FOP管理的国际医师调研：一项修订的Delphi研究

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概述

进行性骨化性纤维发育不良（FOP）是一种进行性异位骨化（HEO）的致残性疾病。这种疾病是由激活素A I型受体（ACVR1，也称为ALK2）的获得性杂合突变引起，这也是一种骨形态发生蛋白（BMP）I型受体。

目前，可以对症状进行改善治疗，但是却没有确定的治疗方法。

虽然对症治疗管理指南被广泛地使用，但却存在地域的差异。为了能够在临床医生之间对理解FOP患者的诊疗达成全球的共识，我们募集了一群具有FOP患者护理经验的医生，组成了专家小组。

通过使用改进后的Delphi方法，在四个主要议题上达成了广泛的国际共识：临床诊断，预防急性发作，患者以及围绕家庭为中心的护理等一些通识的临床管理问题。

这项医生优先考虑的研究为FOP临床管理的标准化提供了基准。

原文

Fibrodysplasia ossificans progressiva (FOP), a disabling disorder of progressive heterotopic ossification (HEO), is caused by heterozygous gain-of- function mutations in Activin receptor A, type I (ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor. Presently, symptomatic management is possible, but no definitive treatments are available. Although extensive guidelines for symptomatic management are widely used, regional preferences exist. In order to understand if there was worldwide consensus among clinicians treating FOP patients, an expert panel of physicians directly involved in FOP patient care was convened. Using a modified Delphi method, broad international consensus was reached on four main topics: diagnosis, prevention of flare-ups, patient and family-centered care and general clinical management issues. This study of physician preferences provides a basis for standardization of clinical management for FOP.

背景

进行性骨化性纤维发育不良（FOP; MIM #135100）是一种罕见的进行性异位骨化致残性疾病，每200万人中的患病率为1例。尚未有过关于民族、种族、性别或地理差异有关的易感性报告。

FOP由来自骨形态发生蛋白I型受体，ACVR1的胞内结构域变异所引起，这种变异驱使骨外骨骼的形成。

ACVR1的突变体表现出轻微的基底过度活跃以及对典型和非典型配体的过度响应。

原文

Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a rare and disabling genetic condition of progressive heterotopic ossification with a point prevalence of approximately 1 per 2 million. No ethnic, racial, gender or geographic predisposition has been reported [1, 2]. FOP results from mutations in the intracellular domain of the bone morphogenetic protein (BMP) type I receptor, ACVR1, which drive extraskeletal bone formation [3–5]. Mutant (mt) ACVR1 exhibits mild basal hyperactivity and hyper-responsiveness to canonical and non-canonical ligands [6–8].

经典型FOP，占全球患者约97%，他们具有两个明显的临床特征：大脚趾畸形和进行性异位骨化（HEO），以及在ACVR1中存在单个激活错义突变（c.617G > A;R206H）。

误诊很普遍。

临床与遗传变异已经有过描述。

在出生时注意到的大脚趾畸形；颈椎原位融合而引起的颈部僵硬是普遍的早期发现。

其他与FOP有关的骨骼异常还包括：拇趾短且畸形、指趾短、宽的股骨颈、髋关节发育不良以及胫骨近端内侧的骨软骨瘤。

原文

Classic FOP, seen in ~97% of patients worldwide is characterized by two clinical features: malformations of the great toes and progressive heterotopic endochondral ossification (HEO), and by a single missense activating mutation in ACVR1 (c.617G > A;R206H) [1–4]. Misdiagnosis is common [9]. Clinical and genetic variants have been described [2, 4]. Malformations of the great toe are noted at birth; neck stiffness due to orthotopic fusion of cervical vertebra is a common early finding. Other skeletal anomalies associated with FOP include short malformed thumbs, clinodactyly, short broad femoral necks, hip dysplasia and proximal medial tibial osteochondromas [4].

