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Fibrodysplasia ossificans progressiva presenting as a neck mass
International Journal of Pediatric Otorhinolaryngology Extra 8 (2013) 128–130
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Extra journal homepage: www.elsevier.com/locate/ijporl
Case report
Fibrodysplasia ossificans progressiva presenting as a neck mass Robert J. Tibesar a,d,*, Lindsay Eisler b,d, Mona M. LaPlant c,1, James D. Sidman a,d,2 a
Children’s ENT and Facial Plastic Surgery, Children’s Hospitals and Clinics of Minnesota, CSC Suite 450, 2530 Chicago Avenue South, Minneapolis, MN 55404, United States USF Health South Tampa Campus, 2 Tampa General Circle, 2nd Floor, #10, Tampa, FL 33606, United States c Rheumatology, Children’s Hospitals and Clinics of Minnesota, Garden View Medical Building Suite 504, Room 5007, 347 North Smith Avenue, St. Paul, MN 55102, United States d Department of Otolaryngology, University of Minnesota, Minneapolis, MN, United States b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 January 2013 Received in revised form 5 August 2013 Accepted 9 August 2013 Available online 5 September 2013
Objective: To report a case of fibrodysplasia ossificans progressiva (FOP) initially presenting as a neck mass and alert the practicing otolaryngologist to the imperative to avoid harmful biopsy. Case: A 2-year-old male presented with a firm left posterior neck mass and bilateral great toe malformations. Imaging was non-diagnostic and after 2 weeks of antibiotics the lesion was larger. At surgical biopsy, the mass was pale, firm, and avascular. Histopathology showed low grade fibromyxoid tissue. Rheumatology service diagnosed FOP based on clinical examination of neck mass, bilateral great toe deformities, stiff joints. Biopsy proved unnecessary and the patient developed heterotopic ossification at the site of surgical trauma. The patient was started on anti-inflammatories and steroids with minimal benefit. This case highlights the need for a broader understanding among clinicians who may encounter patients with FOP regarding the clinical aspects of diagnosis and the potential harm caused by surgical interventions. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Fibrodysplasia ossificans progressiva Neck mass Heterotopic ossification Great toe malformations
1. Introduction Fibrodysplasia ossificans progressive (FOP) is a rare and crippling disease. It is characterized by congenital skeletal malformations of the great toes and progressive heterotopic ossification of connective tissues. This disorder was originally described by Patin in 1648 as ‘‘the woman that turned into wood’’ [1]. FOP causes a progressive immobility as skeletal muscle and soft connective tissue transform into a skeleton of heterotopic bone. Two clinical features define FOP: malformation of the great toes and heterotopic ossification that is progressive and occurs in a specific spatial pattern. No heterotopic ossification is present at birth; malformation of the great toes is the only abnormality initially seen. Typically during the first decade of life, children develop highly inflammatory, painful soft tissue swellings. These events, described as flare-ups, transform soft connective tissue into an armor-like encasement of bone [2]. Flare-ups leading to progressive heterotopic ossification and progressive permanent
* Corresponding author at: Children’s ENT and Facial Plastic Surgery, Children’s Hospitals and Clinics of Minnesota, CSC Suite 450, 2530 Chicago Avenue South, Minneapolis, MN 55404, United States. Tel.: +1 612 874 1292; fax: +1 612 874 0985. E-mail addresses: [email protected] (R.J. Tibesar), [email protected] (L. Eisler), [email protected] (M.M. LaPlant), [email protected] (J.D. Sidman). 1 Tel.: +1 651 220 5862. 2 Tel.: +1 612 874 1292. 1871-4048/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pedex.2013.08.003
immobility can be triggered by minor trauma such as intramuscular injections, muscle fatigue and blunt trauma. Biopsy or attempted surgical removal commonly leads to explosive and painful new heterotopic ossification [3]. Manifestations in the head and neck include neck mass, ankylosis of the temporomandibular joint and conductive hearing loss from middle ear ossification [1]. Patients with FOP develop thoracic insufficiency syndrome from chest wall restriction. Thoracic insufficiency syndrome leads to pneumonia and right-sided heart failure [3]. 2. Case report A 2 year 7 month old boy presented with a tender, firm, poorly defined, left, posterior neck mass (Fig. 1). The mass came on acutely and had been recognized two weeks earlier by the patient’s mother. At time of presentation, the patient’s neck range of motion was limited, but his mother stated that the patient has had neck stiffness since birth. Imaging with computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a non-rim enhancing fluid-like process infiltrating the posterior neck musculature, extending to the occiput (Fig. 2) Infected lymphangioma was first in the differential diagnosis and the patient was treated with intravenous steroids and antibiotics. Over the next two weeks, he failed to show any significant improvement and the mass had now spread down to the neck and involved his left trapezious and shoulder region. Due to the rapid spread of the lesion, its clinical firmness, and progression despite antibiotic
R.J. Tibesar et al. / International Journal of Pediatric Otorhinolaryngology Extra 8 (2013) 128–130
Fig. 1. Clinical photograph of the 2 year, 7 month old male presenting with left sided neck mass. Note the stiffness and diffuse fullness of the neck with extension down the trapezius and scapular region.
