Pay Attention to the Osteochondromas in Fibrodysplasia Ossificans Progressiva

Abstract

Background

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease characterized by malformation of the bilateral great toes and progressive heterotopic ossification. The clinical features of FOP occur due to dysfunction of the bone morphogenetic protein (BMP) signaling pathway induced by the mutant activin A type I receptor/activin‐like kinase‐2 (ACVR1/ALK2) which contributes to the clinical features in FOP. Dysregulation of the BMP signaling pathway causes the development of osteochondroma. Poor awareness of the association between FOP and osteochondromas always results in misdiagnosis and unnecessary invasive operation.

Case Presentation

In this study, we present a case of classical FOP involving osteochondroma. An 18‐year‐old male adolescent, born with deformity of bilateral big toes, complained multiple masses on his back for 1 year. The mass initially emerged with a tough texture and did not cause pain. It was misdiagnosed as an osteochondroma. After two surgeries, the masses became hard and spread around the entire back region. Meanwhile, extensive heterotopic ossification was observed around the back, neck, hip, knee, ribs, and mandible during follow‐up. Osteochondromas were observed around the bilateral knees. No abnormalities were observed in the laboratory blood test results. Whole exome sequencing revealed missense mutation of ACVR1/ALK2 (c.617G > A; p.R206H) in the patient and confirmed the diagnosis of FOP.

Conclusion

In summary, classical FOP always behaves as a bilateral deformity of the big toes, as well as progressive ectopic ossification and osteochondromas in the distal femur and proximal tibia. An understanding of the association between osteochondromas and FOP aids in diagnosis and avoids unnecessary invasive management in patients.

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease characterized by malformation of the bilateral great toes and progressive heterotopic ossification. Classical FOP always behaves as a bilateral deformity of the big toes, as well as progressive ectopic ossification and osteochondromas in the distal femur and proximal tibia. An understanding of the association between osteochondromas and FOP aids in diagnosis and avoids unnecessary invasive management in patients.

Introduction

Fibrodysplasia ossificans progressiva (FOP) is characterized by bilateral congenital hallux valgus and progressive heterotopic endochondral ossification of soft tissue in specific anatomical and temporal patterns. ¹ , ² , ³ , ⁴ It is an extremely rare genetic disease with an incidence of only one in two million people and is the most severe disabling disorder of heterotopic ossification in human. ⁵ Patients with FOP always develop serious joint restrictions with loss of mobility and eventually die due to cardiorespiratory failure or extreme nutritional disturbances because of the severe restrictive chest wall disease or jaw fixation, respectively. ⁶ Owing to its rare morbidity and unpredictable nature, clinicians tend to misdiagnose FOP and perform unnecessary invasive operations on patients. ⁷ The essence of FOP is the mutation of activin A type I receptor/activin‐like kinase‐2 (ACVR1/ALK2), which is a bone morphogenetic protein (BMP) type I receptor. ⁴ The mutantACVR1/ALK2 can induce perturbation of the BMP signaling pathway and cause heterotopic endochondral ossification. ⁸ , ⁹ , ¹⁰ The recurrent c.617G > A (p.R206H) heterozygous missense mutation is found in most cases of the “classical FOP phenotype” which present as bilateral deformity of the great toe and dysregulated osteogenesis, including osteochondromas formation.

Osteochondroma is the outcome of the overgrown cartilage and bone and manifests as a hard and painless mass, which can easily cause confusion and misdiagnosis of FOP in some patients with exostosis. ¹¹ , ¹² , ¹³ Osteochondroma formation strongly correlates with the BMP signaling pathway in which the BMP‐2 plays a critical role. ¹⁴ Likewise, dysfunction of the BMP pathway induced by the mutant ACVR1/ALK2 can facilitate the development of osteochondromas due to FOP by promoting chondrogenesis. ⁹ , ¹⁵ Numerous cases involving the FOP patients together with osteochondromas have been reported, which suggest that there may exist a potential correlation between FOP and osteochondromas. ¹² , ¹³ , ¹⁶ , ¹⁷ , ¹⁸ Moreover, a poor understanding of this association can result in misdiagnosis and unnecessary invasive surgery. In this study, we report the case of a patient with classical FOP patient involving osteochondromas and hope that this case could help us further understand FOP.

