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

doi:10.21203/rs.3.rs-963656/v1

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Case report

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

https://doi.org/10.21203/rs.3.rs-963656/v1

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Background: Fibrodysplasia ossificans 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 fifteen, 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 fifteen to forty years. Conventional radiology indicates the diagnosis and RNA/DNA test confirm it.

Conclusion: Congenital malformation of the great toes in early childhood may be the first clinical sign of FOP. A devastating disease due to its progressive formation of heterotopic ossifications 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.

Internal Medicine

Fibrodysplasia ossificans progressive

FOP

great toe

case report

Fibrodysplasia ossificans 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 ossification (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 significantly (3-6). 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 first decade of life (7-9). We present three young female patients with follow-up from fifteen to twenty-five years. We focus on the great toe and its influence on over-all mobility status for the patients.

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 flection after a fall on the ground. The primary x-ray examination showed extra-skeletal bone masses in the distal anterior part of humerus (figure 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 (figure 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 significant 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 (figures 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 inflammatory soft tissue swellings, flare-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.

A girl, two year and ten months of age, the first 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 calcifications in the region of the cubital fossa (figure 4). Range of motion of the left elbow was restricted. Forty-five degrees lack of extension and flexion 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 calcifications was noted and FOP diagnosis was made (figure 5a, b). Genetic testing was performed at age of six and FOP was confirmed. No surgical procedures were ever made from her six years of age and up to the last follow-up at twenty-five 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-five 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 (figure 6a, b). Today she is wearing special shoes to avoid pain on weight-bearing.

A girl, the first 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 flare-ups. Muscles from proximal to distal part and from dorsal to ventral regions according to topical FOP pattern was affected (figure 7a, b). At age twenty-five, the first flare-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 flare-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 five minutes. Despite her limited mobility, she was free from flare-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 (figure 8a, b). Today at age forty-five, she is free of pain in her feet. In-door was mobility preserved in custom made shoes (figure 9a, b).

The great toe malformation

The great toe malformation is a red flag of FOP in early childhood. Before other clinical signs are present, FOP should be confirmed or excluded through DNA sequencing analysis (10-11). Natural history of FOP has been extensively studied (12-13). Rogers and Geho identified 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 findings. 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 (15-17). Nakashima and co-authors (3) performed a cross-sectional study of thirty-one feet in sixteen FOP patients and concluded that twenty-nine feet (93,5%) showed several degrees of great toe deformity. An analysis of radiographic characteristics of all feet without any follow-up, confirmed that proximal phalanx of the great toe was consistently shortened but morphologically dissimilar from case to case. Additional findings 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 (figure 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 five 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 confirmatory specific 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 specific 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 specific 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. Confirmation of diagnosis by genetic testing is possible, thus avoiding misdiagnosis and devastating surgical interventions.

Management

At present, no specific 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 inflammatory soft tissue swelling, flare-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 efficacy and safety of these drugs have not yet been documented. Infliximab, which is a TNF-alpha inhibitor, may reduce the macrophages activity at the inflammatory 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 difficulty 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).

Isolated congenital malformation of the great toes combined with progressive heterotopic ossifications in the soft tissue may be the first clinical manifestation of FOP calling for a thorough examination of the patient.
Conventional x-ray and RNA/DNA diagnostic test of the ACVR1 gene assure the diagnosis.
Prevention of any trauma, soft tissue infection or surgical intervention including intramuscular injections are recommended.
No curative treatment exists today.

Ethics approval are obtained from hospitals as well as consent for retrospective investigation and long-term follow-up of three patients. Ethics board of “St Catherine” Speciality Hospital (IRB) approved study with reference number: 21/9-1 of Aug 2021. Document is available upon request.

Informed consent for using medical data, as well as, radiographs, photos and other imaging tool are obtained by means of signature from all three patients. Note: at present time our patients are of adult age.

Consent for publication of our patients’ medical data and imaging are obtained from all three patients with signature, providing that in no way their identity could be revealed in the manuscript. Documents are available upon request from corresponding author

Author´s contributions: Maria Kirstine Møller – Madsen (MKMM) has designed patient 1 with supervision from Darko Anticevic (DA). DA has designed patients 2 and 3. The discussion and conclusions are performed of both authors. Both authors read and approved the final version of the manuscript.

Availability of data and materials: The data of three patients presented in this manuscript are available from the corresponding author (DA) on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: There is no funding.

Acknowledgment Thank you to Michel Bach-Hellfritzsch, MD for figure description.

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

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Abstract

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Background

Case 1

Case 2

Case 3

Discussion

The great toe malformation

Genetic tests

Management

Conclusion

Declarations

References

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