Fibrodysplasia ossificans progressiva associated with osteochondromatosis: A case report

Abstract

Fibrodysplasia ossificans progressiva is a rare and severely debilitating genetic disorder affecting approximately 1 in 2 million people. It is characterized by progressive heterotopic ossification of soft tissues, leading to the formation of ectopic bone in extraskeletal areas, as well as congenital malformations of the great toes. FOP can also be considered a disorder of osteochondrogenesis, with most musculoskeletal abnormalities related to dysregulated chondrogenesis, such as heterotopic endochondral ossification, abnormal cartilage formation, growth plate dysplasia, osteochondroma formation, and early arthropathy. The frequent lack of awareness of this disease often results in diagnostic errors, delays in diagnosis, and unnecessary interventions, sometimes with irreversible consequences. We report the case of a 2-year-old girl with no significant medical or family history, presenting with bilateral hallux valgus and firm subcutaneous nodules on the back and lower limbs. A thoracoabdominal and lower limb computed tomography scan revealed muscular ossifications and osteochondromatosis, confirming the diagnosis of fibrodysplasia ossificans progressiva.

Introduction

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare autosomal dominant disorder, with a prevalence estimated at approximately 1 in 1.5 to 2 million people [1]. It occurs without ethnic, racial, sexual, or geographic predisposition. Although most cases are due to sporadic de novo mutations, autosomal dominant inheritance with complete penetrance and variable expression has been confirmed [2]. Initially described by Guy Patin in 1648, the condition was later named "Munchmeyer's disease" after Munchmeyer's report of the first series of cases in 1869 [3]. FOP is characterized by progressive postnatal ossification of skeletal muscles, tendons, ligaments, aponeuroses, and fascia [3,4], along with congenital malformations of the great toes [4]. Ossification episodes follow a characteristic pattern, initially affecting the dorsal, axial, cranial, and proximal parts of the body, before progressing to the ventral, appendicular, caudal, and distal areas [4]. While there is currently no curative treatment for FOP, early diagnosis and prevention of flare-ups can improve patient quality of life. Promising therapeutic approaches are under investigation [5].

Case report

A 2-year-old girl with no notable medical or family history presents with subcutaneous nodules in the scapular, paravertebral, and lower limb regions that have been present for 5 months. Physical examination reveals bilateral hallux valgus, hard, immobile subcutaneous swellings without inflammatory signs. The remainder of the physical examination is unremarkable, and calcium-phosphorus levels are normal. A thoraco-abdominal and lower limb CT scan was performed, revealing ossifications in the subscapular, axillary, and paravertebral muscles (Figs. 1 and 3) as well as sessile bone exostoses at the right lesser trochanters and bilateral femoral regions, with a pedunculated exostosis in the mid-diaphysis of the left femur and left tibia (Figs. 2 and 3). Based on these findings, a diagnosis of FOP was made.

Fig. 1.

Ossifications of the subscapular muscles and the axillary region (A), and the paravertebral muscles (B, C and D).

Fig. 3.

3D reconstructions showing ossifications in the subscapular muscles, axillary region, and paravertebral muscles (A), along with a pedunculated bone exostosis in the mid-diaphysis of the left femur (B), and bilateral hallux valgus (right “C” and left “D”).

Fig. 2.

Sessile bone exostoses at the right lesser trochanter (A) and pedunculated exostoses at the left tibia (B) and mid-diaphysis of the left femur (C and D).

Discussion

FOP, also known as progressive myositis ossificans, is an extremely rare autosomal dominant genetic disorder with an incidence of approximately 1 in 2 million births, with no ethnic, racial, sexual, or geographic predispositions [5]. FOP is characterized by progressive heterotopic ossification, where skeletal muscles and connective tissues, such as tendons, ligaments, and aponeuroses, progressively ossify [3]. Most cases are sporadic, with the exception of some hereditary familial cases [5].

FOP is caused by heterozygous mutations in the Activin A type I receptor (also known as Activin-like kinase 2), which abnormally activates bone morphogenetic protein (BMP) signaling, leading to heterotopic bone formation and other osseous abnormalities, including osteochondromatosis [1,6].

Clinically, the most common signs include a congenital malformation of hallux valgus, often bilateral, and recurrent episodes of heterotopic ossification in response to trauma or occurring spontaneously [7]. These ossifications may be preceded by painful soft tissue swellings. In infants, scalp nodules can be an early indicative sign of the disease [7].

Although children with FOP appear normal at birth, a congenital malformation of the big toes is consistently present in those with the classic form of the disease [4]. In addition to these malformations, other common abnormalities include medial proximal tibial osteochondromas (present in about 90% of patients), fusion of the posterior elements of the cervical spine (approximately 80%), short and wide femoral necks, and conductive hearing loss. Smooth muscles, cardiac muscles, extraocular muscles, as well as the tongue and diaphragm, are spared [2,3], along with thumb and femur malformations [2,8]. Classic FOP is characterized by the presence of big toe malformations and progressive heterotopic ossifications, while "FOP plus" includes atypical manifestations such as infantile glaucoma or Marfan syndrome [2]. Scoliosis is also common due to asymmetrical heterotopic ossifications connecting the trunk to the pelvis [2]. Additionally, fusion of the middle ear ossicles often results in conductive hearing loss, a common feature of FOP [2].

Approximately 87% of FOP patients experience diagnostic delays despite the presence of recurrent painful masses in typical anatomical areas and big toe malformations, which should facilitate a quicker diagnosis [3]. Biopsy is strongly contraindicated in FOP due to the risk of exacerbating bone formation. Flares can be triggered by surgical interventions or iatrogenic trauma, highlighting the need for noninvasive diagnostic procedures [4].

Cardiopulmonary complications, such as pulmonary restriction due to ossification around the thoracic cage, are frequent and a major cause of mortality, often due to pneumonia or thoracic insufficiency syndrome [1].

Although no curative treatment is currently available [8], future advances in identifying the signaling pathways involved in FOP, particularly those regulated by the ACVR1 gene, could facilitate the development of targeted treatments, such as BMP signaling inhibitors [3]. Current strategies primarily focus on managing flares with anti-inflammatory drugs and corticosteroids. Therapies targeting the inhibition of the hyperactive ACVR1 receptor appear promising for the future [4]. However, due to the rarity and complexity of FOP, no controlled clinical trials have yet demonstrated the efficacy of any specific therapy [3].

Conclusion

FOP is a rare and debilitating condition, often diagnosed late despite distinct clinical signs such as toe malformations and heterotopic ossifications. Early diagnosis and appropriate care can significantly mitigate the impact of FOP on patients' quality of life. It is essential to raise awareness among clinicians to avoid unnecessary and potentially harmful interventions. Ongoing research is crucial to developing effective treatments and improving the management of this complex disease.

Patient consent

Written informed consent was obtained from the patient for their anonymized information to be published in this article.