大部分患有经典型FOP的患者，在生命中的第一个十年便会开始经历伴随疼痛的软组织炎性发作（急性发作），接下来便是骨骼肌、筋膜、肌膜、腱膜和韧带的异位骨化。

在没有发生急性发作的情况下也会出现进行性的关节功能障碍，期间伴随或不伴随异位骨化。

骨骼外成骨形成时永久性的，会导致渐进性的活动能力丧失，患者在日常生活中需要给予帮助。

最终，进行性限制性的胸壁疾病和继发性心力衰竭将导致患者死亡，多常见于50岁左右。

临床和基础研究正在为临床开发确定坚实的治疗靶点。

目前，尚无明确的治疗方法。对症治疗较为普遍，但是对症治疗的方法因医而异。

原文

Most individuals with classic FOP experience episodes of painful inflammation of soft tissues (flare-up), followed by heterotopic ossification of skeletal muscle, fascia, tendons, aponeuroses, and ligaments beginning in the first decade of life. Progressive joint dysfunction without flare-up can also occur, with or without HEO. Extraskeletal bone formation is permanent and leads to progressive immobility and need for assistance in performing activities of daily living [10]. Finally, progressive restrictive chest wall disease and secondary cardiac failure lead to death, commonly in the fifth decade [11]. At present, no definitive treatment is available; symptomatic management prevails but varies widely [12]. Basic and clinical research is identifying robust targets for clinical development [1, 7, 8, 13–16].

为了更好地了解临床医生在FOP患者的护理方面是否存在全球性的共识，我们曾在一次国际FOP患者会议上着急了一组直接参与患者管理的医生专家小组来解决上述问题。

原文

In order to better understand if there is worldwide consensus among clinicians in FOP patient care, an expert panel of physicians directly involved in patient management was convened at an international FOP patient meeting to address this issue.

Main text | 正文

共识的过程包括一个五阶段改进的Delphi方法，该方法曾在2016年1月至2016年6月期间进行。

首先，主要研究者 (PI; MDR) 对文献和FOP治疗指南进行了彻底的审查。

其次，PI 建立了一份Email问卷，其中包含与四个重点主题（临床诊断，预防急性发作，患者以及围绕家庭为中心的护理等一些通识的临床管理问题。）相关的综合说明列表。

第三，2016 年4月在意大利Livorno举行的意大利FOP年度患者和家庭会议上，PI 召集了一个由10位国际专家组成的小组。该小组的医生来自10个国家（阿根廷、澳大利亚、巴西、法国、德国、意大利、日本、荷兰、英国和美国）覆盖了五大洲（北美、南美、欧洲、亚洲和澳大利亚）。

第四，要求专家组对说明列表进行分级、修改和排序以供审议。

最后，要求专家组表示同意、部分同意或不同意同意以商定进行评估具体的声明。

原文

The consensus process incorporated a five-step modified Delphi method, which took place between January and June 2016 [17]. First, a thorough review of the literature and FOP Treatment Guidelines was performed by the principal investigator (PI; MDR). Second, an e-mail questionnaire, with a comprehensive list of statements related to four main topics (diagnosis, prevention of flare-ups, patient and family-centered care and general clinical management issues) was established by the PI. Third, a panel of ten international experts was convened by the PI based on physician participation at the annual FOP patient and family meeting of FOP Italia in Livorno, Italy in April, 2016. The panel included physicians from ten countries (Argentina, Australia, Brazil, France, Germany, Italy, Japan, Netherlands, United Kingdom and the United States) and from five continents (North America, South America, Europe, Asia and Australia). Fourth, the expert panel was asked to rank, revise and order statements for consideration. Finally, the panel was asked to indicate agreement, partial agreement or disagreement with specific statements agreed upon for assessment.

专家小组审议的20份声明最终获得了一致批准，并附在报告的表1中。

原文

Twenty statements considered by the expert panel received at least consensus approval and are reported in Table 1.

