Clin Rheumatol DOI 10.1007/s10067-013-2417-x
CASE BASED REVIEW
FOP: still turning into stone Reza Taslimi & Saba Jafarpour & Nahid Hassanpour
Received: 23 August 2013 / Revised: 24 September 2013 / Accepted: 18 October 2013 # Clinical Rheumatology 2013
Abstract Fibrodysplasia ossificans progressiva (FOP) is a rare catastrophic genetic condition of extraskeletal (heterotopic) ossification. One in every two million people is affected worldwide, with no ethnic, racial, gender, or geographic predisposition. Most cases of FOP arise from a spontaneous missense mutation in the gene encoding bone morphogenic protein (BMP) type II receptor (ACVR1/ALK2). Affected individuals are normal at birth apart from malformed great toes. Onset of clinical symptoms is usually in the first decade of life, presenting with episodic emergence of painful rapidly appearing tumor-like soft tissue swellings (flare-ups). Heterotopic bone replaces the skeletal muscles, tendons, ligaments, and connective tissue at the site of the damage through a process of endochondral ossification, causing fixation of joints and permanent limitation of motion. Most affected individuals are confined to wheelchair in the third decade of life. Worldwide rate of misdiagnosis of FOP is very high; clinicians often fail to associate the two classic clinical features of FOP: rapidly developing soft tissue swellings and the abnormal great toes. The current case presents a previously undiagnosed 39-year-old FOP patient, sadly a victim of lack of clinical awareness of this rare condition. As a result of repetitive iatrogenic harm, he has tragically “turned into stone.” Keywords Fibrodysplasia ossificans progressiva (FOP) . Heterotopic ossification . Medical error . Myositis ossificans
Electronic supplementary material The online version of this article (doi:10.1007/s10067-013-2417-x) contains supplementary material, which is available to authorized users.
Case report A 39-year-old man presented with generalized stiffness and severe restriction of body movement. He was unable to move most of his joints, incapable of sitting because his spine was totally fixed like a board (Fig. 1, Electronic supplementary material). Onset of his symptoms dated back to the age of 8, at the time he accidentally noticed a bony prominence in the medial side of his right knee. He underwent a surgical removal of the lesion, with a diagnosis of osteochondroma. Soon after the surgery, the bony prominence recurred and he developed painful swellings in the adjacent site, along with progressive emergence of painful mass-like lesions in his back and neck. His jaw became stiff, and he had difficulty in eating and maintaining good oral hygiene. During a period of 10 years, he underwent several surgeries, most of which included excision of the ectopic bones and release of joint contractures. Difficult intubation was documented in the surgery reports. Family history was negative for similar conditions. Physical examination revealed bilateral malformation of the great toes; monophalangism and hallux valgus were noted (Fig. 2). Ossified tendons, muscle, and ligaments and bony prominences were palpable through the skin at multiple sites. Chest expansion was diminished. Radiologic evaluations showed widespread heterotopic ossification (Fig. 3). Ossification of the paraspinal ligaments and fusion of the vertebral bodies gave the vertebral column a “bamboo spine” appearance (Fig. 4)—a characteristic radiographic finding of advanced ankylosing spondylitis (AS), the presumptive diagnosis with which the patient was referred to our center.
R. Taslimi Imam Khomeini Hospital, Tehran University of Medical Sciences, Pour-Sina St., Keshavarz Blvd., Tehran, Iran S. Jafarpour (*) : N. Hassanpour School of Medicine, Tehran University of Medical Sciences, Pour-Sina St., Keshavarz Blvd., Tehran, Iran e-mail: [email protected]
Introduction At the time heterotopic ossification of fibrodysplasia ossificans progressiva (FOP) was first described by a London
Clin Rheumatol
Fig. 1 The spine was totally fixed. The patient was “frozen” in the demonstrated posture
Fig. 3 Heterotopic ossification in the soft tissue of the right lower extremity (arrows)
physician John Freke in 1736 [1], FOP was a painful mystery to both patients and physicians. FOP is a rare catastrophic genetic disease and the most disabling form of extraskeletal (heterotopic) ossification known to humans. Progressive connective tissue metamorphosis that occurs in this condition ultimately leads to formation of a second skeleton outside the original one, imprisoning the body and causing lifelong obstacle to physical freedom [1–4]. Classical FOP is defined by two characteristic clinical features: malformation of the great toes and progressive heterotopic ossifications. Affected individuals are normal at birth apart from malformed great toes (hallux valgus, malformed first metatarsal, and/or monophalangism) [5] present in all classical cases of FOP [1, 6]. Isolated congenital hallux valgus is less prevalent than FOP [7]. The unique congenital malformation of the great toe is radiologically defined by the presence of one or more of the following features: shortened and sharpened proximal phalanx, hallux valgus angle (HVA) ≥20°, and intermetatarsal angle (IMA) ≥10 [8].
