World Journal of Pediatrics

https://doi.org/10.1007/s12519-019-00302-x

ORIGINAL ARTICLE

Analysis of clinical manifestations and treatment in 26 children

with fibrodysplasia ossificans progressiva in China
Jun‑Mei Zhang1 · Cai‑Feng Li1 · Shuang‑Ying Ke1 · Yu‑Rong Piao1 · Tong‑Xin Han1 · Wei‑Ying Kuang1 · Jiang Wang1 ·
Jiang‑Hong Deng1 · Xiao‑Hua Tan1 · Chao Li1

Received: 20 March 2019 / Accepted: 1 August 2019

© Children’s Hospital, Zhejiang University School of Medicine 2019

Abstract
Background  Fibrodysplasia ossificans progressiva (FOP) is a rare and disabling heritable connective tissue disease that is
difficult to treat. This study seeks to explore the clinical characteristics, clinical manifestations, treatment and prognosis of
FOP to provide a clinical basis for its early diagnosis and treatment.
Methods  Twenty-six children with FOP were retrospectively analyzed in terms of their onset, clinical manifestations, aux-
iliary examinations and treatment.
Results  Among the 26 cases, the youngest age of manifestation of mass was 8 days after birth, and the average age was
3 years and 2 months. The peak age was 2–5 years old. Inflammatory mass and toe-finger deformity are the main early clinical
manifestations of the disease. These inflammatory masses often lead to hard osteogenic deposits that initially mainly involve
the central axis, such as the neck (22/26, 84.6%), back (20/26, 76.9%), and head (13/26, 50%). Toe-finger deformity mainly
manifests as symmetrical great toe deformity, or short and deformed thumb and little finger. The diagnosis of FOP requires
typical clinical manifestations or ACVR1 gene detection. The main therapeutic drugs for FOP include glucocorticoids and
non-steroidal anti-inflammatory drugs. Although not compliant with the recommended medical management of FOP, in
our clinical practice children with uncontrollable illness could be treated using a variety of immunosuppressive agents in
combination.
Conclusions  FOP is a rare autosomal dominant heritable disease. The main clinical manifestations observed in this study were
recurrent inflammatory mass and toe-finger deformity. If the diagnosis and treatment are not performed in a timely manner,
serious complications are likely to affect the prognosis. Therefore, early diagnosis and active treatment should be performed.

Keywords  Clinical manifestation · Fibrodysplasia ossificans progressiva · Inflammatory mass · Treatment

Introduction protein (BMP) receptor. Mutation of the causative gene was

Fibrodysplasia ossificans progressiva (FOP) is a rare and
disabling heritable connective tissue disease, which is char-
acterized by congenital great toe deformity and progressive
heterotopic ossification. FOP is an autosomal dominant
inheritable disease. The mutated gene, ACVR1 (OMIM #
102576) is located on 2q24.1, and encodes the activin A
receptor, type I. ACVR1 is a type I bone morphogenetic
* Cai‑Feng Li
caifeng_li@yeah.net
1
Department of Rheumatology and Immunology, Beijing
Children’s Hospital, Capital Medical University, National
Center for Children’s Health, Nan Li Shi Road No. 56,
Beijing 100045, China
suggested earlier to induce abnormal activation by BMPs,
thus leading to the occurrence of FOP lesions [1]. However,
recent advances regarding the observed mutated ACVR1
indicate that responsiveness to the non-conventional ligand,
activin A, is a major contributor and is the primary cause
of this condition [2]. The main clinical manifestation of this
disease is recurrent painful inflammatory mass, which occa-
sionally spontaneously subsides, but most masses transform
fascia, ligaments, tendons, and skeletal muscles into mature
heterotopic bone. Typical clinical manifestations, combined
with imaging manifestations of heterotopic ossification,
can diagnose the disease clinically, but genetic confirma-
tion of an ACVR1 gene mutation is required to complete the
diagnosis. Detection of a mutation in the ACVR1 gene can
also be used to confirm the disease at an early stage before

