P2.225: Fibrodysplasia Ossificans Progressiva: childhood onset from missense mutation (c.974G>C, p.G325A) in ACVR1

Introduction: Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by congenital hallux malformations preceding progressive heterotopic ossification (HO) of soft tissues. FOP is commonly caused by an activating mutation in activin-A-receptor-type-1 (ACVR1) gene, encoding activin-receptor-like-kinase-2 (ALK2). We report a case of a toddler male presenting with bilateral hallux valgus and occipital and cervical masses, ultimately diagnosed with FOP through genetic testing finding a missense mutation (c.974G>C, p.G325A) of the ACVR1 gene.

Case Description: A 35-month-old male presented with hard, immobile mass on the right occiput and posterior neck. Initial concerns included osteosarcoma or an ossified occipital hematoma from non-accidental trauma. Patient has a midline forehead prominence attributed to impact from frequent falls.
Laboratory findings, including 25-hydroxyvitamin-D, calcium, phosphorus, alkaline phosphatase, lactate dehydrogenase, creatine kinase, and coagulation studies, were within normal limits. CT and MRI of head and neck revealed irregularly enhancing intramuscular mass with internal calcifications, suggesting myositis ossificans. Skeletal survey and physical examination identified bilateral hallux valgus deformity and fusion of the hallux phalanges. Given the ossifications and bilateral hallux valgus deformity, there were concerns for FOP.
Genetic testing (skeletal dysplasia panel) identified an ACVR1 variant (c.974G>C, p.G325A), increasing suspicion for FOP. The biological mother tested negative for this variant, while the father was unavailable for testing. Additional labs, including Vitamin-A, Interleukin-6, and Human Transforming-Growth-Factor-Beta1, were within normal range.
Based on the geneticist's assessment, the presence of the ACVR1 variant (c.974G>C) and physical findings—heterotopic ossification in the right occipital region, lower back, and mid-frontal area, along with bilateral hallux valgus deformity—confirmed the FOP diagnosis, necessitating ongoing management and treatment planning.

Discussion: FOP is a progressive disorder where heterotopic bone forms in soft tissues, often triggered by trauma or inflammation. The most common cause is an activating mutation (activin-like kinase 2 (ALK2) in the ACVR1 gene and can present as early as infancy, with painful flare-ups and congenital bilateral hallux valgus.
This ACVR1 (c.974G>C, p.G325A) variant’s onset of heterotopic ossification has been reported in a 47-year-old case, yet our patient exhibited signs under three years of age. While the variant’s role in early onset disease is unclear, it may indicate a less severe FOP phenotype.
There is no current cure for FOP. Palovarotene, a retinoid that may reduce ossification, is not yet approved for young children due to the risk of premature epiphyseal closure. At this time, management for this patient focuses on trauma prevention, physical therapy, and genetic counseling.

Conclusion: This case highlights the critical need for early recognition of FOP in children with unexplained soft tissue masses and congenital skeletal anomalies. Early diagnosis facilitates genetic counseling and symptom management to slow disease progression. Continued research is necessary to clarify the role of ACVR1 variants in disease severity and management.