Clinical presentation
Fig. 2 Bilateral malformation of the great toes (monophalangism and hallux valgus)
Onset of clinical symptoms is usually in the first decade of life, presenting with painful rapidly appearing tumor-like soft tissue swellings (flare-ups) often preceded by minor local traumas. Lesions typically first emerge in the dorsal and axial parts (i.e., neck and back), spread in a cranio-caudal manner, and later involve the ventral and appendicular parts [1, 9]. In the limbs, swelling is usually diffuse rather than mass like, resembling lymphedema or thrombophlebitis, which is as well a complication commonly seen in advanced FOP [5]. Heterotopic bone replaces the skeletal muscles, tendons, ligaments, and connective tissue at the site of the damage through a process of endochondral ossification, causing fixation of joints and permanent limitation of motion. Cardiac muscle, smooth muscles, and several skeletal muscles including
Fig. 4 Widespread ossification of soft tissue (asterisks); ossification of the paraspinal ligaments and fusion of the vertebral bodies give rise to a “bamboo spine” appearance
Clin Rheumatol
diaphragm, tongue, and extraocular muscles are spared [1]. The mean age of onset of ossification is reported to be 5 [10]. Most FOP patients develop heterotopic ossification under the age of 15 years [2, 11–15]. Episodic bone formation leads to cumulative disability. Most affected individuals are confined to wheelchair in the third decade of life, having a shorter life span than the general population (estimated median life span of 56 years and median age of survival of 40 years) [16]. In addition, although not necessary for making the clinical diagnosis, the presence of some other clinical features that are frequently associated with classic FOP can be highly suggestive of the condition and raise the level of clinical suspicion, leading to an early diagnosis [17]. Proximal tibial osteochondroma is a good example of these features; in a study of 96 individuals with classic FOP, 90 % had osteochondroma of the proximal tibia [18]. Some other associated skeletal anomalies include fusion of the facet joints between C2 and C7, large posterior elements and tall narrow vertebral bodies in the cervical spine, clinodactyly, short malformed thumbs, short broad femoral neck, shallow acetabulum [1], phalangeal shortening, and medial cortex thickening of the tibia [10]. Extra-articular temporomandibular joint (TMJ) ankylosis is common, either spontaneously or post-traumatic, and can cause severe weight loss due to difficulty in eating. It also results in poor oral hygiene. Submandibular swelling is another process that interferes with swallowing, particularly when associated with huge bulging in the anterior cervical region, which can be even life threatening [1]. Hearing impairment occurs in nearly half of the affected individuals, beginning in the childhood or adolescence and gradually progressing over time. Most of the time, hearing impairment is conductive type, probably due to middle ear ossification, but can be sensorineural too if affecting the inner ear [1, 5]. Ankylosis of costovertebral joints, ossification of intercostal and paravertebral muscles, and aponeuroses, along with spinal deformities such as kyphoscoliosis or thoracic lordosis, contribute to thoracic insufficiency syndrome (TIS) [1]. Rightsided heart failure and pneumonia are major life-threatening complications of TIS and the leading causes of death in FOP patients [16]. Subtle traumas, such as falling and bruising, intramuscular injections, nerve blocks in dental procedures, lumbar puncture [19], even viral flu-like infections, and minor muscle fatigue can produce an exaggerated inflammatory response, causing immune-mediated death of skeletal muscles clinically presented as painful flare-ups and triggering the process of heterotopic ossification [1, 2, 5]. Invasive procedures (i.e., biopsy or excision of the mass-like lesions or different surgical interventions) can initiate an outburst of new bone formation and alter the natural history of the disease into a devastating irreversible state of physical limitation [1, 20, 21].
Atypical FOP Atypical FOP, as described by Kaplan et al., comprises a small number of affected individuals that either show great variations in one of the key defining features, such as normal great toe or severe reduction deficits of digits (FOP variants), or have the classic defining features plus one or more atypical features (FOP-plus). Some of the atypical features associated with FOP-plus include the following: intra-articular synovial osteochondromatosis of hips, degenerative joint disease of hips, sparse scalp hair (more prominent in second decade), severe growth retardation, cataracts, retinal detachment, childhood glaucoma, craniopharygioma, persistence of primary teeth in adulthood, cerebral cavernous malformations, diffuse cerebral dysfunction with seizures, mild cognitive impairment, anatomic abnormalities of the cerebellum, polyostotic fibrous dysplasia, primary amenorrhea, hypospadias, and aplastic anemia [5].
Radiologic findings Heterotopic ossification is not usually detected in conventional radiographic studies until 6–12 months after the appearance of the flare-up lesions. Nevertheless, bone scan, computed tomography (CT) and magnetic resonance imaging (MRI), often show some abnormalities. In the early stage, CT shows edema and swelling in the fascial plane and mass-like lesions in the muscle moderately enhanced by IV contrast. After the progression of the disease, calcification and ossification can be clearly observed in the CT images. MRI shows a homogenous soft tissue mass in T2 weighted images, spreading along the fascial plane and showing significant enhancement by the injection of contrast medium [10]. Despite the described features, imaging studies are superfluous as the definitive diagnosis can be simply made clinically by associating the progressive ossification with congenital great toes malformation [22]. The diagnosis can further be confirmed by genetic studies [1].