therapy, there was concern of malignancy. The patient therefore underwent open surgical biopsy of the lesion in the neck. At biopsy, the lesion was pale, gray, firm, avascular and infiltrating the soft tissues. There were no distinct borders to the lesion. Pathologic analysis demonstrated a low-grade fibromyxoid and adipose tissue favoring lipofibromatosis. Clinically, the lesion progressed, and continued to spread down the back, creeping around the rib cage and extending down to the flanks. Comprehensive physical examination revealed congenital bilateral, short, malformed great toes with a valgus deformity. A rheumatology consultation was obtained and a diagnosis of fibrodysplasia ossificans progressive (FOP) was made based on the pathologic findings, great toe deformities (Fig. 3) and stiff joints. Genetic testing confirmed the diagnosis and the patient was started on supportive therapy consisting of non-steroidal anti-inflammatories and corticosteroids as needed for disease flare-ups. Parents were instructed to take all reasonable precautions to avoid trauma, including avoidance of any further surgical biopsy or intramuscular injections.
Fig. 2. Axial CT scan with contrast demonstrating poorly defined, diffuse, amorphous, avascular mass in the left neck with decreased attenuation between muscle groups of the posterior neck.
129
Fig. 3. Clinical photograph of both feet demonstrating the valgus deformity of the great toes.
3. Discussion In cases of FOP, heterotopic ossification progresses in a reliable anatomic and temporal fashion. It follows the pattern of embryonic skeletal formation. Proximal, cranial, and dorsal regions of the body are typically involved first by FOP, followed by peripheral and distal spread. Cardiac muscle, smooth muscle, the diaphragm, tongue and extraocular muscles are universally spared [4]. Outcomes for patients include: confinement to a wheelchair by their third decade, lifelong assistance for activities of daily living, ankylosis of the jaw, and pneumonia or right sided hearth failure from rigid fixation and restriction of the chest wall. The natural history of the disease is marked inexorable disease progression. Median survival is 45 and death typically occurs from complications of thoracic insufficiency syndrome [3]. Misdiagnosis is common, given the rarity of the disease, and failure of clinicians to correctly associate the soft tissue swellings with malformation of the great toes. Common misdiagnoses include juvenile bunions, isolated brachydactyly, aggressive juvenile fibromatosis, lymphedema, or soft tissue sarcomas. As in our case, children frequently undergo unnecessary biopsy in an effort to diagnose the lesion, which exacerbates the progression of the FOP [5]. Kitterman et al. recently published their findings on iatrogenic harm caused by diagnostic errors in FOP [6]. They found that incorrect diagnoses were initially given to 87% of individuals with FOP. This occurred worldwide, regardless of the patient’s ethnicity, geographic background, or 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 were performed. Forty-nine percent of all patients reported permanent loss of mobility resulting from invasive medical interventions that caused posttraumatic heterotopic ossification [6]. To be sure, FOP is the only disorder in which the patient has congenitally short great toes with hallux valgus and firm tumorlike swellings on the back and neck. Diagnosis is therefore entirely clinical and genetic testing is not required, but can be confirmative. Shore et al. recently discovered the gene mutation when they identified linkage of FOP to 2q23–24 [7]. This genetic interval includes the activin A type I receptor gene (ACVR1; OMIM 102576; also known as Alk2 or ActRIA), a receptor for bone morphogenetic protein (BMP). ACVR1 is expressed in many soft tissue types including skeletal muscle and chondrocytes. Constitutive
