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P 780. Misdiagnosis of Child Abuse—Fibrodysplasia Ossificans Progressiva as a Therapy-Relevant Differential Diagnosis in Infancy
30 October 2018 (online)
Background: Fibrodysplasia ossificans progressiva (FOP) is a very rare (incidence approximately 1/2,000,000) and a life-limiting disease, characterized by congenital bilateral hallux valgus in combination with progressive heterotopic enchondral ossification in specific anatomical patterns, preceded by inflammatory responses and soft tissue swelling. It is caused by mutations in the ACVR1/ALK2 gene, which encodes for the “activin receptor IA/activin-like kinase 2,” a type I receptor of the bone morphogenetic protein signaling pathway. The heterotopic ossifications of joints, musculature, connective tissue, and tendons typically begin in the first decade of life with a broad variety of onset. They lead to severe long-term impairment of quality of life due to skeletal deformities, functional stiffening, and chronic pain. The early phenotype of the disease is often misdiagnosed (e.g., as neoplasia or child abuse) leading to overdiagnosis and delay of specific therapy. Surgical intervention can also lead to an aggravation of the disease. The average life expectancy is estimated at ∼40 years. The pathogenesis is still not completely understood. There is currently no curative treatment approach. Specific individual treatment attempts to avoid the initial inflammatory reaction and to modify the secondary ossification.
Case Presentation: We present a male infant born spontaneously at term after unremarkable pregnancy. Initial symptoms at birth were bilateral congenital hallux valgus, as well as a limited motility in the metacarpophalangeal joint of the thumb of the right hand. The newborn period and first week of life passed without remarkable health problems.
For the first time at the age of 1.5 months, an unclear, severe swelling of the head (left parietal) appeared. Previously, there was no relevant trauma. The diagnostic work-up did not show signs of injury, no retinal hemorrhages, or intracranial lesions. The finding was spontaneously regressive. This incident was followed by further inpatient hospital visits due to unexplained comparable swellings of different localizations on the head. The parents were therefore suspected for child abuse. Concrete evidence or other conclusive findings never came up. In addition to a dysfunction of the extension of the cervical spine, physical examination was unremarkable.
At the age of 7 months, the patient showed up in our center for the first time with an acute swelling localized on the forehead and nose region. Due to the characteristic symptom constellation with recurrent soft tissue swellings in combination with bilateral congenital hallux valgus, a molecular genetic testing was initiated under suspicion of FOP. A pathogenic mutation (c.617G> A, p.R206H) in the disease-causing gene ACVR1/ALK2 could be confirmed. Further diagnostic work-up with cranial MRI and MRI of the spine did not show associated malformations. We initiated an anti-inflammatory therapy with NSAIDs as well as prednisone 2 mg/kg over 4 days according to the current expert recommendations.
This led to rapid regression of the swelling.
Due to the exceptionally early disease manifestation and severity indicating a life-limiting course, an individual therapeutic trial has been initiated in consultation with international experts. This includes prednisolone pulses with 20 mg/kg birth weight intravenous and montelukast for specific inhibition of mast-cell activation, as well as repetitive bisphosphonate therapy with neridronate infusions (etidronic acid) for modification of the secondary ossification.
Conclusion: To our knowledge, this is the earliest reported case of FOP. Presentation in infancy is a very rare and an important differential diagnosis to child abuse. Identification of the characteristic constellation of symptoms, consisting of congenital bilateral hallux valgus and unprovoked swelling of the head and shoulder girdle should lead directly to specific genetic diagnostics. An early specific treatment concept for avoiding further trauma (e.g., surgery, intramuscular injections) as well as anti-inflammatory therapy is crucial for the clinical course and subsequent impairment of the patient.
New targeted treatment approaches offer a promising long-term option for improvement of the course of the disease and its associated quality of life.