Introduction

The prevalence of fibrodysplasia ossificans progressiva (FOP) is 0.6 to 1.36 cases per million people worldwide, with no predisposition by ethnicity or sex¹. It is caused by pathogenic variants in the heterozygous state (autosomal dominant inheritance) in the ACVR1 gene (located in 2q24.1) that encodes the activin A receptor type I (ACVR1)². The c.617G>A (p.Arg206His) mutation has been detected in 95% of the cases (classic form)³.

The soft tissue (muscles, tendons, and ligaments) is continuously regenerated in healthy individuals on a daily basis and following trauma⁴. At the cellular level, this happens through various members of the transforming growth factor-beta family (TGF-β). TGF-β family members are classified as osteogenic such as bone morphogenic proteins (BMPs) and non-osteogenic such as activin A. In turn, activin A intervenes in the differentiation of interstitial myogenic and mesenchymal cells during muscle fiber regeneration⁵.

In the classic FOP, a gain of function in the ACVR1 receptor produces the abnormal overactivation of the intracellular signaling pathway by non-osteogenic ligands, causing the transformation of soft tissue precursor cells into chondrocytes and osteoblasts, which are then responsible for heterotopic endochondral bone formation⁴,⁶.

Heterotopic ossification mainly affects the axial, dorsal, and cranial skeleton. This process starts from the central part with progression towards the ventral, appendicular, and caudal regions⁷,⁸. Trauma, surgeries, and intramuscular injections damage the soft tissue and create inflammatory foci, which subsequently undergo heterotopic ossification, causing stiffness and limited movement of adjacent joints⁹.

In patients with the classic form of FOP, shortening and medial deviation or monophalangism of the first metatarsal or both are present from birth¹⁰. Cervical vertebrae fusion (from C2 to C7), high and narrow vertebral bodies, short and wide femoral necks may also be present, as well as osteochondromas in the medial part of the tibia¹¹. These patients frequently present thoracic insufficiency syndrome, which predisposes to frequent pneumonia episodes that are usually an important cause of mortality⁸. Also, they can show conductive hearing loss due to the middle ear’s ossification, while sensorineural hearing loss is also reported due to the affection of the auditory nerve or the cochlea⁷. In the presence of clinical and radiographic suspicion of this disease, the diagnosis is confirmed by molecular studies in search of pathogenic variants in ACVR1⁷,⁹.

This report aims to describe a patient with clinical, radiological, and molecular FOP diagnosis. Awareness of this pathology will allow timely identification of patients with this condition, thus, avoiding unnecessary interventions that worsen their already precarious quality of life.

Clinical case

We report the case of a 10-year-old female patient product of the second pregnancy of healthy non-consanguineous parents and with two apparently healthy siblings. At birth, the patient was hospitalized for 5 days for low birth weight (1700 g) and height (42 cm). Subsequently, the patient showed normal development during infancy and childhood, with no other relevant antecedents. At 6 years of age, two indurated tumors were identified: one of 3.5 cm in the right scapular region and another of 5.5 cm at the dorsal vertebrae level. The patient underwent an orthopedic evaluation, and the biopsy of these tumors concluded myofibromatosis. After performing the diagnostic procedure, the tumors increased in size. The patient also presented joint stiffness of the upper extremities, limitation for rotation and flexion of the neck, and severe scoliosis. The Rheumatology department ruled out inflammatory pathological conditions. The patient underwent reevaluation by the Medical Genetics department. Physical examination indicated that the patient’s weight was found on the 10th percentile and height and head circumference on the 50th percentile. Also, the patient showed reduced neck mobility (rotation and flexion), shoulder, elbow, and wrist joints stiffness, body asymmetry secondary to scoliosis, indurated tumors in the scapular and infrascapular areas (sites where biopsies had been performed), and a right infra-axillary tumor (Figure 1A). Short first toes with medial deviation were observed and present since birth according to the mother (Figure 1B). The anteroposterior feet X-ray showed bilateral fusion of the fourth and fifth metatarsals’ proximal portion and shortening of the phalanges of the first toe with medial deviation. Dorsal, lumbar, and long bone X-rays showed soft tissue calcifications in several regions: the left cervical paravertebral region with an extension towards the left pectoral region (Figures 2A and 2C), the bilateral lumbar paravertebral level (Figure 2B), the left hip joint and femoral metaphyses bony projections (Figures 2B and 2D).

Figure 1 A. Back of the patient with ossification foci on scapulas, dorsal vertebrae (scars from previous surgical procedures), and body asymmetry by scoliosis. B. Shortening of the first toe with medial deviation. 

Figure 2 X-rays of the patient. A. Heterotopic ossification in the left cervical paravertebral region B. Heterotopic ossification in the lumbar paravertebral level bilaterally and the left coxofemoral joint. C. Heterotopic ossification in scapular and infraaxillary region D. Bone protrusions in femoral metaphyses due to heterotopic ossification of the iliotibial ligament. 

Computed tomography of the spine reported scoliosis, heterogeneous, poorly defined, multiple images with calcium depositions in the spine (bilaterally), trapezius, and back muscles (Figure 3).