130
R.J. Tibesar et al. / International Journal of Pediatric Otorhinolaryngology Extra 8 (2013) 128–130
activation of ACVR1 induces alkaline phosphatase activity in C2C12 cells, upregulates BMP4, downregulates BMP antagonists, expands cartilage elements, induces ectopic chondrogenesis and stimulates joint fusions. ACVR1 is therefore a strong candidate gene for FOP, which is associated with similar clinical findings and dysregulation of the BMP signaling pathway [7]. The severe disability of FOP results in low reproductive rates, and few examples of inheritance are known. When observed, genetic transmission is autosomal dominant and can be inherited from either maternally or paternally [7]. Recognition of the characteristic great toe malformations, associated with the lumps on the neck, or back, provides accurate clinical diagnosis in suspected cases of FOP. Although there is no effective treatment, it is imperative to avoid soft-tissue trauma, including biopsies, intramuscular injections, and surgical procedures. All of these interventions risk worsening of the rapidly progressive heterotopic ossification, with resultant permanent musculoskeletal limitation. It needs to be apparent, therefore, that management is supportive and trauma prevention is a major focus of care. The potential harm to the patient of misdiagnosis and inappropriate intervention is significant. Corticosteroids are used during acute flare-ups, but there is no proven efficacy with any therapy in altering the natural progression of the disease [3].
4. Summary In summary, FOP is a rare disease characterized by malformation of the great toes and heterotopic ossification of skeletal muscle and connective tissue. Due to the rarity of this disease and
inadequate transmission of medical knowledge, there is often a delay in diagnosis in cases of FOP. Even worse, there is frequently iatrogenic harm caused by procedures such as biopsy or attempted surgical removal. Unfortunately, these well-intentioned interventions exacerbate the hetertopic ossification and permanent disability. Knowledge of this disease is valuable to otolaryngologists to facilitate early diagnosis and prevent aggressive surgical management which can lead to iatrogenic harm. As in our case, this rare condition can manifest primarily as a neck mass and present a diagnostic challenge for the practicing otolaryngologist.
References [1] G. Buyse, J. Silberstein, N. Goesmans, P. Casear, Fibrodysplasia ossificans progressiva: still turning into wood after 300 years, Eur. J. Pediatr. 154 (1995) 694–699. [2] E.M. Shore, F.S. Kaplan, Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressive, Bone 43 (2008) 427–433. [3] F.S. Kaplan, M.L. Merrer, D.L. Glaser, R.J. Pignolo, R.E. Goldsby, J.A. Kitterman, J. Groppe, E.M. Shore, Fibrodysplasia ossificans progressiva, Best Pract. Res. Clin. Rheumatol. 22 (2008) 191–205. [4] J. Janati, Y. Aghighi, A. Tofighi, A. Akhavan, O. Behrouzan, Radiologic findings in seven patients with fibrodysplasia ossificans progressiva, Arch. Iran. Med. 10 (1) (2007) 88–90. [5] F.S. Kaplan, M. Xu, D.L. Glaser, F. Collins, M. Connor, J. Kitterman, D. Sillence, E. Zackai, V. Ravitsky, M. Zasloff, A. Ganguly, E. Shore, Early diagnosis of fibrodysplasia ossificans progressiva, Pediatrics 121 (5) (2008) 1295–1300. [6] J.A. Kitterman, S. Kantanie, D.M. Rocke, F.S. Kaplan, Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva, Pediatrics 116 (5) (2005) e654–e661. [7] E.M. Shore, M. Xu, G.J. Feldman, D.A. Fenstermacher, T.J. Cho, I.H. Choi, J.M. Connor, P. Delai, D.L. Glaser, M. LeMerrer, R. Morhart, J.G. Rogers, R. Smith, J.T. Triffitt, J.A. Urtizberea, M. Zasloff, M.A. Brown, F.S. Kaplan, A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva, Nat. Genet. 38 (5) (2006) 525–527.
Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology Extra journal homepage: www.elsevier.com/locate/ijporl
Case report
Fibrodysplasia ossificans progressiva presenting as a neck mass Robert J. Tibesar a,d,*, Lindsay Eisler b,d, Mona M. LaPlant c,1, James D. Sidman a,d,2 a
Children’s ENT and Facial Plastic Surgery, Children’s Hospitals and Clinics of Minnesota, CSC Suite 450, 2530 Chicago Avenue South, Minneapolis, MN 55404, United States USF Health South Tampa Campus, 2 Tampa General Circle, 2nd Floor, #10, Tampa, FL 33606, United States c Rheumatology, Children’s Hospitals and Clinics of Minnesota, Garden View Medical Building Suite 504, Room 5007, 347 North Smith Avenue, St. Paul, MN 55102, United States d Department of Otolaryngology, University of Minnesota, Minneapolis, MN, United States b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 January 2013 Received in revised form 5 August 2013 Accepted 9 August 2013 Available online 5 September 2013
Objective: To report a case of fibrodysplasia ossificans progressiva (FOP) initially presenting as a neck mass and alert the practicing otolaryngologist to the imperative to avoid harmful biopsy. Case: A 2-year-old male presented with a firm left posterior neck mass and bilateral great toe malformations. Imaging was non-diagnostic and after 2 weeks of antibiotics the lesion was larger. At surgical biopsy, the mass was pale, firm, and avascular. Histopathology showed low grade fibromyxoid tissue. Rheumatology service diagnosed FOP based on clinical examination of neck mass, bilateral great toe deformities, stiff joints. Biopsy proved unnecessary and the patient developed heterotopic ossification at the site of surgical trauma. The patient was started on anti-inflammatories and steroids with minimal benefit. This case highlights the need for a broader understanding among clinicians who may encounter patients with FOP regarding the clinical aspects of diagnosis and the potential harm caused by surgical interventions. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Fibrodysplasia ossificans progressiva Neck mass Heterotopic ossification Great toe malformations
1. Introduction Fibrodysplasia ossificans progressive (FOP) is a rare and crippling disease. It is characterized by congenital skeletal malformations of the great toes and progressive heterotopic ossification of connective tissues. This disorder was originally described by Patin in 1648 as ‘‘the woman that turned into wood’’ [1]. FOP causes a progressive immobility as skeletal muscle and soft connective tissue transform into a skeleton of heterotopic bone. Two clinical features define FOP: malformation of the great toes and heterotopic ossification that is progressive and occurs in a specific spatial pattern. No heterotopic ossification is present at birth; malformation of the great toes is the only abnormality initially seen. Typically during the first decade of life, children develop highly inflammatory, painful soft tissue swellings. These events, described as flare-ups, transform soft connective tissue into an armor-like encasement of bone [2]. Flare-ups leading to progressive heterotopic ossification and progressive permanent
* Corresponding author at: Children’s ENT and Facial Plastic Surgery, Children’s Hospitals and Clinics of Minnesota, CSC Suite 450, 2530 Chicago Avenue South, Minneapolis, MN 55404, United States. Tel.: +1 612 874 1292; fax: +1 612 874 0985. E-mail addresses: [email protected] (R.J. Tibesar), [email protected] (L. Eisler), [email protected] (M.M. LaPlant), [email protected] (J.D. Sidman). 1 Tel.: +1 651 220 5862. 2 Tel.: +1 612 874 1292. 1871-4048/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pedex.2013.08.003
immobility can be triggered by minor trauma such as intramuscular injections, muscle fatigue and blunt trauma. Biopsy or attempted surgical removal commonly leads to explosive and painful new heterotopic ossification [3]. Manifestations in the head and neck include neck mass, ankylosis of the temporomandibular joint and conductive hearing loss from middle ear ossification [1]. Patients with FOP develop thoracic insufficiency syndrome from chest wall restriction. Thoracic insufficiency syndrome leads to pneumonia and right-sided heart failure [3]. 2. Case report A 2 year 7 month old boy presented with a tender, firm, poorly defined, left, posterior neck mass (Fig. 1). The mass came on acutely and had been recognized two weeks earlier by the patient’s mother. At time of presentation, the patient’s neck range of motion was limited, but his mother stated that the patient has had neck stiffness since birth. Imaging with computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a non-rim enhancing fluid-like process infiltrating the posterior neck musculature, extending to the occiput (Fig. 2) Infected lymphangioma was first in the differential diagnosis and the patient was treated with intravenous steroids and antibiotics. Over the next two weeks, he failed to show any significant improvement and the mass had now spread down to the neck and involved his left trapezious and shoulder region. Due to the rapid spread of the lesion, its clinical firmness, and progression despite antibiotic
R.J. Tibesar et al. / International Journal of Pediatric Otorhinolaryngology Extra 8 (2013) 128–130
Fig. 1. Clinical photograph of the 2 year, 7 month old male presenting with left sided neck mass. Note the stiffness and diffuse fullness of the neck with extension down the trapezius and scapular region.