Table 1 Consensus statements | 表1共识声明

Diagnosis

FOP的明确诊断需要基因确认，在急性发作出现之前确诊的婴儿或儿童需要每年进行临床评估。

对与急性发作出现之前确诊的FOP患者，建议预防急性发作。

原文

Definitive diagnosis of FOP requires genetic confirmation Infants or children diagnosed before the onset of flare-ups need annual clinical assessment.

Prevention of flare-ups | 预防急性发作

预防急性发作包括识别急性发作的已知原因（钝性肌肉创伤、肌肉疲劳、肌肉拉伸、肌肉注射）。

如果发生钝性肌肉损伤，应该考虑口服至少3天的泼尼松，应以预防急性发作。

建议在牙科和外口手术中使用类固醇进行预防。

没有证据表明使用非甾体类抗炎药进行长期治疗可以预防急性发作和进行性异位骨化。

对与通过肌肉注射给药的所有疫苗，建议通过皮下给药的方式进行免疫。

对于其他疫苗，应该与患者或其父母讨论肌肉注射的风险和收益。

急性发作期间不应进行免疫接种。

在牙科手术中，必须避免过度拉伸颞下颌关节和下颚部位。

鼓励全年龄段的活动，但必须避免超出关节能力范围的被动运动。

原文

The prevention of flare-ups involves recognizing known causes of flare-up (blunt muscle trauma, muscle fatigue, muscular stretching, intramuscular injections)

Patient & family care | 患者及家庭护理

每个患者都应该指定一位主治医生；但不一定要是FOP专家。

在诊断时，应该告知患者和家属有关 IFOPA 和本国或地区特定的FOP驰援组织的信息。

应该对患者及其家属进行有关牙科安全护理的教育。

原文

Each patient should have a primary physician; not necessarily an FOP expert

General clinical management issues | 基础临床管理事项

FOP患者应该在儿童时期通过听力测量进行听力障碍的筛查。

职业治疗，专注于增强日常生活的活动能力，这可能有助于改善FOP患者的生活质量。

对于运动受限的患者，建议通过适当的装置或方法预防压疮。

对于呼吸功能不全的患者，应考虑接种流感和肺炎球菌性肺炎疫苗。

对与所有FOP患者，术前都必须咨询那些对与FOP患者全身麻醉方面有经验丰富的专业麻醉师。即使是患者可以完整张口的情况，鼻气管光纤插管仍是首选的全身麻醉方式。

在下颌强直的情况下，应咨询营养师以确保足够的营养。

如果临床检查发现抑郁，建议给予心理支持。

原文

FOP patients should be screened in childhood by audiometry for hearing impairment

Diagnosis | 诊断

大家普遍同意有必要在FOP的患者群体中进行遗传学诊断。

然而，有一位专家强烈反对，并表示“FOP的诊断是临床的”。

其他专家则从概念上同意遗传学诊断的必要性，但从实际出发进行了延期，因为他们国家不具备遗传分析的条件。

大部分专家赞同，即使在临床上能够确诊FOP，由于潜在的拟表型（一种环境影响引起的表现型非遗传性变更），遗传确认更为可取。

所有专家都表示同意，遗传确诊对与没有进行性异位骨化的脚趾畸形患者至关重要，以此排除那些未患FOP的脚趾畸形患者。

所有专家一致认为，FOP国际社区应努力确保所有临床疑似患有FOP的患者都能够进行基因检测，哪怕他们生活在没有ACVR1基因分析条件的国家里。

原文

There was general agreement on the need for genetic diagnosis in FOP. However, one expert strongly disagreed and stated “the diagnosis of FOP is clinical.” Other experts agreed conceptually on the need for genetic diagnosis but deferred on practical grounds because genetic analysis was not available in their countries. Most agreed that even if the diagnosis of FOP was clinically certain, genetic confirmation was desirable due to possible phenocopies. All agreed that genetic diagnosis was essential for patients with toe malformation without HEO, in order to exclude those with toe malformations who did not have FOP. All experts agreed that an international effort by the FOP community should ensure genetic testing be available to all individuals who are clinically suspected of having FOP even if they live in countries where no genetic analysis of ACVR1 is available.