Pathogenesis FOP is an extremely rare genetic disease. One in every two million people is affected by this condition, with no ethnic, racial, gender, or geographic predisposition [23]. FOP can be inherited with autosomal dominant transmission and complete penetrance, but due to low reproductive fitness of the affected individuals, fewer than ten families with autosomal dominant inheritance have been observed. Spontaneous new mutations are responsible for a great majority of cases [1]. Therefore, unaffected parents with a child diagnosed with FOP are unlikely to have a second affected child. However, gonadal
Clin Rheumatol
mosaicism can occur in very rare occasions, so prenatal genetic testing could be considered in these cases. Both genetic and environmental factors have a role in the phenotype of FOP, with genetic factors mostly affecting the prenatal development and environmental factors influencing postnatal progression of the disease [17]. Underlying mechanisms of pathogenesis of the disease remained largely unknown until very recently. FOP demonstrates the pathological process of metamorphosis, which involves one normal tissue or organ system transforming into another [24]. In this process, one mature cell does not transdifferentiate into another; rather, one tissue is destroyed and then replaced by another tissue [3]. The histopathology of this process in FOP is well described, beginning with a catabolic stage associated with muscle cell injury and death, which is characterized by infiltration of lymphocytes, macrophages, and mast cells. An intense anabolic phase immediately follows, characterized by fibroproliferative lesion, further maturing through an endochondral ossification to heterotopic bone that contains marrow elements. In an active FOP lesion, all stages of histological development can be observed simultaneously, suggesting different rates of maturation for different regions within the lesion [8]. With subsequent flare-up episodes, the boney structures ramify and spread through adjacent sites, ultimately forming a second skeleton of heterotopic bone [1]. The classic invariable features of FOP involving both skeletal patterning and heterotopic bone formation strongly indicate involvement of BMP signaling pathway [3]. BMP signaling pathway regulates multiple developmental and postdevelopmental processes from early embryogenesis through adulthood. BMP acts through binding and activating type I and type II BMP receptors, which are serine/threonine kinases with similar functional domains. Type I receptor has a cytoplasmic juxtamembrane region rich in glycine and serine residues (GS domains), which is phosphorylated and activated by active type II BMP receptor and transmits BMP signals to BMP-sensitive target genes. There are four known BMP type I receptors: TSR (ALK1), ACVR1 (ALK2), BMPR1A (ALK3), and BMPR1B (ALK6) [24]. FOP was mapped by genome-wide linkage analysis to a region on chromosome 2q23-24 that includes the gene encoding ACVR1/ALK2. A heterozygous missense activating mutation in the GS activation domain of the ACVR1 was detected in all classically affected individuals. The mutation results in a mutant protein that changes the basal set point and ligand-dependent sensitivity for BMP signaling in connective tissue progenitors. The discovery of the specific FOP gene mutation established a monumental milestone; not only did it help in understanding the disease mechanism and revealing a specific target for therapeutic approaches [3] but also as the first identified human metamorphogene it shed light on the general biological principles of transformation of one normal tissue
into another. It may be possible to harness the gene mutation to create new skeletal tissue for patients with fracture nonunions, osteoporotic fractures, failed spinal fusions, bone loss from trauma or malignancy, and congenital agenesis of skeletal elements [2, 24]. It is important to note that while the specific FOP gene mutation might be necessary for the process of heterotopic ossification, it is not sufficient for the development of episodic flare-ups that cause the progressive and cumulative disability seen in affected individuals. Aberrations of soft tissue microenvironment, immune system, and the altered response of progenitor cells all should be taken into consideration in the complex mechanism of induction of flare-ups [5]. Therefore, innovative therapeutic approaches aim to tackle the disease at different levels: blocking activity of the mutant BMP receptor with soluble BMP antagonists, inhibitory RNA technology, monoclonal antibodies directed against ACVR1, or smallmolecule selective signal transduction inhibitors of ACVR1 receptor activity; inhibiting the inflammatory and/or neuroinflammatory triggers of episodic flare-ups; diverting the responding progenitor cells to a soft tissue fate; and altering the inductive and/or conducive microenvironments that favor the formation of FOP lesions [2].
Diagnosis This case obviously demonstrates how failure to associate the classic clinical features of FOP and make the accurate diagnosis in a timely manner can lead to a disastrous collection of iatrogenic harm. Worldwide rate of misdiagnosis of FOP is very high. In a study of 138 FOP patients from 25 countries, 87 % were initially given incorrect diagnosis [21]. There was an average gap of 4.1 years between the onset of symptoms and ultimate diagnosis of FOP, with a median number of six physicians being consulted before the correct diagnosis. Sixty-seven percent of patients had unnecessary invasive procedures, which caused permanent loss of mobility in nearly half of the patients. When the clinicians fail to associate the rapidly developing soft tissue swellings with the abnormality in the great toes, they often mistake the lesions for neoplasms [21]. There is an extended list of differential diagnoses for those lesions: aggressive juvenile fibromatosis, malignant tumors (i.e., sarcomas), post-traumatic myositis ossificans, tuberculosis, lymphadenopathy, nodular fasciitis, scleroderma, rheumatoid arthritis nodules, osteoma cutis, progressive osseous heteroplasia (POH), Albright hereditary osteodystrophy, Still's disease, Weber–Christian disease, calcinosis interstitialis ossificans, hypervitaminosis D, pseudohypoparathyroidism, and multiple exostosis [10]. In a more advanced stage, involvement of the spine mimics AS [25], as mentioned for the presented patient.
Clin Rheumatol
Nevertheless, the preservation of the sacroiliac joints was not taken into account, a clue that makes this diagnosis highly unlikely. Apart from abnormality of the great toes, the evidence of a proximal tibial osteochndroma was another clue to the diagnosis of FOP in our patient. Unlike multiple hereditary exostosis, malignant transformation of osteochondroma in FOP is not reported. Thus, routine imaging of the osteochondromas is not recommended, and lesions should not be excised due to the consequences of invasive procedures [18].
