Resources on PID

Disease	Contributors	Clinical criteria for a probable diagnosis (= clinical diagnosis)	Suggestions for alternative diagnosis (i.e. if these criteria are not completely fulfilled)
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
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
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]
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