Table 7. Screening landmarks F, AD, ID, SY regarding history and physical findings. Presence of Red flags in > 2 landmarks will trigger whole genome analysis. Abnormal findings in lab investigations are only significant in presence of landmarks F, A, ID, SY.
| Land-mark | Category | Tools | Red Flag |
|---|---|---|---|
| F | Family history | Draw a pedigree§, find inheritance pattern; know geographical distributions of consanguinity$ | – Presence of family members with IEI; family members fulfill other landmarks (see below) |
| A | Atopy disease history | Get details: onset, extent, course | – Onset: at birth/first 1 – 2 months of life – Extent: multiple simultaneous atopic manifestations such as severe asthma, life-threatening anaphylaxis, allergic rhinoconjunctivitis, multiple food allergies, eosinophilic esophagitis and gastroenteritis, protein-losing enteropathy – Course: very severe, not responsive to standard therapy |
| ID | Immunodeficiency, non-atopic past medical history | Evaluate pathological susceptibility to infections, signs of immunodysregulation, past medical history (ELVIS**, GARFIELD,** see next column) |
General
– Failure to thrive+ – Malignancy (e.g., lymphomas, leiomyosarcoma) Pathological susceptibility to infections (ELVIS)** – Unusual, opportunistic pathogens: e.g. pneumocystis – Localization: unusual, e.g., organ abscesses – Course: exceptionally long duration – Intensity: exceptionally severe, e.g., admission to intensive care unit. – Sum: Too many, e.g., in adults, >3 or in children > 6 infections per year which require treatment (including antibiotics) and each lasting more than 4 weeks Immunodysregulation (GARFIELD)** – Granuloma – Autoimmune disease – Recurring fever and chronic inflammation – Unusual eczema – Lymphoproliferation – Chronic, inflammatory bowel Disease |
| SY | Syndromic disease | Skilled examination by experienced physician, clinical geneticist; supplementary use of artificial intelligence (next generation phenotyping (e.g., GestaltMatcher)++ | Key clinical findings such as hypotrichosis, neurodevelopmental delay, skeletal or connective tissue abnormalities (e.g., coarse facies, vascular anomalies, bleeding) |
| ! Caveat !: Except newborn SCID screening, results of conventional laboratory studies are not sufficient to make a definitive diagnosis of PAD. High levels of IgE or eosinophilia do occur in many PADs but are also common in non-primary allergic diseases. Abnormal findings in laboratory investigation count only as significant in the presence of landmarks F, A, ID, SY. | |||
| LI | Lab investigations | SCID newborn screening; full blood count; serum IgG, IgA, IgM, IgE; specific IgE panels to common aeroallergens and food allergens; Skin prick tests; urine glycans, serum tryptase; N- und O-glycosylation in serum transferrin electrophoresis, flow cytometry with immunodeficiency adapted markers; mast cell metabolites (e.g., histamine, leukotriens) in urine | – Pathological TREC screening – Abnormal absolute numbers and relative percentages in full blood count (e.g., cytopenia; neutropenia, lymphopenia, thrombocytopenia, anemia) – Low IgG- SD age-adjusted; IgA < 5 mg/dL – Very high TH2 biomarkers: severe eosinophilia (>5,000 cells/mm3); serum total IgE > 2,000 kU |
IEI = inborn errors of immunity; SCID = severe combined immunodeficiency; PAD = primary atopic disease; TREC = T cell receptor excision circle;SD = standard deviation.&Online resources and instructions on How to Draw a Pedigree - Iowa Institute of Human Genetics (uiowa.edu); (Definition of pedigree - NCI Dictionary of Genetics Terms - NCI (cancer.gov); $Consang.net. **acronyms adapted from the German guideline for Diagnostics in Primary immunodeficiencies (S. Farmand, manuscript in preparation) and [31]; ELVIS = Erreger (pathogens), Lokalisation (localization), Verlauf (course), Intensität (intensity), Summe (sum); GARFIELD = Granulome (granuloma), Autoimmunität (autoimmunity), Rezidivierendes Fieber (recurrent fever), Darmentzündung (chronic inflammatory bowel disease). +Growth hormone evaluation and bone age study if there is short stature; delayed bone age and growth hormone deficiency may be found. ++www.db.gestatmatcher.org.