Treatment Currently, the clinical management of FOP is mainly focused in prophylactic approaches, symptomatic management, and optimization of function. Patients should not be subjected to excessive stretching of the jaw in dental procedures, as well as injection of local anesthesia especially mandibular block. Intramuscular injections should be avoided. Vaccinations should be administered subcutaneously. Venipuncture and IV administration of drugs pose minimal risk. Prevention of falling and improving household safety is crucial. Orotracheal intubation can as well traumatize the TMJ joints and result in disease flare-up. Instead, an awake fiber-optic nasotracheal intubation should be used by an expert anesthesiologist under light sedation [1]. Prophylactic measures against respiratory infection and cardiopulmonary complications of TIS are of vital importance. Provocative spirometry can detect respiratory problems early and may be useful to minimize respiratory complications [5]. All FOP patients should be vaccinated against pneumococcus and influenza. Chest physiotherapy and prompt antibiotic therapy should be administered as soon as early signs of respiratory infection appear. Upper abdominal surgery interferes with diaphragmatic respiration and should be avoided if possible. Sleep studies should be performed, and in case of sleep apnea, patients can benefit from appropriate use of positive pressure ventilation, without supplemental oxygen. In advanced TIS, supplemental oxygen should not be administered in an unmonitored setting as it may suppress the respiratory drive and result in carbon dioxide retention and sudden death [1]. Physical rehabilitation approaches can enhance the general function and ability to fulfill daily activities with minimum assistance. Surgical approach to release the joint contractures is generally not recommended because of the risk of inducing extensive heterotopic ossification and worsening the situation. In very rare occasions, surgery might be beneficial, as in repositioning a joint to improve the patient's overall function [1]. Audiology evaluations and utilization of auditory aids can prevent developmental problems in children with FOP [5].
Pharmacological management of symptoms include prompt use of glucocorticoids in flare-up episodes involving major joints of the appendicular skeleton, as well as nonsteroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors, mast cell stabilizers, and leukotriene inhibitors for chronic pain management [2]. More effective and specific therapeutic approaches are still searched for and under experiment in the research labs [1]. Detailed guidelines for symptomatic management of FOP can be found on the IFOPA website (http://www.ifopa.org/). In conclusion, FOP is a rare disease and, because of its rarity and lack of clinical awareness, is often misdiagnosed, resulting in iatrogenic harm to the patients; as for the most common initial inaccurate diagnosis, neoplasm, the next step would involve invasive procedures. Primary care physicians, pediatrics, radiologists, rheumatologist, and orthopedic surgeons should be informed so that they can spot the readily detectable classic clinical feature of the disease, malformation of the great toes, to establish an early diagnosis and prevent further irreversible injuries.
Disclosures None.
References 1. Kaplan FS, Le Merrer M, Glaser DL, Pignolo RJ, Goldsby R, Kitterman JA, Groppe J, Shore EM (2008) Fibrodysplasia ossificans progressive. Best Pract Res Clin Rheumatol 22(1):191–205 2. Kaplan FS, Chakkalakal SA, Shore EM (2012) Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis. Dis Model Mech 5(6):756–762 3. Kaplan FS, Groppe J, Shore EM (2008) When one skeleton is enough: approaches and strategies for the treatment of fibrodysplasia ossificans progressiva (FOP). Drug Discov Today Ther Strateg 5(4): 255–262 4. Raees-Karami SR, Jafarieh H, Ziyayi V, Shekarriz Foumani R, Aghighi Y (2012) Evaluation of 20 years experience of fibrodysplasia ossificans progressiva in Iran: lessons for early diagnosis and prevention. Clin Rheumatol 31(7):1133–1137 5. Pignolo RJ, Shore EM, Kaplan FS (2011) Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphan J Rare Dis 6:80 6. Dua SG, Purandare NC (2011) Are great toes always abnormal in patients with fibrodysplasia ossificans progressiva? Eur J Pediatr 170(4):541–543 7. Kaplan FS, Glaser DL, Shore EM et al (2005) The phenotype of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3(3–4):183–188 8. Al-Haggar M, Ahmad N, Yahia S, Shams A, Hasaneen B, Hassan Hassan R, Wahba Y, Salem NA, and Abdel-Hady D (2013) Sporadic Fibrodysplasia Ossificans Progressiva in an Egyptian Infant with c.617G>A Mutation in ACVR1 Gene: A Case Report and Review of Literature. Case Rep Genet. 2013: 834605. 9. Pignolo RJ, Suda RK, Kaplan FS (2005) The fibrodysplasia ossificans progressiva lesion. Clin Rev Bone Miner Metab 3:195–200 10. Hashemi J, Shahfarhat A, Beheshtian A (2011) Iran fibrodysplasia ossificans progressiva: report of a case and review of articles. Iran J Radiol 8(2):113–117