therapy, there was concern of malignancy. The patient therefore underwent open surgical biopsy of the lesion in the neck. At biopsy, the lesion was pale, gray, firm, avascular and infiltrating the soft tissues. There were no distinct borders to the lesion. Pathologic analysis demonstrated a low-grade fibromyxoid and adipose tissue favoring lipofibromatosis. Clinically, the lesion progressed, and continued to spread down the back, creeping around the rib cage and extending down to the flanks. Comprehensive physical examination revealed congenital bilateral, short, malformed great toes with a valgus deformity. A rheumatology consultation was obtained and a diagnosis of fibrodysplasia ossificans progressive (FOP) was made based on the pathologic findings, great toe deformities (Fig. 3) and stiff joints. Genetic testing confirmed the diagnosis and the patient was started on supportive therapy consisting of non-steroidal anti-inflammatories and corticosteroids as needed for disease flare-ups. Parents were instructed to take all reasonable precautions to avoid trauma, including avoidance of any further surgical biopsy or intramuscular injections.
Fig. 2. Axial CT scan with contrast demonstrating poorly defined, diffuse, amorphous, avascular mass in the left neck with decreased attenuation between muscle groups of the posterior neck.
129
Fig. 3. Clinical photograph of both feet demonstrating the valgus deformity of the great toes.
3. Discussion In cases of FOP, heterotopic ossification progresses in a reliable anatomic and temporal fashion. It follows the pattern of embryonic skeletal formation. Proximal, cranial, and dorsal regions of the body are typically involved first by FOP, followed by peripheral and distal spread. Cardiac muscle, smooth muscle, the diaphragm, tongue and extraocular muscles are universally spared [4]. Outcomes for patients include: confinement to a wheelchair by their third decade, lifelong assistance for activities of daily living, ankylosis of the jaw, and pneumonia or right sided hearth failure from rigid fixation and restriction of the chest wall. The natural history of the disease is marked inexorable disease progression. Median survival is 45 and death typically occurs from complications of thoracic insufficiency syndrome [3]. Misdiagnosis is common, given the rarity of the disease, and failure of clinicians to correctly associate the soft tissue swellings with malformation of the great toes. Common misdiagnoses include juvenile bunions, isolated brachydactyly, aggressive juvenile fibromatosis, lymphedema, or soft tissue sarcomas. As in our case, children frequently undergo unnecessary biopsy in an effort to diagnose the lesion, which exacerbates the progression of the FOP [5]. Kitterman et al. recently published their findings on iatrogenic harm caused by diagnostic errors in FOP [6]. They found that incorrect diagnoses were initially given to 87% of individuals with FOP. This occurred worldwide, regardless of the patient’s ethnicity, geographic background, or 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 were performed. Forty-nine percent of all patients reported permanent loss of mobility resulting from invasive medical interventions that caused posttraumatic heterotopic ossification [6]. To be sure, FOP is the only disorder in which the patient has congenitally short great toes with hallux valgus and firm tumorlike swellings on the back and neck. Diagnosis is therefore entirely clinical and genetic testing is not required, but can be confirmative. Shore et al. recently discovered the gene mutation when they identified linkage of FOP to 2q23–24 [7]. This genetic interval includes the activin A type I receptor gene (ACVR1; OMIM 102576; also known as Alk2 or ActRIA), a receptor for bone morphogenetic protein (BMP). ACVR1 is expressed in many soft tissue types including skeletal muscle and chondrocytes. Constitutive