Prevention of flare-ups | 预防急性发作

所有专家都同意，应该避免钝性肌肉创伤，肌肉疲劳或关节或软组织的拉伸，用以避免诱发急性发作。

还应该尽可能地避免具有严重损伤或跌倒风险的活动，例如：跑步、骑自行车或接触性运动，但是要针对患者年龄组的发育准则（即，应该允许儿童在发育阶段进行玩耍）

根据年龄、活动受限以及地域文化的规范，计划为每位患者考虑个性化的生活方式，以避免创伤。

原文

All experts agreed that blunt muscle trauma, muscle fatigue, or stretching of the joints or soft tissues should be avoided for fear of triggering flare-ups. Activities with a high risk of injury or falling, such as running, bicycling, or contact sports should also be avoided to the extent possible, but within the developmental norms for a patient’s age group (i.e., children should be allowed to achieve their developmental milestones that involve playing). Individualized lifestyle plans to avoid trauma should be considered for each patient, based on age, limited mobility and cultural norms.

基于临床，在明显的撞击性损伤情况下，早期口服泼尼松可能会有助于预防急性发作。

原文

In case of clinically significant impact injuries, early administration of oral prednisone may be useful to prevent flare-ups.

尽管缺乏严格的临床实证，但是专家们一致认为，在严重创伤后24小时内开始短期口服（3~4天）的皮质类固醇（即泼尼松，剂量为2mg/kg/day）具有合理的预防效果。

由于专门的牙科操作或手术是急性发作的高风险诱发因素，因此在大型牙科处置或手术后，口服类固醇治疗可能具有积极的预防作用。

原文

Despite lack of stringent clinical evidence, the experts agreed that a brief (3–4 day) course of oral corticosteroids (i.e. prednisone at 2 mg/kg/day), started within the first 24 h after major trauma had a plausible preventive effect [10, 12]. Due to the fact that major dental work or surgery is a high-risk trigger for flare-ups, a course of oral steroids before and after major dental work or surgery could have a positive preventive effect [10, 12].

所有专家都同意肌肉注射对FOP患者是危险的操作，因为这可能会在注射部位引发急性发作和异位骨化。

为了防止急性发作，建议能够通过皮下途径给药的疫苗进行皮下注射免疫；对与其他疫苗，应该与患者或其父母家属讨论肌肉注射的风险与收益。

所有专家都同意在急性发作期间不能够进行免疫接种。

原文

All experts agreed that intramuscular injections are dangerous for FOP patients because they may trigger a flare-up and heterotopic ossification at the injection site. To prevent flare-ups, subcutaneous immunization for vaccines that can be administrated by the subcutaneous route is advisable; for all the other vaccines, the riskbenefit ratio of intramuscular administration should be discussed with patients and parents or families. All experts agreed that no immunization should be administered during a flare-up [12].

对与使用现有药物（如非甾体类抗炎药）进行面型治疗，用以减少急性发作存在着普遍的分歧。

FOP的动物模型或临床研究中尚未积累足够多的数据。

然而，正如FOP治疗指南中所述，建议医生谨慎使用药物来控制个别患者的疾病症状。

原文

There was general disagreement about chronic treatment with existing medications such as non-steroidal anti-inflammatory drugs to reduce flare-ups. No adequate data exist in FOP animal models or in clinical studies. However, physician discretion in using medications to control disease symptoms in individual patients is advised, as indicated in the FOP Treatment Guidelines [12].