Clin Rheumatol 11. Rogers JG, Geho WB (1979) Fibrodysplasia ossificans progressiva. A survey of forty-two cases. J Bone Joint Surg 61A:909–914 12. Schroeder HW, Zasloff MA (1980) The hand and foot malformations in fibrodysplasia ossificans progressiva. Johns Hopkins Med J 147:73–78 13. Connor JM, Evans DA (1982) Fibrodysplasia ossificans progressiva: the clinical features and natural history of 34 patients. J Bone Joint Surg 64B:76–83 14. Smith R (1998) Fibrodysplasia (myositis) ossificans progressiva: clinical lessons from a rare disease. Clin Orthop Rel Res 346:7–14 15. Cohen RB, Hahn VG, Tabas JA et al (1993) The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva: a study of forty-four patients. J Bone Joint Surg 75A:215–219 16. Kaplan FS, Zasloff MA, Kitterman JA, Shore EM, Hong CC, Rocke DM (2010) Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 92(3):686–691 17. Kaplan FS, Xu M, Glaser DL, Collins F, Connor M, Kitterman J, Sillence D et al (2008) Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics 121(5):e1295–e1300 18. Deirmengian GK, Hebela NM, O'Connell M, Glaser DL, Shore EM, Kaplan FS (2008) Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J Bone Joint Surg Am 90(2): 366–374
19. Zaghloul KA, Heuer GG, Guttenberg MD, Shore EM, Kaplan FS, Storm PB (2008) Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva. J Neurosurg Pediatr 1(1):91–94 20. Puszczewicz M, Kołczewska A, Zimmermann-Górska I, Majewski D, Ogrodowicz A (2007) Fibrodysplasia ossificans progressiva: case report. Pol Arch Med Wewn 117(1–2):53–56 [Article in Polish] 21. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS (2005) Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 116(5):e654–e661 22. Kaplan FS, Tabas J, Gannon FH, Finkel G, Hahn GV, Zasloff MA (1993) The histopathology of fibrodysplasia ossificans progressiva: an endochondral process. J Bone Joint Surg 75(2):220–230 23. Shore EM, Feldman GJ, Xu M, Kaplan FS (2005) The genetics of fibrodysplasia ossificans progressiva. Clin Rev Bone Miner Metab 3(3– 4):201–204 24. Kaplan FS, Shen Q, Lounev V, Seemann P, Groppe J, Katagiri T, Pignolo RJ, Shore EM (2008) Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP). J Bone Miner Metab 26(6):521–530 25. Bridges AJ, Hsu KC, Singh A, Churchill R, and Miles J (1994) Fibrodysplasia (myositis) ossificans progressiva Semin Arthritis Rheum. 24(3):155–64
CASE BASED REVIEW
FOP: still turning into stone Reza Taslimi & Saba Jafarpour & Nahid Hassanpour
Received: 23 August 2013 / Revised: 24 September 2013 / Accepted: 18 October 2013 # Clinical Rheumatology 2013
Abstract Fibrodysplasia ossificans progressiva (FOP) is a rare catastrophic genetic condition of extraskeletal (heterotopic) ossification. One in every two million people is affected worldwide, with no ethnic, racial, gender, or geographic predisposition. Most cases of FOP arise from a spontaneous missense mutation in the gene encoding bone morphogenic protein (BMP) type II receptor (ACVR1/ALK2). Affected individuals are normal at birth apart from malformed great toes. Onset of clinical symptoms is usually in the first decade of life, presenting with episodic emergence of painful rapidly appearing tumor-like soft tissue swellings (flare-ups). Heterotopic bone replaces the skeletal muscles, tendons, ligaments, and connective tissue at the site of the damage through a process of endochondral ossification, causing fixation of joints and permanent limitation of motion. Most affected individuals are confined to wheelchair in the third decade of life. Worldwide rate of misdiagnosis of FOP is very high; clinicians often fail to associate the two classic clinical features of FOP: rapidly developing soft tissue swellings and the abnormal great toes. The current case presents a previously undiagnosed 39-year-old FOP patient, sadly a victim of lack of clinical awareness of this rare condition. As a result of repetitive iatrogenic harm, he has tragically “turned into stone.” Keywords Fibrodysplasia ossificans progressiva (FOP) . Heterotopic ossification . Medical error . Myositis ossificans
Electronic supplementary material The online version of this article (doi:10.1007/s10067-013-2417-x) contains supplementary material, which is available to authorized users.
Case report A 39-year-old man presented with generalized stiffness and severe restriction of body movement. He was unable to move most of his joints, incapable of sitting because his spine was totally fixed like a board (Fig. 1, Electronic supplementary material). Onset of his symptoms dated back to the age of 8, at the time he accidentally noticed a bony prominence in the medial side of his right knee. He underwent a surgical removal of the lesion, with a diagnosis of osteochondroma. Soon after the surgery, the bony prominence recurred and he developed painful swellings in the adjacent site, along with progressive emergence of painful mass-like lesions in his back and neck. His jaw became stiff, and he had difficulty in eating and maintaining good oral hygiene. During a period of 10 years, he underwent several surgeries, most of which included excision of the ectopic bones and release of joint contractures. Difficult intubation was documented in the surgery reports. Family history was negative for similar conditions. Physical examination revealed bilateral malformation of the great toes; monophalangism and hallux valgus were noted (Fig. 2). Ossified tendons, muscle, and ligaments and bony prominences were palpable through the skin at multiple sites. Chest expansion was diminished. Radiologic evaluations showed widespread heterotopic ossification (Fig. 3). Ossification of the paraspinal ligaments and fusion of the vertebral bodies gave the vertebral column a “bamboo spine” appearance (Fig. 4)—a characteristic radiographic finding of advanced ankylosing spondylitis (AS), the presumptive diagnosis with which the patient was referred to our center.