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the occurrence of heterotopic ossification. At present, the
most frequently used therapeutic drugs are glucocorticoids
and non-steroidal anti-inflammatory drugs (NSAIDs) [3].
FOP is a rare disease. At present, doctors in China gener-
ally lack knowledge regarding FOP, which often leads to
misdiagnosis and missed diagnosis, or delayed treatment,
and the patient may even undergo invasive examination and
treatment, further aggravating the progress of the disease.
Therefore, early and accurate diagnosis is very important
for the prognosis of children with FOP. This study analyzed
the morbidity, clinical manifestations, laboratory examina-
tions, imaging examinations, medication for treatment and
follow-up of 26 children with FOP diagnosed in our hospi-
tal over the past 12 years. The study also summarized the
experience to improve the understanding of the disease, and
help achieve the goal of early diagnosis, early treatment and
improvement of the prognosis of the disease.
Methods
Records of children hospitalized in our hospital from July
2007 to January 2019 and diagnosed as FOP were collected.
There were 14 males and 12 females, with a ratio of 1.17:1.
The age of diagnosis ranged from 1 year and 9 months to
15 years and 3 months, with an average age of 4 years and
6 months. Among them, diagnosis of 10 cases was con-
firmed by detection of the 617G>A (R206H) mutation of the
ACVR1 gene. No ACVR1 gene analysis was performed in the
remaining 16 cases, which were diagnosed by typical clini-
cal manifestations. The morbidity, clinical manifestations,
laboratory examinations, imaging examinations, medication,
follow-up and outcome of 26 children with FOP were sum-
marized and analyzed.
Results
Morbidity
Among the 26 cases, the youngest age of manifestation of
mass was 8 days after birth, and the oldest was 11 years
and 3 months. The average age of manifestation of mass
was 3 years and 2 months. The peak age of manifestation of
mass was 2–5 years old, which occurred in 16 cases. There
were five patients, respectively, whose age of manifesta-
tion of mass was younger than 2 years old, and were older
than 5 years old. All 26 cases of FOP had concealed onset.
The shortest time from initial symptoms to diagnosis was
1 month, while the longest was 10 years. 25 cases showed
chronic protracted course and only 1 case was diagnosed
within 1 month after the occurrence of initial symptoms.
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World Journal of Pediatrics
Clinical manifestation
General manifestation
The 26 children with FOP had no fever, rash, fatigue,
hyperhidrosis, anorexia, emaciation, or other unsuitable
symptoms.
Inflammatory mass and heterogeneous ossification
Among the 26 children with FOP, there were 13 cases
of inflammatory mass that first appeared in the head,
namely eight cases in the neck, four cases in the neck,
chest and back at the same time, and one case in the
lower extremity mass. Among them, six cases had a trau-
matic history before onset, and two cases had surgical
history before onset. The inflammatory masses are hard,
and some have tenderness as well. The small ones resem-
ble large peanuts, while the larger ones resemble eggs,
with a round or oval shape (Fig. 1). They can move in the
early stage, and also can shrink or disappear spontane-
ously. After several weeks or months, they appear repeat-
edly, involving other parts such as the waist, scapula and
axilla, even affecting the movement of the surrounding
joints, leading to the occurrence of deformities such as
scoliosis.
Among the 26 children with FOP, the inflammatory
mass involved the head, submandibular, neck, shoulder,
axilla, chest, thoracolumbar, back, upper limb and lower
limb. The details are shown in Table 1. The most common
sites of involvement in children with FOP were the neck
(22/26, 84.6%), back (20/26, 76.9%), head (13/26, 50%)
and shoulder (12/26, 46.2%); the waist and axilla were also
vulnerable, while the upper limb, lower limb and lower
jaw were less involved.
Skeleton deformity
The most common skeletal deformity in children with FOP
is great toe deformity, characterized by short or valgus
toes. The 26 children all had bilateral great toe deformity,
including 12 children with short toe, nine children with
hallux valgus, and five children with short toe and hallux
valgus.
Other common skeletal deformities in children with
FOP include short and deformed thumbs (Fig. 2), cur-
vature of fingers, short and wide femoral neck, proximal
medial tibial osteochondroma, and cervical deformity. Of
the 26 cases, 11 cases had short thumbs, five had short lit-
tle fingers, and three had a history of chondromatosis; and
two cases had cervical lamina fusion deformity.
World Journal of Pediatrics