Patient and family-centered care | 患者和以家庭为中心的护理

专家小组同意以患者和家庭为中心的护理的总体目标。

对与任何患者，都应该将患者和家庭的知识、价值观、信仰和文化背景纳入到FOP患者的护理计划中，并宣贯。

医生应该用肯定和有效的方式与患者和家属进行沟通和分享完整无偏差的信息，以便让患者有效地参与决策过程。

原文

The panel of experts agreed with the over-arching goal of patient and family-centered care. Patient and family knowledge, values, beliefs and cultural backgrounds should be incorporated into the planning and delivery of care of FOP patients, as with any patient. The physician should communicate and share complete and unbiased information with patients and families in ways that are affirming and useful and in order to allow the patient to effectively participate in the decision-making process.

与任何罕见病一样，建议采用多学科会诊的方法，由不同的专家赖提供综合的医疗护理与社会支持。

但是，每位患者都应该寻求并确定一名主治医生来协调所有的护理。

专家小组一致认为，应该确定至少一位在FOP方面具有内科、外科、麻醉、物理治疗、职业治疗和牙科专业知识的本国或地域医院，用以优化FOP患者的护理，并将任何所需的医疗护理和程序风险降至最低.

为了保持护理的连续性，家庭医生和其他当地治疗的医生应即刻获得有关患者和FOP的通识知识与信息。

提供给患者和/或家属的急救卡有助于总结FOP的特定问题或疑虑。

原文

As with any rare disease, a multidisciplinary approach to comprehensive medical care and social support by different specialists is advisable. However, each patient should seek and establish a primary physician to coordinate all care. The panel of experts agreed that at least one national or regional center with medical, surgical, anesthesia, physical therapy, occupational therapy and dental expertise in FOP should be identified to optimize care for FOP patients and to minimize risks from any needed medical care and procedures. For continuity of care, knowledge and information concerning the patient specifically and FOP in general should be immediately available to the family doctor as well as to other locally-treating physicians. An emergency card provided to the patient and/or the family is useful in order to summarize FOP-specific issues/concerns.

在诊断时，应该告知患者和家属国际FOP协会以及本国特定的FOP组织。IFOPA - 刊登FOP相关临床试验的主要门户网站[http://www.ifopa.org]

该提议对于提供患者和家庭支持的资源以及为促进患者联络和熟悉FOP的工作人员至关重要。

原文

At the time of diagnosis, patients and families should be informed about the International FOP Association (IFOPA - the primary portal for announcing FOP related clinical trials

http://www.ifopa.org

General clinical management issues | 基础临床管理事项

首选是对患有FOP的婴儿、儿童和成人进行年度的临床评估，但总是无法如愿。

应该尽早开始口腔预防以及进行常规口腔随访。

对患者及其家属进行牙科安全护理和预防的教育至关重要，特别是在儿童时期，重点是卫生和预防龋齿。

有关口腔护理的详细信息，请参阅FOP治疗指南[12]。

原文

Annual clinical assessment of infants, children and adults with FOP is preferable but not always achievable. Dental prophylaxis and routine follow-up should begin as early as possible. The education of patients and their families on safe dental care and prophylaxis is essential, especially during childhood years, focusing on hygiene and prevention of caries. Details concerning oral care are available in the FOP Treatment Guidelines [12].

专家小组就避免主要牙科手术（智齿常规拔除、根管治疗等）达成共识。

由于异位骨化和颞下颌关节强直的风险，必须避免下颌阻滞。常规牙科程序（清洁、补牙）应该谨慎进行。

在下颌锁定的情况下，需要咨询营养师以确保足够的营养。

原文

The expert panel reached consensus about major dental procedures (routine extraction of wisdom teeth, root canal, etc.) which should be avoided. Mandibular blocks must be avoided due to the risk of HEO and temporomandibular joint ankylosis. Routine dental procedures (cleaning, carrie fillings) should proceed with caution. In case of locked jaw, the consultation of a dietician to ensure adequate nutrition is desirable.

