Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov 11;15(1):39411.
doi: 10.1038/s41598-025-23081-0.

Argo Delphi consensus statement on red flags and clinical gateways towards rare disease diagnosis

Giuseppe Limongelli  1   2 , Fabio De Iaco  3 , Marta Mosca  4 , Leandro Pecchia  5 , Gaetano Piccinocchi  6 , Luca Sangiorgi  7 , Maurizio Scarpa  8 , Davide Cafiero  9 , Lucia Politi  9 , Fabio Tedone  9 , Amalia Forte  9 , Martina Caiazza  10   11 , Chiara De Stasio  10   11 , Anna Fusco  10   11 , Barbara Morgillo  12 , Iris Scala  13 , Annalisa Scopinaro  14 , Paola Facchin  15 ; Argo Working Group
Collaborators, Affiliations

Argo Delphi consensus statement on red flags and clinical gateways towards rare disease diagnosis

Giuseppe Limongelli et al. Sci Rep. .

Abstract

People living with a rare disease can wait months to years for a confirmed diagnosis after symptom onset, mainly due to low prevalence, lack of awareness of primary healthcare professionals, heterogeneous clinical presentation and/or peculiar inheritance patterns. This consensus paper aims to establish a set of guidelines to assist healthcare professionals-also without a specialized expertise in rare diseases-in optimizing the diagnostic pathway for these conditions. During Phase 1 of a real-time Delphi study, ten experts defined 26 statements addressing the identification of clinical features ("red flags", domain 1) and non-clinical tools/conditions ("clinical gateways", domain 2) that could trigger/support the diagnostic suspect of a rare disease. During Phase 2, the survey was extended to a multidisciplinary panel of 55 experts to reach a consensus on statements. Consensus was reached on 22 out of 26 statements across the two domains. Family history, clusters of birth defects, unusual presentations of common disease, neurodevelopmental delays or decline, and severe pathology emerged as key indicators to improve the identification and referral of cases of rare disease and should be integrated into primary care practices. Education, increased awareness in the community and use of technology are possible gateways to facilitate early diagnosis in rare disease.

Keywords: Consensus statement; Diagnostic odyssey; Early diagnosis; Primary care; Rare diseases.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethical approval: Ethical approval was waived by the Azienda dei Colli-Vanvitelli (Campania 2) Ethics Committee (Italy) for this study, as it did not involve clinical trials or patient data. Competing interests: M.C., F.D.I., C.D.S., P.F., A. Fusco, G.L., B.M., L. Pecchia, L.S., I.S., A.S., report no competing interests. D.C., L.Politi, A.Forte and F.T. work for Helaglobe which served as consultant for Abiogen, Alexion, AOP health, Apellis, Convatec, Daichii-sankyo, Doctolib, Fidia, Gore, GSK, Hologic, Lilly, Mirum, Molteni, Orphalan, Recordati rare diseases, SOBI, Theramex, Tillotts, UCB, Uriach, Visufarma. G.P. reported receiving a Research grant from Zambon, Spark tx. He also received fees for participation in Clinical Studies sponsored by Synageva, Biomarin, Amicus tx, as a speaker from Takeda Shire, Sanofi Genzyme, Amicus tx, Biomarin and for Travel reimbursements from Shire Takeda, Sanofi Genzyme, Medifood, Vitaflo, Recordati, Piam farmaceutici. M.M. reported receiving honoraria as Advisor or speaker for AstraZeneca, Abbvie, GSK, Lilly, UCB, Biogen, BMS, Idorsia, Molteni, Otsuka, Roche, Novartis. M.S. reported fee for advisory boards and research grants from Alexion, Biomarin, Chiesi, Denali, Ultragenix, Sanofi, Takeda.

Figures

Fig. 1
Fig. 1
Overall design of the study.
See this image and copyright information in PMC

References

    1. Tisdale, A. et al. The IDeaS initiative: pilot study to assess the impact of rare diseases on patients and healthcare systems. Orphanet. J. Rare Dis.16, 429 (2021). - DOI - PMC - PubMed
    1. Vaisitti, T. et al. The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy. Orphanet. J. Rare Dis.16, 374 (2021). - DOI - PMC - PubMed
    1. Schieppati, A., Henter, J. I., Daina, E. & Aperi, A. Why rare diseases are an important medical and social issue. Lancet371, 2039–2041 (2008). - DOI - PubMed
    1. Baynam, G. et al. Global health for rare diseases through primary care. Lancet Glob. Health12, e1192–e1199 (2024). - DOI - PubMed
    1. Walkowiak, D. & Domaradzki, J. Are rare diseases overlooked by medical education? Awareness of rare diseases among physicians in Poland: an explanatory study. Orphanet J. Rare Dis.16, 400 (2021). - DOI - PMC - PubMed

Publication types

LinkOut - more resources