Congenital Malformation of The Great Toe in Children. Did You Exclude Fibrodysplasia Ossicans Progressiva – FOP.

Background: Fibrodysplasia ossicans progressiva (FOP) is an ultra-rare and severely disabling genetic disorder. The worldwide prevalence is approximately 1 per 2 million. Heterozygous mutations in ACVR1/ALK2 gene exist in all sporadic and familial cases of FOP. The primary aim of this study is to describe the clinical course of three children suffering from FOP and followed for fteen, twenty-two and forty years, respectively Secondary aim is to provide clinical advice on how to diagnose the condition with special reference to the great toes malformation and give current best therapeutic approaches. Results: All three cases characterized with malformed great toes initially followed by progressive loss of mobility for a period from fteen to forty years. Conventional radiology indicates the diagnosis and RNA/DNA test conrm it. Conclusion: Congenital malformation of the great toes in early childhood may be the rst clinical sign of FOP. A devastating disease due to its progressive formation of heterotopic ossications in soft tissue even after minor injuries. Leading to progressive immobility, skeletal deformities, chronic pain, growth defects and disabling joint stiffness. No curative treatment exists today. Management is symptomatic combined with a prophylactic lifestyle avoiding blunt and pointed trauma including surgery.


Background
Fibrodysplasia ossi cans progressiva (FOP) is a rare disease. The worldwide prevalence of FOP is approximately 1 per 2 million. There is no known ethnic, racial, gender, or geographic predisposition (1). Classical FOP is an autosomal dominant genetic condition caused by a recurrent activating mutation in the gene ACVR1/ALK2 encoding Activin A receptor type 1. It is a bone morphogenetic protein (BMP) type 1 receptor (2). The mutation in the BMP exists in all sporadic and familial cases of FOP (4). Overactive BMP signalling pathway is the underlying cause of the heterotopic ossi cation (HO). FOP is characterized by congenital malformation of the medial ray of the feet, especially of the big toe. HOs involve muscles of the head, neck and back in the early childhood followed by shoulders and extremities. FOP affects the quality of life signi cantly (3)(4)(5)(6). Most patients suffering from FOP become dependent on a wheelchair cause cumulative immobility. Further, lifelong personal assistance in daily activities must be foreseen.
Although, the great toe malformation is a hallmark of FOP, information about natural history of the great toe malformation is scarce. In addition, delay in diagnosis of FOP is a result of frequent temporal failure to associate malformations of the great toes, present at birth, with onset of HOs in the rst decade of life (7)(8)(9). We present three young female patients with follow-up from fteen to twenty-ve years. We focus on the great toe and its in uence on over-all mobility status for the patients.

Case 1
A girl, nine years of age, born 1996 referred to our hospital because of pain and swelling at the right humeral bone combined with restricted range of motion in the elbow ection after a fall on the ground.

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The primary x-ray examination showed extra-skeletal bone masses in the distal anterior part of humerus ( gure 1). Excision of the exostosis was performed. Recurrence was found after a few weeks. A second excision was done, and the child was referred to a rheumatologist for further examination. The diagnosis, FOP was obtained, and further surgery was avoided. X-rays of the forefoot was obtained and showed great toes deformities ( gure 2). Biological immunosuppressive medication was initiated to control the hyperactive BMP signalling pathway and thus limiting the bone regeneration. The medical treatment continued for three years with limited effects on the clinical symptoms. Eighteen years old, she suffered from a left pertrochanteric fracture after a fall. Standard osteosynthesis was performed despite the diagnosis obtained. Conventional x-rays three years later showed fracture healing but also signi cant HO in the adjacent soft tissue and physical examination showed progressive restricted range of motion in the left hip to full stiffness. One year later, she had a dislocated left patellar fracture. Non-operative treatment was advised. The patella showed healing with progressive HO. Excessive bone formation in the adjacent soft tissue ( gures 3a, b, c). Dual energy X-ray absorption-scanning (DXA-scanning) revealed osteoporosis and zoledronic acid injections acid was initiated, subcutaneously. In addition to the progressive immobility co-morbidities as urinary tract infections, unilateral hydronephrosis and nephrolithiasis was observed. Later the patient reported classic episodes of painful in ammatory soft tissue swellings, are-ups in the region of the sterno-cleido-mastoid muscle. Diffuse multifocal tissue swelling of the neck was detected using magnetic resonance imaging (MRI). The diffuse soft tissue swelling responded to subcutaneous corticosteroid injection. Genetic testing for FOP was not available at the time of diagnosis. Today she is twenty-four years old and full-time wheel-chair user and dependent of a personal caregiver. Educated and working as social worker. She is still followed in the outpatient clinic.

