Table 1 Proposed clinical and laboratory criteria for rare and orphan diseases screening

Clinical red flags for rare and orphan diseases

1.

Intermittent or persistent episodes of inflammation unexplained by infections or neoplasia

2.

Severe, persistent or unusual recurrent infections

3.

Multiple and/or severe autoimmunity at any age

4.

Family history of inherited conditions

5.

Multiorgan infiltrates in the absence of infection or neoplasia

6.

Joint hypermobility with or without evidence of vascular lesions such as aneurysm, dissection, or ischemia

7.

Organic signs of storage disease, including nephrotic syndrome, heart failure, hepatosplenomegaly, or peripheral neuropathy, in the absence of autoimmunity, infection, neoplasia, or drug reaction

8.

Unusual signs of vasculitis, cutaneous ischemia, or multiorgan symptoms unexplained by systemic vasculitides and with exclusion of secondary causes

9.

Atypical skin, neurological, or joint symptoms with epidemiological history of Rickettsia or Borrelia exposure

Laboratory red flags for rare and orphan diseases

1.

Persistent or recurrent episodes of elevated inflammatory markers, such as ESR, CRP, or SAA, in the absence of neoplasia or infection

2.

Peripheral hypereosinophilia and/or eosinophilic tissue infiltration in the absence of neoplasia or adverse drug reaction

3.

Persistent complement reduction, hypogammaglobulinemia, deficient vaccine response, altered lymphocyte immunophenotyping in the absence of infection, neoplasia, or autoimmune disease activity

4.

Granulomatous or histiocytic tissue lesion in the absence of infection or neoplasia

5.

Tissue amyloid or lysosomal deposit in anatomopathological analyses

6.

Monostotic or polyostotic bone lesions documented by imaging or histopathology, including sclerotic, lytic, or mixed lesions in the absence of infection or neoplasia