Clinical Immunology 198 (2019) 19–30 Contents lists available at ScienceDirect Clinical Immunology journal homepage: www.elsevier.com/locate/yclim Review Article The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management T Reza Yazdania, Saba Fekrvanda, Sepideh Shahkaramia, Gholamreza Azizib, Bobak Moazzamia, ⁎ Hassan Abolhassania,c, Asghar Aghamohammadia, a Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran b Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran c Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden ARTICLE INFO ABSTRACT Keywords: Hyper Immunoglobulin M syndrome (HIGM) is a rare primary immunodeficiency disorder characterized by low Primary immunodeficiency disorders or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM. Various X-linked and Hyper-IgM syndrome autosomal recessive/dominant mutations have been reported as the underlying cause of the disease. Based on Class switch recombination the underlying genetic defect, the affected patients present a variety of clinical manifestations including pul- Somatic hyper mutation monary and gastrointestinal complications, autoimmune disorders, hematologic abnormalities, lymphoproli- DNA repair defects feration and malignancies which could be controlled by multiple relevant therapeutic approaches. Herein, the epidemiology, pathogenesis, clinical manifestations, diagnosis, management, prognosis and treatment in pa- tients with HIGM syndrome have been reviewed. 1. Introduction alpha (PIK3R1), tumor necrosis factor receptor superfamily member 13B (TACI/TNFRSF13B), inducible T-cell costimulator (ICOS), CD19,B Hyper-immunoglobulin M syndrome (HIGM) was first described in cell-activating factor receptor (BAFF-R/TNFRSF13C), LPS Responsive 1961 by Rosen et al. [1] and molecularly was defined in 1992 with a Beige-Like Anchor Protein (LRBA), phospholipase C gamma-2 (PLCG2), report of a mutation in the CD40 ligand (CD40L) gene [2]. This syn- Bruton tyrosine kinase (BTK) and signaling lymphocyte activation drome is also known as immunoglobulin class switch recombination molecule-associated protein (SAP)[2,5–10]. Although less frequent (Ig-CSR) deficiencies. Ig-CSR deficiencies are a group of rare inherited cases of the HIGM syndrome with autosomal recessive inheritance have primary immunodeficiency disorders (PIDs) characterized by low or been reported in previous studies, the X-linked Hyper-IgM syndrome absent serum levels of IgG, IgA and IgE, whereas the IgM concentration (X-HIGM), which is caused by CD40L mutations, is the most common is either normal or increased [3,4]. form of HIGM and accounts for about 65–70% of all cases [3,11]. HIGM To date, in addition to CD40L mutations in several genes responsible predisposes affected individuals to recurrent and prolonged infections for B cell signaling, Ig-CSR, somatic hypermutation and DNA repair including opportunistic infections, neutropenia, autoimmune disease mechanism involved in presentation of HIGM phenotype, including and cancer [12]. Immunoglobulin replacement is an effective treatment CD40L, CD40, nuclear factor-kappa-B essential modulator (NEMO/ for decreasing chronic infections in patients with HIGM, however in IKKγ), inhibitor of kappa light chain gene enhancer in B cells, alpha patients with combined immunodeficiency hematopoietic stem cell (IκBα), nuclear factor kappa-B subunit 1 (NKFB1), activation-induced transplantation (HSCT) should be considered [13]. cytidine deaminase (AICDA), uracil-DNA glycosylase (UNG), ataxia Patients with HIGM syndrome could have distinct clinical infectious telangiectasia mutated (ATM), post meiotic segregation increased 2 complications based on the genetic characteristic and exact type of the (PMS2), MutS Homolog 6 (MSH6), MutS Homolog 2 (MSH2), INO80, syndrome, which makes it a challenge for clinicians and researchers. the gene encoding Nibrin/Nijmegen breakage syndrome 1 (NBS1/ Majority of autosomal forms of HIGM are presented as a typical hu- NBN), meiotic recombination 11-Like Protein A (MRE11), recombina- moral PID; however the X-linked and autosomal dominant forms show tion activating gene 2 (RAG2), phosphatidylinositol 3-kinase catalytic the spectrum of clinical manifestations similar to the combined im- delta (PIK3CD), phosphatidylinositol 3-kinase regulatory subunit 1 munodeficiency disorders [14]. Early diagnosis and appropriate ⁎ Corresponding author at: Children’s Medical Center Hospital, 62 Qarib St., Keshavarz Blvd., Tehran 14194, Iran. E-mail address: [email protected] (A. Aghamohammadi). https://doi.org/10.1016/j.clim.2018.11.007 Received 4 November 2018; Accepted 11 November 2018 Available online 13 