Case 2
A girl, two year and ten months of age, the rst child of healthy non-consanguineous parents, was admitted to hospital due to painful and hard swelling in the left cubital fossa after a fall on the ground.
One month earlier, she had received intramuscular injections unrelated to the fall at a regional hospital three weeks after the fall. As a consequence of the injections, she developed additional swelling in the left axilla and anteromedial left arm. Her laboratory tests were within normal range. Radiographic images showed four small rice grain like extra-articular calci cations in the region of the cubital fossa ( gure 4).
Range of motion of the left elbow was restricted. Forty-ve degrees lack of extension and exion up to one hundred twenty degrees. Movement of left shoulder and elbow caused pain. Due to great toe deformity, she was referred to a paediatric orthopaedic surgeon for further examination. Great toe shortness and valgus deformity with painful swelling and muscular calci cations was noted and FOP diagnosis was made ( gure 5a, b). Genetic testing was performed at age of six and FOP was con rmed. No surgical procedures were ever made from her six years of age and up to the last follow-up at twentyve years. She reported almost normal life activities, with some precautions, until she was nine years of age. At that time, she developed HOs in the muscle of right thigh with limitation of motion in the right hip and knee joint. At age eleven, she was using under-arm crutches. At age thirteen and half she was using wheelchair out-door. During the growth period treatment was symptomatic and supportive only. At the last follow-up, at twenty-ve years of age she suffered from additional HOs at left sterno-cleido-mastoid muscle, and at muscle latissimus dorsi to muscle illio-costalis lumborum, as well as in the muscles of nuchae, submandibular and rectus abdominis. The phalangeal bones of the great toes developed fusion ( gure 6a, b). Today she is wearing special shoes to avoid pain on weight-bearing.

Case 3
A girl, the rst child of healthy non-consanguineous parents was born in her family home 1975. She has three healthy siblings. Family history FOP negative. The patient has short great toes, noted by parents, but with no attention from healthcare providers. Muscle swelling after a fall gave indication for biopsy twice in two different countries. First biopsy at age four years due to painful mass in a muscle of left scapula region. Second biopsy obtained in different country at age eleven and half year of the paravertebral muscles. Based on malformations of great toes and histology of the biopsies the diagnosis of FOP was made. Genetic testing was not available at that time. In the following years, she had multiple are-ups. Muscles from proximal to distal part and from dorsal to ventral regions according to topical FOP pattern was affected ( gure 7a, b). At age twenty-ve, the rst are-up at the right great toe was observed. Co-morbidities as urological, allergic, dental, and upper respiratory tract pathologies was stated. A special medical team with relevant competences followed her frequently. She was given a "FOP passport" to be shown to any medical professionals, in case of emergency. At age thirty-three years recurrent are-ups at both great toes took place. Joint fusions of both great toes became more severe. At age of thirty-four years, she was not able to walk or stand more than approximately ve minutes. Despite her limited mobility, she was free from are-ups for four years approximately. Right great toe and second toe were completely fused and impacted to each other at the age of forty-two. This condition gave basis for skin sores, local infection, and pain. After months of failed conservative management amputation of the second toe took place ( gure 8a, b). Today at age forty-ve, she is free of pain in her feet. In-door was mobility preserved in custom made shoes ( gure 9a, b).

