Primary Immunodeficiency Initially Identified as Sarcoidosis

Introduction Sarcoidosis is a granulomatous disease with an incidence of up to 18 in 100,000 in some populations. Symptoms range from asymptomatic benign lesions to organ failure, with up to 90% of patients presenting with lung involvement. Sarcoidosis is often a diagnosis of exclusion: inflammation, lymphadenopathy, and sterile granulomata without an identifiable cause. Granuloma formation occurs in primary immunodeficiencies, but the full landscape of these deficiencies and their association with sarcoid is not fully understood. Results We looked retrospectively at patients initially diagnosed with sarcoidosis referred to the National Institutes of Health (NIH). Many people had refractory inflammation or had a diagnosis of sarcoidosis in the setting of other immune dysfunction such as common variable immunodeficiency (CVID). Within this group of 37 patients with completed whole-genome or whole-exome sequencing, 22 had pathogenic variants, likely pathogenic variants, or variants of unknown significance in relevant candidate genes including SP110, GATA2, NFKBIA, NFKB1, IRF8, CTLA-4, NCF1, SLC26A9, RFX5, MEFV, GFI1, PLCG2, STAT1, BACH2, IKZF3, JAK1, ADCY10, and STXBP2. Conclusion This study highlights the diseases often gathered under the diagnosis “sarcoid”. Prior studies have highlighted immune dysregulation within multiple pathways, including the interferon-gamma (IFN-γ) response pathway (GATA2, STAT1, NFKBIA, and IRF8), Th17.1 signaling (STAT1 and IRF8), and inflammasome response (IRF8, MEFV, and PLCG2), as being important in granuloma formation. Numerous mutations within this cohort have previously been associated with common immunodeficiencies (RFX5, NFKBIA, SP110, and IKZF3) or predominant antibody deficiencies (NFKB1). This cohort also showed defects of phagocyte number or function (GFI1, NCF1, and GATA2). Within this study, two variants were identified that are not associated with immunodeficiencies, including SLC26A9, an ion transporter for chloride previously identified in atypical cystic fibrosis, and ADCY10, a catalyst for the formation of cAMP. Though it is possible that some of these variants may not be causal or even relevant to the formation of granulomas, this cohort shows how some patients presenting with lymphadenopathy and sterile granulomata in various organs were identified to have Mendelian traits underlying their diagnoses of sarcoidosis. Table 1.Subject IDGenetic Defect IdentifiedAllele Frequency gnomAD v4.1.0Classification (ClinVar)ZygosityCADD ScoreInheritance PatternOrgan InvolvementInfection History1NFKBIA (IkBa) (c.691G>T, p.Asp231Tyr)4.7e-5VUSHet27.3ADCNS, Exocrine, CutaneousNTM, EBV2CTLA4 (c.567+5G>C)0PathogenicHet26ADOcular, LN, Cutaneous, Pulmonary3No defect identifiedOcular, Cutaneous, PulmonaryEBV4NCF1 (p47phox Deficient CGD) (c.75_76del, p.Tyr26fs)8.5e-4PathologicHomo35ARPulmonary, Exocrine, LNS. capitis5No defect identifiedCutaneousSphingomonas paucimobilis6No defect identifiedPulmonaryM. avium8No defect identifiedPulmonary, Neuro, LNJCV9No defect identifiedPulmonarydisseminated M. tilbergii11NCF1 (p47phox Deficient CGD) (c.75_76del, p.Tyr26fs)8.5e-4PathologicHomo38ARPulmonary12NCF1 (p47phox Deficient CGD) (c.75_76del, p.Tyr26fs)8.5e-4PathologicHomo38ARMSK, Ocular, SplenicA. fumigatus141q41 222762100-224070013HetHepatic, PulmonaryS. pneumo1.308 Mb-1.636 Mb LossIFIH1NOD2LRBAFAT4KMT2D15SP110 (c.1428_1429del, p.Tyr476Ter)1.8e-6Not ReportedHet34ARCutaneousM. chelonae16SLC26A9 (c.1459G>A, p.Ala487Thr)6.9e-5Not ReportedHet20.8PulmonaryMAC17GATA2 (c.1021_1024dup, p.Ala342GlyfsTer43)0PathologicHetNAADPulmonary18No defect identifiedPulmonary, Cutaneous19IRF8 (c. 536C>T, p.Ala179Val)6.5e-6VUSHet17.54AR/ADNeuroMAC20No defect identifiedPulmonary, GIMAC23GATA2 (c.1021_1024dup, p.Ala342GlyTer43)0PathogenicHetNAADBM25STXBP2 (c.1001 C>T, p.Pro334Leu)4e-5Likely pathogenicHomo29.9ARHepatic26No defect identifiedPulmonary27No defect identifiedPulmonary28NFKB1 (c.1513A>C, p.Lys505Gln)6.85e-7VUSHet26.2ADPulmonary, Cardiac29RFX5 (c.353+2T>G)1.8e-4Likely pathogenicHet33ARPulmonary, Cutaneous30IKZF3 (c.244G>A, p.Glu82Lys)1.4e-4VUSHet23.6ADHepatic, OcularRecurrent Pneumonia31No defect identifiedPulmonaryEBV32No defect identifiedCardiac33No defect identifiedNeuroVZV34MEFV (c.289C>A, p.Gln97Lys)9.43e-5VUSHet9.8AD/ARPulmonary, Hepatic35GFI1 (c.200G>A, p.Arg67Lys)3.4e-5VUSHet21.2ARPulmonaryAspergillus, pneumocystis36PLCG2 (c.2931C>G, p.Tyr977Ter)6.19e-7VUSHet38ADPulmonary, Splenic, CutaneousRecurrent sinusitis37STAT1 (c.736G>A, p.Ala246Thr)0VUSHet24ADPulmonaryHistoplasmosis38BACH2 (c.2327 C>T, p.Pro776Leu)1.8e-5VUSHet16.9ADPulmonary39No defect identifiedPulmonary40ADCY10 (c.4477del, p.Leu1493SerfsTer24)3e-4PathogenicHet33ADPulmonary41No defect identifiedPulmonary42No defect identifiedCardiac43JAK1 (c.1078C>T, p.Arg360Trp)5.9e-5VUSHet25.1AD/ART1DM, Pulmonary, OcularHistoplasmosis