Case Presentation

An 18‐year‐old boy complained of multiple masses on his back after two surgical resections performed 1 year ago (Figure 1). He had no hereditary history of any disease. A painless swelling originated on his left scapula 4 years ago, and the clinician diagnosed it as osteochondromas combined with exostoses exhibited at the femur and tibia on radiography (Figures 2A and 3A). The patient underwent resection of the mass on the back, and the pathological findings revealed osteochondromas with abundant hyperplastic bone and cartilage (Figure 3A,B). However, no cartilage cap structure was observed. The mass appeared at the incision site 3 weeks later, which was considered recurrence. A second surgical resection was performed, followed by the recurrence of a painful mass with redness in the surrounding areas and swelling at the drainage port (Figure 2A). No special treatment was performed. In the next 3 months, the disease progressed rapidly, and a similar mass appeared on the whole body, including the back and hip. The patient visited our hospital for further management. We performed his detailed physical examination and found multiple bone masses of various sizes on the back, ribs, humerus, and hip, which caused stiffness of the spine, shoulder, and hip. Because of the “armor‐like” lesions on the back, he presented with scoliosis to the left. Importantly, we noticed a bilateral valgus deformity of the big toes, which was considered inherent based on the information provided by his mother (Figure 1B). No abnormalities were observed in the laboratory blood test results. Radiology revealed the typical “armor‐like” ossification band formation on the back, ribs, humerus, and hip (Figure 4A–D). Considering the progressive process of heterotopic ossification and the typical deformity of the bilateral big toes, we considered a diagnosis of FOP. To verify the diagnosis, we conducted whole‐exome sequencing using blood samples, and the results demonstrated a heterozygous mutation in ACVR1 (c.617G > A; p.R206H) (Figure 4I).

FIGURE 1.

Timeline of this disease.

FIGURE 2.

(A) Multiple masses on the back (red arrow); (B) Bilateral valgus deformity of the great toes.

FIGURE 3.

(A) Radiograph of the knee for consecutive 5 years demonstrated that the osteochondromas located at the bilateral distal femurs and proximal tibias kept constant in the morphology, volume and character. (B) Pathology of the mass revealed the osteochondromas with plenty of hyperplastic bone and cartilage.

FIGURE 4.

Heterotopic ossifications. (A) The “armor‐like” ossification band on the back. (B) The heterotopic ossification of the right 8th rib and scoliosis to left. (C) and (D) The heterotopic ossification at bilateral hips and proximal humerus. (D‐H) The new formed heterotopic ossification at right thigh, bilateral knees, neck and the mandible after stopping taking the indomethacin. (I) The heterozygous mutation of the ACVR1 (c.617G>A; p.R206H) in this patient.

The patient was then required to regularly take 25 mg of indomethacin per day. The patient reported no new recurrent mass in the first 3 months and felt relief from pain and joint stiffness. However, several masses appeared at the neck, thigh, knee, and even mandible after the patient stopped taking indomethacin because of side effects in the gastrointestinal tract (Figure 4E–H). Progressive mandibular ossification causes dysphagia. After taking the indomethacin, no apparent newborn heterotopic ossification mass occurred during the follow‐up. The patient complained of mild and tolerable dyspepsia and stomach ache. At the same time, the patient was advised to avoid invasive management such as biopsy, resection or injection, and undergo radiography and computed tomography each year. Up to the last follow‐up, the heterotopic ossification in this patient was stable, and no obvious new mass was found in physical examination and imaging examination.

Discussion

FOP is an extremely rare disease characterized by abnormal skeletal development and unpredicted progressive ectopic osteogenesis in the soft tissue, such as tendon, ligament and aponeurosis and muscle. FOP can be evoked by trauma and other invasive operations such as surgical excision, biopsy, and intravenous infusion. ¹⁹ In this case, the first‐born swelling at the left scapula formed without an exact incentive an it extended to multiple swellings just 3 weeks after the first operation. A second operation emerged this disorder. Both of the two operations accelerated the disease progression, implying that surgery was an intense trigger to this patient. Hence, any invasive operation should be avoided in patients with FOP because the trigger may deteriorate the lesions locally and systematically.