Figure 3 Tomography with a 3D reconstruction of the patient where heterotopic ossification is observed in posterior soft tissues, extending from the skull base to the lumbar region (A), involving paravertebral and infrascapular muscles (B). Fusion is observed along the tenth left posterior costal arch and dorsal kyphoscoliosis (C). 

The diagnosis of fibrodysplasia ossificans progressiva was established based on the radiological findings and physical examination. Subsequently, molecular studies were carried out at the Instituto Nacional de Rehabilitación (National Institute of Rehabilitation). Sanger sequencing of ACVR1 reported the pathogenic variant in heterozygous state c.617G>A (p.Arg206His) in exon 6. Upon diagnosis confirmation, preventive measures were indicated, such as the use of protective cushions, administration of intramuscular injections only of vital importance, and not allowing surgical removal of the tumors.

The patient’s last evaluation showed limitation of arm elevation above the 180° plane, difficulty in dressing and writing, and pain when remaining in a sitting or standing position for long periods. An audiological evaluation reported probable ossification of the middle ear ossicles. An MRI of the ear was indicated but has not been performed to date. The patient continues to be monitored by the Orthopedic and Rehabilitation services to treat scoliosis and for physical therapy and pain management with non-steroidal anti-inflammatory drugs, which, so far, have been sufficient to reduce the discomfort caused by tumors and joint stiffness.

Discussion

Based on clinical and radiological features and the molecular results of the ACVR1 sequencing, the classic FOP form with the most frequently reported pathogenic variant worldwide was diagnosed. The evolution in the present case is similar to previous reports in patients with the same variant, with heterotopic ossification foci appearing in the back, neck, and scapulas between one and 15 years of age, bilateral shortening with a medial deviation of the first toe since birth (virtually pathognomonic) and progression of the disease with the appearance of more ossification foci, and ankylosis limiting movement¹²-¹⁴. This mutation leads to the abnormal function of ACVR1, resulting in increased activation of the BMP pathway (osteogenic ligand) when exposed to the inflammatory stimulus secondary to trauma, giving rise to heterotopic ossification foci. FOP timely diagnosis allows avoiding unnecessary procedures that aggravate the clinical presentation. Due to late diagnosis, most patients have already undergone invasive studies that aggravate their condition. As this disease is highly disabling, it must be suspected in the presence of heterotopic ossification foci. Shortening of the first toe identification provides an excellent opportunity for clinical suspicion from the first years of life, allowing the differential diagnosis with entities that also present heterotopic ossifications, such as disorders of GNAS inactivation and Klippel Feil syndrome¹⁵,¹⁶.

Once the FOP diagnosis has been established, the following preventive measures can improve the quality of life: restriction of physical activities to avoid falls or other traumas (without being strict, since the functional state of the joints must be maintained); physical rehabilitation, which should be focused on exercises that avoid passive movement—that can result in tissue inflammation leading to ossification—and exercises that help patients perform their daily activities. Intramuscular injections should be avoided as much as possible (subcutaneous injections and venipuncture do not represent the same risk). Dental care is also important; however, it is necessary to avoid keeping the mouth open for prolonged periods to prevent joint ankylosis. Removal of the tumors should be avoided, as it will cause a recurrence of heterotopic ossification foci and, thus, disease progression¹⁷.

Interdisciplinary treatment by Pneumology (for evaluating lung function), Physical Medicine and Rehabilitation, Orthopedics, and Audiology services is important¹⁷. Due to the autosomal dominant inheritance pattern of this disease, the offspring’s risk for an affected individual is 50% per gestational event regardless of the sex of the product. Although family cases are very infrequent, comprehensive genetic counseling should be offered, including planning and preventing complications in the pre-pregnancy stage since this kind of pregnancy is classified as a high obstetric risk. The patient should be advised on the offspring’s risk of developing the disease and the obstetric risks (thromboembolism due to prolonged immobilization, respiratory distress due to restrictive lung disease, delivery complications due to pelvic muscles’ ossification, prematurity, and fetal distress)¹⁷. Some studies on diagnosis during pregnancy have reported shortening and medial deviation of the first metatarsal on structural ultrasound, leading to suspicion of this disease¹⁸. As no curative treatment currently exists, therapy is primarily directed at supportive measures such as those mentioned above. Non-steroidal anti-inflammatory drugs and corticosteroids are used to decrease excessive inflammation and control pain; some drugs such as bisphosphonates and leukotriene inhibitors are also used but with little efficacy⁶. Currently, therapies aimed at slowing the progression and preventing the formation of ossification foci are being developed⁶. In phase 2 clinical study, promising results have been shown: evidence showed a decrease in the size of heterotopic ossification foci and arrest of disease progression using a selective retinoic acid receptor gamma agonist (palovarotene)¹⁹,²⁰.

Manifestations of this condition are incapacitating and seriously affect the quality of life, for which a timely diagnosis is imperative to prevent situations that trigger ossification foci. In this case, comprehensive genetic counseling was provided, including a broad explanation of the condition’s natural history. The patient and the family were made aware of the risks of recurrence for the parents of the index case (less than 1% because it is a de novo variant) and for the patient’s offspring (50%). The patient started an interdisciplinary treatment that has been of great benefit to the patient.