R. Taslimi Imam Khomeini Hospital, Tehran University of Medical Sciences, Pour-Sina St., Keshavarz Blvd., Tehran, Iran S. Jafarpour (*) : N. Hassanpour School of Medicine, Tehran University of Medical Sciences, Pour-Sina St., Keshavarz Blvd., Tehran, Iran e-mail: [email protected]
Introduction At the time heterotopic ossification of fibrodysplasia ossificans progressiva (FOP) was first described by a London
Clin Rheumatol
Fig. 1 The spine was totally fixed. The patient was “frozen” in the demonstrated posture
Fig. 3 Heterotopic ossification in the soft tissue of the right lower extremity (arrows)
physician John Freke in 1736 [1], FOP was a painful mystery to both patients and physicians. FOP is a rare catastrophic genetic disease and the most disabling form of extraskeletal (heterotopic) ossification known to humans. Progressive connective tissue metamorphosis that occurs in this condition ultimately leads to formation of a second skeleton outside the original one, imprisoning the body and causing lifelong obstacle to physical freedom [1–4]. Classical FOP is defined by two characteristic clinical features: malformation of the great toes and progressive heterotopic ossifications. Affected individuals are normal at birth apart from malformed great toes (hallux valgus, malformed first metatarsal, and/or monophalangism) [5] present in all classical cases of FOP [1, 6]. Isolated congenital hallux valgus is less prevalent than FOP [7]. The unique congenital malformation of the great toe is radiologically defined by the presence of one or more of the following features: shortened and sharpened proximal phalanx, hallux valgus angle (HVA) ≥20°, and intermetatarsal angle (IMA) ≥10 [8].
Clinical presentation
Fig. 2 Bilateral malformation of the great toes (monophalangism and hallux valgus)
Onset of clinical symptoms is usually in the first decade of life, presenting with painful rapidly appearing tumor-like soft tissue swellings (flare-ups) often preceded by minor local traumas. Lesions typically first emerge in the dorsal and axial parts (i.e., neck and back), spread in a cranio-caudal manner, and later involve the ventral and appendicular parts [1, 9]. In the limbs, swelling is usually diffuse rather than mass like, resembling lymphedema or thrombophlebitis, which is as well a complication commonly seen in advanced FOP [5]. Heterotopic bone replaces the skeletal muscles, tendons, ligaments, and connective tissue at the site of the damage through a process of endochondral ossification, causing fixation of joints and permanent limitation of motion. Cardiac muscle, smooth muscles, and several skeletal muscles including
Fig. 4 Widespread ossification of soft tissue (asterisks); ossification of the paraspinal ligaments and fusion of the vertebral bodies give rise to a “bamboo spine” appearance
Clin Rheumatol
diaphragm, tongue, and extraocular muscles are spared [1]. The mean age of onset of ossification is reported to be 5 [10]. Most FOP patients develop heterotopic ossification under the age of 15 years [2, 11–15]. Episodic bone formation leads to cumulative disability. Most affected individuals are confined to wheelchair in the third decade of life, having a shorter life span than the general population (estimated median life span of 56 years and median age of survival of 40 years) [16]. In addition, although not necessary for making the clinical diagnosis, the presence of some other clinical features that are frequently associated with classic FOP can be highly suggestive of the condition and raise the level of clinical suspicion, leading to an early diagnosis [17]. Proximal tibial osteochondroma is a good example of these features; in a study of 96 individuals with classic FOP, 90 % had osteochondroma of the proximal tibia [18]. Some other associated skeletal anomalies include fusion of the facet joints between C2 and C7, large posterior elements and tall narrow vertebral bodies in the cervical spine, clinodactyly, short malformed thumbs, short broad femoral neck, shallow acetabulum [1], phalangeal shortening, and medial cortex thickening of the tibia [10]. Extra-articular temporomandibular joint (TMJ) ankylosis is common, either spontaneously or post-traumatic, and can cause severe weight loss due to difficulty in eating. It also results in poor oral hygiene. Submandibular swelling is another process that interferes with swallowing, particularly when associated with huge bulging in the anterior cervical region, which can be even life threatening [1]. Hearing impairment occurs in nearly half of the affected individuals, beginning in the childhood or adolescence and gradually progressing over time. Most of the time, hearing impairment is conductive type, probably due to middle ear ossification, but can be sensorineural too if affecting the inner ear [1, 5]. Ankylosis of costovertebral joints, ossification of intercostal and paravertebral muscles, and aponeuroses, along with spinal deformities such as kyphoscoliosis or thoracic lordosis, contribute to thoracic insufficiency syndrome (TIS) [1]. Rightsided heart failure and pneumonia are major life-threatening complications of TIS and the leading causes of death in FOP patients [16]. Subtle traumas, such as falling and bruising, intramuscular injections, nerve blocks in dental procedures, lumbar puncture [19], even viral flu-like infections, and minor muscle fatigue can produce an exaggerated inflammatory response, causing immune-mediated death of skeletal muscles clinically presented as painful flare-ups and triggering the process of heterotopic ossification [1, 2, 5]. Invasive procedures (i.e., biopsy or excision of the mass-like lesions or different surgical interventions) can initiate an outburst of new bone formation and alter the natural history of the disease into a devastating irreversible state of physical limitation [1, 20, 21].