Diagnosis, Manifestation, and Mechanism of FOP

Diagnosis of FOP requires a combination of clinical presentation and gene sequencing results. Detection of the mutant ACVR1 leads to the definite diagnosis of FOP. ²⁰ Mutations of ACVR1 mainly occur in the glycine‐serine (GS) and the PK domains. Mutant GS domain intensely improves the activity of the receptor once the BMP ligands reach the threshold while the mutant PK domain increases the sensitivity of the receptor toward low level of the ligands. ¹⁷ For high‐frequency and typical manifestations, the c.617G > A (p.R206H) heterozygous missense mutation in the GS activation domain is considered to be the classical mutation of FOP. ¹⁷ , ¹⁸ Meanwhile, there are also other mutation types of ACVR1 and the clinical manifestations vary in different types (Table 1). ¹⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ Mutant ACVR1 was the cause of the heterotopic ossification. The activated BMP/smads signaling pathway induced by the mutant ACVR1 enhanced chondrogenic differentiation and promotes the heterotopic ossification formation in FOP. ³⁰

TABLE 1.

Mutations of ACVR1 in FOP patients.

Codon	Nucleotide	Reference
R206H	605G > T	Qi et al. 21
R206H	617G > A	Shore et al. 10
Q207E	c.619C > G	Haupt et al. 22
R202I	605G > T	Petrie et al. 23
G325A	974G > C	Whyte et al. 24
G328W	c.982G > A	Qi et al. 21
G328W	c.982G > T	Kaplan et al. 25
G328E	c.983G > A	Kaplan et al. 25
G328E	c.982G > T	Qi et al. 21
G328R	c.983G > A	Petrie et al. 23
G356D	1067G > A	Furuya et al. 26
R258S	774G > C	Bocciardi et al. 27
R258G	774G > T	Ratbi et al. 28 and Eresen‐Yazıcıoğlu et al. 29
R375P	c.1124G > C	Kaplan et al. 25
P197_F198 del insL	c.590_592delCT	Kaplan et al. 25

It is worth noting that the mutated ACVR1 is responsible for the classical manifestation of bilateral deformity of big toes. Among developing fingers and toes, ACVR1 transcripts were widely detected in the process of finger and toe formation during the early embryonic development, and it was not until the embryo was 14.5 days older that it was gradually confined to the cartilage membrane. ³¹ , ³² Some studies even observed the FOP foot shape by ultrasound before delivery. ³³ Similarly, in knock‐in mouse with mosaic expression of ACVR1R206h/+mice, the deformity of the first digits of hind limb and heterotopic ossification after birth were also observed, and the deformity of the first and the fifth digits of hind limb were more serious than that of other toes, but surprisingly, these two digits were not preferentially expressed by ACVR1R206h/+mice. ³¹ , ³⁴ , ³⁵ Towler and others think that this may be the reason of digit‐specific difference, that is, the first digit specifically leads to the deformity of both big toes. ³⁶ Meanwhile, there are also theories that this is caused by changing Tü ring reaction–diffusion coefficients which includes BMP pathway and Wnt signaling pathway. ³⁷ , ³⁸ In a word, the big toe deformity observed in animal models and human bodies is closely related to ACVR1 mutation, and its specific mechanism needs further mechanism research and computer modeling to verify.

Relationship between FOP and Osteochondroma

Mutant ACVR1 was also related to the born of the osteochondroma. ³⁹ In this case, except the progressive ectopic ossification, we also observed osteochondromas in the distal femurs and proximal tibias. Previous studies have reported the osteochondromas in the femur, tibia, phalanges, humerus, and submandibular. ¹² , ¹³ , ¹⁶ , ¹⁷ , ¹⁸ However, the coincidence of the appearance of osteochondroma in FOP remains controversial. ¹² Some studies even regarded osteochondroma in the long bone as a coincidence despite of the high frequency. ¹⁸ , ⁴⁰ Neglecting the connection between osteochondroma and FOP is also an important reason for misdiagnosis in addition to its rarity. In fact, only two studies have attempted to illustrate the rationality of osteochondromas located at the distal femoral and proximal medial tibia in FOP patients ¹² , ¹³ (Table 2). Osteochondroma is thought to the result from the abnormal activation of the bone morphogenetic protein/Indian hedgehog /parathyroid hormone‐related peptide (BMP/Ihh/PTHrP) signaling pathway caused by the mutant‐ACVR1. Mutaant‐ACVR1 with structural activity strongly stimulates the expression of Ihh in chondrocytes, thereby regulating the negative feedback loop of IHH/PTHrP promoting abnormal endochondral osteogenesis around the joints and perichondrium, and finally induces the formation of osteochondroma. ¹² , ¹⁵ Therefore, the existence of osteochondroma in FOP is not only a coincidence but also a necessity, knowing which is of great help to the mechanism of FOP.