130
R.J. Tibesar et al. / International Journal of Pediatric Otorhinolaryngology Extra 8 (2013) 128–130
activation of ACVR1 induces alkaline phosphatase activity in C2C12 cells, upregulates BMP4, downregulates BMP antagonists, expands cartilage elements, induces ectopic chondrogenesis and stimulates joint fusions. ACVR1 is therefore a strong candidate gene for FOP, which is associated with similar clinical findings and dysregulation of the BMP signaling pathway [7]. The severe disability of FOP results in low reproductive rates, and few examples of inheritance are known. When observed, genetic transmission is autosomal dominant and can be inherited from either maternally or paternally [7]. Recognition of the characteristic great toe malformations, associated with the lumps on the neck, or back, provides accurate clinical diagnosis in suspected cases of FOP. Although there is no effective treatment, it is imperative to avoid soft-tissue trauma, including biopsies, intramuscular injections, and surgical procedures. All of these interventions risk worsening of the rapidly progressive heterotopic ossification, with resultant permanent musculoskeletal limitation. It needs to be apparent, therefore, that management is supportive and trauma prevention is a major focus of care. The potential harm to the patient of misdiagnosis and inappropriate intervention is significant. Corticosteroids are used during acute flare-ups, but there is no proven efficacy with any therapy in altering the natural progression of the disease [3].
4. Summary In summary, FOP is a rare disease characterized by malformation of the great toes and heterotopic ossification of skeletal muscle and connective tissue. Due to the rarity of this disease and
inadequate transmission of medical knowledge, there is often a delay in diagnosis in cases of FOP. Even worse, there is frequently iatrogenic harm caused by procedures such as biopsy or attempted surgical removal. Unfortunately, these well-intentioned interventions exacerbate the hetertopic ossification and permanent disability. Knowledge of this disease is valuable to otolaryngologists to facilitate early diagnosis and prevent aggressive surgical management which can lead to iatrogenic harm. As in our case, this rare condition can manifest primarily as a neck mass and present a diagnostic challenge for the practicing otolaryngologist.
References [1] G. Buyse, J. Silberstein, N. Goesmans, P. Casear, Fibrodysplasia ossificans progressiva: still turning into wood after 300 years, Eur. J. Pediatr. 154 (1995) 694–699. [2] E.M. Shore, F.S. Kaplan, Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressive, Bone 43 (2008) 427–433. [3] F.S. Kaplan, M.L. Merrer, D.L. Glaser, R.J. Pignolo, R.E. Goldsby, J.A. Kitterman, J. Groppe, E.M. Shore, Fibrodysplasia ossificans progressiva, Best Pract. Res. Clin. Rheumatol. 22 (2008) 191–205. [4] J. Janati, Y. Aghighi, A. Tofighi, A. Akhavan, O. Behrouzan, Radiologic findings in seven patients with fibrodysplasia ossificans progressiva, Arch. Iran. Med. 10 (1) (2007) 88–90. [5] F.S. Kaplan, M. Xu, D.L. Glaser, F. Collins, M. Connor, J. Kitterman, D. Sillence, E. Zackai, V. Ravitsky, M. Zasloff, A. Ganguly, E. Shore, Early diagnosis of fibrodysplasia ossificans progressiva, Pediatrics 121 (5) (2008) 1295–1300. [6] J.A. Kitterman, S. Kantanie, D.M. Rocke, F.S. Kaplan, Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva, Pediatrics 116 (5) (2005) e654–e661. [7] E.M. Shore, M. Xu, G.J. Feldman, D.A. Fenstermacher, T.J. Cho, I.H. Choi, J.M. Connor, P. Delai, D.L. Glaser, M. LeMerrer, R. Morhart, J.G. Rogers, R. Smith, J.T. Triffitt, J.A. Urtizberea, M. Zasloff, M.A. Brown, F.S. Kaplan, A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva, Nat. Genet. 38 (5) (2006) 525–527.