Atypical FOP Atypical FOP, as described by Kaplan et al., comprises a small number of affected individuals that either show great variations in one of the key defining features, such as normal great toe or severe reduction deficits of digits (FOP variants), or have the classic defining features plus one or more atypical features (FOP-plus). Some of the atypical features associated with FOP-plus include the following: intra-articular synovial osteochondromatosis of hips, degenerative joint disease of hips, sparse scalp hair (more prominent in second decade), severe growth retardation, cataracts, retinal detachment, childhood glaucoma, craniopharygioma, persistence of primary teeth in adulthood, cerebral cavernous malformations, diffuse cerebral dysfunction with seizures, mild cognitive impairment, anatomic abnormalities of the cerebellum, polyostotic fibrous dysplasia, primary amenorrhea, hypospadias, and aplastic anemia [5].
Radiologic findings Heterotopic ossification is not usually detected in conventional radiographic studies until 6–12 months after the appearance of the flare-up lesions. Nevertheless, bone scan, computed tomography (CT) and magnetic resonance imaging (MRI), often show some abnormalities. In the early stage, CT shows edema and swelling in the fascial plane and mass-like lesions in the muscle moderately enhanced by IV contrast. After the progression of the disease, calcification and ossification can be clearly observed in the CT images. MRI shows a homogenous soft tissue mass in T2 weighted images, spreading along the fascial plane and showing significant enhancement by the injection of contrast medium [10]. Despite the described features, imaging studies are superfluous as the definitive diagnosis can be simply made clinically by associating the progressive ossification with congenital great toes malformation [22]. The diagnosis can further be confirmed by genetic studies [1].
Pathogenesis FOP is an extremely rare genetic disease. One in every two million people is affected by this condition, with no ethnic, racial, gender, or geographic predisposition [23]. FOP can be inherited with autosomal dominant transmission and complete penetrance, but due to low reproductive fitness of the affected individuals, fewer than ten families with autosomal dominant inheritance have been observed. Spontaneous new mutations are responsible for a great majority of cases [1]. Therefore, unaffected parents with a child diagnosed with FOP are unlikely to have a second affected child. However, gonadal
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mosaicism can occur in very rare occasions, so prenatal genetic testing could be considered in these cases. Both genetic and environmental factors have a role in the phenotype of FOP, with genetic factors mostly affecting the prenatal development and environmental factors influencing postnatal progression of the disease [17]. Underlying mechanisms of pathogenesis of the disease remained largely unknown until very recently. FOP demonstrates the pathological process of metamorphosis, which involves one normal tissue or organ system transforming into another [24]. In this process, one mature cell does not transdifferentiate into another; rather, one tissue is destroyed and then replaced by another tissue [3]. The histopathology of this process in FOP is well described, beginning with a catabolic stage associated with muscle cell injury and death, which is characterized by infiltration of lymphocytes, macrophages, and mast cells. An intense anabolic phase immediately follows, characterized by fibroproliferative lesion, further maturing through an endochondral ossification to heterotopic bone that contains marrow elements. In an active FOP lesion, all stages of histological development can be observed simultaneously, suggesting different rates of maturation for different regions within the lesion [8]. With subsequent flare-up episodes, the boney structures ramify and spread through adjacent sites, ultimately forming a second skeleton of heterotopic bone [1]. The classic invariable features of FOP involving both skeletal patterning and heterotopic bone formation strongly indicate involvement of BMP signaling pathway [3]. BMP signaling pathway regulates multiple developmental and postdevelopmental processes from early embryogenesis through adulthood. BMP acts through binding and activating type I and type II BMP receptors, which are serine/threonine kinases with similar functional domains. Type I receptor has a cytoplasmic juxtamembrane region rich in glycine and serine residues (GS domains), which is phosphorylated and activated by active type II BMP receptor and transmits BMP signals to BMP-sensitive target genes. There are four known BMP type I receptors: TSR (ALK1), ACVR1 (ALK2), BMPR1A (ALK3), and BMPR1B (ALK6) [24]. FOP was mapped by genome-wide linkage analysis to a region on chromosome 2q23-24 that includes the gene encoding ACVR1/ALK2. A heterozygous missense activating mutation in the GS activation domain of the ACVR1 was detected in all classically affected individuals. The mutation results in a mutant protein that changes the basal set point and ligand-dependent sensitivity for BMP signaling in connective tissue progenitors. The discovery of the specific FOP gene mutation established a monumental milestone; not only did it help in understanding the disease mechanism and revealing a specific target for therapeutic approaches [3] but also as the first identified human metamorphogene it shed light on the general biological principles of transformation of one normal tissue
into another. It may be possible to harness the gene mutation to create new skeletal tissue for patients with fracture nonunions, osteoporotic fractures, failed spinal fusions, bone loss from trauma or malignancy, and congenital agenesis of skeletal elements [2, 24]. It is important to note that while the specific FOP gene mutation might be necessary for the process of heterotopic ossification, it is not sufficient for the development of episodic flare-ups that cause the progressive and cumulative disability seen in affected individuals. Aberrations of soft tissue microenvironment, immune system, and the altered response of progenitor cells all should be taken into consideration in the complex mechanism of induction of flare-ups [5]. Therefore, innovative therapeutic approaches aim to tackle the disease at different levels: blocking activity of the mutant BMP receptor with soluble BMP antagonists, inhibitory RNA technology, monoclonal antibodies directed against ACVR1, or smallmolecule selective signal transduction inhibitors of ACVR1 receptor activity; inhibiting the inflammatory and/or neuroinflammatory triggers of episodic flare-ups; diverting the responding progenitor cells to a soft tissue fate; and altering the inductive and/or conducive microenvironments that favor the formation of FOP lesions [2].
