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Peer-reviewedCC BY 4.0Frontiers in Endocrinology

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

  • Lijia Cui1,2
  • Quanshi Ouyang1,2
  • Jian Guo2
  • Wanping Cai1,2
  • Qianqian Pang1,2
  • Yue Chi1,2
  • Ruizhi Jiajue1,2
  • Xiang Li1,2
  • Wei Liu1,2
  • Yan Jiang1,2
  • Ou Wang1,2
  • Mei Li1,2
3 more authors
  • Xiaoping Xing1,2
  • Qiming Xu3
  • Weibo Xia1,2
  1. 1Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
  2. 2State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
  3. 3Department of Orthopedic Oncology, Beijing Jishuitan Hospital, Capital Medical University
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Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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Cite

BibTeXRIS
BibTeX
@article{cui2026diagnostic,
  title = {{The diagnostic journey of fibrodysplasia ossificans progressiva: evidence from a national cohort of 114 patients}},
  author = {Lijia Cui and Quanshi Ouyang and Jian Guo and Wanping Cai and Qianqian Pang and Yue Chi and Ruizhi Jiajue and Xiang Li and Wei Liu and Yan Jiang and Ou Wang and Mei Li and Xiaoping Xing and Qiming Xu and Weibo Xia},
  journal = {Frontiers in Endocrinology},
  year = {2026},
  month = oct,
  doi = {10.3389/fendo.2026.1941326},
  url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1941326/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - The diagnostic journey of fibrodysplasia ossificans progressiva: evidence from a national cohort of 114 patients
AU  - Lijia Cui
AU  - Quanshi Ouyang
AU  - Jian Guo
AU  - Wanping Cai
AU  - Qianqian Pang
AU  - Yue Chi
AU  - Ruizhi Jiajue
AU  - Xiang Li
AU  - Wei Liu
AU  - Yan Jiang
AU  - Ou Wang
AU  - Mei Li
AU  - Xiaoping Xing
AU  - Qiming Xu
AU  - Weibo Xia
PY  - 2026
DA  - 2026/10/14
JO  - Frontiers in Endocrinology
DO  - 10.3389/fendo.2026.1941326
UR  - https://www.frontiersin.org/articles/10.3389/fendo.2026.1941326/full
AB  - Background: 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.  Methods: 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.  Results: 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.  Conclusion: 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.
SN  - 1664-2392
ER  -