AUTHOR=Sharifinejad Niusha , Azizi Gholamreza , Chavoshzadeh Zahra , Mahdaviani Seyed Alireza , Alan Mahnaz Seifi , Tavakol Marzieh , Sadri Homa , Nabavi Mohammad , Ebrahimi Sareh Sadat , Shirkani Afshin , Vosughi Motlagh Ahmad , Safarirad Molood , Aghamahdi Fatemeh , Nazari Farzad , Delavari Samaneh , Jamee Mahnaz , Fayyaz Farimah , Samimisedeh Parham , Matani Rahman , Esmaeili Marzie , Yazdani Reza , Rezaei Nima , Abolhassani Hassan 

TITLE=Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1023127

DOI=10.3389/fimmu.2022.1023127

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Combined immune deficiencies (CIDs) with associated or syndromic features are a highly heterogeneous subgroup of inherited immune disorders. These patients represent specific clinical complications with an increased risk of autoimmune conditions.</p></sec><sec><title>Methods</title><p>We analyzed data of monogenic patients with syndromic CIDs adopted from the Iranian inborn errors of immunity registry up to January 2022. A comprehensive comparison in terms of demographic, clinical, and immunological features was performed between patients with and without autoimmunity and also among four mutation groups with the most registered cases including <italic>ATM</italic>, <italic>STAT3 (AD-LOF)</italic>, <italic>DNMT3B/ZBTB24</italic>, and <italic>WAS</italic> mutations.</p></sec><sec><title>Results</title><p>A total of 137 patients with monogenic syndromic CIDs were included. Most commonly mutated genes were the <italic>ATM</italic> [80 (58.4%)] and <italic>STAT3 (AD-LOF)</italic> [19 (13.9%)], followed by <italic>DNMT3B</italic> [11 (8%)], and <italic>WAS</italic> [11 (8%)]. More than 18% of all patients with syndromic CIDs, including most <italic>DNMT3B/ZBTB24</italic> mutations patients, were clinically diagnosed with antibody deficiencies before genetic evaluation. Patients with <italic>ATM</italic> and <italic>WAS</italic> mutations had the latest age of onset and the lowest age of diagnosis, respectively. Autoimmune disorders were diagnosed in 24 patients at a median age of 3.5 (2.6-6.0) years, 70.6% of which were diagnosed prior to the diagnosis of immunodeficiency. Lymphoproliferation, particularly hepatosplenomegaly, was significantly higher in patients with autoimmunity (<italic>p=0.004</italic>). Syndromic CID patients with autoimmunity had significantly lower IgG levels. Hematologic autoimmunity mainly immune thrombocytopenic purpura was the most frequent autoimmunity among major groups of <italic>ATM</italic>, <italic>STAT3 (AD-LOF)</italic>, <italic>DNMT3B/ZBTB24</italic>, and <italic>WAS</italic> mutations, however <italic>ATM-</italic>mutated patients present more diversified involved organs including rheumatologic, gastrointestinal and dermatologic autoimmunity.</p></sec><sec><title>Conclusion</title><p>About 18% of patients with monogenic syndromic CIDs developed autoimmunity, mainly in the form of hematological immune diseases. Autoimmunity could be an early-onset involvement with a potential diagnostic impact on suspicious cases of syndromic CIDs.</p></sec>