在需要全身麻醉的手术中，必须避免颞下颌关节过度拉伸。

大多数FOP患者有颈椎融合、开口受限或颞下颌关节强直，这使得无法完成口腔插管。

在这些情况下，鼻气管光纤插管是优选。

在保持张口能力的患者中，颞下颌关节过度拉伸会引起急性发作和骨化；因此，即使在这些清醒的患者中，鼻气管纤维插管也是优选。

术前必须咨询在FOP患者全身麻醉方面有经验丰富的麻醉师，而且如果光纤插管前需要气管切开术，则必须有经验丰富的耳鼻喉科医生在场。

患者的固定必须一丝不苟，并要考虑使用保温毯或带衬垫的床垫，以尽量减少软组织的创伤。

原文

In case of procedures requiring general anesthesia, overstretching of the temporal-mandibular joint must be avoided. Most FOP patients have fusion of cervical vertebrae, limited mouth opening or ankylosis of the temporalmandibular joint, making oral intubation impossible. In these cases, naso-tracheal fiberoptic intubation is preferred. In patients who retain mouth opening, overstretching of the temporal-mandibular joint can cause flare-ups and ossification; therefore even in these patients awake, naso-tracheal fiberoptic intubation is preferred. An anesthesiologist highly experienced with general anesthesia for FOP patients must be consulted pre-operatively and an experienced otolaryngologist must be available in case tracheostomy is necessary prior to fiberoptic intubation. The positioning of the patient must be meticulous and the use of an air warming blanket or a padded transfer mattress is to be considered in order to minimize soft tissue trauma [12, 18].

如果可能，应在 6 岁以后开始肺功能评估。

专家小组不建议进行常规影像学随访，因为辐射风险的效益比不高。

原文

Pulmonary function evaluation should begin after 6 years of age, if possible. The Expert Panel does not recommend routine radiographic follow-up due to the unjustified radiation risk-benefit ratio.

大约50%的FOP患者在儿童时期会出现听力障碍。

如果临床需要，应考虑听力测试。如果听力损失会干扰日常生活肿的学习或活动，应考虑使用助听器[19]。

原文

Approximately 50% of FOP patients develop hearing impairment during childhood. Audiometry should be considered if clinically warranted. In case of hearing loss that interferes with learning or activities of daily living, the use of hearing aids should be considered [19].

为了预防或延缓继发于活动受限的肌肉萎缩，建议进行无肌肉创伤或拉伸风险的轻度体力活动（例如游泳），使患者能够在安全、低影响的环境下进行主动的能力范围内的运动锻炼。

应避免传统的物理治疗，包括超范围的被动活动，因为存在过度拉伸和软组织损伤的风险。

然而，在可能的情况下，可以进行膈肌呼吸练习和身姿训练，以维持和改善呼吸功能，特别是对于胸壁动力学严重受损的年长患者。

原文

In order to prevent or delay the onset of muscle atrophy secondary to mobility limitations, light physical activity without risk of muscle trauma or stretching (e.g., swimming), that allows patients to perform active range of motion exercise in a safe, low-impact environment, is recommended. Traditional physiotherapy, including passive range of motion, should be avoided, due to the risk of over-stretching and soft tissue injuries. Nevertheless, diaphragmatic breathing exercises and postural re-education can be performed when possible, in order to maintain and improve respiratory function, especially in older patients in whom chest wall dynamics is severely compromised [12].

专注于增强日常生活活动的职业治疗可能有助于改善 FOP 患者的生活质量。

此外，物理治疗和任何适应性义肢都应瞄准患者的舒适度，而不要试图纠正机体的生物力学或机体的缺陷。

原文

Occupational therapy, focused on enhancing activities of daily living, may be useful to improve the quality of life of FOP patients. In addition, the goals of physical therapy and any adaptive prosthetics should be clearly focused on patient comfort, rather than trying to correct biomechanical or anatomic defects [12].

