The diagnostic journey of fibrodysplasia ossificans progressiva: evidence from a national cohort of 114 patients

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder caused by gain-of-function variants in ACVR1 , characterized by congenital great-toe malformations, recurrent inflammatory soft-tissue swellings, and progressive heterotopic ossification (HO). Early lesions may resemble neoplastic, inflammatory, infectious, or trauma-related conditions, whereas invasive procedures can trigger additional HO. We performed a cross-sectional analysis of 114 patients with molecularly confirmed FOP enrolled in the National Rare Diseases Registry System of China. The diagnostic journey was reconstructed to evaluate diagnostic delay, misdiagnosis, missed diagnostic opportunities, and patient-reported outcomes after high-risk procedures. Patients were recruited from 23 provinces or regions. Diagnostic delay exceeded 3 years in 34.5% patients and 10 years in 9.7% patients. FOP was not considered at the first hospital visit in 85 of 114 patients (74.6%), and 72 of 114 (63.2%) reported misdiagnosis. Among misdiagnosed patients, tumor-related diagnoses were most common (36/72, 50.0%), followed by orthopedic or congenital (13/72, 18.1%) and inflammatory or infectious diagnoses (12/72, 16.7%). 102 of 114 patients (89.5%) reported congenital great-toe malformation. Biopsy was reported by 51 patients (44.7%), of whom 41 (80.4%) reported subsequent worsening; 22 of 25 patients (88.0%) who underwent HO excision reported recurrence or new lesions at the surgical site. Diagnostic errors remained common in FOP. Biopsy and HO excision were also frequently reported in FOP patients and were often followed by patient-reported worsening or recurrence. These findings provide a rationale for prospective evaluation of an early-recognition pathway emphasizing examination of the great toes, avoidance of invasive procedures when FOP is suspected, ACVR1 testing, and specialist referral.