Diagnosis This case obviously demonstrates how failure to associate the classic clinical features of FOP and make the accurate diagnosis in a timely manner can lead to a disastrous collection of iatrogenic harm. Worldwide rate of misdiagnosis of FOP is very high. In a study of 138 FOP patients from 25 countries, 87 % were initially given incorrect diagnosis [21]. There was an average gap of 4.1 years between the onset of symptoms and ultimate diagnosis of FOP, with a median number of six physicians being consulted before the correct diagnosis. Sixty-seven percent of patients had unnecessary invasive procedures, which caused permanent loss of mobility in nearly half of the patients. When the clinicians fail to associate the rapidly developing soft tissue swellings with the abnormality in the great toes, they often mistake the lesions for neoplasms [21]. There is an extended list of differential diagnoses for those lesions: aggressive juvenile fibromatosis, malignant tumors (i.e., sarcomas), post-traumatic myositis ossificans, tuberculosis, lymphadenopathy, nodular fasciitis, scleroderma, rheumatoid arthritis nodules, osteoma cutis, progressive osseous heteroplasia (POH), Albright hereditary osteodystrophy, Still's disease, Weber–Christian disease, calcinosis interstitialis ossificans, hypervitaminosis D, pseudohypoparathyroidism, and multiple exostosis [10]. In a more advanced stage, involvement of the spine mimics AS [25], as mentioned for the presented patient.
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Nevertheless, the preservation of the sacroiliac joints was not taken into account, a clue that makes this diagnosis highly unlikely. Apart from abnormality of the great toes, the evidence of a proximal tibial osteochndroma was another clue to the diagnosis of FOP in our patient. Unlike multiple hereditary exostosis, malignant transformation of osteochondroma in FOP is not reported. Thus, routine imaging of the osteochondromas is not recommended, and lesions should not be excised due to the consequences of invasive procedures [18].
Treatment Currently, the clinical management of FOP is mainly focused in prophylactic approaches, symptomatic management, and optimization of function. Patients should not be subjected to excessive stretching of the jaw in dental procedures, as well as injection of local anesthesia especially mandibular block. Intramuscular injections should be avoided. Vaccinations should be administered subcutaneously. Venipuncture and IV administration of drugs pose minimal risk. Prevention of falling and improving household safety is crucial. Orotracheal intubation can as well traumatize the TMJ joints and result in disease flare-up. Instead, an awake fiber-optic nasotracheal intubation should be used by an expert anesthesiologist under light sedation [1]. Prophylactic measures against respiratory infection and cardiopulmonary complications of TIS are of vital importance. Provocative spirometry can detect respiratory problems early and may be useful to minimize respiratory complications [5]. All FOP patients should be vaccinated against pneumococcus and influenza. Chest physiotherapy and prompt antibiotic therapy should be administered as soon as early signs of respiratory infection appear. Upper abdominal surgery interferes with diaphragmatic respiration and should be avoided if possible. Sleep studies should be performed, and in case of sleep apnea, patients can benefit from appropriate use of positive pressure ventilation, without supplemental oxygen. In advanced TIS, supplemental oxygen should not be administered in an unmonitored setting as it may suppress the respiratory drive and result in carbon dioxide retention and sudden death [1]. Physical rehabilitation approaches can enhance the general function and ability to fulfill daily activities with minimum assistance. Surgical approach to release the joint contractures is generally not recommended because of the risk of inducing extensive heterotopic ossification and worsening the situation. In very rare occasions, surgery might be beneficial, as in repositioning a joint to improve the patient's overall function [1]. Audiology evaluations and utilization of auditory aids can prevent developmental problems in children with FOP [5].
Pharmacological management of symptoms include prompt use of glucocorticoids in flare-up episodes involving major joints of the appendicular skeleton, as well as nonsteroidal anti-inflammatory agents, cyclooxygenase-2 inhibitors, mast cell stabilizers, and leukotriene inhibitors for chronic pain management [2]. More effective and specific therapeutic approaches are still searched for and under experiment in the research labs [1]. Detailed guidelines for symptomatic management of FOP can be found on the IFOPA website (http://www.ifopa.org/). In conclusion, FOP is a rare disease and, because of its rarity and lack of clinical awareness, is often misdiagnosed, resulting in iatrogenic harm to the patients; as for the most common initial inaccurate diagnosis, neoplasm, the next step would involve invasive procedures. Primary care physicians, pediatrics, radiologists, rheumatologist, and orthopedic surgeons should be informed so that they can spot the readily detectable classic clinical feature of the disease, malformation of the great toes, to establish an early diagnosis and prevent further irreversible injuries.
Disclosures None.
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