Fibrodysplasia ossificans progressiva: Diagnosis with ultrasound

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare connective tissue disease, diagnosed by genetic testing. This is the first report in English literature wherein an ultrasound examination suggested this specific diagnosis. In this case, a two month old girl presented with bi‐parieto‐occipital swellings that were being managed as subgaleal haematoma. The parents were anxious that there was no resolution of the swellings. The suspicion of FOP was raised during the ultrasound examination where a review of the images prompted a questioning of the parents about other lesions in the body. Ultrasound examination of a lump in the thigh revealed calcifications in the vastus lateralis muscle. The appearances on the ultrasound combined with the presence of hallucis valgi suggested a diagnosis of FOP. The diagnosis was subsequently confirmed by genetic studies. This case highlights the need for good communication between the physician, patient and the imaging department.

Case report

A two‐month‐old girl presented to the emergency department with an abnormal head shape thought to be due to right posterior deformational plagiocephaly. Skull X‐rays were performed to rule out craniosynostosis. The metopic, sagittal, coronal and lambdoid sutures were patent. However, prominent bi‐parieto‐occipital soft tissues were noted on the radiographs (Figure 1). These were thought to be subgaleal haematoma compatible with the history of ventouse delivery.

Figure 1.

Plain skull radiograph demonstrating prominent parieto‐occipital soft tissue swellings bilaterally.

A CT scan at three months was undertaken as the lumps did not resolve and also to allay parental anxiety. This demonstrated a right posterior deformational plagiocephaly. The bi‐parieto‐occipital soft tissue swellings were noted and were thought to be subgaleal haematoma resulting from the preceding ventouse delivery (Figure 2).

Figure 2.

CT scan of the head demonstrating subgaleal soft tissue swellings bilaterally.

A skeletal survey (including skull X‐rays) a week later was performed for deformity of the great toes. It revealed halluces valgi deformities. The survey also demonstrated flexion and valgus angulation at the first metatarsophalangeal joints bilaterally (Figure 3). There was no interval change in the appearance of the bi‐parieto‐occipital presumed subgaleal haematomata on the skull X‐ray. They had not shown signs of resolution as clinically expected. It was not possible to arrive at a definite diagnosis or generate a meaningful list of differential considerations at this stage. Hence, an ultrasound correlation was recommended.

Figure 3.

Plain radiograph of the feet demonstrating flexion and valgus angulation at the first metatarsophalangeal joints (a) right foot and (b) left foot.

At four months of age, an ultrasound of the occipital lumps was performed. It demonstrated solid immobile subgaleal soft tissue mass lesions of mixed echogenicity (Figure 4). Colour Doppler demonstrated that they did have some internal vascularity (Figure 5). They did not cause any mass effect upon the underlying skull vault. No obvious shadow‐casting calcific densities were associated with these lesions. These appearances excluded the possibility of resolving subgaleal haematoma and prompted a discussion with the parents regarding lumps elsewhere. They said there had been a lump on the left thigh that was no longer evident. Ultrasound assessment of the left thigh revealed shadow‐casting calcifications in the vastus lateralis muscle (Figure 6). The appearances on the ultrasound combined with the hallucis valgi suggested a diagnosis of FOP, subsequently confirmed by genetic testing. The submitted DNA was used as template for amplification and sequencing of Exon 4 of ACVR1 gene. The findings were heterozygous for a germline mutation, that is a single base substitution c617G>A in the coding sequence of the ACVR1 gene (nucleotide numbering starts with the ‘A’ nucleotide of the first coding amino acid, methionine, of the ACVR1 mRNA). The single base substitution leads to a missense mutation, p. Arg206His, in the translated ACVR1 protean. This mutation has been previously reported​ to be associated with the fibrodysplasia ossificans progressive disease.¹

Figure 4.

Parasagittal (a) and transverse (b) ultrasound images of the left occipital swelling demonstrating a solid subgaleal soft tissue mass lesion of mixed echogenicity.

Figure 5.

Transverse colour Doppler image of the lesion demonstrating minimal internal vascularity arguing against a haematoma.

Figure 6.

Longitudinal (a) and transverse (b) ultrasound images of the vastus lateralis muscle demonstrating shadow‐casting calcifications.

We have been unable to find any reference to diagnosis of FOP previously being made using ultrasound.

Discussion

Fibrodysplasia ossificans progressiva is a severely disabling autosomal dominant disease where the body's connective tissues progressively ossify.² FOP was previously known as myositis ossificans progressiva, meaning a muscular inflammation that gradually turns into bone. But as this disease also affects ligaments and articular capsules, the name was changed to FOP in 1970 by Victor McKusick.³

FOP is an extremely rare connective tissue disease with a worldwide prevalence of approximately 1 case in 2 million individuals.⁴ The disease affects all ethnic groups, with a predilection for males at a proportion of 4:1.⁵ FOP is caused by an autosomal dominant allele on chromosome 2q23‐24, with all affected individuals demonstrating identical heterozygous mutation (617G ‐‐> A; R206H) in the glycine‐serine (GS) activation domain of ACVR1, a BMP type I receptor.¹, ⁶ While there have been five small multi‐generational families with FOP described, most cases are caused by spontaneous mutation in the gametes. The gene alters the body's repair mechanism, causing connective tissues (i.e. muscles, tendons, fasciae and ligaments) to be ossified spontaneously and also following minor injury.

