation helps to preserve health and function despite great impairment. Present and future rehabilitation approaches to enhance activities of daily living, mobility, education, vocation, and sexuality are discussed.     

Fibrodysplasia ossificans progressiva and progressive osseous heteroplasia

Heterotopic ossification (HO) as a primary clinical finding is uncommon, but it occurs in two human genetic disorders: fibrodysplasia ossific, ans progressiva (FOP) and progressive osseous heteroplasia (POH). In these disorders, the progression and stages of the ectopic bone formation appear normal, but disregulation of cell differentiation leads to improper induction of bone formation—in other words, normal bone forms in the wrong place at the wrong time. Cases of POH were initially recognized following misdiagnosis as FOP. However, POH can be distinguished from FOP by several criteria: the presence of cutaneous ossification, the absence of congenital malformations of the skeleton, the absence of inflammatory tumor-like swellings, the asymmetric mosaic distribution of lesions, the absence of predictable regional patterns of HO, and the predominance of intramembranous rather than endochondral ossification. Both FOP and POH are rare conditions, with most cases apparently the result of a de novo (spontaneous) mutation: however, when inherited, both are transmitted through an autosomal-dominant inheritance pattern. Although FOP can be inherited from either a mother or a father, POH is only inheried paternally. Consistent with this parental inheritance pattern, POH patients carry inactivating mutations of the GNAS gene, a gene that is regulated through genomic imprinting and allele-specific gene expression. The genetic cause of FOP remains undetermined. A combination of clinical and genetic evaluations can identify FOP and POH, two distinct disorders of extensive HO.     

The phenotype of fibrodysplasia ossificans progressiva

The phenotype of fibrodysplasia ossificans progressiva (FOP) includes two defining features: congenital malformation of the great toes and progressive heterotopic ossification in characteristic anatomic patterns. Additional common features include proximal medial tibial osteochondromas, orthotopic fusions of the posterior elements of the cervical spine, broad short femoral necks, and conductive hearing loss. The FOP phenotype supports that the primary molecular pathology involves the bone morphogenetic protein (BMP)-signaling pathway directly or a BMP-interacting pathway.     

Dysregulation of BMP4 receptor trafficking and signaling in fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant genetic disorder of aberrant joint formation and heterotopic bone formation, and is the result of a mutation in an as-yet-unidentified gene. Dysregulated signaling pathways can be investigated as a method to identify the consequences of the mutated gene responsible for FOP and to identify potential therapeutic targets. Candidate signaling pathways for FOP are those whose dysregulation during embryonic development could account for the malformation of the great toes and whose postnatal dysregulation could explain the progressive heterotopic endochondral ossification that is such a disabling feature of the disorder. Signaling pathways that fit these criteria are the bone morphogenic protein (BMP)-signaling pathway and its interacting pathways. A large body of data suggests that the BMP4-signaling pathway is dysregulated in FOP.     

Fibrodysplasia ossificans progressiva: case report

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by widespread soft tissue ossification and congenital stigmata of the extremities. We report the case of a 33-year-old woman with clinical and radiological features of FOP. She was born with bilateral hallux valgus and at the age of 10 presented swelling and ossification of the left scapula. During the course of the disease numerous crises were observed. In this patient authors noticed FOP exacerbation after a surgical operation.     

Oral and dental health care and anesthesia for persons with fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a devastating genetic disorder with profound oral and dental health care issues. Most patients with FOP eventually develop heterotopic ossification of the chewing muscles with resultant ankylosis of the temporom andibular joints. Preventive and restorative dental care, as well as endodontic, periodontic, and orthodontic care present therapeutic challenges to the dental practitioner, the anesthesiologist, and to the FOP patient throughout his or her life.     

Rarely occurring mutation of ACVR1 gene in Moroccan patient with fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare autosomal dominant disorder characterized by postnatal progressive heterotopic ossification of the connective tissue and congenital malformation of the big toes. Recently, FOP has been associated with a specific mutation of ACVR1, the gene coding for a bone morphogenetic protein type I receptor. We report the case of a Moroccan patient with FOP carrying a rarely occurring mutation of ACVR1 gene.     

Three pairs of monozygotic twins with fibrodysplasia ossificans progressiva

Genetic and environmental factors affect the phenotype of fibrodysplasia ossificans progressiva (FOP) but their relative effects are unknown. We studied three pairs of monozygotic twins with FOP and found that, within each pair, congenital toe malformations were identical. However, postnatal beterotopic ossification varied greatly depending on life history and environmental exposure. This study shows that genetic determinants strongly influence disease phenotype during prenatal development and that environmental factors strongly influence postnatal progression of the disease.     