Discussion
The great toe malformation The great toe malformation is a red ag of FOP in early childhood. Before other clinical signs are present, FOP should be con rmed or excluded through DNA sequencing analysis (10)(11). Natural history of FOP has been extensively studied (12)(13). Rogers and Geho identi ed forty patients out of forty-two having great toe abnormalities (14). Connor and Evans studied thirty-four patients with FOP. All of them had characteristic skeletal malformations including abnormal great toes. Great toe malformations can be divided into four subtypes based on clinical and radiological ndings. The most frequent is type I representing a short great toe without valgus deviation and without lateral deviation at the metatarsophalangeal joint. Type II, III and IV are less frequent (15)(16)(17). Nakashima and co-authors (3) performed a cross-sectional study of thirty-one feet in sixteen FOP patients and concluded that twentynine feet (93,5%) showed several degrees of great toe deformity. An analysis of radiographic characteristics of all feet without any follow-up, con rmed that proximal phalanx of the great toe was consistently shortened but morphologically dissimilar from case to case. Additional ndings were occurrence of the fusion between the distal and proximal phalanx. In patients presented in this study with longitudinal follow-up of more than twenty years of age, temporal pattern of the great toe interphalangeal bony fusion was observed in all ( gure 6b and 7b). In case three the focus was on the natural history of HO manifestation. All patients presented had characteristic congenital malformations of the great toes. The mean age of clinical onset of HO was approximately ve years. Cohen et al. mention that the HO progression are seen in patterns proximal to distal, axial to appendicular and dorsal to ventral. Jaw involvement was late in almost all patients (13). It is of interest that in presented case one and two FOP started in the elbow region. The oldest patient, case three, was subject for two biopsy despites of correct diagnosis. In the 1970 to 1990 biopsy was often performed in FOP patients Kitterman et al. in 2005 (7). Unfortunately, the diagnosis of FOP is often delayed because of the rareness and challenging clinical picture. In the cases presented an early con rmatory speci c genetic test may have changed the treatment strategy, especially the surgical interventions.

Genetic tests
Few case reports describe the applicability of the rapid genetic testing to prepare a speci c personalized treatment plan prior to development of clinical symptoms (3,8). In 2006 it became possible to detect the ACVR1 single gene mutation for FOP, which resulted in an accelerated research on how to apply the optimal management of FOP (22)(23). The discovery of the FOP gene provided a highly speci c target for future drug development that holds promise for altering not just the symptoms of the disease but also the disease itself (24). Still the diagnosis of FOP is primarily made by the clinical assessment of the patient. Con rmation of diagnosis by genetic testing is possible, thus avoiding misdiagnosis and devastating surgical interventions.

Management
At present, no speci c management of FOP exists. It is evident that the innate immune system, the macrophages, neutrophils, and natural killer cells play an important role in the in ammatory soft tissue swelling, are-ups. Hence, it has been of interest to use biological immunosuppressive therapeutics. The literature describes targeting the BMP signalling pathways at different levels or targeting cellular components important in the extra-skeletal bone regeneration may be useful (18)(19)24). In our case one, three different biological therapeutics had been prescribed. The e cacy and safety of these drugs have not yet been documented. In iximab, which is a TNF-alpha inhibitor, may reduce the macrophages activity at the in ammatory response and thereby be helpful to reduce the sporadic soft tissue swelling. The formation of HO in FOP is described in the literature as an episodic rather than a continuous process related to soft tissue swelling following infections, trauma, immunizations, and iatrogenic harms (24). These episodes are usually preserved with corticosteroids and prevention of trauma. However, a frequent use of corticosteroids for swellings in the trunk and neck opposite to swelling in the extremities, is not recommended due to the di culty in assessing the onset of the swelling. Due to the complexity of FOP pathogenesis, the use of a combination of drugs with different targets, which can act in synergy, might be helpful (23). Availability of data and materials: The data of three patients presented in this manuscript are available from the corresponding author (DA) on reasonable request.

Figure 1
Lateral radiograph of the right elbow (patient 1). On the anterior side of the elbow joint an osseous bridge is connecting the supracondylar part of the humerus with the ulnar tuberosity. Otherwise, normal joint.

Figure 2
Standing dorsal-plantar (DP) radiograph of both feet (patient 1). Symmetrical ndings, with medial angulation of the head of the rst metatarsal bone. The proximal phalanx is articulating with the lateral side of the head, worsening the clinical appearance of the hallux valgus. In the rst toe there is only one bone, and the toe appears shorter than normal. Otherwise, normal ndings.  Radiograph of left elbow (patient 2, three years old) with heterotropic ossi cation in the cubital fossa. Figure 5 a, b. Photo and radiograph (patient 2, ve and a half years old). Clinically the patient seems to have hallux valgus, however the radiograph shows what looks like a large accessory epiphysis in the distal part of the rst metatarsal bone, articulating on the lateral side with the phalanx. The proximal part of the phalanx is cone shaped, and the middle of the bone there seems to be a physis. Figure 6 a, b. Photo and radiograph (patient 2, 25-years). With maturation of the bones the large distal accessory physis of the metatarsal bone has fused with the proximal part of the bone. The physis in the phalanx has also fused, with only one bone in the great toe, articulating on the lateral side of the metatarsal head.