November 2018 1521-6616/ © 2018 Published by Elsevier Inc. R. Yazdani et al. Clinical Immunology 198 (2019) 19–30 management of HIGM patients would be performed more efficiently by 3.1. CD40L and CD40 mutations knowing the clinical phenotypes along with associated immunological and genetic parameters. The most prevalent type of HIGM is the X-linked CD40L deficiency accounting for almost 65–70 % of all cases, exclusively observed in male subjects [24,35]. The CD40L gene is located at X chrmosome 2. Epidemiology [36,37] which encodes CD40L (CD154), a member of tumor necrosis factor (TNF) family made-up of 3 functional domains: intracellular, The prevalence of HIGM varies in different ethnicities across the transmembrane and extracellular [38]. More than 100 unique muta- world. According to US X-HIGM registry, the prevalence of X-HIGM was tions including single amino acid substitutions, truncations, in-frame or approximately 1 in 1,000,000 live births from 1984–1993 [15]. The out-of-frame deletions, nonsense, missense, insertion and splice-site estimated frequency of CD40L deficiency is 2:1,000,000 in males [15]. mutations have been reported among X-HIGM patients (http:// Although there are few data available on the frequency of AICDA de- structure.bmc.lu.se/idbase/CD40Lbase). These mutation mostly affect ficiency, this disorder is estimated to affect less than 1:1,000,000 in- the extracellular domain, resulting in a defective geometrical folding of dividuals [16]. Globally, all forms of HIGM constitute 0.3–2.9% of all CD40L or preventing the CD40L/CD40 binding [6,15,39–42]. Ab- patients with PIDs. In 2014, a multicenter report on PID by Jeffrey normalities in the promoter region of the CD40L gene [43] have been Modell Foundation (JMF) indicated ~880 HIgM patients (2.3% of also identified to be responsible for X-HIGM [3]. Defective T cell co- 37,532 antibody deficient patients and 1.2% of all 77,193 PID patients). stimulation in CD40L-deficiency leads to combined T- (cellular) and B- In this report CD40L deficiency ranked as 28th frequent type of PID (372 cell (humoral) immunodeficiency [24,44]. patients, 42.2% of all HIgM patients, 272 patients from US) worldwide. CD40, a unique receptor of CD40L, is a member of the TNF receptor Of note, CD40 deficiency (92 patients, 71 patients from US) was more family that is expressed on APCs (B cells, monocytes, macrophages and common genetic defect compared to AID deficiency (81 patients, 71 dendritic cells). CD40 deficiency is one of the autosomal recessive types patients from US), however majority of the CD40 deficient patients of HIGM syndromes [44,45]. Reported biallelic mutations in the gene have not been reported in details [17]. A study of 7430 PID patients encoding CD40, consist of a single amino acid change in a highly from the European Society for Immune Deficiency (ESID) demonstrated conserved area of an extra-cellular cysteine-rich domain, a 6-bp dele- that 3.08% of PID patients enrolled had CSR defects, the most prevalent tion in exon 4 and a cryptic splice site resulting in skipping of exon 5 being CD40L deficiency with a frequency of 1.16% [18]. According to [29,46]. Therefore there are many underreported patients with CD40 the national registry in Spain, the incidence rate of all forms of HIGM is deficiency according to IDbase (http://structure.bmc.lu.se/idbase/ 1 per 20 million live births which X-HIGM represents about 65–70% of CD40base) and JMF global report [17]. Similar to CD40L deficiency, all cases [19]. Studies are inadequate to provide racial and ethnic data defects in CD40 also result in combined immunodeficiency. regarding X-HIGM incidence. The US X-HIGM registry reported the racial background of 75 patients, as 52 of the patients were white, 12 3.2. AICDA and UNG mutations were black, 9 were Asian, 1 was both black and Asian, and 1 was white and Asian [15]. B cell intrinsic defects including defects of AICDA and UNG genes A retrospective study of the Registry of the ESID on 56 affected comprise two other autosomal recessive types of HIGM syndromes. AID males showed a 20% survival rate in individuals aged ~25 years [20]. and UNG enzymes have a crucial role in CSR and SHM processes The US X-HIGM Registry reported that 11 out of 61 surviving patients [23,47]. AID generates deoxyuracils by deaminating deoxycytosine in were aged 20 years or older [15]. The leading cause of death was the switch regions of the immunoglobulin heavy chain genes during pneumonia, encephalitis or malignancy. Other patients died of liver CSR [48], afterwards, UNG removes deoxyuracils from DNA as a part of failure secondary to sclerosing cholangitis