在异位骨化患者中，建议使用适当的方法，以减轻对骨骼突出部位的压力。

在运动受限的患者中，经常变换体位对于预防褥疮至关重要。

其他策略包括保持该身体部位的清洁以防止感染、监测皮肤状况和保持足够的营养[12]。

原文

In patients with HO, the use of appropriate methods is recommended in order to reduce pressure over bony prominences. In patients with limited motion, frequent position changes are essential for preventing pressure sores. Other strategies include keeping the area clean in order to prevent infections, monitoring skin conditions and maintaining adequate nutrition [12].

专家小组一致认为，识别抑郁，焦虑或其他情绪问题，以及育儿压力和隐忍行为，应该促进心理和/或专门的社会服务支持。

原文

The panel reached consensus that the identification of depression, anxiety or other emotional problems, as well as parenting stress and coping behaviors should prompt psychological and/or specialized social service support.

Conclusion | 结论

这里对专家组审议的大多数发言达成了广泛的共识（表1）。然而，有一些例外值得注意，包括但不限于长期使用非甾体抗炎药来预防进行性异位骨化。专家小组同意在这一有争议的问题上存在不同意见，但对需要额外的医学循证数据达成了共识。

原文

There was broad consensus on most of the statements considered by the panel (Table 1). However, there were some notable exceptions including – but not limited to – the chronic use of non-steroidal anti-inflammatory medications to prevent HEO. The expert panel agreed to disagree on this contentious issue but reached consensus on the need for additional evidence-based data.

首先，专家小组仅限于参加 2016 年在意大利Livorno举行的意大利FOP患者和家庭会议的人员，这并不一定能够反映该领域在全球专业知识领域中的全部问题。

其次，考虑的议题主要集中在预防上，并有意回避那些有争议的对症管理议题，例如缓解性药物。第三，FOP的治疗指南是由全球临床专家发布的共识性文件，预计将于2018年修订，它将像过去一样用以全面解决FOP的核心临床管理问题 [12]。

尽管如此，这项调查将帮助医生对FOP患者进行当代的临床管理，聚焦预防管理的关键领域，并为未来的共识性指南提供信息。

最后，本研究报告的共识声明并非旨在替代医生的专业独立判断，因为这些共识无法解答获取临床护理的地域性差异，也无法解答针对FOP患者个体和家庭的最佳指导建议。

原文

First, the panel of experts assembled was limited to those attending the FOP Italia Patient and Family Meeting in Livorno, Italy in 2016 and did not necessarily reflect the totality of global expertise in this field. Second, the generation of topics for consideration focused primarily on prevention and purposely circumvented controversial topics of symptomatic management such as palliative medications. Third, the FOP Treatment Guidelines, a consensus document published by clinical experts worldwide, and whose revision is anticipated in 2018, will comprehensibly address the central management issues in FOP as it has in the past [12]. Nevertheless, this survey will assist physicians in the contemporary clinical management of FOP patients, circumscribe critical areas of preventive management, and inform future consensus guidelines. Finally, the consensus statements reported in this study are not intended to substitute for the independent professional judgment of treating physicians as they cannot account for regional heterogeneity of access to clinical care or the best advice and guidance for individual FOP patients and families.

References | 参考文献

Kaplan FS, Pignolo RJ, Shore EM. From mysteries to medicines: drug development for fibrodysplasia ossificans progressive. Expert Opin Orphan Drugs. 2013;1:637–49.

Hüning I, Gillessen-Kaesbach G. Fibrodysplasia ossificans progressiva: clinical course, genetic mutations and genotype-phenotype correlation. Mol Syndromol. 2014;5:201–11.

Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho T-J, Choi IH, Connor JM, Delai P, Glaser DL, Le Merrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2016;38:525–7.

Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Carroll L, Delai P, Fastnacht-Urban E, Forman SJ, Gillessen-Kaesbach G, Hoover-Fong J, Köster B, Pauli RM, Reardon W, Zaidi S-A, Zasloff M, Morhart R, Mundlos S, Groppe J, Shore EM. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat. 2009;30:379–90.

Chakkalakal SA, Zhang D, Culbert AL, Convente MR, Caron RJ, Wright AC, Maidment AD, Kaplan FS, Shore EM. An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva. J Bone Miner Res. 2012;27:1746–56.

Shen Q, Little SC, Xu M, Haupt J, Ast C, Katagiri T, Mundlos S, Seemann P, Kaplan FS, Mullins MC, Shore EM. The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J Clin Invest. 2009;119:3462–72.

Hatsell SJ, Idone V, Wolken DM, Huang L, Kim HJ, Wang L, Wen X, Nannuru KC, Jimenez J, Xie L, Das N, Makhoul G, Chernomorsky R, D’Ambrosio D, Corpina RA, Schoenherr CJ, Feeley K, Yu PB, Yancopoulos GD, Murphy AJ, Economides AN. ACVR1(R206H) receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci Transl Med. 2015;7(303):ra137.

Hino K, Ikeya M, Horigome K, Matsumoto Y, Ebise H, Nishio M, Sekiguchi K, Shibata M, Nagata S, Matsuda S, Toguchida J. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc Natl Acad Sci U S A. 2015;112:15438–43.

Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005; 116(5):e654–61. Epub 2005 Oct 17.

Pignolo RJ, Bedford-Gay C, Liljesthrom M, Durbin-Johnson BP, Shore EM, Rocke DM, Kaplan FS. The natural history of flare-ups in fibrodysplasia ossificans progressiva: a comprehensive global assessment. J Bone Miner Res. 2016;31:650–6.

Kaplan FS, Zasloff MA, Kitterman JA, Shore EM, Hong CC, Rocke DM. Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am. 2010;92:686–91.

Kaplan FS, Shore EM, Pignolo RJ, The International Clinical Consortium on FOP. The medical management of fibrodysplasia ossificans progressiva: current treatment considerations. Clin Proc Intl Clin Consort FOP. 2011;4:1–Available from www.ifopa.org.

Hong CC, Yu PB. Applications of small molecule BMP inhibitors in physiology and disease. Cytokine Growth Factor Rev. 2009;20:409–18.

Shimono K, Tung WE, Macolino C, Chi AH, Didizian JH, Mundy C, Chandraratna RA, Mishina Y, Enomoto-Iwamoto M, Pacifici M, Iwamoto M. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-gamma agonists. Nat Med. 2011;17:454–60.

Chakkalakal SA, Uchibe K, Convente MR, Zhang D, Economides AN, Kaplan FS, Pacifici M, Iwamoto M, Shore EM. Palovarotene inhibits heterotopic ossification and maintains limb mobility and growth in mice with the human ACVR1 (R206H) fibrodysplasia ossificans progressiva (FOP) mutation. J Bone Miner Res. 2016;31:1666–75.

Wang H, Lindborg C, Lounev V, Kim JH, McCarrick-Walmsley R, Xu M, Mangivani L, Groppe JC, Shore EM, Schipani E, Kaplan FS, Pignolo RJ. Cellular hypoxia promotes heterotopic ossification by amplifying BMP signaling. J Bone Miner Res. 2016;31:1652–65.

Limestone HA, Turoff M. The Delphi Method: Techniques and Applications http://is.njit.edu/pubs/delphibook/delphibook.pdf. 2002

Kilmartin E, Grunwald Z, Kaplan FS, Nussbaum BL. General anesthesia for dental procedures in patients with fibrodysplasia ossificans progressiva: a review of 42 cases in 30 patients. Anesth Analg. 2014;118:298–301.

Levy CE, Lash AT, Janoff HB, Kaplan FS. Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva. Am J Audiol. 1999;8:29–33.

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