Fig. 1  Inflammatory mass of fibrodysplasia ossificans progressiva

Table 1  Parts involved by inflammatory mass and heterotopic ossification (n = 26)

Involved part Head Submandibular Neck Shoulder Axilla Chest Back Waist Upper limb Lower limb

Number of patients 13 1 22 12 5 4 20 8 2 2
Occurrence rate, % 50 3.8 84.6 46.2 19.2 15.3 76.9 30.8 7.7 7.7

Laboratory examination

Before treatment, the monitored blood routine leucocytes,

hemoglobin and platelets were shown to be normal in all
26 children, and C-reactive protein was also normal. Only
one child had an increase in erythrocyte sedimentation rate
(31 mm/hour). Electrolyte, liver and kidney function, myo-
cardial enzymes and coagulation function were all normal.
Anti-nuclear antibodies (ANA) were low titer-positive in
five children, with all of them being ≤ 1:80. The spectra of
ds-DNA and anti-extractable nuclear antigens antibodies
Fig. 2  Short and deformed thumb of children with  fibrodysplasia
were negative, and rheumatoid factor was negative.
ossificans progressiva
Imaging examination

Involvement of important organs
There was no clinical manifestation of chest distress,
shortness of breath, wheezing, panic or other cardiopulmo-
nary involvement in any of the 26 cases, but seven cases
showed mild ventilatory dysfunction. The audiometry of
four cases showed conductive deafness. One child had
recurrent convulsions during the course of the disease.
No renal involvement was found in any of the 26 children.
All 26 children were examined by X-ray to determine the
heterotopic ossification. Under X-ray, irregular strip-like,
sheet-like, band-like and branched high-density ossifica-
tion of soft tissue in the later stage of lesions could be seen.
Some skeletons fused with each other to form bridges and
pseudojoints (Fig. 3). Local soft tissue swelling could also
be seen in the early stage of the lesions.
The X-ray features of the feet of the children
with toe deformity were valgus of the big toe, poor