TABLE 2.

Literature review on the diagnosis and treatment of osteochondromas in FOP.

Literatures	Patients with osteochondromas	Diagnosis	Treatment
Deirmengian et al. 12	86	Physical examination, radiographs, or histopathological	No mentioned
Kaplan et al. 64	1	Physical examination, radiographs, and histopathological	Resection
Cremin et al. 18	1	Radiographs	Resection
Morales‐Piga et al. 13	17	Radiographs and magnetic resonance imaging (MRI)	2 patients with resection
Sharma et al. 65	1	Clinical features and Radiographs	No mentioned

In addition, dysregulated BMP signaling caused by the inactivation mutation EXT1/EXT2 also exists in multiple hereditary exostoses that are always misdiagnosed as FOP. ⁴¹ The common BMP/Ihh/PTHrP pathway exists in multiple heredity exostoses and osteochondromas in FOP. ¹² The BMP/Ihh/PTHrP negative feedback loop is disturbed directly by the mutant ACVR1 and indirectly by the mutant EXT1/EXT2, promoting the formation of osteochondroma in FOP and the hereditary multiple exostoses, respectively. ¹² , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ Therefore, the similar mechanism makes the appearance of osteochondroma in FOP more reasonable. As osteochondromas are common in FOP, clinicians tend to mix hereditary multiple exostoses (HME) and FOP, as in this case, wherein the patient was diagnosed with HME and received incorrect management in the early phase. There are some similarities between these two diseases, including the presence of hard and painless mass in the distal femur or proximal tibia and the broad femoral neck and wide metaphysis. ⁴ , ¹² , ¹³ Indeed, we can differentiate them in terms of aspects such as the tumor morphology, symmetry, metaphyseal widening, associated symptoms, malignant degeneration and the affected gene. ¹¹ , ¹² In addition, though response to excision was considered as an extra clue of the FOP, excision was definitely not recommended in the FOP unless in life‐threatening situations. ¹² , ¹⁶ In this case, osteochondromas were symmetrically located in the femur and tibia, without associated bursitis, pain, or neuropathy. In addition, the exostoses did not show any changes in morphology or any sign of malignancy. More importantly, gene sequencing confirmed a c.617G > A (p.R206H) heterozygous missense mutation in ACVRA1. Thus, we revised the diagnosis to FOP rather than hereditary multiple exostoses. Indeed, except for the different features of the exostosis, we can also distinguish the FOP and HME from the location of the lesions, in which the heterotopic ossification in FOP often formed first in the neck and upper back region while the exostosis in HME often occur in relation to the long bones. ⁴⁶

Osteochondroma is one of the developmental phenotypes of dysregulated osteochondrogenesis of FOP and is an orthotopic lesions in skeletal modeling. ¹² , ¹³ , ³⁹ ACVR1 is widely expressed in the perichondrium and periosteum, and mutant ACVR1 can promote the differentiation of chondrocytes and formation of cartilage cap, thus promoting the formation of osteochondroma. ¹⁵ At the same time, heterotopic ossification is a typical feature of FOP, which is correlated with inflammation, immunity, mechanosensing and tissue stiffness in the microenvironment, and activated BMP/p‐smads pathway. ³ , ¹⁹ , ²⁰ Both the osteochondromas and heterotopic ossification are well‐recognized features of FOP, but their relationship and the interaction between them during natural history have not been determined. In this case, along with the heterotopic ossification, we also paid more attention to the development of osteochondroma around the bilateral knee joints during long‐term follow‐up (Figure 3A). During the course, no significant changes in the shape, volume and amount of osteochondromas around the bilateral knee and no tendency for malignant transformation was observed, which was consistent with the findings of previous studies. ¹² , ¹³ We also noticed that scattered heterotopic ossification occurred around the knee joint (Figure 3A and Figure 4E–G), but the heterotopic ossification process seemed to have no effect on osteochondroma, which was also reported in a previous study. ¹³ In other words, the formation of bone exostoses is not related to the location and degree of heterotopic ossification. ¹³ Moreover, the attachment to bone is another difference between HO and osteochondromas, in which osteochondromas have a relation with bone while HO is not necessarily attached to bone and HO can also form in muscle without any attachment to bone. ¹¹ , ¹² , ¹³ Those findings can help us have a more profound understanding toward the heterotopic ossification and osteochondromas in FOP.