Patients who have FOP have been described as having two skeletons. A normotopic one was formed during embryogenesis and a heterotopic one following birth.⁷ Children born with FOP have a generally normal normotopic skeleton with the exception of malformations of the great toes with shortening of the first metatarsal and proximal phalanx. This feature of FOP is seen in nearly all affected individuals at birth. It is only in the first decade of life that they begin to develop painful soft tissue swellings thought to be related to muscle trauma.⁸ At first, the lesions are painful, erythematous, warm and tender. After several weeks, the swelling subsides and there is decrease in the pain, tenderness and erythema. It is only after the swelling has disappeared that the patient is left with a hard non‐tender lesion, that is, a new area of heterotopic ossification.⁹ Over time, the disease process slowly transforms muscles, tendons, ligaments and articular capsules into heterotopic bone. As the ossification process progresses, joints become immobile due to the extra‐articular ankylosis which renders movement impossible. Interestingly, the diaphragm and tongue are spared in FOP as are the cardiac, extra‐ocular and smooth muscles.⁴ The anatomical progression of heterotopic bone formation occurs in the same order in almost all patients with FOP.¹⁰ Changes are first noted in the upper back area of the body followed by the lower back, cranial and proximal regions of the body. Later on, changes occur in the ventral, appendicular, caudal and distal regions of the body. The prognosis of FOP is very poor. By the age of 20, most patients are bedridden and are unable to swallow food leading to malnutrition. By the age of 40 because of failing respiratory function, they succumb to complications of thoracic insufficiency syndrome.¹¹ Unfortunately, there is no cure or effective treatment to alter the natural history of the disease.¹²

Clinically, the differential diagnosis of FOP is dependent on the stage of the disease. At birth, the characteristic toe deformities may be confused with skeletal dysplasia or brachydactyly. Later on, when inflammatory lesions begin to develop, a fibrocystic or arthropathic process is often considered. As joint immobility occurs, various inflammatory arthropathies are suspected. Advanced cases of FOP resemble arthrogryposis multiplex congenita.¹³ Clinical suspicions can be confirmed by DNA testing of the ACVR1 gene. It is important to avoid unnecessary biopsies in children suspected of having FOP as the site of biopsy can exacerbate progression of the condition.¹⁴ Understanding radiographic changes that occur with FOP is important to avoid misdiagnosis, harmful procedures and biopsies.¹⁵

The characteristic great toe malformations and soft tissue ossification are the characteristic radiographic features of FOP traditionally demonstrated with plain radiography. This is often the first diagnostic test performed as it is relatively inexpensive, commonly available and demonstrates bone abnormalities very well. Limitations of plain radiographs include inability to detect lesions in the early inflammatory stage prior to heterotopic bone development. Bone scans may be useful for localising heterotopic ossification before any abnormalities can be seen by plain radiography. However, usefulness of bone scanning in early diagnosis of FOP flare‐ups has not been well‐established.¹⁶ Magnetic resonance imaging (MRI) however has been shown to be very good for detecting subtle soft tissue swelling, oedema and early detection of preosseous lesions, which is generally not visible on other modalities.¹⁷ The main limitation of scanning young patients with MRI includes the necessity for sedation or general anaesthesia to limit movement for the duration of relatively long image acquisition times. MRI also is incompatible with claustrophobic patients. Compared to MRI, computed tomography (CT) provides much better bony resolution of heterotopic bone formation. It also has the ability to reconstruct 3‐dimensional images which allows for volumetric measurement of heterotopic bone. CT does not however provide the same contrast resolution of soft tissue oedema like MRI, limiting its value in early stages of flare‐up in FOP muscles.¹⁸ While CT has the advantages of being a quicker examination with greater patient tolerance than MRI, it does expose the patient to potentially harmful ionising radiation. Ultrasound does have the advantages of not utilising ionising radiation, is widely available, inexpensive, relatively quick and well tolerated by almost all patients. McAteer et al. in 1990 first described the use of ultrasound to investigate flare‐up lesions in a patient known to have FOP. The ultrasound demonstrated an increase in the thickness of the soft tissues with separation of the muscle fascicular planes by echogenic material not causing acoustic shadowing.¹⁹ It is important to avoid intramuscular injections as they may trigger new bone formation. Ultrasound has also been used in patients with FOP to guide subcutaneous injections.²⁰ The authors have been unable to find any English literature where the diagnosis of FOP has been strongly suggested on an ultrasound examination. This led to an early confirmatory diagnostic genetic testing and the avoidance of further unnecessary harmful diagnostic examinations. At four months of age, this is the second youngest patient diagnosed with FOP.²¹ However, the authors note that an antenatal ultrasound detected hallux valgi that prompted an amniocentesis, leading to an in‐utero diagnosis of FOP.²²

Conclusion

Fibrodysplasia ossificans progressiva is an extremely rare connective tissue disease caused by a genetic mutation affecting the body's repair mechanism. As a result, fibrous tissues such as muscles, tendons and ligaments tend to be progressively ossified. This is the first report of FOP being diagnosed with ultrasound. This condition was diagnosed after maintaining a high index of clinical suspicion and questioning the parents about any other lesions in the body. This case highlights the importance of good communication between the patient, sonographer and radiologist. Knowledge of this condition should lead to early genetic testing and avoidance of invasive diagnostic tests to prevent iatrogenic harm.

Authorship declaration

The authors acknowledge that the authorship listing conforms with the journal's authorship policy, and that all authors are in agreement with the content of the submitted manuscript.

Conflict of interest

The authors have no conflict of interest to declare.