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Fig. 3  X-ray of the right knee revealed irregular strip bone density in
the dorsal side of the right knee
metatarsophalangeal joint alignment, or joint fusion, joint
deformation, irregular metatarsal, and phalangeal bone mor-
phology (Fig. 4).
In computed tomography (CT) examination, the typi-
cal manifestations of heterotopic ossification are multiple
irregular intramuscular high density, bone density shadow or
punctate calcification foci in the muscles, and partial fusion
with adjacent bone (Fig. 5). Early soft tissue masses showed
extensive soft tissue thickening on CT.
Fig. 4  X-ray of feet in children with FOP showed the valgus of the
big toe, phalangeal fusion, irregular shape and poor joint alignment
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World Journal of Pediatrics
Fig. 5  Computed tomography  reconstruction revealed irregular large
patches of bone-like density in the bilateral posterior cervical and
dorsal muscles
Other ancillary examinations
Local ultrasonography of disease region showed severe
local swelling, significant involvement of the superficial
fascia, deep fascia and muscular layer, and disappearance
of the normal texture of muscle fibers. Some areas were
even replaced by the echoes of fibrous cords. Calcification
plaques could be seen in the muscular layer in the middle
and late stages of the disease.
Local magnetic resonance imaging may be performed in
patients who have not yet developed calcification in the early
stage of the disease, thus suggesting swelling of soft tissues
or strip-like low signal changes in the muscles.
The disease should not be examined by pathology when-
ever possible, as any surgical trauma is highly likely to
aggravate the disease and rapidly accelerate its progress.
Analysis of ACVR1 gene is required to confirm the diagnosis
of this disease.
Treatment and follow‑up
Therapeutic drugs for this disease include glucocorticoids
(oral 1–2 mg/kg/day), and NSAIDs. Although not compliant
with the recommended medical management of FOP, in our
clinical practice children with uncontrollable illness could
be treated using a variety of immunosuppressive agents in
combination, such as methotrexate (10–15 mg/m2/week) or
cyclosporine (3–5 mg/kg/day). Among the 26 cases, the par-
ents of three patients refused treatment, and six cases were
treated with glucocorticoids and NSAIDs without using
immunosuppressive agents, nor were they followed up on.
World Journal of Pediatrics
Three cases were treated with NSAIDs, glucocorticoids and
cyclosporine. Eight cases were treated with NSAIDs, glu-
cocorticoids and methotrexate. After hospital discharge, the
masses in the above-mentioned patients were significantly
reduced, and some disappeared. Six children were initially
treated with NSAIDs, glucocorticoids and methotrexate.
Their inflammatory masses did not subside significantly, and
new ones still appeared. After cyclosporine was added, the
disease condition was controlled, no new masses appeared,
and the original ones were reduced. There were regular
follow-up treatments performed for these patients, and no
complications were found. One of the children with convul-
sions did not convulse again after discharge from hospital.
Discussion
It is said that the condition was first described by Guy Patin
in 1692 when he wrote about the woman who turned to
wood; that Von Dusch in 1868 first used the name myositis
ossificans progressiva; and that Munchmeyer (1869) first
gave a comprehensive description of the disease with an
account of 12 cases-hence the eponym “Munchmeyer’s dis-
ease”. Rosenstirn (1918) thought that a better name would
be fibrocellulitis ossificans progressiva; Fairbank (1950)
suggested the term “fibrositis ossificans progressiva",
and McKusick (1960), following Bauer and Bode (1940),
favoured “fibrodysplasia ossificans progressiva" [4]. FOP is
a rare disease. Its morbidity is related to the mutation of the
ACVR1 gene. The most common mutation site as confirmed
by current studies is R206H. Other sites include L196P,
R258S, P197/F198L, R202I, Q207E, G325A, G328W/
G328E/G328R, G356D, R375P [5–10]. The onset of most
of the children begins between the ages of 2 and 4. The
worldwide incidence rate is about 1/2,000,000. There are
no racial, ethnic, gender and geographical differences in the
disease onset [11]. The results showed that the average age
of onset was 3 years and 2 months, which was consistent
with previous reports. There was no significant gender dif-
ference in the incidence of the disease, and the proportion of
males was slightly higher than that of females.
The main manifestations of FOP patients were recurrent
inflammatory mass and great toe deformity. Most patients
had the first painful soft tissue mass within 5 years of age,
involving the back, mid-axis, head and proximal end, pro-
gressively developing from top to bottom, and then reaching
the ventral limbs, tailbone and limbs. Inflammatory lesions
in different parts show different symptoms and signs. If the
lesion occurs in the head, neck or trunk, it typically begins
more rapidly with soft tissue mass. If the lesion occurs in
the limbs, children are more likely to complain of decreased
joint mobility, and may lack soft tissue mass. If inflamma-
tory lesions occur in the spine, the child may show signs
of scoliosis [12]. In this study, 25 children suffered from
recurrent mass and ossification around the central axis (onset
from the head, neck and back), and one child’s onset began
from limited flexion of the lower limbs. The most common
sites of involvement of children with FOP in this study were
the neck (22/26, 84.6%), back (20/26, 76.9%), and head
(13/26, 50%), the waist and axilla were also involved, while
the upper limb, lower limb and lower jaw were less involved.
This is consistent with the previous research showing that
the axes were involved first and limbs were involved later. In
this study, eight cases of children with inflammatory lesions
were induced by trauma or surgery or the increase of the
original inflammatory mass. As was reported before [13],
most patients in this study progressed to heterotopic lesions
without evidence of inflammatory flares.
Congenital malformation of the great toe is typically the
earliest clinical manifestation in children with FOP. The
proximal metatarsal of the great toe is usually abnormal in
shape, and fused with the distal first toe. The first toe is
also abnormal in shape. Fusion of the middle phalanx of
the second to fifth phalanges with the distal phalanges is
also often visible. These deformities are typically bilaterally
symmetrical [14]. In this study, 26 children with bilateral
big toe deformity were bilaterally symmetrical, which was
consistent with previous research. In addition to congenital
big toe deformity, other skeletal deformities often occur,
including thumb deformity, cervical vertebra deformity,
short and wide femoral neck, and proximal medial tibial
osteochondroma.
According to research performed around the world, tho-
racic insufficiency syndrome, hearing impairment, kidney
stones and temporomandibular joint stiffness are common
complications in children with FOP, yet they are easily
ignored by clinicians [15]. Temporomandibular joint is the
latest joint involved in the natural course of FOP [16, 17]. In
this study, pulmonary function in seven children indicated
mild ventilation dysfunction, hearing examination in four
children indicated conductive deafness, and one child exhib-
ited repeated convulsions during the course of the disease.
None of the 26 children had renal involvement.
Internationally performed studies have reported that
the erythrocyte sedimentation rate of children with FOP
may increase, especially in the active stage of disease [18].
According to the results of laboratory tests in the present
study, only one child showed an elevated erythrocyte sedi-
mentation rate before treatment, which may be related to
disease activity. Only five cases of ANA were low titer-pos-
itive among the 26 cases, all of which were less than 1:80,
which was not significant to perform diagnosis of FOP. The
diagnostic criteria for this disease include typical clinical
manifestations and ACVR1 gene mutations.
Guidelines for symptomatic management of disease
flare-ups have been published, and highlight the anecdotal
13