Management of FOP

Understanding the mechanism of the FOP is vital to its management despite the lack of effective treatments available nowadays. ⁴⁷ , ⁴⁸ , ⁴⁹ High‐dose corticosteroids are limited to relieve the early inflammatory flare‐ups that occur spontaneously or after trauma (especially the ossification in the coronal process) in brief time, considering the difficulty in evaluating the onset of adverse events. ³ , ⁴ , ⁵⁰ Nonsteroidal anti‐inflammatory such as indomethacin are used to suppress the inflammation in flare‐ups. ⁴⁷ , ⁵¹ , ⁵² In this patient, the indomethacin was effective in controlling the newly developed mass and relieving the symptoms. After discontinuing indomethacin, the patient complained of a new mass in the submaxilla and a more serious joint movement disorder. However, the efficiency of indomethacin varies in patients and it cannot alter the natural history of FOP. At the same time, long‐term application of indomethacin may bring about some side effects such as the gastrointestinal upset as in this case. Thus, indomethacin must be used cautiously and we recommend a trial of indomethacin to control the painful and recurrent soft‐tissue swelling. ⁴ In addition, both diphosphate and retinol vitamin A have been reported to be effective in improving patients symptoms and even in imaging examinations in several cases. ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷

Recently, some medicines targeting the BMP signaling pathway have shown potential in managing FOP. For example, RARγ agonists, can inhibit chondrogenesis by reducing the phosphorylation levels of smads and thus downregulating the BMP/ACVR1/smads signaling pathway. ³⁵ , ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² Palovarotene, one of the RARγ agonists, is the first anti‐FOP drug in a multicenter phase 3 trial and shows great latent capacity in terms of efficacy and safety. ³⁵ , ⁵⁹ , ⁶³ According to the updated data, the annual average new heterotopic ossification volume of the patients who were treated with palovarotene decreased by 62%, compared with that in control groups. ⁶³ Meanwhile, considering its effect in osteochondromas, the enormous potential of palovarotene in the management of FOP is inspiring. ⁵⁸ Surgical resection is contraindicated in FOP patients because of the recurrence risk at the operation site and can be an intense trigger to flares‐up, as shown in the present case. ² , ³ , ²⁰ Resection in special sites such as the jaw and other major joints, if necessary, is supported until heterotopic ossification matures, followed by high‐dose corticosteroids and careful postoperative nursing. ⁵⁰ However, the prognosis of the operation is always unsatisfactory, thus it must be executed by weighing the benefits and risks. Nonetheless, treatment of this rare, variable, fluctuant disease is still faint, and further exploration of the underlying mechanism of FOP is urgently needed.

Conclusion

In this case, we report a classical FOP with bilateral deformity of the big toes, progressive ectopic ossification, and osteochondroma around the knees. Clinicians are advised to pay attention to the association between osteochondroma and FOP, which could assist in diagnosis of FOP and avoid unnecessary invasive management.

Author Contributions

Longqing Li and Minxun Lu collected and analyzed data and drafted the manuscript. Xuanhong He, Chang Zou, and Chuanxi Zheng performed the statistical analysis. Yitian Wang, Fan Tang, Yi Luo and Yong Zhou interpreted the data. All listed authors have each made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data. Professor Li Min and Professor Chongqi Tu designed the project and participated in revising it critically for content, and have approved the final version of the submitted manuscript.

Conflict of Interest Statement

All named authors have no conflicts of interest to disclose in relation to this article.

Ethics Statement

This study was approved by the Ethical Committee of West China Hospital. The patient and his parents agreed to participate in this study and signed the written informed consent.