Disease | Contributors | Clinical criteria for a probable diagnosis (= clinical diagnosis) | Suggestions for alternative diagnosis (i.e. if these criteria are not completely fulfilled) |
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Autoimmune lymphoproliferative syndrome (ALPS) | David Edgar, Stephan Ehl, Frederic RieuxLaucat and Benedicte Neven | At least one of the following: • splenomegaly • lymphadenopathy (>3 nodes, >3 months, non-infectious, non-malignant) • autoimmune cytopenia (>/= 2 lineages) • history of lymphoma • affected family member AND at least one of the following: • TCRab+CD3+CD4-CD8- of TCRab+CD3+ T cells > 6% • elevated biomarkers (at least 2 of the following): • sFASL > 200pg/ml • Vitamin B12 > 1500ng/L • IL-10 > 20pg/ml • Impaired FAS mediated apoptosis |
For patients with lymphoproliferation and/or autoimmunity who do not fulfil these criteria, please consider the following diagnoses: • CVID • Combined immunodeficiencies • Unclassified disorders of immune dysregulation |
Familial hemophagocytic lymphohistiocytosis syndromes (FHLH) | Stephan Ehl, Genevieve de Saint Basile, Gritta Janka | At least one of the following: • at least 1 episode of HLH (at least 5/8 criteria as defined by the Histiocyte Society) • affected family member AND at least one of the following: • recurrent disease (>4 weeks after initiating treatment for first episode) • persistent disease (no full remission can be achieved) • partial albinism • absent or significantly decreased Perforin expression in flow cytometry • at least one assay with absent degranulation (NK or CTL) or two assays with reduced degranulation • at least 2 assays with absent NK cell cytotoxicity |
For patients with incomplete criteria, please consider Unclassified disorders of immune dysregulation. |
Chediak Higashi syndrome (CHS) | Nizar Mahlaoui, David Edgar Stephan Ehl, Genevieve de Saint Basile, Despina Moshous | At least one of: • recurrent bacterial infections • episode of hemophagocytic lymphohistiocytosis (HLH) • Neutropenia • reduced lymphocyte degranulation/cytotoxicity • affected family member AND one of: • Typical hair shaft abnormalities • Presence of intracytoplasmic typical giant granules on blood or bone marrow smears |
Immunodeficiency with partial albinism |
Griscelli syndrome type 2 | Nizar Mahlaoui, David Edgar Stephan Ehl, Genevieve de Saint Basile, Despina Moshous | At least one of the following: • episode of hemophagocytic lymphohistiocytosis (HLH) • reduced lymphocyte degranulation/cytotoxicity • affected family member AND Typical hair shaft abnormalities AND Absence of giant granules on blood smear |
Immunodeficiency with partial albinism |
Hermansky-Pudlak syndrome (type 2) | Nizar Mahlaoui, Stephan Ehl | Oculocutaneous albinism AND Chronic neutropenia AND at least one of the following: • bleeding diathesis • recurrent infections • hemophagocytic lymphohistiocytosis (HLH) AND Defective cytotoxicity caused by impaired degranulation |
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X-linked lymphoproliferative syndrome (XLP) | Nizar Mahlaoui, Stephan Ehl | Male individual (or female with severely skewed X-chromosome inactivation) AND two of the following: • at least 1 episode of HLH (according to the Histiocyte Society criteria) • affected family member • abnormal EBV response • Hypogammaglobulinemia • Inflammatory Bowel Disease • Vasculitis • Lymphoid Neoplasm, especially if EBV-associated AND at least one of the following minor criteria: • decreased or absent SAP (for XLP1) or XIAP (for XLP2) expression assessed by Flow Cytometry • reduced frequency of iNKT cells (< 0.02% of T cells) • Normal Perforin expression in flow cytometry • Normal degranulation (NK or CTL) assays or Normal NK cell cytotoxicity assays AND No partial albinism AND Normal work-up for metabolic diseases |
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APECED / APS1 with CMC - Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) | Nizar Mahlaoui, Frank.vandeVe erdonk (Radboud), Desa Lilic | Look for at least 2 of the following: • chronic mucocutaneous candidiasis (oral, oesophageal (difficulty swallowing) genital, skin, nails) – confirm with culture • autoimmune hypoparathyroidism / hypocalcemia • autoimmune adrenocortical failure (Addison’s disease) • other autoimmune: hypergonadotropic hypogonadism, alopecia, vitiligo, autoimmune hepatitis, type 1 diabetes, gastrointestinal dysfunction • other: ectodermal dystrophy: dental enamel hypoplasia, nail dystrophy Diagnostic tests (specific for APECED / APS1): • organ-specific autoantibodies (parathyroid, adrenal, gonads, islet cell) • anti-cytokine autoantibodies (IFNα & ω and/or IL17A /IL17F/ IL22) [comment: sensitivity & specificity >95% (Kisand et al, Eur J Immunol 2011), can replace AIRE genotyping as >70 known mutations] |
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FOXP3 deficiency (IPEX) | Nizar Mahlaoui David Edgar Stephan Ehl, Hans Ochs, Benedicte Neven | At least one of • Severe and protracted enteropathy with villous atrophy in a male infant • Severe, often multiple endocrinopathies AND Exclusion of hypogammaglobulinaemia AND at least one of the following: • Low or absent Foxp3 expression by CD4+CD25+ on flow analysis • No overt T cell defect (proliferations are normal) • Elevated IgA and IgE levels • Normal CD25 expression |
Combined immunodeficiency |