utility of glucocorticoids in managing new flare-ups affect-
ing the function of major joints in the appendicular skel-
eton. Non-steroidal anti-inflammatory medications, cyclo-
oxygenase-2 inhibitors, leukotriene inhibitors and mast
cell stabilizers are useful anecdotally in managing chronic
discomfort and ongoing flare-ups, but, to date, there is no
proven efficacy with any therapy in altering the natural his-
tory of the disease [19]. At present, there have been many
studies performed on small molecule biological agents for
FOP, and there are two clinical trials ongoing, one with a
small molecule, Palovarotene, and one with an anti-activin
A antibody [20, 21]. In our study, the main drugs for FOP
treatment are NSAIDs, glucocorticoids and immunosup-
pressive agents. Immunosuppressive agents include meth-
otrexate and cyclosporine. A total of 17 children were fol-
lowed up on regularly in this study, and were treated with
NSAIDs, glucocorticoids and immunosuppressive agents.
During the follow-up period, no new masses appeared, the
original soft tissue mass basically disappeared, and joint
activity was improved.
In addition to drug therapy, children with FOP should
avoid viral infections and soft tissue trauma, including
biopsy, intramuscular injection, surgery and oral mandibu-
lar block, as these may induce rapid progressive heterotopic
ossification, and thus lead to permanent loss of function in
the affected area.
The diagnosis of FOP is clinical (skeletal malformations
including malformed great toes; soft tissue swelling and pro-
gressive heterotopic ossification), but requires genetic con-
firmation (ACVR1 gene mutation). If FOP is suspected, all
elective procedures such as surgeries, biopsies, and immu-
nizations should be deferred until a definitive diagnosis is
made.
In brief, FOP is a rare disease. In this paper, the clinical
manifestations, diagnosis and treatment of 26 children with
FOP admitted to Beijing Children’s Hospital were analyzed
and studied. The purpose of this study is to improve the
clinicians’ understanding of children with FOP, achieve the
goal of early diagnosis and treatment, reduce the invasive
examination leading to deterioration of the condition, and
improve the prognosis, thereby reducing the mortality rate
and occurrence of complications. If the clinician is aware
of the condition and common features are observed, FOP is
not difficult to diagnose. Though there is currently no cure
or treatment that has been found effective, two clinical trials
with Palovarotene and an anti-activin A antibody will give
patients hope.
Author contributions  JMZ is first author. CFL is corresponding author.
SYK designed the study. YRP did a lot of work during the follow-
up of children with FOP. TXH, WYK, JW, JHD, XHT and CL were
involved in diagnosing and treating the patients. All authors have read
and approved the final manuscript.
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World Journal of Pediatrics
Funding None.
Compliance with ethical standards 
Ethical approval  This study was approved by the Ethics Commit-
tee of Beijing Children’s Hospital. Informed consent was obtained
from parents of all subjects.
Conflict of interest  No financial or nonfinancial benefits have been re-
ceived or will be received from any party related directly or indirectly
to the subject of this article.
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