A severely disabling disorder: fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare hereditary disorder characterised by progressive heterotopic ossification of the soft tissues. The resulting progressive immobilisation of the limbs, jaw and chest wall generally leads to severe disability. We present an 18-year-old girl with advanced FOP. She had three operative interventions to excise her ectopic bones but all resulted in failure. Treatment strategies for this disorder should include the avoidance of exacerbating factors. Received: 7 July 2000 / Accepted: 20 October 2000     

Multiple epiphyseal dysplasia: clinical and radiographic features, differential diagnosis and molecular basis

Multiple epiphyseal dysplasia is one of the more common skeletal dysplasias but it can still be difficult to diagnose. The presenting signs are often rheumatological ('joint pain') or neurological ('myopathy') in nature, and the cardinal feature of skeletal dysplasia (short stature) may not be present. A radiographic skeletal survey is necessary to delineate the pattern of generalized delayed epiphyseal ossification and changes in epiphyseal contour. Once the diagnosis of multiple epiphyseal dysplasia has been established, careful examination of the radiographs can help to determine which genes should be analysed. Mutations in at least six different genes can cause multiple epiphyseal dysplasia, and it can be either dominant or recessive. Molecular diagnosis is important for accurate prognosis and genetic counselling.     

The Spectrum of Myositis Ossiticans in Haemophilia

Myositis ossificans (MO) refers to non-neoplastic heterotopic soft tissue ossification that can have several aetiologies. Broadly it can be classified into three categories based on aetiology [1]. MO traumatica, the most common form occurs secondary to acute or chronic trauma. MO can also be associated with neurological disorders and in rare cases is congenital. The latter (progressive MO) is a genetic disorder in which congenital osseous abnormalities are associated with progressive soft tissue calcification. Despite an increased tendency to soft tissue bleeds, MO has been rarely reported in haemophilia. We treated three adolescents with haemophilia and MO of varying degrees of severity and outcome.     

Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva

Patients with fibrodysplasia ossificans progressiva (FOP) develop thoracic insufficiency syndrome (TIS), which can lead to life-threatening complications. Features contributing to TIS in patients with FOP include costovertebral malformations with orthotopic ankylosis of the costovertebral joints; ossification of intercostal muscles, paravertebral muscles, and aponeuroses; and progressive spinal deformity, including kyphoscoliosis or thoracic lordosis. Pneumonia and right-sided congestive heart failure are the major life-threatening hazards that result from TIS in patients with FOP. Prophylactic measures to maximize pulmonary function, minimize respiratory compromise, and prevent influenza and pneumonia may be helpful in decreasing the morbidity and mortality from TIS in patients with FOP.     

阿仑膦酸钠治疗进行性骨化性肌炎1例报告

进行性骨化性纤维增殖不良症(fibrodysplasia ossificans progressiva,FOP)也称进行性骨化性肌炎(myositis ossificans progressiva,MOP),是一种灾难性罕见的先天性致残性疾病,以自发产生的肌肉炎症或肌肉受损伤诱导的进行性异位成骨为特征,并导致关节融合和活动障碍。本文报道了一例经典型FOP患者的诊断的治疗。该患者为38岁女性,生后即可见拇趾缩短畸形,4岁起由外伤诱导后全身多处出现皮下包块,包块消退后邻近原包块的关节逐渐变强直和固定。24岁起全身肌肉和骨骼疼痛伴全身浮肿,X线片显示全身多关节周围有异位骨化灶,用Alendronate治疗1个月后全身疼痛和浮肿逐渐消退,6个月后双手掌指关节、指间关节、双膝关节和双腕关节活动度有不同程度的好转,腹部皮下包块不断缩小。氨基二膦酸盐治疗FOP的效果和机制值得进一步研究。     

电子束计算机断层摄影术在小儿复杂先天性心脏病诊断中的应用

目的 :评价电子束计算机断层摄影术 (EBCT)在小儿复杂先天性心脏病 (先心病 )诊断中的价值。　　方法 :对 2 6例患者经胸常规超声心动图 (TTE)诊断为复杂先心病 ,同时做 EBCT增强单层容积扫描 ,并由计算机工作站进行图像三维重建。其中 9例又做了常规心血管造影 ,11例经外科手术 ,进行对照研究。　　结果 :全组 11种复杂先心病共 6 1处畸形 ,其中心内畸形 2 1处 ,EBCT与 TTE均作出正确诊断。然而 ,心外大血管畸形及心室—大血管连接异常诊断中两者有明显差别 ,在 40处畸形中 ,EBCT过多诊断 1处 (动脉导管未闭 ) ,手术证实为假阳性 ,EBCT诊断符合率为 97.5 % (39/ 40 ) ;TTE诊断 35处 (误诊 1处 ,漏诊 4处 ) ,TTE诊断符合率 87.5 % (35 / 40 )。EBCT与TTE诊断的正确率有显著差异 (χ2 =3.936 ,P<0 .0 5 )。TTE与 EBCT相结合使诊断的总准确率提高到 98.4% (6 0 / 6 1)。　　结论 :EBCT对复杂先心病中某些畸形的检出优于 TTE。EBCT血管造影与 TTE及心血管造影相结合 ,可提高对复杂先心病诊断的准确率 ,以指导手术。